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1.  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 μg/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.
Clinical trial registered with (NCT 00112164).
PMCID: PMC2542435  PMID: 18565951
acute respiratory distress syndrome; acute lung injury; activated protein C; ventilator-free days; mortality
2.  Occupational Exposures Are Associated with Worse Morbidity in Patients with Chronic Obstructive Pulmonary Disease 
Rationale: Links between occupational exposures and morbidity in individuals with established chronic obstructive pulmonary disease (COPD) remain unclear.
Objectives: To determine the impact of occupational exposures on COPD morbidity.
Methods: A job exposure matrix (JEM) determined occupational exposure likelihood based on longest job in current/former smokers (n = 1,075) recruited as part of the Subpopulations and Intermediate Outcomes in COPD Study, of whom 721 had established COPD. Bivariate and multivariate linear regression models estimated the association of occupational exposure with COPD, and among those with established disease, the occupational exposure associations with 6-minute-walk distance (6MWD), the Modified Medical Research Council Dyspnea Scale (mMRC), the COPD Assessment Test (CAT), St. George’s Respiratory Questionnaire (SGRQ), 12-item Short-Form Physical Component (SF-12), and COPD exacerbations requiring health care utilization, adjusting for demographics, current smoking status, and cumulative pack-years.
Measurements and Main Results: An intermediate/high risk of occupational exposure by JEM was found in 38% of participants. In multivariate analysis, those with job exposures had higher odds of COPD (odds ratio, 1.44; 95% confidence interval, 1.04–1.97). Among those with COPD, job exposures were associated with shorter 6MWDs (−26.0 m; P = 0.006); worse scores for mMRC (0.23; P = 0.004), CAT (1.8; P = 0.003), SGRQ (4.5; P = 0.003), and SF-12 Physical (−3.3; P < 0.0001); and greater odds of exacerbation requiring health care utilization (odds ratio, 1.55; P = 0.03).
Conclusions: Accounting for smoking, occupational exposure was associated with COPD risk and, for those with established disease, shorter walk distance, greater breathlessness, worse quality of life, and increased exacerbation risk. Clinicians should obtain occupational histories from patients with COPD because work-related exposures may influence disease burden.
PMCID: PMC4384767  PMID: 25562375
chronic obstructive pulmonary disease; occupational exposure; work-related; quality of life; job exposure matrix
3.  The Impact of Allergy and Pulmonary Specialist Care on Emergency Asthma Utilization in a Large Managed Care Organization 
Health Services Research  2005;40(5 Pt 1):1443-1465.
To evaluate the longitudinal impact of asthma specialist care on the risk of emergency department (ED) visits and hospitalization for asthma.
Data Sources/Study Setting
A prospective cohort study using both telephone survey and computerized utilization data.
Study Design
We recruited a prospective cohort of 4,742 adult members of a closed panel managed care organization who were hospitalized for asthma (the “baseline hospitalization”).
Data Collection/Extraction Methods
Visits to asthma specialists were ascertained from computerized utilization databases. Specialist visits after baseline hospitalization were defined as time-dependent covariates. An alternative analysis defined specialist visits during the year preceding baseline hospitalization. A subcohort of 596 subjects completed telephone interviews.
Principal Findings
Compared with subjects who received no specialist visits after baseline hospitalization, treatment by allergists (hazard ratio (HR) 1.04; 95 percent confidence interval (CI) 0.87–1.26) or pulmonologists (HR 0.92; 95 percent CI 0.71–1.19) was not associated with a reduction in the risk of future ED visits for asthma in the entire cohort, controlling for age, sex, race, recent asthma medication dispensing, and pharmacy benefits status. There was also no association between allergist visits and the risk of subsequent hospitalizations for asthma (HR 0.93; 95 percent CI 0.75–1.14). In contrast, visits to pulmonologists (HR 0.74; 95 percent CI 0.55–0.99) were related to a reduced risk of rehospitalization.
Pulmonary specialist visits appeared to reduce the risk of hospitalization for asthma, whereas asthma specialist visits did not reduce the risk of ED visits. In the context of comprehensive prepaid health care, the benefit of specialist care was modest.
PMCID: PMC1361198  PMID: 16174142
Asthma; pulmonary disease (specialty); treatment outcome
4.  Longer term exposure to secondhand smoke and health outcomes in COPD: Impact of urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
Nicotine & Tobacco Research  2009;11(8):945-953.
Secondhand smoke (SHS) contains respiratory irritants and has the potential to adversely affect adults with chronic obstructive pulmonary disease (COPD), but few studies have evaluated the impact of SHS on COPD.
We used data from 72 nonsmoking participants in a cohort study of COPD. Urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was measured as an indicator of longer term SHS exposure, whereas urine cotinine was assessed as a measure of more recent exposure. The impact of SHS exposure on COPD-related health status was examined using multivariate linear regression (controlling for age, sex, race, educational attainment, and smoking history). Health status was measured using a validated COPD severity score, reported dyspnea, a standard health status measure (Short Form-12), and activity restriction.
The urine NNAL-to-creatinine ratio (per interquartile increment) was associated with greater COPD severity (mean score increase 1.7 points; 95% CI 0.6–2.8; p = .0003). Higher urine NNAL was also related to greater dyspnea, poorer physical health status, and more restricted activity (p ≤ .05 in all cases). When considered simultaneously, longer term exposure (NNAL) had a greater negative impact on COPD status than shorter term exposure (cotinine).
Urine NNAL can be used to estimate longer term SHS exposure and negatively affects a number of health outcomes among adults with COPD. Screening for and prevention of SHS exposure among persons with COPD may be beneficial.
PMCID: PMC2711983  PMID: 19587064
5.  Risk adjustment for health care financing in chronic disease: What are we missing by failing to account for disease severity? 
Medical care  2013;51(8):740-747.
Adjustment for differing risks among patients is usually incorporated into newer payment approaches, and current risk models rely on age, gender, and diagnosis codes. It is unknown the extent to which controlling additionally for disease severity improves cost prediction. Failure to adjust for within-disease variation may create incentives to avoid sicker patients. We address this issue among patients with chronic obstructive pulmonary disease (COPD).
Cost and clinical data were collected prospectively from 1,202 COPD patients at Kaiser Permanente. Baseline analysis included age, gender, and diagnosis codes (using the Diagnostic Cost Group Relative Risk Score [RRS]) in a general linear model predicting total medical costs in the following year. We determined whether adding COPD severity measures—FEV1, 6 minute walk test, dyspnea score, body-mass index, and BODE Index (composite of the other four measures)—improved predictions. Separately, we examined household income as a cost predictor.
Mean costs were $12,334/year. Controlling for RRS, each ½ standard deviation worsening in COPD severity factor was associated with $629 to $1,135 in increased annual costs (all p<0.01). The lowest stratum of FEV1 (<30% normal) predicted $4,098 (95%CI $576–$8,773) additional costs. Household income predicted excess costs when added to the baseline model (p=0.038), but this became non-significant when also incorporating BODE Index.
Disease severity measures explain significant cost variations beyond current risk models, and adding them to such models appears important to fairly compensate organizations that accept responsibility for sicker COPD patients. Appropriately controlling for disease severity also accounts for costs otherwise associated with lower socioeconomic status.
PMCID: PMC3714354  PMID: 23703646
chronic disease; COPD; financing; health care costs; health care markets; health care reform; risk adjustment; socioeconomic factors
6.  Population-Based Efficacy Modeling of Omalizumab in Patients with Severe Allergic Asthma Inadequately Controlled with Standard Therapy 
The AAPS Journal  2013;15(2):559-570.
Omalizumab, a recombinant humanized monoclonal antibody, is the first approved anti-immunoglobulin E (IgE) agent for the treatment of subjects with moderate to severe persistent allergic asthma that are inadequately controlled by the standard of care. The objective of this study was to quantitatively characterize relationships between serum free IgE and pulmonary function (as measured by forced expiratory volume in 1 s [FEV1]) as well as serum free IgE and airway inflammation (as measured by fractional exhaled nitric oxide [FeNO]) using population-based efficacy models. Data were collected from patients in the EXTRA trial who received omalizumab or placebo 150 to 375 mg subcutaneously every 2 or 4 weeks from week 0 to 48 with constant standard of care as background therapy. None of the covariates evaluated, including demographics, disease status, and baseline pharmacodynamic biomarkers, were significant in explaining the variability in the FEV1 or FeNO response to omalizumab. Results from the efficacy models further confirmed the current omalizumab dosing rationale based on the mean target free IgE level of 25 ng/ml and quantified the variability for the target. In addition, the resulting population models could be used to predict population FEV1 or FeNO response for omalizumab and/or other anti-IgE therapeutics for which PK-IgE models are constructed.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-013-9463-9) contains supplementary material, which is available to authorized users.
PMCID: PMC3675747  PMID: 23413101
asthma; FEV1; IgE; omalizumab; population modeling
7.  Development of disability in chronic obstructive pulmonary disease: beyond lung function 
Thorax  2010;66(2):108-114.
COPD is a major cause of disability, but little is known about how disability develops in this condition.
We analyzed data from the FLOW (Function, Living, Outcomes, and Work) Study which enrolled 1,202 Kaiser Permanente Northern California members with COPD at baseline and re-evaluated 1,051 subjects at 2 year follow-up. We tested the specific hypothesis that the development of specific non-respiratory impairments (abnormal body composition and muscle strength) and functional limitations (decreased lower extremity function, poor balance, mobility-related dyspnea, reduced exercise performance, and decreased cognitive function) will determine the risk of disability in COPD, after controlling for respiratory impairment (FEV1 and oxygen saturation). The Valued Life Activities Scale was used to assess disability in terms of a broad range of daily activities. The primary disability outcome measure was defined as an increase in the proportion of activities that cannot be performed of 3.3% or greater from baseline to 2-year follow-up (the estimated minimal important difference). Multivariable logistic regression was used for analysis.
Respiratory impairment measures were related to an increased prospective risk of disability (multivariate OR 1.75; 95% CI 1.26 to 2.44 for 1 litre decrement of FEV1 and OR 1.57 per 5% decrement in oxygen saturation; 95% CI 1.13 to 2.18). Non-respiratory impairment (body composition and lower extremity muscle strength) and functional limitations (lower extremity function, exercise performance, and mobility-related dyspnea) were all associated with an increased longitudinal risk of disability after controlling for respiratory impairment (p<0.05 in all cases). Non-respiratory impairment and functional limitations were predictive of prospective disability, above-and-beyond sociodemographic characteristics, smoking status, and respiratory impairment (area under the receiver operating characteristic curve increased from 0.65 to 0.75; p<0.001).
Development of non-respiratory impairment and functional limitations, which reflect the systemic nature of COPD, appear to be critical determinants of disablement. Prevention and treatment of disability require a comprehensive approach to the COPD patient.
PMCID: PMC3111223  PMID: 21047868
8.  The influence of anxiety on health outcomes in COPD 
Thorax  2010;65(3):229-234.
Psychological functioning is an important determinant of health outcomes in chronic lung disease. To better define the role of anxiety in COPD, we studied the inter-relations between anxiety and COPD in a large cohort of COPD subjects and a matched control group.
We used data from the FLOW (Function, Living, Outcomes, and Work) cohort (n=1,202) of COPD and matched controls (n=302) without COPD. Anxiety was measured using the Anxiety subscale of the Hospital Anxiety and Depression Scale.
COPD was associated with a greater risk of anxiety in multivariable analysis (OR 1.85; 95% CI 1.072 to 3.18). Among patients with COPD, anxiety was related to poorer health outcomes including worse submaximal exercise performance (less distance walked during the Six Minute Walk Test: -66.3 feet for anxious vs. non-anxious groups; 95% CI -127.3 to -5.36 feet) and a greater risk of self-reported functional limitations (OR 2.41; 95% CI 1.71 to 3.41). COPD subjects with anxiety had a higher longitudinal risk of COPD exacerbation in Cox proportional hazards analysis after controlling for covariates (HR 1.39; 95% CI 1.007 to 1.90).
COPD is associated with a higher risk of anxiety. Once anxiety develops among COPD patients, it is related to poorer health outcomes. Further research is needed to determine whether systematic screening and treatment of anxiety in COPD will improve health outcomes and prevent functional decline and disability.
PMCID: PMC3111227  PMID: 20335292
9.  Socioeconomic status, race, and COPD health outcomes 
Although COPD is a common cause of death and disability, little is known about the effects of socioeconomic status (SES) and race-ethnicity on health outcomes.
We aimed to determine the independent impacts of SES and race-ethnicity on COPD severity status, functional limitations, and acute exacerbations of COPD among patients with access to health care. Data were used from the FLOW cohort study of 1,202 Kaiser Permanente Northern California Medical Care Plan members with COPD.
Lower educational attainment and household income were consistently related to greater disease severity, poorer lung function, and greater physical functional limitations in cross-sectional analysis. Black race was associated with greater COPD severity, but these differences were no longer apparent after controlling for SES variables and other covariates (comorbidities, smoking, body mass index, and occupational exposures). Both lower education and income were independently related to a greater prospective risk of acute COPD exacerbation (HR 1.5; 95% CI 1.01 to 2.1; and HR 2.1; 95% CI 1.4 to 3.4, respectively).
Low SES is a risk factor for a broad array of adverse COPD health outcomes. Clinicians and disease management programs should consider SES as a key patient-level marker of risk for poor outcomes.
PMCID: PMC3017471  PMID: 19854747
10.  COPD and cognitive impairment: the role of hypoxemia and oxygen therapy 
Several studies have shown an association between chronic obstructive pulmonary disease (COPD) and cognitive impairment. These studies have been limited by methodological issues such as diagnostic uncertainty, cross-sectional design, small sample size, or lack of appropriate referent group. This study aimed to elucidate the association between COPD and the risk of cognitive impairment compared to referent subjects without COPD. In patients with established COPD, we evaluated the impact of disease severity and impairment of respiratory physiology on cognitive impairment and the potential mitigating role of oxygen therapy.
We used the Function, Living, Outcomes and Work (FLOW) cohort study of adults with COPD (n = 1202) and referent subjects matched by age, sex, and race (n = 302) to study the potential risk factors for cognitive impairment among subjects with COPD. Cognitive impairment was defined as a Mini-Mental State Exam score of <24 points. Disease severity was using Forced Expiratory Volume in one second (FEV1); the validated COPD Severity Score; and the BMI (Body Mass Index), Obstruction, Dyspnea, Exercise Capacity (BODE) Index. Multivariable analysis was used to control for confounding by age, sex, race, educational attainment, and cigarette smoking.
COPD was associated with a substantive risk of cognitive impairment compared to referent subjects (odds ratio [OR] 2.42; 95% confidence interval [CI] 1.043–6.64). Among COPD patients, none of the COPD severity measures were associated with the risk of cognitive impairment (P > 0.20 in all cases). Low baseline oxygen saturation was related to increased risk of cognitive impairment (OR for oxygen saturation ≤88% (OR 5.45; 95% CI 1.014–29.2; P = 0.048). Conversely, regular use of supplemental oxygen therapy decreased the risk for cognitive impairment (OR 0.14; 95% CI 0.07–0.27; P < 0.0001).
COPD is a major risk factor for cognitive impairment. Among patients with COPD, hypoxemia is a major contributor and regular use of home oxygen is protective. Health care providers should consider screening their COPD patients for cognitive impairment.
PMCID: PMC2939681  PMID: 20856825
chronic obstructive pulmonary disease
11.  Occupational exposures and the risk of COPD: dusty trades revisited 
Thorax  2008;64(1):6-12.
The contribution of occupational exposures to chronic obstructive pulmonary disease (COPD) and, in particular, their potential interaction with cigarette smoking remains underappreciated.
We used data from the FLOW study of 1,202 subjects with COPD (of which 742 had disease classified as Stage II or above by Global Obstructive Lung Disease [GOLD] criteria) and 302 referent subjects matched by age, sex, and race, recruited from a large managed care organization. Occupational exposures were assessed using two methods: self-reported exposure to vapors, gas, dust, or fumes on the longest held job (VGDF) and a job exposure matrix (JEM) for probability of exposure based on occupation. Multivariate analysis was used to control for age, sex, race, and smoking history. The odds ratio (OR) and the adjusted population attributable fraction (PAF) associated with occupational exposure were calculated.
VGDF exposure was associated with an increased risk of COPD (OR 2.11; 95% CI 1.59-2.82) and a PAF of 31% (95% CI 22-39%). The risk associated with high probability of workplace exposure by JEM was similar (OR 2.27; 95% CI 1.46-3.52), although the PAF was lower (13%; 95% CI 8 to 18%). These estimates were not substantively different when the analysis was limited to COPD GOLD Stage II or above. Joint exposure to both smoking and occupational factors markedly increased the risk of COPD (OR 14.1; 95% CI 9.33-21.2).
Workplace exposures are strongly associated with an increased risk of COPD. On a population level, prevention of both smoking and occupational exposures, and especially both together, is needed to prevent the global burden of disease.
PMCID: PMC2775075  PMID: 18678700
Pulmonary disease; chronic obstructive; occupational exposure
12.  Risk factors for death among adults with severe asthma 
Mortality risk in adult asthma is poorly understood, especially the interplay between race, disease severity, and health-care access.
To examine mortality risk factors in adult asthma.
In a prospective cohort study of 865 adults with severe asthma in a closed-panel managed-care organization, we used structured interviews to assess baseline sociodemographics, asthma history, and health status. Subjects were followed until death or end of study, with a two-year average follow-up time. We used Cox proportional hazards regression to evaluate the impact of sociodemographics, cigarette smoking, and validated measures of perceived asthma control, physical health status, and severity-of-asthma on the risk of death.
We confirmed 123 deaths, a mortality rate of 6.7 per 100 person-years. In analysis adjusted for sociodemographics and tobacco history, higher severity-of-asthma scores (hazard ratios [HR], 1.11 per ½ standard deviation increase in severity-of-asthma score; 95% confidence interval [CI], 1.01 - 1.23) and lower perceived asthma control scores (HR, 0.91 per ½ standard deviation increase in perceived asthma control score, 95% CI, 0.83 - 0.99) were each associated with risk of all-cause mortality. In the same adjusted analysis, African American race was not associated with an increased mortality risk relative to white race (HR 0.63; 95% CI 0.35 - 1.12).
In a large managed-care organization in which access to care is unlikely to vary widely, greater severity-of-asthma scores and poorer perceived asthma control scores are each associated with increased mortality risk among adults with severe asthma, but African Americans are not at increased risk of death relative to whites.
PMCID: PMC2767233  PMID: 18727467
asthma; mortality; risk factors; prospective studies; severity of illness index
13.  COPD as a Systemic Disease: Impact on Physical Functional Limitations 
The American journal of medicine  2008;121(9):789-796.
Although chronic obstructive pulmonary disease (COPD) has a major impact on physical health, the specific impact of COPD on physical functional limitations has not been clearly characterized. We aimed to elucidate the physical functional limitations that are directly attributable to COPD compared to a matched referent group without the condition.
We used the FLOW (Function, Living, Outcomes, and Work) cohort study of adults with COPD (n=1,202) and referent subjects matched by age, sex, and race (n=302) to study the impact of COPD on the risk of a broad array of functional limitations using validated measures: lower extremity function (Short Physical Performance Battery, SPPB), submaximal exercise performance (Six Minute Walk Test, SMWT), standing balance (Functional Reach Test), skeletal muscle strength (manual muscle testing with dynamometry), and self-reported functional limitation (standardized item battery). Multivariate analysis was used to control for confounding by age, sex, race, height, educational attainment, and cigarette smoking.
COPD was associated with poorer lower extremity function (mean SPPB score decrement for COPD vs. referent -1.0 points; 95% CI -1.25 to -0.73 pts) and less distance walked during the SMWT (-334 feet; 95% CI -384 to -282 ft). COPD was also associated with weaker muscle strength in every muscle group tested, including both the upper and lower extremities (p<0.0001 in all cases) and with a greater risk of self-reported functional limitation (OR 6.4; 95% CI 3.7 to 10.9).
A broad array of physical functional limitations were specifically attributable to COPD. COPD affects a multitude of body systems remote from the lung.
PMCID: PMC2548403  PMID: 18724969
pulmonary disease, chronic obstructive; disability evaluation; outcomes assessment
14.  Trends in the incidence of noncardiogenic acute respiratory failure: the role of race 
Critical Care Medicine  2012;40(5):1532-1538.
We sought to examine trends in the race-specific incidence of acute respiratory failure in the United States.
Retrospective cohort study.
We used the National Hospital Discharge Survey (NHDS) database (1992-2007), an annual survey of approximately 500 hospitals weighted to provide national hospitalization estimates.
All incident cases of noncardiogenic acute respiratory failure hospitalized in the United States.
Measurements and Main Results
We identified noncardiogenic acute respiratory failure by the presence of ICD–9 codes for respiratory failure or pulmonary edema (518.4, 518.5, 518.81, 518.82) and mechanical ventilation (96.7x), excluding congestive heart failure. Incidence rates were calculated using yearly census estimates standardized to the age and sex distribution of the 2000 census population. Annual cases of noncardiogenic acute respiratory failure increased from 86,755 in 1992 to 323,474 in 2007. Noncardiogenic acute respiratory failure among black Americans increased from 56.4 (95% CI 39.7 – 73.1) to 143.8 (95% CI 123.8 – 163.8) cases per 100,000 in 1992 and 2007, respectively. Among white Americans, the incidence of noncardiogenic acute respiratory failure increased from 31.2 (95% CI 26.2-36.5) to 94.0 (95% CI 86.7 – 101.2) cases per 100,000 in 1992 and 2007, respectively. The average annual incidence of noncardiogenic acute respiratory failure over the entire study period was 95.1 (95% CI 93.9 – 96.4) cases per 100,000 for black Americans compared to 66.5 (95% CI 65.8 – 67.2) cases per 100,000 for white Americans (rate ratio = 1.43, 95% CI 1.42-1.44). Overall in–hospital mortality was greater for other-race Americans, but only among patients with ≥ 2 organ failures (57% [95% CI 56-59%] for other-race, 51% [95% CI, 50-52%] for white, 50% [95% CI, 49-51%] for black).
The incidence of noncardiogenic acute respiratory failure in the United States increased between 1992 and 2007. Black and other-race Americans are at greater risk of developing noncardiogenic acute respiratory failure compared to white Americans.
PMCID: PMC3329645  PMID: 22511134
Respiratory failure; health status disparities; epidemiology; National Hospital Discharge Survey; international classification of diseases; acute lung injury
15.  The impact of SHS exposure on health status and exacerbations among patients with COPD 
Secondhand smoke (SHS) is a major contributor to indoor air pollution. Because it contains respiratory irritants, it may adversely influence the clinical course of persons with chronic obstructive pulmonary disease (COPD). We used data from nonsmoking members of the FLOW cohort of COPD (n = 809) to elucidate the impact of SHS exposure on health status and exacerbations (requiring emergency department visits or hospitalization). SHS exposure was measured by a validated survey instrument (hours of exposure during the past week). Physical health status was measured by the SF-12 Physical Component Summary Score and disease-specific health-related quality of life (HRQL) by the Airways Questionnaire 20-R. Health care utilization for COPD was determined from Kaiser Permanente Northern California computerized databases. Compared to no SHS exposure, higher level SHS exposure was associated with poorer physical health status (mean score decrement −1.78 points; 95% confidence interval [CI] −3.48 to −0.074 points) after controlling for potential confounders. Higher level SHS exposure was also related to poorer disease-specific HRQL (mean score increment 0.63; 95% CI 0.016 to 1.25) and less distance walked during the Six-Minute Walk test (mean decrement −50 feet; 95% CI −102 to 1.9). Both lower level and higher level SHS exposure was related to increased risk of emergency department (ED) visits (hazard ratio [HR] 1.40; 95% CI 0.96 to 2.05 and HR 1.41; 95% CI 0.94 to 2.13). Lower level and higher level SHS exposure were associated with a greater risk of hospital-based care for COPD, which was a composite endpoint of either ED visits or hospitalizations for COPD (HR 1.52; 95% CI 1.06 to 2.18 and HR 1.40; 95% CI 0.94 to 2.10, respectively). In conclusion, SHS was associated with poorer health status and a greater risk of COPD exacerbation. COPD patients may comprise a vulnerable population for the health effects of SHS.
PMCID: PMC2685143  PMID: 19516915
chronic obstructive pulmonary disease; chronic bronchitis; pulmonary emphysema; tobacco smoke pollution
16.  Pulmonary Function and the Risk of Functional Limitation in Chronic Obstructive Pulmonary Disease 
American journal of epidemiology  2008;167(9):1090-1101.
The authors’ objective was to analyze the impact of respiratory impairment on the risk of physical functional limitations among adults with chronic obstructive pulmonary disease (COPD). They hypothesized that greater pulmonary function decrement would result in a broad array of physical functional limitations involving organ systems remote from the lung, a key step in the pathway leading to overall disability. The authors used baseline data from the Function, Living, Outcomes, and Work (FLOW) study, a prospective cohort study of adults with COPD recruited from northern California in 2005–2007. They studied the impact of pulmonary function impairment on the risk of functional limitations using validated measures: lower extremity function (Short Physical Performance Battery), submaximal exercise performance (6-Minute Walk Test), standing balance (Functional Reach Test), skeletal muscle strength (manual muscle testing with dynamometry), and self-reported functional limitation (standardized item battery). Multiple variable analysis was used to control for confounding by age, sex, race, height, educational attainment, and cigarette smoking. Greater pulmonary function impairment, as evidenced by lower forced expiratory volume in 1 second (FEV1), was associated with poorer Short Physical Performance Battery scores and less distance walked during the 6-Minute Walk Test. Lower forced expiratory volume in 1 second was also associated with weaker muscle strength and with a greater risk of self-reported functional limitation (p < 0.05). In conclusion, pulmonary function impairment is associated with multiple manifestations of physical functional limitation among COPD patients. Longitudinal follow-up can delineate the impact of these functional limitations on the prospective risk of disability, guiding preventive strategies that could attenuate the disablement process.
PMCID: PMC2610529  PMID: 18343879
pulmonary disease; chronic obstructive
17.  The Impact of a “Low-Intensity” Versus “High-Intensity” Medical Intensive Care Unit on Patient Outcomes in Critically Ill Veterans 
To determine whether a low-intensity versus high-intensity medical intensive care unit (MICU) format in a Veterans Affairs (VA) hospital setting improves patient outcomes, as measured by duration of mechanical ventilation (MV), ventilator-free days (VFDs), and hospital mortality.
Retrospective cohort study.
Medical intensive care unit at the San Francisco Veterans Affairs Medical Center (SFVAMC).
On July 1, 2004, the SFVAMC transitioned from a low-intensity MICU to a high-intensity MICU. All patients admitted to the MICU who required MV for 18 months before (n = 96) and 18 months after (n = 131) the transition were included in the analysis.
We prospectively defined the primary outcome measure as the difference in the median duration of MV between groups. Secondary outcomes included VFDs and hospital mortality. Continuous variables were compared using the Wilcoxon rank sum test; dichotomous variables were compared using Fisher exact test.
Main results
The low-intensity and high-intensity MICU groups were similar in age, gender, weight, and admitting diagnosis (P > .27 in all cases). Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were 22.0 in the low-intensity era and 20.0 in the high-intensity era (P = .048). Median duration of MV was significantly lower in the high-intensity MICU format compared to the low-intensity MICU format (102 vs 61 hours, P for log-rank test = .0052). After controlling for covariates, there were 4.2 more VFDs in the high-intensity era (95% CI 1.9 to 6.6 days). The high-intensity era was associated with a reduced hospital mortality rate (27% vs 40%) and an adjusted odds ratio of 0.34 (95% CI 0.15 to 0.74).
For critically ill veterans admitted to an MICU requiring MV, a high-intensity ICU structure is associated with more favorable mechanical ventilatory outcomes and lower mortality.
PMCID: PMC3577353  PMID: 20444736
closed intensive care unit; open intensive care unit; mechanical ventilation; ventilator-free days; outcomes; high-intensity; low-intensity
18.  Higher Urine Nitric Oxide Is Associated with Improved Outcomes in Patients with Acute Lung Injury 
Rationale: Nitrogen oxide (NO) species are markers for oxidative stress that may be pathogenic in acute lung injury (ALI).
Objectives: We tested two hypotheses in patients with ALI: (1) higher levels of urine NO would be associated with worse clinical outcomes, and (2) ventilation with lower Vt would reduce urine NO as a result of less stretch injury.
Methods: Urine NO levels were measured by chemiluminescence in 566 patients enrolled in the National Heart Lung and Blood Institute Acute Respiratory Distress Syndrome Network trial of 6 ml/kg versus 12 ml/kg Vt ventilation. The data were expressed corrected and uncorrected for urine creatinine (Cr).
Results: Higher baseline levels of urine NO to Cr were associated with lower mortality (odds ratio, 0.43 per log(10) increase in the ratio), more ventilator-free days (mean increase, 1.9 d), and more organ-failure–free days (mean increase, 2.3 d) on multivariate analysis (p < 0.05 for all analyses). Similar results were obtained using urine NO alone. NO to Cr levels were higher on Day 3 in the 6 ml/kg than in the 12 ml/kg Vt group (p = 0.04).
Conclusions: Contrary to our hypothesis, higher urine NO was associated with improved outcomes in ALI at baseline and after treatment with the 6 ml/kg Vt strategy. Higher endogenous NO may reflect less severe lung injury and better preservation of the pulmonary and systemic endothelium or may serve a protective function in patients with ALI.
PMCID: PMC1899263  PMID: 17082495
acute respiratory distress syndrome; nitrogen oxide species; pulmonary endothelium; tidal volume; pulmonary edema
19.  Active and Passive Cigarette Smoking and Acute Lung Injury after Severe Blunt Trauma 
Rationale: Cigarette smoking has been demonstrated in laboratory studies to have effects on lung epithelial and endothelial function similar to those observed in acute lung injury (ALI). However, the association between active and passive cigarette smoke exposure and susceptibility to ALI has not been prospectively studied.
Objectives: We hypothesized that both active and passive cigarette smoke exposure would be associated with increased susceptibility to ALI after severe blunt trauma.
Methods: We measured levels of cotinine, a metabolite of nicotine and validated biomarker of tobacco use, in plasma samples obtained immediately on arrival at the emergency department from 144 adult subjects after severe blunt trauma. Patients were then followed for the development of ALI.
Measurements and Main Results: Increasing quartiles of plasma cotinine were associated with the development of ALI (odds ratio [OR] for developing ALI in highest cotinine quartile, 3.25; 95% confidence interval [CI], 1.22–8.68; P = 0.017 for trend across quartiles). Moderate to heavy passive smoke exposure was associated with nearly the same odds of developing ALI as active smoking (OR for moderate to heavy passive smoking compared with no exposure or low level exposure, 3.03; 95% CI, 1.15–8.04; OR for active smoking, 2.77; 95% CI, 1.28–5.99). This association persisted after adjusting for other predictors of ALI, including Injury Severity Score and alcohol abuse.
Conclusions: Both moderate to heavy passive smoking and active smoking are independently associated with the development of ALI after severe blunt trauma. This finding has important implications both for public health and for understanding the pathogenesis of ALI.
PMCID: PMC3136993  PMID: 21471091
cigarette smoking; acute lung injury; acute respiratory distress syndrome; cotinine; secondhand smoke exposure
20.  Use of risk reclassification with multiple biomarkers improves mortality prediction in acute lung injury 
Critical Care Medicine  2011;39(4):711-717.
Multiple single biomarkers have been associated with poor outcomes in acute lung injury; however, no single biomarker has sufficient discriminating power to clearly indicate prognosis. Using both derivation and replication cohorts, we tested novel risk reclassification methods to determine whether measurement of multiple plasma biomarkers at the time of acute lung injury diagnosis would improve mortality prediction in acute lung injury.
Analysis of plasma biomarker levels and prospectively collected clinical data from patients enrolled in two randomized controlled trials of ventilator therapy for acute lung injury.
Intensive care units of university hospitals participating in the National Institutes of Health Acute Respiratory Distress Syndrome Network.
Subjects enrolled in a trial of lower tidal volume ventilation (derivation cohort) and subjects enrolled in a trial of higher vs. lower positive end-expiratory pressure (replication cohort).
Measurements and Main Results
The plasma biomarkers were intercellular adhesion molecule-1, von Willebrand factor, interleukin-8, soluble tumor necrosis factor receptor-1, and surfactant protein-D. In the derivation cohort (n = 547), adding data on these biomarkers to clinical predictors (Acute Physiology and Chronic Health Evaluation III score) at the time of study enrollment improved the accuracy of risk prediction, as reflected by a net reclassification improvement of 22% (95% confidence interval 13% to 32%; p < .001). In the replication cohort (n = 500), the net reclassification improvement was 17% (95% confidence interval 7% to 26%; p < .001). A reduced set of three biomarkers (interleukin-8, soluble tumor necrosis factor receptor-1, and surfactant protein-D) had nearly equivalent prognostic value in both cohorts.
When combined with clinical data, plasma biomarkers measured at the onset of acute lung injury can improve the accuracy of risk prediction. Combining three or more biomarkers may be useful for selecting a high-risk acute lung injury population for enrollment in clinical trials of novel therapies.
PMCID: PMC3260884  PMID: 21283009
acute respiratory distress syndrome; biological marker; pulmonary edema; risk prediction; risk reclassification
21.  Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury* 
Critical Care Medicine  2007;35(12):2755-2761.
To identify biological and clinical predictors of acute kidney injury in subjects with acute lung injury.
Secondary data analysis from a multicenter, randomized clinical trial.
Intensive care units in ten university medical centers.
A total of 876 patients enrolled in the first National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Network trial.
Study subjects were randomized to receive a low tidal volume ventilation strategy and pharmacologic therapy with ketoconazole or lisofylline in a factorial design.
Measurements and Main Results
We tested the association of baseline levels of interleukin-6, interleukin-8, interleukin-10, von Willebrand factor, tumor necrosis factor-α, type I and II soluble tumor necrosis factor receptors (sTNFR-I and -II), protein C, plasminogen activator inhibitor-1 (PAI-1), surfactant protein-A, surfactant protein-D, and intracellular adhesion molecule-1 with subsequent acute kidney injury. Of 876 study participants who did not have end-stage renal disease, 209 (24%) developed acute kidney injury, defined as a rise in serum creatinine of >50% from baseline over the first four study days. The 180-day mortality rate for subjects with acute kidney injury was 58%, compared with 28% in those without acute kidney injury (p < .001). Interleukin-6, sTNFR-I, sTNFR-II, and PAI-1 levels were independently associated with acute kidney injury after adjustment for demographics, interventions, and severity of illness. A combination of clinical and biological predictors had the best area under the receiver operating characteristic curve, and the contribution of sTNFR-I and PAI-1 to this model was highly significant (p = .0003).
Elevations in PAI-1, interleukin-6, and the sTNFRs in subjects with acute kidney injury suggest that disordered coagulation, inflammation, and neutrophil–endothelial interactions play important roles in the pathogenesis of acute kidney injury. The combination of these biological and clinical risk factors may have important and additive value in predictive models for acute kidney injury.
PMCID: PMC3293249  PMID: 18074478
acute kidney injury; acute lung injury; acute respiratory distress syndrome; biological marker; predictive value; interleukin-6; soluble tumor necrosis factor receptor; plasminogen activator inhibitor-1
22.  Comparison of Urine Cotinine and the Tobacco-Specific Nitrosamine Metabolite 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol (NNAL) and Their Ratio to Discriminate Active From Passive Smoking 
Nicotine & Tobacco Research  2011;13(3):202-208.
Cotinine is the most widely used biomarker to distinguish active versus passive smoking. However, there is an overlap in cotinine levels when comparing light or occasional smokers versus heavily exposed passive smokers. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a tobacco-specific nitrosamine measurable in urine with a much longer half-life than cotinine. The aim of the study was to determine optimal cutoff points to discriminate active versus passive smokers and to compare sensitivity and specificity for the use of cotinine, NNAL, and the ratio of the NNAL/cotinine in urine.
Cotinine and NNAL were measured in urine of 373 active smokers and 228 passive smokers.
Geometric mean cotinine levels were 2.03 ng/ml (interquartile interval: 0.43–8.60) and 1,043 ng/ml (658–2,251) and NNAL levels were 5.80 pg/ml (2.28–15.4) and 165 pg/ml (90.8–360) pg/ml in passive and active smokers, respectively. NNAL/cotinine ratio in urine was significantly higher for passive smokers when compared with active smokers (2.85 vs. 0.16, p < .01). The receiver operating characteristics analysis determined optimal cutoff points to discriminate passive versus active smokers: 31.5 ng/ml for cotinine (sensitivity: 97.1% and specificity: 93.9%), 47.3 pg/ml for NNAL (87.4% and 96.5%), and 0.74 × 10−3 for NNAL/cotinine ratio (97.3% and 87.3%).
Both urine cotinine and NNAL are sensitive and specific biomarkers for discriminating the source of tobacco smoke exposure. Cotinine is the best overall discriminator when biomarkers are measured while a person has ongoing exposure to tobacco smoke. NNAL because of its long half-life would be particularly useful when there is a delay between exposure and biomarker measurement. The NNAL/cotinine ratio provides similar sensitivity but poorer specificity at discriminating passive versus active smokers when compared with NNAL alone.
PMCID: PMC3045466  PMID: 21330276
23.  Respiratory and skeletal muscle strength in COPD: Impact on exercise capacity and lower extremity function 
We sought to quantify the impact of respiratory muscle and lower extremity strength on exercise capacity and lower extremity function in patients with chronic obstructive pulmonary disease (COPD).
In 828 persons with COPD, we assessed the impact of reduced respiratory (maximum inspiratory pressure, MIP) and lower extremity muscle strength (quadriceps, QS) on exercise capacity (6 Minute Walk Distance, 6MWT) and lower extremity function (LEF, Short Physical Performance Battery). Multiple regression analyses taking into account key covariates, including lung function and smoking, tested the associations between muscle strength and exercise and functional capacity.
For each ½ standard deviation (0.5 SD) decrement in QS, men walked 18.3 meters less during 6MWT (95% CI −24.1 to −12.4); women 25.1 meters less (95% CI −31.1 to −12.4). For each 0.5 SD decrement in MIP, men walked 9.4 meters less during 6MWT (95% CI – 15.2 to −3.6); women 8.7 meters less (95% CI −14.1 to −3.4). For each 0.5 SD decrease in QS, men had a 1.32 higher odds (95% CI: 1.11 to 1.15) of poor LEF; women, 1.87 higher odds (95% CI: 1.54 to 2.27). Lower MIP (per 0.5 SD) was associated with increased odds of poor LEF in women (OR 1.18, 95% CI: 1.00 to 1.39), but not in men (OR 1.10, 95% CI: 0.93 to 1.31).
In COPD, reduced respiratory and lower extremity muscle strength are associated with decreased exercise and functional capacity. Muscle weakness is likely an important component of impairment and disability in patients with COPD.
PMCID: PMC3085880  PMID: 21240003
Respiratory and skeletal muscle; chronic obstructive pulmonary disease; exercise capacity; lower extremity function
24.  Urine cotinine underestimates exposure to the tobacco-derived lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in passive compared to active smokers 
Cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are widely used biomarkers for tobacco-derived nicotine and the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), respectively. The discrepancy between cotinine levels in relation to disease risk comparing active vs. passive smoking suggests a non-linear tobacco smoke dose-response and/or that cotinine is not providing an accurate measure of exposure to tobacco smoke toxic constituents from secondhand smoke.
Cotinine and NNAL were measured in urine of 373 active smokers and 228 passive smokers.
Average cotinine levels were 1,155 (IQR 703-2,715) for active smokers and 1.82 (0.45-7.33) ng/mg creatinine for passive smokers. Average NNAL levels were 183 (103-393) and 5.19 (2.04-11.6) pg/mg creatinine, respectively. NNAL/cotinine ratio in urine was significantly higher for passive smokers when compared to active smokers (2.85×103 vs. 0.16×103, p<0.0001).
Passive smoking is associated with a much higher ratio of NNAL/cotinine in the urine compared to active smoking.
Cotinine measurement leads to an underestimation of exposure to the carcinogen NNK from second-hand smoke when compared with active smoking.
PMCID: PMC2976834  PMID: 20805316
cotinine; NNAL; smokers; tobacco smoke; exposure
25.  Sub-Picogram Per Milliliter Determination of the Tobacco-Specific Carcinogen Metabolite 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in Human Urine Using Liquid Chromatography - Tandem Mass Spectrometry 
Analytical chemistry  2008;80(21):8115-8121.
Exposure to secondhand tobacco smoke (SHS) has been linked to increased risk for a number of diseases, including lung cancer. The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is of particular interest due to its potency and its specificity in producing lung tumors in animals. The NNK metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in urine is frequently used as a biomarker for exposure. Due to its long half-life (40-45 days), NNAL may provide a long-term, time-averaged measure of exposure. We developed a highly sensitive liquid chromatography – tandem mass spectrometry (LC-MS/MS) method for determination of NNAL in human urine. The method involves liquid-liquid extraction followed by conversion to the hexanoate ester derivative. This derivative facilitates separation from interfering urinary constituents by extraction and chromatography, and enhances detection with electrospray ionization mass spectrometry. The lower limit of quantitation is 0.25 pg/mL for 5 mL urine specimens. Applications to studies of people with a range of different SHS exposure levels is described.
PMCID: PMC3167662  PMID: 18841944

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