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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 www.clinicaltrials.gov (NCT 00112164).
doi:10.1164/rccm.200803-419OC
PMCID: PMC2542435  PMID: 18565951
acute respiratory distress syndrome; acute lung injury; activated protein C; ventilator-free days; mortality
2.  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.
doi:10.1208/s12248-013-9463-9
PMCID: PMC3675747  PMID: 23413101
asthma; FEV1; IgE; omalizumab; population modeling
3.  Trends in the incidence of noncardiogenic acute respiratory failure: the role of race 
Critical Care Medicine  2012;40(5):1532-1538.
Objective
We sought to examine trends in the race-specific incidence of acute respiratory failure in the United States.
Design
Retrospective cohort study.
Setting
We used the National Hospital Discharge Survey (NHDS) database (1992-2007), an annual survey of approximately 500 hospitals weighted to provide national hospitalization estimates.
Patients
All incident cases of noncardiogenic acute respiratory failure hospitalized in the United States.
Interventions
None
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).
Conclusions
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.
doi:10.1097/CCM.0b013e31824518f2
PMCID: PMC3329645  PMID: 22511134
Respiratory failure; health status disparities; epidemiology; National Hospital Discharge Survey; international classification of diseases; acute lung injury
4.  The Impact of a “Low-Intensity” Versus “High-Intensity” Medical Intensive Care Unit on Patient Outcomes in Critically Ill Veterans 
Objective
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.
Design
Retrospective cohort study.
Setting
Medical intensive care unit at the San Francisco Veterans Affairs Medical Center (SFVAMC).
Patients
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.
Measurements
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).
Conclusions
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.
doi:10.1177/0885066610366933
PMCID: PMC3577353  PMID: 20444736
closed intensive care unit; open intensive care unit; mechanical ventilation; ventilator-free days; outcomes; high-intensity; low-intensity
5.  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.
Introduction
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.
Methods
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.
Results
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).
Discussion
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.
doi:10.1093/ntr/ntp091
PMCID: PMC2711983  PMID: 19587064
6.  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
7.  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.
doi:10.1164/rccm.201011-1802OC
PMCID: PMC3136993  PMID: 21471091
cigarette smoking; acute lung injury; acute respiratory distress syndrome; cotinine; secondhand smoke exposure
8.  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.
Objective
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.
Conclusions
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.
doi:10.1111/j.1475-6773.2005.00410.x
PMCID: PMC1361198  PMID: 16174142
Asthma; pulmonary disease (specialty); treatment outcome
9.  Use of risk reclassification with multiple biomarkers improves mortality prediction in acute lung injury 
Critical Care Medicine  2011;39(4):711-717.
Objective
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.
Design
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.
Setting
Intensive care units of university hospitals participating in the National Institutes of Health Acute Respiratory Distress Syndrome Network.
Patients
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).
Interventions
None.
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.
Conclusions
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.
doi:10.1097/CCM.0b013e318207ec3c
PMCID: PMC3260884  PMID: 21283009
acute respiratory distress syndrome; biological marker; pulmonary edema; risk prediction; risk reclassification
10.  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.
Objective
To identify biological and clinical predictors of acute kidney injury in subjects with acute lung injury.
Design
Secondary data analysis from a multicenter, randomized clinical trial.
Setting
Intensive care units in ten university medical centers.
Patients
A total of 876 patients enrolled in the first National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Network trial.
Interventions
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).
Conclusions
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
11.  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.
Objectives:
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.
Methods:
Cotinine and NNAL were measured in urine of 373 active smokers and 228 passive smokers.
Results:
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%).
Conclusions:
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.
doi:10.1093/ntr/ntq237
PMCID: PMC3045466  PMID: 21330276
12.  Respiratory and skeletal muscle strength in COPD: Impact on exercise capacity and lower extremity function 
PURPOSE
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).
METHODS
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.
RESULTS
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).
CONCLUSION
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.
doi:10.1097/HCR.0b013e3182033663
PMCID: PMC3085880  PMID: 21240003
Respiratory and skeletal muscle; chronic obstructive pulmonary disease; exercise capacity; lower extremity function
13.  Urine cotinine underestimates exposure to the tobacco-derived lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in passive compared to active smokers 
Objectives
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.
Methods
Cotinine and NNAL were measured in urine of 373 active smokers and 228 passive smokers.
Results
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).
Conclusions
Passive smoking is associated with a much higher ratio of NNAL/cotinine in the urine compared to active smoking.
Impact
Cotinine measurement leads to an underestimation of exposure to the carcinogen NNK from second-hand smoke when compared with active smoking.
doi:10.1158/1055-9965.EPI-10-0497
PMCID: PMC2976834  PMID: 20805316
cotinine; NNAL; smokers; tobacco smoke; exposure
14.  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.
doi:10.1021/ac8009005
PMCID: PMC3167662  PMID: 18841944
15.  Biomarkers increase detection of active smoking and secondhand smoke exposure in critically ill patients 
Critical care medicine  2011;39(1):40-45.
Objectives
The association between tobacco smoke exposure and critical illness is not well studied, largely because obtaining an accurate smoking history from critically ill patients is difficult. Biomarkers can provide quantitative data on active and secondhand cigarette smoke exposure. We sought to compare cigarette smoke exposure as measured by biomarkers to exposure by self-report in a cohort of critically ill patients and to determine how well biomarkers of cigarette smoke exposure correlate with each other in this population.
Design, Setting, and Patients
Serum and urine cotinine and trans-3′-hydroxycotinine, urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and hair and nail nicotine levels were measured in 60 subjects enrolled in an observational cohort of critically ill subjects at a tertiary academic medical center in Tennessee. Smoking history was obtained from patients, their surrogates, or the medical chart. Cigarette smoke exposure as measured by biomarkers was compared to exposure by history.
Measurements and Main Results
By smoking history, 29 subjects were identified as smokers, 28 were identified as nonsmokers, and 3 were identified as unknown. The combination of serum cotinine and urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol identified 27 of the 28 nonsmokers by history either as active smokers (n = 6, 21%) or as exposed to secondhand smoke (n = 21, 75%). All biomarker levels were strongly correlated with each other (r = .69–.95, p < .0001).
Conclusions
The combination of serum cotinine and urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol identified considerably more active smokers than did smoking history and detected a high prevalence of secondhand smoke exposure in a critically ill population. These markers will be important for future studies investigating the relationship between active smoking and secondhand smoke exposure and critical illness.
doi:10.1097/CCM.0b013e3181fa4196
PMCID: PMC3148017  PMID: 20935560
biomarkers; cigarette smoking; cotinine; NNAL; critically ill
16.  Depressive Symptoms among Adults with Asthma from a Longitudinal Observational Cohort 
Aims
Individuals with asthma may be at increased risk of depression, but few studies have identified precursors to depression onset. The study goal was to identify risk factors for depression onset among a community-based sample of adults with asthma.
Methods
Data were from 3 telephone interviews of a longitudinal cohort (n=439) conducted at 2-year intervals. The Center for Epidemiologic Studies Depression scale (CESD) measured depressive symptoms. Multiple regression analyses tested associations of sociodemographic and health-related variables with depression prevalence (cross-sectional analyses) and incident depression (longitudinal analyses).
Results
15% of subjects were classified as “depressed” (CESD≥23) at each interview. Individuals depressed at baseline were more likely to drop out (OR=1.76 [95% CI 1.05, 2.96]). Low perceived control of asthma (measured with the Perceived Control of Asthma Questionnaire [PCAQ]) exhibited the most consistent association with depression. Lower PCAQ was cross-sectionally associated with depression (OR=0.51 per 0.5 SD difference in PCAQ [0.35, 0.75]). Depression onset was noted in 38 individuals. Decrease in perceived control at follow-up was associated with depression onset (OR=7.47 [2.15, 26.01]).
Conclusions
Low perceived control of asthma predicted depression onset among adults with asthma. This risk factor may respond to self-management education.
doi:10.4104/pcrj.2010.00012
PMCID: PMC3127241  PMID: 20169291
asthma; depression; perceived control
17.  Development of disability in chronic obstructive pulmonary disease: beyond lung function 
Thorax  2010;66(2):108-114.
Background
COPD is a major cause of disability, but little is known about how disability develops in this condition.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1136/thx.2010.137661
PMCID: PMC3111223  PMID: 21047868
18.  The influence of anxiety on health outcomes in COPD 
Thorax  2010;65(3):229-234.
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1136/thx.2009.126201
PMCID: PMC3111227  PMID: 20335292
19.  Socioeconomic status, race, and COPD health outcomes 
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1136/jech.2009.089722
PMCID: PMC3017471  PMID: 19854747
20.  Matrix metalloproteinase-9 predicts pulmonary status declines in α1-antitrypsin deficiency 
Respiratory Research  2011;12(1):35.
Background
Matrix metalloproteinase-9 (MMP-9) may be important in the progression of emphysema, but there have been few longitudinal clinical studies of MMP-9 including pulmonary status and COPD exacerbation outcomes.
Methods
We utilized data from the placebo arm (n = 126) of a clinical trial of patients with alpha1-antitrypsin deficiency (AATD) and emphysema to examine the links between plasma MMP-9 levels, pulmonary status, and COPD exacerbations over a one year observation period. Pulmonary function, computed tomography lung density, incremental shuttle walk test (ISWT), and COPD exacerbations were assessed at regular intervals over 12 months. Prospective analyses used generalized estimating equations to incorporate repeated longitudinal measurements of MMP-9 and all endpoints, controlling for age, gender, race-ethnicity, leukocyte count, and tobacco history. A secondary analysis also incorporated highly-sensitive C-reactive protein levels in predictive models.
Results
At baseline, higher plasma MMP-9 levels were cross-sectionally associated with lower FEV1 (p = 0.03), FVC (p < 0.001), carbon monoxide transfer factor (p = 0.03), resting oxygen saturation (p = 0.02), and ISWT distance walked (p = 0.02) but were not associated with radiographic lung density or total lung capacity (TLC). In longitudinal analyses, MMP-9 predicted a further decline in transfer factor (p = 0.04) and oxygen saturation (p < 0.001). MMP-9 also predicted worsening lung density (p = 0.003), increasing TLC (p = 0.02), and more frequent COPD exacerbations over follow-up (p = 0.003). Controlling additionally for hs-CRP levels did not substantively change the longitudinal associations between MMP-9 and these outcomes.
Conclusions
Increased plasma MMP-9 levels generally predicted pulmonary status declines, including worsening transfer factor and lung density as well as greater COPD exacerbations in AATD-associated emphysema.
doi:10.1186/1465-9921-12-35
PMCID: PMC3073899  PMID: 21429222
21.  Screening for Depression in Chronic Obstructive Pulmonary Disease 
COPD  2009;6(6):452-458.
Depression and chronic obstructive pulmonary disease (COPD) are major causes of disability. Identifying COPD patients at risk for depression would facilitate the alleviation of an important comorbidity conferring additional risk for poor outcomes. The purpose of this study was to determine the utility of a brief screening measure, the 15-item Geriatric Depression Scale (GDS-15), in detecting the mood disorders in persons with COPD. This is a cross-sectional study of 188 persons with COPD, stratified by age (65 and older versus less than 65) and COPD severity using Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging. Screening cut-points were empirically derived using threshold selection methods and receiver operating characteristic (ROC) curves were estimated. The GDS-15 was used as a screening measure and diagnoses of Major Depressive Disorder (MDD) or other mood disorders were determined using a “gold standard” standardized structured clinical interview. Of the 188 persons with COPD, 25% met criteria for any mood disorder and 11% met criteria for MDD. Optimal threshold estimations suggested a GDS cut score of 5, which yielded adequate sensitivity and specificity in detecting MDD (81% and 87%, respectively) and correctly classified 86% of participants. To detect the presence of any mood disorder, a cut score of 4 was suggested yielding sensitivity and specificity of 67% and 82%, respectively; correctly classifying 79%. These results suggest that mood disorders are relatively common among persons with COPD. The GDS-15 is a useful screening measure to identify patients at risk for depression.
doi:10.3109/15412550903341463
PMCID: PMC2981409  PMID: 19938969
Chronic Obstructive Pulmonary Disease; Depression; Screening; Validity
22.  COPD and cognitive impairment: the role of hypoxemia and oxygen therapy 
Background:
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.
Methods:
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.
Results:
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).
Conclusion:
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
23.  Further Exploration of the Links between Occupational Exposure and Chronic Obstructive Pulmonary Disease 
Objective
To examine occupational risk for COPD.
Methods
We randomly recruited 233 subjects aged 55-75 reporting a physician's diagnosis of COPD, emphysema or chronic bronchitis. Interviews assessed cigarette smoking and longest-held job, identifying exposure to vapors, gas, dust, or fumes (VGDF). Lung function was assessed in n=138. Comparison data were derived from a sample of referents without COPD.
Results
VGDF was reported by 123 (53%) of 233 cases vs. 577 (34%) of 1709 referents. VGDF was associated with COPD (Odds Ratio [OR] 2.5; 95% CI 1.9 to 3.4); the population attributable fraction [PAF] was 32%. In the lung function subset, the FEV1/FVC was <70% in 79 (57%); 35 (44%) reported VGDF associated with an OR=1.6 (95% CI 0.99 to 2.6) and PAF 17%.
Conclusions
These data support an important role for occupational exposures in COPD.
doi:10.1097/JOM.0b013e3181a7dd4e
PMCID: PMC2741692  PMID: 19528835
COPD; chronic bronchitis; occupation; attributable fraction
24.  A Simple Clinical Predictive Index for Objective Estimates of Mortality in Acute Lung Injury 
Critical care medicine  2009;37(6):1913-1920.
Objective
We sought to develop a simple point score that would accurately capture the risk of hospital death for patients with acute lung injury (ALI).
Design
This is a secondary analysis of data from two randomized trials. Baseline clinical variables collected within 24 hours of enrollment were modeled as predictors of hospital mortality using logistic regression and bootstrap resampling to arrive at a parsimonious model. We constructed a point score based on regression coefficients.
Setting
Medical centers participating in the Acute Respiratory Distress Syndrome Clinical Trials network (ARDSnet).
Patients
Model development: 414 patients with non-traumatic ALI participating in the low tidal volume arm of the ARDSnet ARMA study. Model validation: 459 patients participating in the ARDSnet ALVEOLI study.
Interventions
None
Measurements and Main Results
Variables comprising the prognostic model were: hematocrit <26% (1 point), bilirubin ≥ 2 mg/dl (1 point), fluid balance greater than 2.5 liters positive (1 point), and age (1 point for age 40–64, 2 points for age ≥ 65 years). Predicted mortality (95% confidence interval) for 0, 1, 2, 3, and 4+ point totals was 8% (5–14%), 17% (12–23%), 31% (26–37%), 51% (43–58%), and 70% (58–80%), respectively. There was excellent agreement between predicted and observed mortality in the validation cohort. Observed mortality for 0, 1, 2, 3, and 4+ point totals in the validation cohort was 12%, 16%, 28%, 47%, and 67%, respectively. Compared to the APACHE III score, areas under the receiver operating characteristic curve for the point score were greater in the development cohort (0.72 vs. 0.67, p=0.09) and lower in the validation cohort (0.68 vs. 0.75, p=0.03).
Conclusions
Mortality in ALI patients can be predicted using an index of four readily-available clinical variables with good calibration. This index may help inform prognostic discussions, but validation in non-clinical trial populations is necessary before widespread use.
doi:10.1097/CCM.0b013e3181a009b4
PMCID: PMC2731230  PMID: 19384214
Acute respiratory distress syndrome; acute lung injury; Respiratory Distress Syndrome; Adult; Human ARDS; Statistical Model; logistic models; mortality determinants; Mortality; In-Hospital; Acute Physiology and Chronic Health Evaluation; APACHE III; Bayesian Prediction; Prognosis
25.  An integrated model of environmental factors in adult asthma lung function and disease severity: a cross-sectional study 
Environmental Health  2010;9:24.
Background
Diverse environmental exposures, studied separately, have been linked to health outcomes in adult asthma, but integrated multi-factorial effects have not been modeled. We sought to evaluate the contribution of combined social and physical environmental exposures to adult asthma lung function and disease severity.
Methods
Data on 176 subjects with asthma and/or rhinitis were collected via telephone interviews for sociodemographic factors and asthma severity (scored on a 0-28 point range). Dust, indoor air quality, antigen-specific IgE antibodies, and lung function (percent predicted FEV1) were assessed through home visits. Neighborhood socioeconomic status, proximity to traffic, land use, and ambient air quality data were linked to the individual-level data via residential geocoding. Multiple linear regression separately tested the explanatory power of five groups of environmental factors for the outcomes, percent predicted FEV1 and asthma severity. Final models retained all variables statistically associated (p < 0.20) with each of the two outcomes.
Results
Mean FEV1 was 85.0 ± 18.6%; mean asthma severity score was 6.9 ± 5.6. Of 29 variables screened, 13 were retained in the final model of FEV1 (R2 = 0.30; p < 0.001) and 15 for severity (R2 = 0.16; p < 0.001), including factors from each of the five groups. Adding FEV1 as an independent variable to the severity model further increased its explanatory power (R2 = 0.25).
Conclusions
Multivariate models covering a range of individual and environmental factors explained nearly a third of FEV1 variability and, taking into account lung function, one quarter of variability in asthma severity. These data support an integrated approach to modeling adult asthma outcomes, including both the physical and the social environment.
doi:10.1186/1476-069X-9-24
PMCID: PMC2887801  PMID: 20487557

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