David J Lederer | Columbia University Medical Center (original) (raw)

Papers by David J Lederer

Research paper thumbnail of Primary graft dysfunction: Long-term physical function outcomes among lung transplant recipients

Heart & Lung: The Journal of Acute and Critical Care, 2016

Adults with primary graft dysfunction (PGD) after lung transplantation are at increased risk for ... more Adults with primary graft dysfunction (PGD) after lung transplantation are at increased risk for pulmonary and functional impairment. No prior studies have described the long-term (within 1.5 years of transplant) cardiopulmonary exercise testing (CPET) results in adults with grade 3 PGD. The objective of this study was to compare the functional outcomes of lung transplant patients with and without grade 3 PGD via CPET and six-minute talk tests (6MWD). 243 adults underwent lung transplantation between 2003 and 2010, 128 (53%) of whom underwent CPET and 6MWD within 12-18 months of transplantation. The primary measure of exposure was grade 3 PGD at 72 h, however grade 3 PGD within 72 h was also assessed. In addition, the impact of potential confounding variables was explored. Approximately one-third (32%) of the 243 patients experienced grade 3 PGD within 72 h; among these, 15 (6%) had grade 3 PGD at the 72 h time point. There were no differences in CPET or 6MWD between those with and without grade 3 PGD at 72 h despite a longer length of hospital stay and lower pulmonary function. Similar results were seen for patients with and without grade 3 PGD within 72 h, with the exception of a lower heart rate on CPET. Participants with grade 3 PGD are able to achieve functional outcomes comparable to those without PGD.

Research paper thumbnail of Polysomnographic Measurement of Sleep Duration and Bodily Pain Perception in the Sleep Heart Health Study

Sleep, Jan 3, 2016

To determine whether total sleep time (TST) and specific sleep stage duration are associated with... more To determine whether total sleep time (TST) and specific sleep stage duration are associated with bodily pain perception and whether sex, age, or subjective sleepiness modifies this relationship. Data from adults ages 39-90 y (n = 5,199) who took part in the Sleep Heart Health Study Exam 1 were analyzed. TST, rapid eye movement (REM) sleep time, and slow wave sleep (SWS) time were measured by unattended, in-home nocturnal polysomnography. Bodily pain perception was measured via the Short Form-36 questionnaire bodily pain component. We used logistic regression to examine associations between total and individual sleep stage durations and bodily pain perception controlling for age, sex, race, body mass index, apnea-hypopnea index, antidepressant use, and important cardiovascular conditions (smoking [pack-years], history of diabetes, and history of percutaneous coronary intervention and/or coronary artery bypass graft). In the fully adjusted model, REM sleep time and SWS time were not ...

Research paper thumbnail of Idiopathic Pulmonary Fibrosis on the Internet. Let's Calm the Sea of (Mis)information

American journal of respiratory and critical care medicine, Jan 15, 2016

Research paper thumbnail of Reply: Disparities in Access to Lung Transplantation-More Than Meets the Eye

American journal of respiratory and critical care medicine, 2016

Research paper thumbnail of Survival Benefit of Lung Transplantation in the Modern Era of Lung Allocation

Annals of the American Thoracic Society, Feb 1, 2017

Lung transplantation is an accepted and increasingly employed treatment for advanced lung disease... more Lung transplantation is an accepted and increasingly employed treatment for advanced lung diseases, but the anticipated survival benefit of lung transplantation is poorly understood. To determine whether and for which patients lung transplantation confers a survival benefit in the modern era of U.S. lung allocation. Data on 13,040 adults listed for lung transplantation between May 2005 and September 2011 were obtained from the United Network for Organ Sharing. A structural nested accelerated failure time model was used to model the survival benefit of lung transplantation over time. The effects of patient, donor, and transplant center characteristics on the relative survival benefit of transplantation were examined. Overall, 73.8% of transplant recipients were predicted to achieve a 2-year survival benefit with lung transplantation. The survival benefit of transplantation varied by native disease group (P = 0.062), with 2-year expected benefit in 39.2 and 98.9% of transplants occurr...

Research paper thumbnail of Obstructive Sleep Apnea and Subclinical Interstitial Lung Disease in MESA

Annals of the American Thoracic Society, Jan 14, 2017

Obstructive sleep apnea (OSA) has been postulated to contribute to idiopathic pulmonary fibrosis ... more Obstructive sleep apnea (OSA) has been postulated to contribute to idiopathic pulmonary fibrosis by promoting alveolar epithelial injury via tractional forces and intermittent hypoxia. To determine whether OSA is associated with subclinical interstitial lung disease (ILD) and with biomarkers of alveolar epithelial injury and remodeling. We performed cross-sectional analyses of 1,690 community-dwelling adults who underwent 15-channel in-home polysomnography and thoracic computed tomography (CT) imaging in the Multi-Ethnic Study of Atherosclerosis. We measured the obstructive apnea-hypopnea index (oAHI) from polysomnography and high attenuation areas (HAA) and interstitial lung abnormalities (ILA) from CT. Serum matrix metalloproteinase-7 (MMP-7) and surfactant protein-A (SP-A) were measured by ELISA in 99 participants. We used generalized linear models to adjust for potential confounders. The mean age was 68 years, and the mean forced vital capacity was 97% predicted. The median oAHI...

Research paper thumbnail of Genome-wide association study of subclinical interstitial lung disease in MESA

Respiratory research, Jan 18, 2017

We conducted a genome-wide association study (GWAS) of subclinical interstitial lung disease (ILD... more We conducted a genome-wide association study (GWAS) of subclinical interstitial lung disease (ILD), defined as high attenuation areas (HAA) on CT, in the population-based Multi-Ethnic Study of Atherosclerosis Study. We measured the percentage of high attenuation areas (HAA) in the lung fields on cardiac CT scan defined as voxels with CT attenuation values between -600 and -250 HU. Genetic analyses were performed in MESA combined across race/ethnic groups: non-Hispanic White (n = 2,434), African American (n = 2,470), Hispanic (n = 2,065) and Chinese (n = 702), as well as stratified by race/ethnicity. Among 7,671 participants, regions at genome-wide significance were identified for basilar peel-core ratio of HAA in FLJ35282 downstream of ANRIL (rs7852363, P = 2.1x10(-9)) and within introns of SNAI3-AS1 (rs140142658, P = 9.6x10(-9)) and D21S2088E (rs3079677, P = 2.3x10(-8)). Within race/ethnic groups, 18 additional loci were identified at genome-wide significance, including genes relat...

Research paper thumbnail of Refining Low Physical Activity Measurement Improves Frailty Assessment in Advanced Lung Disease and Survivors of Critical Illness

Annals of the American Thoracic Society, Jan 11, 2017

The frail phenotype has gained popularity as a clinically relevant measure in adults with advance... more The frail phenotype has gained popularity as a clinically relevant measure in adults with advanced lung disease and critical illness survivors. Since respiratory disease and chronic illness can greatly limit physical activity, the measurement of participation in traditional leisure-time activities as a frailty component may lead to substantial misclassification of frailty in pulmonary and critical care patients. To test and validate replacing the Duke Activities Scale Index (DASI), a simple 12-item questionnaire, for the Minnesota Leisure Time Activities (MLTA), a detailed questionnaire covering 18 leisure time activities, as the measure of low activity in the Fried frailty phenotype instrument (FFP). In separate multi-center prospective cohort studies of adults with advanced lung disease who were candidates for lung transplantation and older survivors of acute respiratory failure, we assessed the FFP using either the MLTA or the DASI. For both the DASI and MLTA, we evaluated conten...

Research paper thumbnail of Plasma Soluble Receptor for Advanced Glycation Endproducts in Idiopathic Pulmonary Fibrosis

Annals of the American Thoracic Society, 2017

The receptor for advanced glycation endproducts (RAGE) is underexpressed in IPF lung, yet the rol... more The receptor for advanced glycation endproducts (RAGE) is underexpressed in IPF lung, yet the role of RAGE in human lung fibrosis remains uncertain. To examine (1) the association between IPF risk and variation at rs2070600, a functional missense variant in AGER (the gene that codes for RAGE), and (2) the associations between plasma soluble RAGE (sRAGE) levels with disease severity and time to death or lung transplantation in IPF. We genotyped the rs2070600 SNP in 108 adults with IPF and 324 race/ethnicity-matched controls. We measured plasma sRAGE by ELISA in 103 adults with IPF. We used generalized linear and additive models as well as Cox models to control for potential confounders. We repeated our analyses in 168 (genetic analyses) and 177 (sRAGE analyses) adults with other forms of ILD. There was no association between rs2070600 variation among adults with IPF (p = 0.31). Plasma sRAGE levels were lower among adults with IPF and other forms of ILD compared to controls (p<0.00...

Research paper thumbnail of Race, Ethnicity, Health Insurance, and Mortality in Older Survivors of Critical Illness

Critical Care Medicine, 2017

To determine whether minority race or ethnicity is associated with mortality and mediated by heal... more To determine whether minority race or ethnicity is associated with mortality and mediated by health insurance coverage among older (≥ 65 yr old) survivors of critical illness. A retrospective cohort study. Two New York City academic medical centers. A total of 1,947 consecutive white (1,107), black (361), and Hispanic (479) older adults who had their first medical-ICU admission from 2006 through 2009 and survived to hospital discharge. None. We obtained demographic, insurance, and clinical data from electronic health records, determined each patient&amp;amp;amp;amp;#39;s neighborhood-level socioeconomic data from 2010 U.S. Census tract data, and determined death dates using the Social Security Death Index. Subjects had a mean (SD) age of 79 years (8.6 yr) and median (interquartile range) follow-up time of 1.6 years (0.4-3.0 yr). Blacks and Hispanics had similar mortality rates compared with whites (adjusted hazard ratio, 0.92; 95% CI, 0.76-1.11 and adjusted hazard ratio, 0.92; 95% CI, 0.76-1.12, respectively). Compared to those with commercial insurance and Medicare, higher mortality rates were observed for those with Medicare only (adjusted hazard ratio, 1.43; 95% CI, 1.03-1.98) and Medicaid (adjusted hazard ratio, 1.30; 95% CI, 1.10-1.52). Medicaid recipients who were the oldest ICU survivors (&amp;amp;amp;amp;gt; 82 yr), survivors of mechanical ventilation, and discharged to skilled-care facilities had the highest mortality rates (p-for-interaction: 0.08, 0.03, and 0.17, respectively). Mortality after critical illness among older adults varies by insurance coverage but not by race or ethnicity. Those with federal or state insurance coverage only had higher mortality rates than those with additional commercial insurance.

Research paper thumbnail of The Frailty Phenotype and Palliative Care Needs of Older Survivors of Critical Illness

Journal of the American Geriatrics Society, Jan 6, 2017

To assess symptoms in older intensive care unit (ICU) survivors and determine whether post-ICU fr... more To assess symptoms in older intensive care unit (ICU) survivors and determine whether post-ICU frailty identifies those with the greatest palliative care needs. A prospective cohort study. Urban tertiary care hospital and community hospital. Medical ICU survivors of mechanical ventilation aged 65 and older (N = 125). Baseline measurements of the Edmonton Symptom Assessment Scale (ESAS), categorized as mild (0-3), moderate (4-6), and severe (7-10), and the frailty phenotype were made during the week before hospital discharge. Functional recovery was defined as a return to a Katz activity of daily living dependency count less than or equal to the prehospitalization dependency count within 3 months. In the last 29 participants recruited, we made additional assessments of fatigue and ESAS both at baseline and 1 month after discharge. Fatigue was the most-prevalent moderate to severe symptom (74%), followed by dyspnea (53%), drowsiness (50%), poor appetite (47%), pain (45%), depression (...

Research paper thumbnail of Chest Fat Quantification via CT Based on Standardized Anatomy Space in Adult Lung Transplant Candidates

PloS one, 2017

Overweight and underweight conditions are considered relative contraindications to lung transplan... more Overweight and underweight conditions are considered relative contraindications to lung transplantation due to their association with excess mortality. Yet, recent work suggests that body mass index (BMI) does not accurately reflect adipose tissue mass in adults with advanced lung diseases. Alternative and more accurate measures of adiposity are needed. Chest fat estimation by routine computed tomography (CT) imaging may therefore be important for identifying high-risk lung transplant candidates. In this paper, an approach to chest fat quantification and quality assessment based on a recently formulated concept of standardized anatomic space (SAS) is presented. The goal of the paper is to seek answers to several key questions related to chest fat quantity and quality assessment based on a single slice CT (whether in the chest, abdomen, or thigh) versus a volumetric CT, which have not been addressed in the literature. Unenhanced chest CT image data sets from 40 adult lung transplant ...

Research paper thumbnail of Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis

The Lancet. Respiratory medicine, 2017

In clinical trials of idiopathic pulmonary fibrosis, rates of all-cause mortality are low. Thus p... more In clinical trials of idiopathic pulmonary fibrosis, rates of all-cause mortality are low. Thus prospective mortality trials are logistically very challenging, justifying the use of pooled analyses or meta-analyses. We did pooled analyses and meta-analyses of clinical trials of pirfenidone versus placebo to determine the effect of pirfenidone on mortality outcomes over 120 weeks. We did a pooled analysis of the combined patient populations of the three global randomised phase 3 trials of pirfenidone versus placebo-Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY 004 and 006; trial durations 72-120 weeks) and Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND 016; 52 weeks)-for all-cause mortality, treatment-emergent all-cause mortality, idiopathic-pulmonary-fibrosis-related mortality, and treatment-emergent idiopathic-pulmonary-fibrosis-related mortality at weeks...

Research paper thumbnail of Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial

The Lancet. Respiratory medicine, 2017

Lysyl oxidase-like 2 (LOXL2) catalyses collagen cross-linking and is implicated in the pathogenes... more Lysyl oxidase-like 2 (LOXL2) catalyses collagen cross-linking and is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the efficacy and safety of simtuzumab, a monoclonal antibody against LOXL2, in patients with IPF. In this randomised, double-blind, phase 2 trial, we recruited patients aged 45-85 years with definite IPF diagnosed prior to 3 years of screening from 183 hospitals and respiratory clinics in 14 countries. Eligible patients, stratified by baseline forced vital capacity (FVC), serum LOXL2 (sLOXL2) concentrations, and pirfenidone and nintedanib use, were randomly assigned (1:1) to inject 125 mg/mL simtuzumab or placebo subcutaneously once a week. The primary endpoints were progression-free survival, defined as time to all-cause death or a categorical decrease from baseline in FVC % predicted, in the intention-to-treat population, in patients with sLOXL2 concentrations in the 50th percentile or higher, and in pa...

Research paper thumbnail of Rheumatoid arthritis-associated autoantibodies and subclinical interstitial lung disease: the Multi-Ethnic Study of Atherosclerosis

Thorax, Jan 8, 2016

Adults with interstitial lung disease (ILD) often have serologic evidence of autoimmunity of unce... more Adults with interstitial lung disease (ILD) often have serologic evidence of autoimmunity of uncertain significance without overt autoimmune disease. We examined associations of rheumatoid arthritis (RA)-associated antibodies with subclinical ILD in community-dwelling adults. We measured serum rheumatoid factor (RF) and anticyclic citrullinated peptide antibody (anti-CCP) and high attenuation areas (HAAs; CT attenuation values between -600 and -250 Hounsfield units) on cardiac CT in 6736 community-dwelling US adults enrolled in the Multi-Ethnic Study of Atherosclerosis. We measured interstitial lung abnormalities (ILAs) in 2907 full-lung CTs at 9.5-year median follow-up. We used generalised linear and additive models to examine associations between autoantibodies and both HAA and ILA, and tested for effect modification by smoking. In adjusted models, HAA increased by 0.49% (95% CI 0.11% to 0.86%) per doubling of RF IgM and by 0.95% (95% CI 0.50% to 1.40%) per RF IgA doubling. ILA pr...

Research paper thumbnail of Efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis with more preserved lung function

European Respiratory Journal, 2016

This post hoc analysis examined the differences in idiopathic pulmonary fibrosis disease progress... more This post hoc analysis examined the differences in idiopathic pulmonary fibrosis disease progression and the effects of pirfenidone in patients stratified by more preserved versus less preserved baseline lung function status using forced vital capacity (FVC) or GAP (gender, age and physiology) index stage.Efficacy outcomes, i.e. FVC, 6-min walking distance (6MWD) and dyspnoea (University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ)), were analysed at 12 months in patients randomised to pirfenidone 2403 mg·day(-1) or placebo in the pooled phase 3 CAPACITY/ASCEND population (n=1247), with subgroups stratified by baseline FVC ≥80% versus &amp;amp;lt;80% or GAP stage I versus II-III. Treatment-by-subgroup interaction was tested based on a rank ANCOVA model; factors in the model included study, region, treatment, subgroup and treatment-by-subgroup interaction term.Patients with both more preserved (FVC ≥80% or GAP stage I) and less preserved (FVC &amp;amp;lt;80% or GAP stage II-III) lung function at baseline demonstrated clinically significant disease progression at 12 months in terms of categorical decline in FVC, 6MWD and UCSD SOBQ. The magnitude of pirfenidone treatment effect was comparable between subgroups, regardless of whether lung function was classified using FVC or GAP index stage.These findings support the initiation of treatment with pirfenidone, irrespective of stage of baseline lung function in this patient population.

Research paper thumbnail of Adipose Gene Expression Profile Changes with Lung Allograft Reperfusion

American Journal of Transplantation, 2016

Obesity is a risk factor for primary graft dysfunction, a form of lung injury resulting from isch... more Obesity is a risk factor for primary graft dysfunction, a form of lung injury resulting from ischemia reperfusion after lung transplantation, but the impact of ischemia reperfusion on adipose tissue is unknown. We evaluated differential gene expression in thoracic visceral adipose tissue (VAT) before and after lung reperfusion. Total RNA was isolated from thoracic VAT sampled from 6 subjects enrolled in the Lung Transplant Body Composition study before and after allograft reperfusion and quantified using the Human Gene 2.0 ST array. KEGG pathway analysis revealed enrichment for genes involved in complement and coagulation cascades and Jak-STAT signaling pathways. Overall, 72 genes were upregulated and 56 genes were down-regulated in the post-reperfusion time compared with baseline. Long pentraxin-3 (PTX3), a gene and plasma protein previously associated with PGD, was the most upregulated gene (19.5 fold increase, p=0.04). Fibronectin leucine rich transmembrane protein (FLRT3), a gene associated with cell adhesion and receptor signaling, was the most down-regulated gene (4.3 fold decrease, p=0.04). Ischemia reperfusion has a demonstrable impact on gene expression in visceral adipose tissue in our pilot study of non-obese, non-PGD lung transplant recipients. Future evaluation will focus on differential adipose tissue gene expression and the development of PGD after transplant. This article is protected by copyright. All rights reserved.

Research paper thumbnail of Living with Interstitial Lung Disease: How Do We Best Meet the Educational Needs of Our Patients?

Annals of the American Thoracic Society, 2016

Research paper thumbnail of Socioeconomic Barriers to Lung Transplantation

American Journal of Respiratory and Critical Care Medicine, Mar 5, 2013

Research paper thumbnail of Donor lung assessment using selective pulmonary vein gases

European Journal of Cardio-Thoracic Surgery, 2016

Standard donor lung assessment relies on imaging, challenge gases and subjective interpretation o... more Standard donor lung assessment relies on imaging, challenge gases and subjective interpretation of bronchoscopic findings, palpation and visual assessment. Central gases may not accurately represent true quality of the lungs. We report our experience using selective pulmonary vein gases to corroborate the subjective judgement. Starting, January 2012, donor lungs have been assessed by intraoperative bronchoscopy, palpation and visual judgement of lung collapse upon temporary disconnection from ventilator, central gases from the aorta and selective pulmonary vein gases. Partial pressure of oxygen (pO2) &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;300 mmHg on FiO2 of 1.0 was considered low. The results of the chest X-ray and last pO2 in the intensive care unit were also collected. Post-transplant primary graft dysfunction and survival were monitored. To date, 259 consecutive brain-dead donors have been assessed and 157 transplants performed. Last pO2 in the intensive care unit was poorly correlated with intraoperative central pO2 (Spearman&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s rank correlation rs = 0.29). Right inferior pulmonary vein pO2 was associated (Mann-Whitney, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) with findings at bronchoscopy [clean: median pO2 443 mmHg (25th-75th percentile range 349-512) and purulent: 264 mmHg (178-408)]; palpation [good: 463 mmHg (401-517) and poor: 264 mmHg (158-434)] and visual assessment of lung collapse [good lung collapse: 429 mmHg (320-501) and poor lung collapse: 205 mmHg (118-348)]. Left inferior pulmonary pO2 was associated (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) with findings at bronchoscopy [clean: 419 mmHg (371-504) and purulent: 254 mmHg (206-367)]; palpation [good: 444 mmHg (400-517) and poor 282 mmHg (211-419)] and visual assessment of lung collapse [good: 420 mmHg (349-496) and poor: 246 mmHg (129-330)]. At 72 h, pulmonary graft dysfunction 2 was in 21/157 (13%) and pulmonary graft dysfunction 3 in 17/157 (11%). Ninety-day and 1-year mortalities were 6/157 (4%) and 13/157 (8%), respectively. Selective pulmonary vein gases provide corroborative objective support to the findings at bronchoscopy, palpation and visual assessment. Central gases do not always reflect true function of the lungs, having high false-positive rate towards the individual lower lobe gas exchange. Objective measures of donor lung function may optimize donor surgeon assessment, allowing for low pulmonary graft dysfunction rates and low 90-day and 1-year mortality.

Research paper thumbnail of Primary graft dysfunction: Long-term physical function outcomes among lung transplant recipients

Heart & Lung: The Journal of Acute and Critical Care, 2016

Adults with primary graft dysfunction (PGD) after lung transplantation are at increased risk for ... more Adults with primary graft dysfunction (PGD) after lung transplantation are at increased risk for pulmonary and functional impairment. No prior studies have described the long-term (within 1.5 years of transplant) cardiopulmonary exercise testing (CPET) results in adults with grade 3 PGD. The objective of this study was to compare the functional outcomes of lung transplant patients with and without grade 3 PGD via CPET and six-minute talk tests (6MWD). 243 adults underwent lung transplantation between 2003 and 2010, 128 (53%) of whom underwent CPET and 6MWD within 12-18 months of transplantation. The primary measure of exposure was grade 3 PGD at 72 h, however grade 3 PGD within 72 h was also assessed. In addition, the impact of potential confounding variables was explored. Approximately one-third (32%) of the 243 patients experienced grade 3 PGD within 72 h; among these, 15 (6%) had grade 3 PGD at the 72 h time point. There were no differences in CPET or 6MWD between those with and without grade 3 PGD at 72 h despite a longer length of hospital stay and lower pulmonary function. Similar results were seen for patients with and without grade 3 PGD within 72 h, with the exception of a lower heart rate on CPET. Participants with grade 3 PGD are able to achieve functional outcomes comparable to those without PGD.

Research paper thumbnail of Polysomnographic Measurement of Sleep Duration and Bodily Pain Perception in the Sleep Heart Health Study

Sleep, Jan 3, 2016

To determine whether total sleep time (TST) and specific sleep stage duration are associated with... more To determine whether total sleep time (TST) and specific sleep stage duration are associated with bodily pain perception and whether sex, age, or subjective sleepiness modifies this relationship. Data from adults ages 39-90 y (n = 5,199) who took part in the Sleep Heart Health Study Exam 1 were analyzed. TST, rapid eye movement (REM) sleep time, and slow wave sleep (SWS) time were measured by unattended, in-home nocturnal polysomnography. Bodily pain perception was measured via the Short Form-36 questionnaire bodily pain component. We used logistic regression to examine associations between total and individual sleep stage durations and bodily pain perception controlling for age, sex, race, body mass index, apnea-hypopnea index, antidepressant use, and important cardiovascular conditions (smoking [pack-years], history of diabetes, and history of percutaneous coronary intervention and/or coronary artery bypass graft). In the fully adjusted model, REM sleep time and SWS time were not ...

Research paper thumbnail of Idiopathic Pulmonary Fibrosis on the Internet. Let's Calm the Sea of (Mis)information

American journal of respiratory and critical care medicine, Jan 15, 2016

Research paper thumbnail of Reply: Disparities in Access to Lung Transplantation-More Than Meets the Eye

American journal of respiratory and critical care medicine, 2016

Research paper thumbnail of Survival Benefit of Lung Transplantation in the Modern Era of Lung Allocation

Annals of the American Thoracic Society, Feb 1, 2017

Lung transplantation is an accepted and increasingly employed treatment for advanced lung disease... more Lung transplantation is an accepted and increasingly employed treatment for advanced lung diseases, but the anticipated survival benefit of lung transplantation is poorly understood. To determine whether and for which patients lung transplantation confers a survival benefit in the modern era of U.S. lung allocation. Data on 13,040 adults listed for lung transplantation between May 2005 and September 2011 were obtained from the United Network for Organ Sharing. A structural nested accelerated failure time model was used to model the survival benefit of lung transplantation over time. The effects of patient, donor, and transplant center characteristics on the relative survival benefit of transplantation were examined. Overall, 73.8% of transplant recipients were predicted to achieve a 2-year survival benefit with lung transplantation. The survival benefit of transplantation varied by native disease group (P = 0.062), with 2-year expected benefit in 39.2 and 98.9% of transplants occurr...

Research paper thumbnail of Obstructive Sleep Apnea and Subclinical Interstitial Lung Disease in MESA

Annals of the American Thoracic Society, Jan 14, 2017

Obstructive sleep apnea (OSA) has been postulated to contribute to idiopathic pulmonary fibrosis ... more Obstructive sleep apnea (OSA) has been postulated to contribute to idiopathic pulmonary fibrosis by promoting alveolar epithelial injury via tractional forces and intermittent hypoxia. To determine whether OSA is associated with subclinical interstitial lung disease (ILD) and with biomarkers of alveolar epithelial injury and remodeling. We performed cross-sectional analyses of 1,690 community-dwelling adults who underwent 15-channel in-home polysomnography and thoracic computed tomography (CT) imaging in the Multi-Ethnic Study of Atherosclerosis. We measured the obstructive apnea-hypopnea index (oAHI) from polysomnography and high attenuation areas (HAA) and interstitial lung abnormalities (ILA) from CT. Serum matrix metalloproteinase-7 (MMP-7) and surfactant protein-A (SP-A) were measured by ELISA in 99 participants. We used generalized linear models to adjust for potential confounders. The mean age was 68 years, and the mean forced vital capacity was 97% predicted. The median oAHI...

Research paper thumbnail of Genome-wide association study of subclinical interstitial lung disease in MESA

Respiratory research, Jan 18, 2017

We conducted a genome-wide association study (GWAS) of subclinical interstitial lung disease (ILD... more We conducted a genome-wide association study (GWAS) of subclinical interstitial lung disease (ILD), defined as high attenuation areas (HAA) on CT, in the population-based Multi-Ethnic Study of Atherosclerosis Study. We measured the percentage of high attenuation areas (HAA) in the lung fields on cardiac CT scan defined as voxels with CT attenuation values between -600 and -250 HU. Genetic analyses were performed in MESA combined across race/ethnic groups: non-Hispanic White (n = 2,434), African American (n = 2,470), Hispanic (n = 2,065) and Chinese (n = 702), as well as stratified by race/ethnicity. Among 7,671 participants, regions at genome-wide significance were identified for basilar peel-core ratio of HAA in FLJ35282 downstream of ANRIL (rs7852363, P = 2.1x10(-9)) and within introns of SNAI3-AS1 (rs140142658, P = 9.6x10(-9)) and D21S2088E (rs3079677, P = 2.3x10(-8)). Within race/ethnic groups, 18 additional loci were identified at genome-wide significance, including genes relat...

Research paper thumbnail of Refining Low Physical Activity Measurement Improves Frailty Assessment in Advanced Lung Disease and Survivors of Critical Illness

Annals of the American Thoracic Society, Jan 11, 2017

The frail phenotype has gained popularity as a clinically relevant measure in adults with advance... more The frail phenotype has gained popularity as a clinically relevant measure in adults with advanced lung disease and critical illness survivors. Since respiratory disease and chronic illness can greatly limit physical activity, the measurement of participation in traditional leisure-time activities as a frailty component may lead to substantial misclassification of frailty in pulmonary and critical care patients. To test and validate replacing the Duke Activities Scale Index (DASI), a simple 12-item questionnaire, for the Minnesota Leisure Time Activities (MLTA), a detailed questionnaire covering 18 leisure time activities, as the measure of low activity in the Fried frailty phenotype instrument (FFP). In separate multi-center prospective cohort studies of adults with advanced lung disease who were candidates for lung transplantation and older survivors of acute respiratory failure, we assessed the FFP using either the MLTA or the DASI. For both the DASI and MLTA, we evaluated conten...

Research paper thumbnail of Plasma Soluble Receptor for Advanced Glycation Endproducts in Idiopathic Pulmonary Fibrosis

Annals of the American Thoracic Society, 2017

The receptor for advanced glycation endproducts (RAGE) is underexpressed in IPF lung, yet the rol... more The receptor for advanced glycation endproducts (RAGE) is underexpressed in IPF lung, yet the role of RAGE in human lung fibrosis remains uncertain. To examine (1) the association between IPF risk and variation at rs2070600, a functional missense variant in AGER (the gene that codes for RAGE), and (2) the associations between plasma soluble RAGE (sRAGE) levels with disease severity and time to death or lung transplantation in IPF. We genotyped the rs2070600 SNP in 108 adults with IPF and 324 race/ethnicity-matched controls. We measured plasma sRAGE by ELISA in 103 adults with IPF. We used generalized linear and additive models as well as Cox models to control for potential confounders. We repeated our analyses in 168 (genetic analyses) and 177 (sRAGE analyses) adults with other forms of ILD. There was no association between rs2070600 variation among adults with IPF (p = 0.31). Plasma sRAGE levels were lower among adults with IPF and other forms of ILD compared to controls (p<0.00...

Research paper thumbnail of Race, Ethnicity, Health Insurance, and Mortality in Older Survivors of Critical Illness

Critical Care Medicine, 2017

To determine whether minority race or ethnicity is associated with mortality and mediated by heal... more To determine whether minority race or ethnicity is associated with mortality and mediated by health insurance coverage among older (≥ 65 yr old) survivors of critical illness. A retrospective cohort study. Two New York City academic medical centers. A total of 1,947 consecutive white (1,107), black (361), and Hispanic (479) older adults who had their first medical-ICU admission from 2006 through 2009 and survived to hospital discharge. None. We obtained demographic, insurance, and clinical data from electronic health records, determined each patient&amp;amp;amp;amp;#39;s neighborhood-level socioeconomic data from 2010 U.S. Census tract data, and determined death dates using the Social Security Death Index. Subjects had a mean (SD) age of 79 years (8.6 yr) and median (interquartile range) follow-up time of 1.6 years (0.4-3.0 yr). Blacks and Hispanics had similar mortality rates compared with whites (adjusted hazard ratio, 0.92; 95% CI, 0.76-1.11 and adjusted hazard ratio, 0.92; 95% CI, 0.76-1.12, respectively). Compared to those with commercial insurance and Medicare, higher mortality rates were observed for those with Medicare only (adjusted hazard ratio, 1.43; 95% CI, 1.03-1.98) and Medicaid (adjusted hazard ratio, 1.30; 95% CI, 1.10-1.52). Medicaid recipients who were the oldest ICU survivors (&amp;amp;amp;amp;gt; 82 yr), survivors of mechanical ventilation, and discharged to skilled-care facilities had the highest mortality rates (p-for-interaction: 0.08, 0.03, and 0.17, respectively). Mortality after critical illness among older adults varies by insurance coverage but not by race or ethnicity. Those with federal or state insurance coverage only had higher mortality rates than those with additional commercial insurance.

Research paper thumbnail of The Frailty Phenotype and Palliative Care Needs of Older Survivors of Critical Illness

Journal of the American Geriatrics Society, Jan 6, 2017

To assess symptoms in older intensive care unit (ICU) survivors and determine whether post-ICU fr... more To assess symptoms in older intensive care unit (ICU) survivors and determine whether post-ICU frailty identifies those with the greatest palliative care needs. A prospective cohort study. Urban tertiary care hospital and community hospital. Medical ICU survivors of mechanical ventilation aged 65 and older (N = 125). Baseline measurements of the Edmonton Symptom Assessment Scale (ESAS), categorized as mild (0-3), moderate (4-6), and severe (7-10), and the frailty phenotype were made during the week before hospital discharge. Functional recovery was defined as a return to a Katz activity of daily living dependency count less than or equal to the prehospitalization dependency count within 3 months. In the last 29 participants recruited, we made additional assessments of fatigue and ESAS both at baseline and 1 month after discharge. Fatigue was the most-prevalent moderate to severe symptom (74%), followed by dyspnea (53%), drowsiness (50%), poor appetite (47%), pain (45%), depression (...

Research paper thumbnail of Chest Fat Quantification via CT Based on Standardized Anatomy Space in Adult Lung Transplant Candidates

PloS one, 2017

Overweight and underweight conditions are considered relative contraindications to lung transplan... more Overweight and underweight conditions are considered relative contraindications to lung transplantation due to their association with excess mortality. Yet, recent work suggests that body mass index (BMI) does not accurately reflect adipose tissue mass in adults with advanced lung diseases. Alternative and more accurate measures of adiposity are needed. Chest fat estimation by routine computed tomography (CT) imaging may therefore be important for identifying high-risk lung transplant candidates. In this paper, an approach to chest fat quantification and quality assessment based on a recently formulated concept of standardized anatomic space (SAS) is presented. The goal of the paper is to seek answers to several key questions related to chest fat quantity and quality assessment based on a single slice CT (whether in the chest, abdomen, or thigh) versus a volumetric CT, which have not been addressed in the literature. Unenhanced chest CT image data sets from 40 adult lung transplant ...

Research paper thumbnail of Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis

The Lancet. Respiratory medicine, 2017

In clinical trials of idiopathic pulmonary fibrosis, rates of all-cause mortality are low. Thus p... more In clinical trials of idiopathic pulmonary fibrosis, rates of all-cause mortality are low. Thus prospective mortality trials are logistically very challenging, justifying the use of pooled analyses or meta-analyses. We did pooled analyses and meta-analyses of clinical trials of pirfenidone versus placebo to determine the effect of pirfenidone on mortality outcomes over 120 weeks. We did a pooled analysis of the combined patient populations of the three global randomised phase 3 trials of pirfenidone versus placebo-Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes (CAPACITY 004 and 006; trial durations 72-120 weeks) and Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND 016; 52 weeks)-for all-cause mortality, treatment-emergent all-cause mortality, idiopathic-pulmonary-fibrosis-related mortality, and treatment-emergent idiopathic-pulmonary-fibrosis-related mortality at weeks...

Research paper thumbnail of Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial

The Lancet. Respiratory medicine, 2017

Lysyl oxidase-like 2 (LOXL2) catalyses collagen cross-linking and is implicated in the pathogenes... more Lysyl oxidase-like 2 (LOXL2) catalyses collagen cross-linking and is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the efficacy and safety of simtuzumab, a monoclonal antibody against LOXL2, in patients with IPF. In this randomised, double-blind, phase 2 trial, we recruited patients aged 45-85 years with definite IPF diagnosed prior to 3 years of screening from 183 hospitals and respiratory clinics in 14 countries. Eligible patients, stratified by baseline forced vital capacity (FVC), serum LOXL2 (sLOXL2) concentrations, and pirfenidone and nintedanib use, were randomly assigned (1:1) to inject 125 mg/mL simtuzumab or placebo subcutaneously once a week. The primary endpoints were progression-free survival, defined as time to all-cause death or a categorical decrease from baseline in FVC % predicted, in the intention-to-treat population, in patients with sLOXL2 concentrations in the 50th percentile or higher, and in pa...

Research paper thumbnail of Rheumatoid arthritis-associated autoantibodies and subclinical interstitial lung disease: the Multi-Ethnic Study of Atherosclerosis

Thorax, Jan 8, 2016

Adults with interstitial lung disease (ILD) often have serologic evidence of autoimmunity of unce... more Adults with interstitial lung disease (ILD) often have serologic evidence of autoimmunity of uncertain significance without overt autoimmune disease. We examined associations of rheumatoid arthritis (RA)-associated antibodies with subclinical ILD in community-dwelling adults. We measured serum rheumatoid factor (RF) and anticyclic citrullinated peptide antibody (anti-CCP) and high attenuation areas (HAAs; CT attenuation values between -600 and -250 Hounsfield units) on cardiac CT in 6736 community-dwelling US adults enrolled in the Multi-Ethnic Study of Atherosclerosis. We measured interstitial lung abnormalities (ILAs) in 2907 full-lung CTs at 9.5-year median follow-up. We used generalised linear and additive models to examine associations between autoantibodies and both HAA and ILA, and tested for effect modification by smoking. In adjusted models, HAA increased by 0.49% (95% CI 0.11% to 0.86%) per doubling of RF IgM and by 0.95% (95% CI 0.50% to 1.40%) per RF IgA doubling. ILA pr...

Research paper thumbnail of Efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis with more preserved lung function

European Respiratory Journal, 2016

This post hoc analysis examined the differences in idiopathic pulmonary fibrosis disease progress... more This post hoc analysis examined the differences in idiopathic pulmonary fibrosis disease progression and the effects of pirfenidone in patients stratified by more preserved versus less preserved baseline lung function status using forced vital capacity (FVC) or GAP (gender, age and physiology) index stage.Efficacy outcomes, i.e. FVC, 6-min walking distance (6MWD) and dyspnoea (University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ)), were analysed at 12 months in patients randomised to pirfenidone 2403 mg·day(-1) or placebo in the pooled phase 3 CAPACITY/ASCEND population (n=1247), with subgroups stratified by baseline FVC ≥80% versus &amp;amp;lt;80% or GAP stage I versus II-III. Treatment-by-subgroup interaction was tested based on a rank ANCOVA model; factors in the model included study, region, treatment, subgroup and treatment-by-subgroup interaction term.Patients with both more preserved (FVC ≥80% or GAP stage I) and less preserved (FVC &amp;amp;lt;80% or GAP stage II-III) lung function at baseline demonstrated clinically significant disease progression at 12 months in terms of categorical decline in FVC, 6MWD and UCSD SOBQ. The magnitude of pirfenidone treatment effect was comparable between subgroups, regardless of whether lung function was classified using FVC or GAP index stage.These findings support the initiation of treatment with pirfenidone, irrespective of stage of baseline lung function in this patient population.

Research paper thumbnail of Adipose Gene Expression Profile Changes with Lung Allograft Reperfusion

American Journal of Transplantation, 2016

Obesity is a risk factor for primary graft dysfunction, a form of lung injury resulting from isch... more Obesity is a risk factor for primary graft dysfunction, a form of lung injury resulting from ischemia reperfusion after lung transplantation, but the impact of ischemia reperfusion on adipose tissue is unknown. We evaluated differential gene expression in thoracic visceral adipose tissue (VAT) before and after lung reperfusion. Total RNA was isolated from thoracic VAT sampled from 6 subjects enrolled in the Lung Transplant Body Composition study before and after allograft reperfusion and quantified using the Human Gene 2.0 ST array. KEGG pathway analysis revealed enrichment for genes involved in complement and coagulation cascades and Jak-STAT signaling pathways. Overall, 72 genes were upregulated and 56 genes were down-regulated in the post-reperfusion time compared with baseline. Long pentraxin-3 (PTX3), a gene and plasma protein previously associated with PGD, was the most upregulated gene (19.5 fold increase, p=0.04). Fibronectin leucine rich transmembrane protein (FLRT3), a gene associated with cell adhesion and receptor signaling, was the most down-regulated gene (4.3 fold decrease, p=0.04). Ischemia reperfusion has a demonstrable impact on gene expression in visceral adipose tissue in our pilot study of non-obese, non-PGD lung transplant recipients. Future evaluation will focus on differential adipose tissue gene expression and the development of PGD after transplant. This article is protected by copyright. All rights reserved.

Research paper thumbnail of Living with Interstitial Lung Disease: How Do We Best Meet the Educational Needs of Our Patients?

Annals of the American Thoracic Society, 2016

Research paper thumbnail of Socioeconomic Barriers to Lung Transplantation

American Journal of Respiratory and Critical Care Medicine, Mar 5, 2013

Research paper thumbnail of Donor lung assessment using selective pulmonary vein gases

European Journal of Cardio-Thoracic Surgery, 2016

Standard donor lung assessment relies on imaging, challenge gases and subjective interpretation o... more Standard donor lung assessment relies on imaging, challenge gases and subjective interpretation of bronchoscopic findings, palpation and visual assessment. Central gases may not accurately represent true quality of the lungs. We report our experience using selective pulmonary vein gases to corroborate the subjective judgement. Starting, January 2012, donor lungs have been assessed by intraoperative bronchoscopy, palpation and visual judgement of lung collapse upon temporary disconnection from ventilator, central gases from the aorta and selective pulmonary vein gases. Partial pressure of oxygen (pO2) &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;300 mmHg on FiO2 of 1.0 was considered low. The results of the chest X-ray and last pO2 in the intensive care unit were also collected. Post-transplant primary graft dysfunction and survival were monitored. To date, 259 consecutive brain-dead donors have been assessed and 157 transplants performed. Last pO2 in the intensive care unit was poorly correlated with intraoperative central pO2 (Spearman&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s rank correlation rs = 0.29). Right inferior pulmonary vein pO2 was associated (Mann-Whitney, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) with findings at bronchoscopy [clean: median pO2 443 mmHg (25th-75th percentile range 349-512) and purulent: 264 mmHg (178-408)]; palpation [good: 463 mmHg (401-517) and poor: 264 mmHg (158-434)] and visual assessment of lung collapse [good lung collapse: 429 mmHg (320-501) and poor lung collapse: 205 mmHg (118-348)]. Left inferior pulmonary pO2 was associated (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) with findings at bronchoscopy [clean: 419 mmHg (371-504) and purulent: 254 mmHg (206-367)]; palpation [good: 444 mmHg (400-517) and poor 282 mmHg (211-419)] and visual assessment of lung collapse [good: 420 mmHg (349-496) and poor: 246 mmHg (129-330)]. At 72 h, pulmonary graft dysfunction 2 was in 21/157 (13%) and pulmonary graft dysfunction 3 in 17/157 (11%). Ninety-day and 1-year mortalities were 6/157 (4%) and 13/157 (8%), respectively. Selective pulmonary vein gases provide corroborative objective support to the findings at bronchoscopy, palpation and visual assessment. Central gases do not always reflect true function of the lungs, having high false-positive rate towards the individual lower lobe gas exchange. Objective measures of donor lung function may optimize donor surgeon assessment, allowing for low pulmonary graft dysfunction rates and low 90-day and 1-year mortality.