Search

Background: The coronavirus disease 2019 (COVID-19) pandemic challenges hospital leaders to make time-sensitive, critical decisions about clinical operations and resource allocations., Objective: To estimate the timing of surges in clinical demand and the best- and worst-case scenarios of local COVID-19-induced strain on hospital capacity, and thus inform clinical operations and staffing demands and identify when hospital capacity would be saturated., Design: Monte Carlo simulation instantiation of a susceptible, infected, removed (SIR) model with a 1-day cycle., Setting: 3 hospitals in an academic health system., Patients: All people living in the greater Philadelphia region., Measurements: The COVID-19 Hospital Impact Model (CHIME) (http://penn-chime.phl.io) SIR model was used to estimate the time from 23 March 2020 until hospital capacity would probably be exceeded, and the intensity of the surge, including for intensive care unit (ICU) beds and ventilators., Results: Using patients with COVID-19 alone, CHIME estimated that it would be 31 to 53 days before demand exceeds existing hospital capacity. In best- and worst-case scenarios of surges in the number of patients with COVID-19, the needed total capacity for hospital beds would reach 3131 to 12 650 across the 3 hospitals, including 338 to 1608 ICU beds and 118 to 599 ventilators., Limitations: Model parameters were taken directly or derived from published data across heterogeneous populations and practice environments and from the health system's historical data. CHIME does not incorporate more transition states to model infection severity, social networks to model transmission dynamics, or geographic information to account for spatial patterns of human interaction., Conclusion: Publicly available and designed for hospital operations leaders, this modeling tool can inform preparations for capacity strain during the early days of a pandemic., Primary Funding Source: University of Pennsylvania Health System and the Palliative and Advanced Illness Research Center.

Objectives: Body mass index (BMI) is associated with acute kidney injury (AKI) after trauma, but underlying mechanisms are unclear. Body mass index correlates with both excess adiposity and increased muscle mass. Since the latter could predispose to severe rhabdomyolysis after trauma, we hypothesized that the BMI-AKI association may be partially explained by a direct relationship of BMI with serum creatine kinase (CK)., Methods: Prospective cohort study of 463 critically ill patients admitted to a level I trauma center from 2005 to 2015 with Injury Severity Score of >15 and serum CK measured in the first 7 days. We defined AKI by AKI Network creatinine criteria. We used simple linear regression to determine the association of BMI with peak CK and multivariable logistic regression to adjust the BMI-AKI association for peak CK and confounders., Results: Median age was 43 years, 350 (76%) were male, 366 (79%) had blunt mechanism, and median Injury Severity Score was 24. Body mass index was associated with peak CK (R = 0.05, p < 0.001). Acute kidney injury developed in 148 patients (32%), and median time to peak CK was 29 hours (interquartile range, 15-56 hours) after presentation. Body mass index was significantly associated with AKI in multivariable models adjusted for age, race, sex, diabetes, injury mechanism and severity, and red blood cell transfusions (odds ratio [OR], 1.31 per 5 kg/m; 95% confidence interval [CI], 1.09-1.58; p = 0.004). Adding peak CK to the model partially attenuated the association of BMI with AKI (OR, 1.26 per 5 kg/m; 95% CI, 1.04-1.52; p = 0.018), and peak CK was also associated with AKI (OR, 1.19 per natural log; 95% CI, 1.00-1.41; p = 0.049). Peak CK remained associated with AKI when restricted to patients with values of <5,000 U/L (OR, 1.31 per natural log; 95% CI, 1.01-1.69; p = 0.043)., Conclusion: Serum CK correlated with BMI and partially attenuated the association of BMI with AKI after major trauma, suggesting that excess muscle injury may contribute to the BMI-AKI association., Level of Evidence: Epidemiologic study, level III.

Background: Lung transplant patients experience significant physical symptoms and psychological stress that affect their quality of life. Palliative care is an interdisciplinary specialty associated with improved symptom management and enhanced quality of life. Little, however, is known about the palliative care needs of lung transplant patients and the role it plays in their care., Aim: The aim of this integrative review was to synthesize the literature describing the palliative care needs, the current role, and factors influencing the integration of palliative care in the care of lung transplant patients., Design/data Sources: We searched PubMed, Scopus, CINAHL, and Embase to identify English-language, primary studies focused on palliative care in adult lung transplantation. Study quality was evaluated using Strengthening the Report of Observational studies in Epidemiology and Consolidated Criteria for Reporting Qualitative Research criteria., Results: Seven articles were included in the review. Most were single-center, descriptive studies. Two studies used qualitative and 5 used quantitative methodologies. Collectively, these studies suggest that palliative care is typically consulted for physical and psychological symptom management, although consultation is uncommon and often occurs late in the lung transplant process. We found no studies that systematically assessed palliative needs. Misperceptions about palliative care, communication challenges, and unrealistic patient/family expectations are identified barriers to the integration. While limited, evidence suggests that palliative care can be successfully integrated into lung transplant patient management., Conclusions: Empirical literature about palliative care in lung transplantation is sparse. Further research is needed to define the needs and opportunities for integration into the care of these patients.

Introduction: Cardiac complications (CC) after injury are rare but contribute disproportionately to mortality. Variability in rates of CC and failure to rescue (FTR) after CC (FTR-C) within trauma systems may suggest opportunities for improvement, but we have not yet demonstrated the ability to identify high and low performers. We examined center-level rates of CC and FTR-C in a mature trauma system with the hypothesis that high-performing centers for each of these outcomes could be identified., Methods: Using a statewide trauma registry from 2007-2015, we developed multivariable logistic regression models on CC and FTR-C including patient demographics, physiology, comorbidity, and injury data. Predicted probabilities of each outcome were summed to generate expected event rates, which were compared to observed event rates to generate centerlevel observed-to-expected (O:E) ratios. We measured internal consistency between CC and FTR-C for centers using Cronbach's alpha., Results: Cardiac complications occurred in 5,079/278,042 (1.8%; center-level range: 0.9-3.8%) of included patients (median age 55 (IQR 34-76), 84% Caucasian, 60% male, 92% blunt, median ISS 9 (IQR5-16)). Death after CC occurred in 982/5,097 patients for an FTR-C rate of 19.3% (center-level range: 7.8-30.4%). 10/27 centers were high-performers (95% confidence interval for O:E ratio <1) for CC and 2/27 centers were high-performers for FTR-C, but internal consistency between these metrics was poor (alpha = 0.31)., Conclusion: Rates of CC and FTR-C vary significantly between hospitals in mature trauma systems but high-performing centers can be identified. Inconsistent performance between metrics suggests unknown institutional factors underlie performance for CC and FTR., (Copyright © 2020. Published by Elsevier Ltd.)

Tacrolimus exhibits unpredictable pharmacokinetics (PKs) after lung transplant, partly explained by cytochrome P450 (CYP)-enzyme polymorphisms. However, whether exposure variability during the immediate postoperative period affects outcomes is unknown, and pharmacogenetic dosing may be limited by residual PK variability. We estimated adjusted associations between early postoperative tacrolimus concentrations and acute kidney injury (AKI) and acute cellular rejection (ACR), and identified clinical and pharmacogenetic factors that explain postoperative tacrolimus concentration variability in 484 lung transplant patients. Increasing tacrolimus concentration was associated with higher AKI risk (hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.20-1.96 per 5-mg/dL); and increasing AKI severity (odds ratio 1.29; 95% CI 1.04-1.60 per 5-mg/dL), but not ACR (HR 1.02; 95% CI 0.73-1.42). A model with clinical and pharmacogenetic factors explained 42% of concentration variance compared with 19% for pharmacogenetic factors only. Early tacrolimus exposure was independently associated with AKI after lung transplantation, but not ACR. Clinical factors accounted for substantial residual tacrolimus concentration variability not explained by CYP-enzyme polymorphisms., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation, but the immunologic mechanisms are poorly understood. Innate lymphoid cells (ILC) are a heterogeneous family of immune cells regulating pathologic inflammation and beneficial tissue repair. However, whether changes in donor-derived lung ILC populations are associated with PGD development has never been examined. Objectives: To determine whether PGD in chronic obstructive pulmonary disease or interstitial lung disease transplant recipients is associated with alterations in ILC subset composition within the allograft. Methods: We performed a single-center cohort study of lung transplantation patients with surgical biopsies of donor tissue taken before, and immediately after, allograft reperfusion. Donor immune cells from 18 patients were characterized phenotypically by flow cytometry for single-cell resolution of distinct ILC subsets. Changes in the percentage of ILC subsets with reperfusion or PGD (grade 3 within 72 h) were assessed. Measurements and Main Results: Allograft reperfusion resulted in significantly decreased frequencies of natural killer cells and a trend toward reduced ILC populations, regardless of diagnosis (interstitial lung disease or chronic obstructive pulmonary disease). Seven patients developed PGD (38.9%), and PGD development was associated with selective reduction of the ILC2 subset after reperfusion. Conversely, patients without PGD exhibited significantly higher ILC1 frequencies before reperfusion, accompanied by elevated ILC2 frequencies after allograft reperfusion. Conclusions: The composition of donor ILC subsets is altered after allograft reperfusion and is associated with PGD development, suggesting that ILCs may be involved in regulating lung injury in lung transplant recipients.

Rationale: Acute respiratory distress syndrome (ARDS) lacks known causal biomarkers. Plasma concentrations of sRAGE (soluble receptor for advanced glycation end products) strongly associate with ARDS risk. However, whether plasma sRAGE contributes causally to ARDS remains unknown. Objectives: Evaluate plasma sRAGE as a causal intermediate in ARDS by Mendelian randomization (MR), a statistical method to infer causality using observational data. Methods: We measured early plasma sRAGE in two critically ill populations with sepsis. The cohorts were whole-genome genotyped and phenotyped for ARDS. To select validated genetic instruments for MR, we regressed plasma sRAGE on genome-wide genotypes in both cohorts. The causal effect of plasma sRAGE on ARDS was inferred using the top variants with significant associations in both populations ( P  < 0.01, R 2  > 0.02). We applied the inverse variance-weighted method to obtain consistent estimates of the causal effect of plasma sRAGE on ARDS risk. Measurements and Main Results: There were 393 European and 266 African ancestry patients in the first cohort and 843 European ancestry patients in the second cohort. Plasma sRAGE was strongly associated with ARDS risk in both populations (odds ratio, 1.86; 95% confidence interval [1.54-2.25]; 2.56 [2.14-3.06] per log increase). Using genetic instruments common to both populations, plasma sRAGE had a consistent causal effect on ARDS risk with a β estimate of 0.50 (95% confidence interval [0.09-0.91] per log increase). Conclusions: Plasma sRAGE is genetically regulated during sepsis, and MR analysis indicates that increased plasma sRAGE leads to increased ARDS risk, suggesting plasma sRAGE acts as a causal intermediate in sepsis-related ARDS.

Background: Critically ill patients who develop ARDS have substantial associated morbidity and mortality. Circulating mitochondrial DNA (mtDNA) released during critical illness causes endothelial dysfunction and lung injury in experimental models. This study hypothesized that elevated plasma mtDNA is associated with ARDS in critically ill patients with trauma and sepsis., Methods: Plasma mtDNA concentrations were measured at ED presentation and approximately 48 h later in separate prospective cohorts of critically ill patients with trauma and sepsis. ARDS was classified according to the Berlin definition. The association of mtDNA with ARDS was tested by using multivariable logistic regression, adjusted for covariates previously shown to contribute to ARDS risk in each population., Results: ARDS developed in 41 of 224 (18%) trauma patients and in 45 of 120 (38%) patients with sepsis. Forty-eight-hour mtDNA levels were significantly associated with ARDS (trauma: OR, 1.58/log copies/μL; 95% CI, 1.14-2.19 [P = .006]; sepsis: OR, 1.52/log copies/μL; 95% CI, 1.12-2.06 [P = .007]). Plasma mtDNA on presentation was not significantly associated with ARDS in either cohort. In patients with sepsis, 48-h mtDNA was more strongly associated with ARDS among those with a nonpulmonary infectious source (OR, 2.20/log copies/μL; 95% CI, 1.36-3.55 [P = .001], n = 69) than those with a pulmonary source (OR, 1.04/log copies/μL; 95% CI, 0.68-1.59 [P = .84], n = 51; P = .014 for interaction)., Conclusions: Plasma mtDNA levels were associated with incident ARDS in two critical illness populations. Given supportive preclinical data, our findings suggest a potential link between circulating mtDNA and lung injury and merit further investigation as a potentially targetable mediator of ARDS., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Enrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors., Methods: In a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies., Measurements and Main Results: An admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor., Conclusions: Thresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials.

Background: Obesity is associated with an increased risk of primary graft dysfunction (PGD) after lung transplantation. The contribution of specific adipose tissue depots is unknown., Methods: We performed a prospective cohort study of adult lung transplant recipients at 4 U.S. transplant centers. We measured cross-sectional areas of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) on chest and abdominal computed tomography (CT) scans and indexed each measurement to height. 2 We used logistic regression to examine the associations of adipose indices and adipose classes with grade 3 PGD at 48 or 72 hours, and Cox proportional hazards models to examine survival. We used latent class analyses to identify the patterns of adipose distribution. We examined the associations of adipose indices with plasma biomarkers of obesity and PGD., Results: A total of 262 and 117 subjects had available chest CT scans and underwent protocol abdominal CT scans, respectively. In the adjusted models, a greater abdominal SAT index was associated with an increased risk of PGD (odds ratio 1.9, 95% CI 1.02-3.4, p = 0.04) but not with survival time. VAT indices were not associated with PGD risk or survival time. A greater abdominal SAT index correlated with greater pre- and post-transplant leptin (r = 0.61, p < 0.001, and r = 0.44, p < 0.001), pre-transplant IL-1RA (r = 0.25, p = 0.04), and post-transplant ICAM-1 (r = 0.25, p = 0.04). We identified 3 latent patterns of adiposity. The class defined by high thoracic and abdominal SAT had the greatest risk of PGD., Conclusions: Subcutaneous, but not visceral, adiposity is associated with an increased risk of PGD after lung transplantation., (Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

BACKGROUNDInnate immune activation impacts lung transplant outcomes. Dectin-1 is an innate receptor important for pathogen recognition. We hypothesized that genotypes reducing dectin-1 activity would be associated with infection, graft dysfunction, and death in lung transplant recipients.METHODSWe assessed the rs16910526 CLEC7A gene polymorphism Y238X, which results in dectin-1 truncation, in 321 lung allograft recipients at a single institution and in 1,129 lung allograft recipients in the multicenter Lung Transplant Outcomes Group (LTOG) cohort. Differences in dectin-1 mRNA, cytokines, protein levels, immunophenotypes, and clinical factors were assessed.RESULTSY238X carriers had decreased dectin-1 mRNA expression (P = 0.0001), decreased soluble dectin-1 protein concentrations in bronchoalveolar lavage (P = 0.008) and plasma (P = 0.04), and decreased monocyte surface dectin-1 (P = 0.01) compared with wild-type subjects. Y238X carriers had an increased risk of fungal pathogens (HR 1.17, CI 1.0-1.4), an increased risk of graft dysfunction or death (HR 1.6, CI 1.0-2.6), as well increased mortality in the UCSF cohort (HR 1.8, CI 1.1-3.8) and in the LTOG cohort (HR 1.3, CI 1.1-1.6), compared with wild-type CLEC7A subjects.CONCLUSIONIncreased rates of graft dysfunction and death associated with this dectin-1 polymorphism may be amplified by immunosuppression that drives higher fungal burden from compromised pathogen recognition.FUNDINGThe UCSF Nina Ireland Program for Lung Health Innovative Grant program, the Clinical Sciences Research & Development Service of the VA Office of Research and Development, and the Joel D. Cooper Career Development Award from the International Society for Heart and Lung Transplantation.

Rationale: The oropharyngeal microbiome is a primary source of lung microbiota, contributes to lower respiratory infection, and is also a driver of oral health. Objectives: We sought to understand oropharyngeal microbial communities in advanced lung disease, community dynamics after lung transplantation, and ecological features of dysbiosis. Methods: Oropharyngeal wash samples were obtained from individuals with end-stage disease awaiting transplantation ( n  = 22) and longitudinally from individuals at 6 weeks, 3 months, and 6 months after transplantation ( n  = 33), along with healthy control subjects ( n  = 14). Bacterial 16S and fungal internal transcribed spacer rRNA regions were deep-sequenced, and bacterial community respiratory patterns were imputed from taxonomic composition. Results: Healthy subjects' oropharyngeal microbiomes showed a gradient of community types reflecting relative enrichment of strictly anaerobic, aerobic, or facultative anaerobic bacteria. Patients with end-stage lung disease showed severe dysbiosis by both taxonomic composition and respiration phenotypes, with reduced richness and diversity, increased facultative and decreased aerobic bacteria, and absence of communities characterized by obligate aerobes. In patients at 6 weeks and 3 months post-transplant, richness and diversity were intermediate between healthy and pretransplant subjects, with near-normal distribution of community types. However, by 6 months post-transplant, oropharyngeal wash resembled the low-diversity facultative-dominated profile of pretransplant subjects. Community ecotype correlated with Candida abundance. Conclusions: End-stage lung disease is associated with marked upper respiratory tract dysbiosis involving both community structure and respiratory metabolism profiles of constituent bacteria. Dynamic changes occur after lung transplantation, with partial normalization early but later appearance of severe dysbiosis similar to pretransplant patients. Aberrant oropharyngeal communities may predispose to abnormal lung microbiota and infection risk both in advanced lung disease and after transplantation.

Frailty is a state of decreased physiologic reserve associated with poor outcomes before and after lung transplantation. Obesity, particularly central obesity characterized by excess proinflammatory visceral adipose tissue (VAT), is associated with incident frailty in middle-aged and older adults. The association between VAT and frailty in advanced lung disease, however, is unknown. In two, nonoverlapping multicenter cohorts of adults listed for lung transplantation, we measured VAT area on bioelectrical impedance assay (BIA) in one cohort and cross-sectional VAT and subcutaneous adipose tissue (SAT) areas on abdominal computed tomography (CT) in the other. We identified a nonlinear relationship between greater VAT by BIA and frailty. In fully adjusted piecewise regression models, every 20 cm 2 increase in VAT area was associated with 50% increased odds of frailty in subjects with high VAT (95% CI 1.2-1.9, P < .001), and 10% decreased odds of frailty (95% CI 0.7-1.04, P = .12) in subjects with low VAT. Compared to frail subjects with low VAT, those with high VAT were more likely to have low grip strength and less likely to have weight loss, suggesting that mechanisms of frailty may differ by VAT. Further investigation of mechanisms linking VAT and frailty may identify new targets for prevention and treatment., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Sedation minimization and ventilator liberation protocols improve outcomes but are challenging to implement. We sought to demonstrate proof-of-concept and impact of an electronic application promoting sedation minimization and ventilator liberation., Design: Multi-ICU proof-of-concept study and a single ICU before-after study., Setting: University hospital ICUs., Patients: Adult patients receiving mechanical ventilation., Interventions: An automated application consisting of 1) a web-based dashboard with real-time data on spontaneous breathing trial readiness, sedation depth, sedative infusions, and nudges to wean sedation and ventilatory support and 2) text-message alerts once patients met criteria for a spontaneous breathing trial and spontaneous awakening trial. Pre-intervention, sedation minimization, and ventilator liberation were reviewed daily during a multidisciplinary huddle. Post-intervention, the dashboard was used during the multidisciplinary huddle, throughout the day by respiratory therapists, and text alerts were sent to bedside providers., Measurements and Main Results: We enrolled 115 subjects in the proof-of-concept study. Spontaneous breathing trial alerts were accurate (98.3%), usually sent while patients were receiving mandatory ventilation (88.5%), and 61.9% of patients received concurrent spontaneous awakening trial alerts. We enrolled 457 subjects in the before-after study, 221 pre-intervention and 236 post-intervention. After implementation, patients were 28% more likely to be extubated (hazard ratio, 1.28; 95% CI, 1.01-1.63; p = 0.042) and 31% more likely to be discharged from the ICU (hazard ratio, 1.31; 95% CI, 1.03-1.67; p = 0.027) at any time point. After implementation, the median duration of mechanical ventilation was 2.20 days (95% CI, 0.09-4.31 d; p = 0.042) shorter and the median ICU length of stay was 2.65 days (95% CI, 0.13-5.16 d; p = 0.040) shorter, compared with the expected durations without the application., Conclusions: Implementation of an electronic dashboard and alert system promoting sedation minimization and ventilator liberation was associated with reductions in the duration of mechanical ventilation and ICU length of stay., Competing Interests: Dr. Anderson’s institution received grant support funding from National Institutes of Health (NIH) (HL140482)/National Heart, Lung, and Blood Institute and the American Thoracic Society Foundation, and he received funding from the NIH/National Institute of Neurological Disorders and Stroke (Loan Repayment Grant). Drs. Anderson and Christie (HL115354) received support for article research from the NIH. Dr. Christie’s institution received funding from GlaxoSmithKline and Bristol-Myers Squibb. Dr. Schweickert received funding from Arjo and the American College of Physicians. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Prior studies of post-lung transplant acute kidney injury (AKI) have not accounted for confounding effects of primary graft dysfunction (PGD). We sought to test the impact of PGD on AKI risk factors and on the association of AKI with mortality., Methods: We included patients transplanted at the University of Pennsylvania from 2005-12, defined AKI using consensus criteria during transplant hospitalization, and defined PGD as grade 3 at 48-72 hours. We used multivariable logistic regression to test the impact of PGD on AKI risk factors and Cox models to test association of AKI with one-year mortality adjusting for PGD and other confounders., Results: Of 299 patients, 188 (62.9%) developed AKI with 142 (75%) cases occurring by postoperative day 4. In multivariable models, PGD was strongly associated with AKI (OR 3.76, 95% CI 1.72-8.19, P = .001) but minimally changed associations of other risk factors with AKI. Both AKI (HR 3.64, 95% CI 1.68-7.88, P = .001) and PGD (HR 2.55, 95% CI 1.40-4.64, P = .002) were independently associated with one-year mortality., Conclusions: Post-lung transplant AKI risk factors and association of AKI with mortality were independent of PGD. AKI may therefore be a target for improving lung transplant mortality rather than simply an epiphenomenon of PGD., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Primary graft dysfunction (PGD) is the leading cause of early mortality after lung transplantation. Anti-collagen type-V (col(V)) immunity has been observed in animal models of ischemia-reperfusion injury (IRI) and in PGD. We hypothesized that collagen type-V is an innate danger signal contributing to PGD pathogenesis., Methods: Anti-col(V) antibody production was detected by flow cytometric assay following cultures of murine CD19+ splenic cells with col.(V). Responding murine B cells were phenotyped using surface markers. RNA-Seq analysis was performed on murine CD19+ cells. Levels of anti-col(V) antibodies were measured in 188 recipients from the Lung Transplant Outcomes Group (LTOG) after transplantation., Results: Col(V) induced rapid production of anti-col(V) antibodies from murine CD19+ B cells. Subtype analysis demonstrated innate B-1 B cells bound col.(V). Col(V) induced a specific transcriptional signature in CD19+ B cells with similarities to, yet distinct from, B cell receptor (BCR) stimulation. Rapid de novo production of anti-col(V) Abs was associated with an increased incidence of clinical PGD after lung transplant., Conclusions: This study demonstrated that col.(V) is an rapidly recognized by B cells and has specific transcriptional signature. In lung transplants recipients the rapid seroconversion to anti-col(V) Ab is linked to increased risk of grade 3 PGD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF), the scarring of lung parenchyma resulting in the loss of lung function, remains a fatal disease with a significant unmet medical need. Patients with severe IPF often develop acute exacerbations resulting in the rapid deterioration of lung function, requiring transplantation. Understanding the pathophysiological mechanisms contributing to IPF is key to develop novel therapeutic approaches for end-stage disease. We report here RNA-sequencing analyses of lung tissues from a cohort of patients with transplant-stage IPF (n=36), compared with acute lung injury (ALI) (n=11) and nondisease controls (n=19), that reveal a robust gene expression signature unique to end-stage IPF. In addition to extracellular matrix remodelling pathways, we identified pathways associated with T-cell infiltration/activation, tumour development, and cholesterol homeostasis, as well as novel alternatively spliced transcripts that are differentially regulated in the advanced IPF lung versus ALI or nondisease controls. Additionally, we show a subset of genes that are correlated with percent predicted forced vital capacity and could reflect disease severity. Our results establish a robust transcriptomic fingerprint of an advanced IPF lung that is distinct from previously reported microarray signatures of moderate, stable or progressive IPF and identifies hitherto unknown candidate targets and pathways for therapeutic intervention in late-stage IPF as well as biomarkers to characterise disease progression and enable patient stratification., Competing Interests: Conflict of interest: P. Sivakumar has nothing to disclose. Conflict of interest: J.R. Thompson has nothing to disclose. Conflict of interest: R. Ammar has nothing to disclose. Conflict of interest: M. Porteous has nothing to disclose. Conflict of interest: C. McCoubrey has nothing to disclose. Conflict of interest: E. Cantu III has nothing to disclose. Conflict of interest: K. Ravi has nothing to disclose. Conflict of interest: Y. Zhang has nothing to disclose. Conflict of interest: Y. Luo has nothing to disclose. Conflict of interest: D. Streltsov has nothing to disclose. Conflict of interest: M.F. Beers reports grants from Bristol-Myers Squibb during the conduct of the study. Conflict of interest: G. Jarai has nothing to disclose. Conflict of interest: J.D. Christie reports grants from the NIH and Bristol-Myers Squibb during the conduct of the study and grants from the NIH, GlaxoSmithKline and Bristol-Myers Squibb outside the submitted work.

Acute kidney injury (AKI) is common after lung transplantation, but molecular markers remain poorly studied. The endothelial activation markers soluble thrombomodulin (sTM), protein C, and plasminogen activator inhibitor-1 (PAI-1) are implicated in kidney microcirculatory injury in animal models of AKI. We tested the association of 6-hour postreperfusion plasma levels of these markers with posttransplant AKI severity in patients enrolled in the Lung Transplant Outcomes Group prospective cohort study at the University of Pennsylvania during two eras: 2004-06 (n = 61) and 2013-15 (n = 67). We defined AKI stage through postoperative day 5 using Kidney Disease Improving Global Outcomes creatinine criteria. We used multivariable ordinal logistic regression to determine the association of each biomarker with AKI, adjusted for primary graft dysfunction and extracorporeal life support. AKI occurred in 57 (45%) patients across both eras: 28 (22%) stage 1, 29 (23%) stage 2-3. Higher sTM and lower protein C plasma levels were associated with AKI stage in each era and remained so in multivariable models utilizing both eras (sTM: OR 1.76 [95% CI 1.19-2.60] per standard deviation, P = .005; protein C: OR 0.54 [1.19-2.60], P = .003). We conclude that 6-hour postreperfusion plasma sTM and protein C levels are associated with early postlung transplant AKI severity., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Necroptosis, a form of programmed cell death mediated by receptor interacting serine/threonine-protein kinase-3 (RIPK3), is implicated in murine models of acute respiratory distress syndrome (ARDS). We hypothesized that plasma RIPK3 concentrations in sepsis and trauma would be associated with ARDS development and that plasma RIPK3 would reflect changes in lung tissue RIPK3 in a murine model of systemic inflammation., Methods: We utilized prospective cohort studies of critically ill sepsis (n = 120) and trauma (n = 180) patients and measured plasma RIPK3 at presentation and 48 h. Patients were followed for 6 days for ARDS by the Berlin definition. We used multivariable logistic regression to determine the association of plasma RIPK3 with ARDS in each cohort, adjusting for confounders. In mice, we determined whether plasma and lung tissue RIPK3 levels rise concomitantly 4 h after injection with lipopolysaccharide and ZVAD-FMK, an apoptosis inhibitor., Results: The change in plasma RIPK3 from presentation to 48 h (ΔRIPK3) was associated with ARDS in sepsis (OR 1.30, 95% CI 1.03-1.63, per ½ standard deviation) and trauma (OR 1.79, 95% CI 1.33-2.40). This association was not evident for presentation RIPK3 levels. Secondary analyses showed similar findings for the association of ΔRIPK3 with acute kidney injury and 30-day mortality. Mice injected with lipopolysaccharide and ZVAD-FMK had significantly higher plasma (p < 0.001) and lung (p = 0.005) RIPK3 than control mice., Conclusions: The change in plasma RIPK3 from presentation to 48 h in both sepsis and trauma patients is independently associated with ARDS, and plasma RIPK3 may reflect RIPK3 activity in lung tissue.

Endobronchial stents are increasingly used to treat airway complications in multiple conditions including lung transplantation but little is known about the biofilms that form on these devices. We applied deep sequencing to profile luminal biofilms of 46 endobronchial stents removed from 20 subjects primarily with lung transplantation-associated airway compromise. Microbial communities were analyzed by bacterial 16S rRNA and fungal ITS marker gene sequencing. Corynebacterium was the most common bacterial taxa across biofilm communities. Clustering analysis revealed three bacterial biofilm types: one low diversity and dominated by Corynebacterium; another was polymicrobial and characterized by Staphylococcus; and the third was polymicrobial and associated with Pseudomonas, Streptococcus, and Prevotella. Biofilm type was significantly correlated with stent material: covered metal with the Staphylococcus-type biofilm, silicone with the Corynebacterium-dominated biofilm, and uncovered metal with the polymicrobial biofilm. Subjects with sequential stents had frequent transitions between community types. Fungal analysis found Candida was most prevalent, Aspergillus was common and highly enriched in two of three stents associated with airway anastomotic dehiscence, and fungal taxa not typically considered pathogens were highly enriched in some stents. Thus, molecular analysis revealed a complex and dynamic endobronchial stent biofilm with three bacterial types that associate with stent material, a central role for Corynebacterium, and that both expected and unexpected fungi inhabit this unique niche. The current work provides a foundation for studies to investigate the relationship between stent biofilm composition and clinical outcomes, mechanisms of biofilm establishment, and strategies for improved stent technology and use in airway compromise., Competing Interests: The authors have declared that no competing interests exist.

Solid organ transplantation disrupts virus-host relationships, potentially resulting in viral transfer from donor to recipient, reactivation of latent viruses, and new viral infections. Viral transfer, colonization, and reactivation are typically monitored using assays for specific viruses, leaving the behavior of full viral populations (the "virome") understudied. Here we sought to investigate the temporal behavior of viruses from donor lungs and transplant recipients comprehensively. We interrogated the bronchoalveolar lavage and blood viromes during the peritransplant period and 6-16 months posttransplant in 13 donor-recipient pairs using shotgun metagenomic sequencing. Anelloviridae, ubiquitous human commensal viruses, were the most abundant human viruses identified. Herpesviruses, parvoviruses, polyomaviruses, and bacteriophages were also detected. Anelloviridae populations were complex, with some donor organs and hosts harboring multiple contemporaneous lineages. We identified transfer of Anelloviridae lineages from donor organ to recipient serum in 4 of 7 cases that could be queried, and immigration of lineages from recipient serum into the allograft in 6 of 10 such cases. Thus, metagenomic analyses revealed that viral populations move between graft and host in both directions, showing that organ transplantation involves implantation of both the allograft and commensal viral communities., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Rationale: Currently, no safe and effective pharmacologic interventions exist for acute kidney injury (AKI). One reason may be that heterogeneity exists within the AKI population, thereby hampering the identification of specific pathophysiologic pathways and therapeutic targets., Objective: The aim of this study was to identify and test whether AKI subphenotypes have prognostic and therapeutic implications., Methods: First, latent class analysis methodology was applied independently in two critically ill populations (discovery [n = 794] and replication [n = 425]) with AKI. Second, a parsimonious classification model was developed to identify AKI subphenotypes. Third, the classification model was applied to patients with AKI in VASST (Vasopressin and Septic Shock Trial; n = 271), and differences in treatment response were determined. In all three populations, AKI was defined using serum creatinine and urine output., Measurements and Main Results: A two-subphenotype latent class analysis model had the best fit in both the discovery (P = 0.004) and replication (P = 0.004) AKI groups. The risk of 7-day renal nonrecovery and 28-day mortality was greater with AKI subphenotype 2 (AKI-SP2) relative to AKI subphenotype 1 (AKI-SP1). The AKI subphenotypes discriminated risk for poor clinical outcomes better than the Kidney Disease: Improving Global Outcomes stages of AKI. A three-variable model that included markers of endothelial dysfunction and inflammation accurately determined subphenotype membership (C-statistic 0.92). In VASST, vasopressin compared with norepinephrine was associated with improved 90-day mortality in AKI-SP1 (27% vs. 46%, respectively; P = 0.02), but no significant difference was observed in AKI-SP2 (45% vs. 49%, respectively; P = 0.99) and the P value for interaction was 0.05., Conclusions: This analysis identified two molecularly distinct AKI subphenotypes with different clinical outcomes and responses to vasopressin therapy. Identification of AKI subphenotypes could improve risk prognostication and may be useful for predictive enrichment in clinical trials.

Rationale: In the United States, an algorithm known as the "match-run" creates an ordered ranking of potential recipients for available lung allografts. A potential recipient's match-run position, or "sequence number," is available to the transplant center when contacted with a lung offer. Lung offers with higher sequence numbers may be interpreted as a crowd-sourced evaluation of poor organ quality, though the association between the sequence number at which a lung is accepted and its recipient's post-transplant outcomes is unclear., Objectives: We sought to evaluate the primary reasons provided when a lung offer was refused by a transplant center, transplant center and donor/organ factors associated with a higher sequence number at acceptance, and the association of the sequence number at acceptance with post-transplant mortality and graft failure., Methods: Match-run outcomes for lung offers that occurred in the United States from May 2007 through June 2014 were merged with recipient follow-up data through December 2017. Associations between the sequence number at the time of acceptance and selected transplant center and donor characteristics were estimated using multivariable logistic and multinomial regression models. The associations between the final sequence number and recipient survival and graft survival were estimated using multivariable time-to-event models., Results: Of 10,981 lung offer acceptances, nearly 70% were accepted by one of the top 10 ranked candidates. Higher median annual center volume and potential indicators of organ quality (e.g., abnormal chest radiograph or bronchoscopy) were associated with a higher sequence number at acceptance. There was weak evidence for a small positive relationship between the sequence number at acceptance and both mortality and graft failure. For example, the unadjusted and adjusted hazard ratios for death associated with the log-sequence number at acceptance were 1.019 (95% confidence interval, 1.001-1.038) and 1.011 (95% confidence interval, 0.989-1.033), respectively. On the absolute scale, using the multivariable model, a 10-fold increase in the sequence number translated into a 0.8% absolute decline in the predicted 5-year survival., Conclusions: Acceptance of a donor lung offer at a later point in the match-run was associated with measurable indicators of organ quality, but not with clinically meaningful differences in post-transplant mortality or graft failure.

The acute respiratory distress syndrome (ARDS) phenotype was first described over 50 years ago and since that time significant progress has been made in understanding the biologic processes underlying the syndrome. Despite this improved understanding, no pharmacologic therapies aimed at the underlying biology have been proven effective in ARDS. Increasingly, ARDS has been recognized as a heterogeneous syndrome characterized by subphenotypes with distinct clinical, radiographic, and biologic differences, distinct outcomes, and potentially distinct responses to therapy. The Berlin Definition of ARDS specifies three severity classifications: mild, moderate, and severe based on the PaO 2 to FiO 2 ratio. Two randomized controlled trials have demonstrated a potential benefit to prone positioning and neuromuscular blockade in moderate to severe phenotypes of ARDS only. Precipitating risk factor, direct versus indirect lung injury, and timing of ARDS onset can determine other clinical phenotypes of ARDS after admission. Radiographic phenotypes of ARDS have been described based on a diffuse versus focal pattern of infiltrates on chest imaging. Finally and most promisingly, biologic subphenotypes or endotypes have increasingly been identified using plasma biomarkers, genetics, and unbiased approaches such as latent class analysis. The potential of precision medicine lies in identifying novel therapeutics aimed at ARDS biology and the subpopulation within ARDS most likely to respond. In this review, we discuss the challenges and approaches to subphenotype ARDS into clinical, radiologic, severity, and biologic phenotypes with an eye toward the future of precision medicine in critical care., Competing Interests: Dr. Calfee reports grants from NIH, grants and personal fees from GlaxoSmithKline, grants and personal fees from Bayer, personal fees from CSL Behring, personal fees from Prometic, personal fees from Roche/Genentech, personal fees from Quark, outside the submitted work. Dr. Christie reports grants from NIH, during the conduct of the study; grants from NIH, grants from GlaxoSmithKline, and grants from Bristol Meyers Squibb outside the submitted work; and has served as an advisory board member for Onspira Therapeutics. Dr. Reilly reports grants from National Institutes of Health, during the conduct of the study., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Rationale: Exposure to air pollution has molecular and physiologic effects on the lung that may increase the risk of acute respiratory distress syndrome (ARDS) after injury., Objectives: To determine the association of short- and long-term air pollutant exposures and ARDS risk after severe trauma., Methods: We analyzed data from a prospective cohort of 996 critically ill patients presenting with acute trauma and an injury severity score greater than 15. Exposures to ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide, and particulate matter less than 2.5 μm were assessed by weighted averages of daily levels from all monitors within 50 km of the geocoded location of a patient's residence. Patients were followed for 6 days for the development of ARDS according to Berlin Criteria. The association between each exposure and ARDS was determined via multivariable logistic regression adjusting for potential confounders., Measurements and Main Results: ARDS developed in 243 (24%) patients. None of the short-term exposures averaged over the 3 days before presentation was associated with ARDS, except sulfur dioxide, which demonstrated a nonlinear association. Nitrogen dioxide, sulfur dioxide, and particulate matter less than or equal to 2.5 μm in aerodynamic diameter exposure over the 6 weeks before presentation was significantly associated with ARDS (P < 0.05). All long-term exposures (3 yr) were associated with ARDS (P < 0.01) in adjusted models, despite exposure levels largely below U.S. and European Union air quality standards., Conclusions: Long-term low- to moderate-level air pollutant exposure is associated with a greater risk of developing ARDS after severe trauma and represents a novel and potentially modifiable environmental risk factor for ARDS.

Purpose: A causal biomarker for acute respiratory distress syndrome (ARDS) could fuel precision therapy options. Plasma angiopoietin-2 (ANG2), a vascular permeability marker, is a strong candidate on the basis of experimental and observational evidence. We used genetic causal inference methods-Mendelian randomization and mediation-to infer potential effects of plasma ANG2., Methods: We genotyped 703 septic subjects, measured ICU admission plasma ANG2, and performed a quantitative trait loci (QTL) analysis to determine variants in the ANGPT2 gene associated with plasma ANG2 (p < 0.005). We then used linear regression and post-estimation analysis to genetically predict plasma ANG2 and tested genetically predicted ANG2 for ARDS association using logistic regression. We estimated the proportion of the genetic effect explained by plasma ANG2 using mediation analysis., Results: Plasma ANG2 was strongly associated with ARDS (OR 1.59 (95% CI 1.35, 1.88) per log). Five ANGPT2 variants were associated with ANG2 in European ancestry subjects (n = 404). Rs2442608C, the most extreme cis QTL (coefficient 0.22, 95% CI 0.09-0.36, p = 0.001), was associated with higher ARDS risk: adjusted OR 1.38 (95% CI 1.01, 1.87), p = 0.042. No significant QTL were identified in African ancestry subjects. Genetically predicted plasma ANG2 was associated with ARDS risk: adjusted OR 2.25 (95% CI 1.06-4.78), p = 0.035. Plasma ANG2 mediated 34% of the rs2442608C-related ARDS risk., Conclusions: In septic European ancestry subjects, the strongest ANG2-determining ANGPT2 genetic variant is associated with higher ARDS risk. Plasma ANG2 may be a causal factor in ARDS development. Strategies to reduce plasma ANG2 warrant testing to prevent or treat sepsis-associated ARDS.

Purpose: The objective of this study is to describe the relationship between two quantitative muscle ultrasound measures, the rectus femoris cross-sectional area (RF-CSA) and quadriceps muscle thickness, with volitional measures of strength and function in critically ill patients with sepsis., Materials and Methods: We performed a prospective study of patients admitted to a medical ICU with sepsis and shock or respiratory failure. We examined the association of two ultrasound measurements - the RF-CSA and quadriceps muscle thickness - with strength and function at day 7. Strength was determined using the Medical Research Council Score and function using Physical Function in the ICU Test, scored., Results: Twenty-nine patients were enrolled; 19 patients had outcome testing performed. Over 7days, RF-CSA and thickness decreased by an average of 23.2% and 17.9%, respectively. The rate of change per day of RF-CSA displayed a moderate correlation with strength (ρ 0.51, p-value 0.03) on day 7. Baseline and day 7 RF-CSA did not show a significant correlation with either outcome. Quadriceps muscle thickness did not significantly correlate with either outcome., Conclusions: Muscle atrophy as detected by the rate of change in RF-CSA moderately correlated with strength one week after sepsis admission., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Emergency department thoracotomy (EDT) must be rapid and well-executed. Currently there are no defined benchmarks for EDT procedural milestones. We hypothesized that trauma video review (TVR) can be used to define the 'normative EDT' and generate procedural benchmarks. As a secondary aim, we hypothesized that data collected by TVR would have less missingness and bias than data collected by review of the Electronic Medical Record (EMR)., Methods: We used continuously recording video to review all EDTs performed at our centre during the study period. Using skin incision as start time, we defined four procedural milestones for EDT: 1. Decompression of the right chest (tube thoracostomy, finger thoracostomy, or clamshell thoracotomy with transverse sternotomy performed in conjunction with left anterolateral thoracotomy) 2. Retractor deployment 3. Pericardiotomy 4. Aortic Cross-clamp. EDTs with any milestone time ≥ 75 th percentile of time or during which a milestone was omitted were identified as outliers. We compared rates of missingness in data collected by TVR and EMR using McNemar's test., Results: 44 EDTs were included from the study period. Patients had a median age of 30 [IQR 25-44] and were predominantly African-American (95%) males (93%) with penetrating trauma (95%). From skin incision, median times in minutes to milestones were as follows: right chest decompression: 2.11 [IQR 0.68-2.83], retractor deployment 1.35 [IQR 0.96-1.85], pericardiotomy 2.35 [IQR 1.85-3.75], aortic cross-clamp 3.71 [IQR 2.83-5.77]. In total, 28/44 (64%) of EDTs were either high outliers for one or more benchmarks or had milestones that were omitted. For all milestones, rates of missingness for TVR data were lower than EMR data (p < 0.001)., Conclusions: Video review can be used to define normative times for the procedural milestones of EDT. Steps exceeding the 75 th percentile of time were common, with over half of EDTs having at least one milestone as an outlier. Data quality is higher using TVR compared to EMR collection. Future work should seek to determine if minimizing procedural technical outliers improves patient outcomes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Acute respiratory distress syndrome (ARDS) is a severe form of lung injury characterized by damage to the epithelial barrier with subsequent pulmonary edema and hypoxic respiratory failure. ARDS is a significant medical problem in intensive care units with associated high care costs. There are many potential causes of ARDS; however, alveolar injury associated with mechanical ventilation, termed ventilator-induced lung injury (VILI), remains a well-recognized contributor. It is thus critical to understand the mechanism of VILI. Based on our published preliminary data, we hypothesized that the endoplasmic reticulum (ER) stress response molecule Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) plays a role in transmitting mechanosensory signals the alveolar epithelium., Methods: ER stress signal responses to mechanical stretch were studied in ex-vivo ventilated pig lungs. To explore the effect of PERK inhibition on VILI, we ventilated live rats and compared lung injury parameters to non-ventilated controls. The effect of stretch-induced epithelial ER Ca 2+ signaling on PERK was studied in stretched alveolar epithelial monolayers. To confirm the activation of PERK in human disease, ER stress signaling was compared between ARDS and non-ARDS lungs., Results: Our studies revealed increased PERK-specific ER stress signaling in response to overstretch. PERK inhibition resulted in dose-dependent improvement of alveolar inflammation and permeability. Our data indicate that stretch-induced epithelial ER Ca 2+ release is an activator of PERK. Experiments with human lung tissue confirmed PERK activation by ARDS., Conclusion: Our study provides evidences that PERK is a mediator stretch signals in the alveolar epithelium.

Frailty is associated with increased mortality among lung transplant candidates. We sought to determine the association between frailty, as measured by the Short Physical Performance Battery (SPPB), and mortality after lung transplantation. In a multicenter prospective cohort study of adults who underwent lung transplantation, preoperative frailty was assessed with the SPPB (n = 318) and, in a secondary analysis, the Fried Frailty Phenotype (FFP; n = 299). We tested the association between preoperative frailty and mortality following lung transplantation with propensity score-adjusted Cox models. We calculated postestimation marginalized standardized risks for 1-year mortality by frailty status using multivariate logistic regression. SPPB frailty was associated with an increased risk of both 1- and 4-year mortality (adjusted hazard ratio [aHR]: 7.5; 95% confidence interval [CI]: 1.6-36.0 and aHR 3.8; 95%CI: 1.8-8.0, respectively). Each 1-point worsening in SPPB was associated with a 20% increased risk of death (aHR: 1.20; 95%CI: 1.08-1.33). Frail subjects had an absolute increased risk of death within the first year after transplantation of 12.2% (95%CI: 3.1%-21%). In secondary analyses, FFP frailty was associated with increased risk of death within the first postoperative year (aHR: 3.8; 95%CI: 1.1-13.2) but not over longer follow-up. Preoperative frailty is associated with an increased risk of death after lung transplantation., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Rationale: Genetic factors are involved in acute respiratory distress syndrome (ARDS) susceptibility. Identification of novel candidate genes associated with increased risk and severity will improve our understanding of ARDS pathophysiology and enhance efforts to develop novel preventive and therapeutic approaches., Objectives: To identify genetic susceptibility targets for ARDS., Methods: A genome-wide association study was performed on 232 African American patients with ARDS and 162 at-risk control subjects. The Identify Candidate Causal SNPs and Pathways platform was used to infer the association of known gene sets with the top prioritized intragenic SNPs. Preclinical validation of SELPLG (selectin P ligand gene) was performed using mouse models of LPS- and ventilator-induced lung injury. Exonic variation within SELPLG distinguishing patients with ARDS from sepsis control subjects was confirmed in an independent cohort., Measurements and Main Results: Pathway prioritization analysis identified a nonsynonymous coding SNP (rs2228315) within SELPLG, encoding P-selectin glycoprotein ligand 1, to be associated with increased susceptibility. In an independent cohort, two exonic SELPLG SNPs were significantly associated with ARDS susceptibility. Additional support for SELPLG as an ARDS candidate gene was derived from preclinical ARDS models where SELPLG gene expression in lung tissues was significantly increased in both ventilator-induced (twofold increase) and LPS-induced (5.7-fold increase) murine lung injury models compared with controls. Furthermore, Selplg -/- mice exhibited significantly reduced LPS-induced inflammatory lung injury compared with wild-type C57/B6 mice. Finally, an antibody that neutralizes P-selectin glycoprotein ligand 1 significantly attenuated LPS-induced lung inflammation., Conclusions: These findings identify SELPLG as a novel ARDS susceptibility gene among individuals of European and African descent.

Background: Delirium significantly affects post-operative outcomes, but the incidence, risk factors, and long-term impact of delirium in lung transplant recipients have not been well studied., Methods: We analyzed 155 lung transplant recipients enrolled in the Lung Transplant Outcomes Group (LTOG) cohort at a single center. We determined delirium incidence by structured chart review, identified risk factors for delirium, determined whether plasma concentrations of 2 cerebral injury markers (neuron-specific enolase [NSE] and glial fibrillary acidic protein [GFAP]) were associated with delirium, and determined the association of post-operative delirium with 1-year survival., Results: Fifty-seven (36.8%) patients developed post-operative delirium. Independent risk factors for delirium included pre-transplant benzodiazepine prescription (relative risk [RR] 1.82; 95% confidence interval [CI] 1.08 to 3.07; p = 0.025), total ischemic time (RR 1.10 per 30-minute increase; 95% CI 1.01 to 1.21; p = 0.027), duration of time with intra-operative mean arterial pressure <60 mm Hg (RR 1.07 per 15-minute increase; 95% CI 1.00 to 1.14; p = 0.041), and Grade 3 primary graft dysfunction (RR 2.13; 95% CI 1.27 to 3.58; p = 0.004). Ninety-one (58.7%) patients had plasma available at 24 hours. Plasma GFAP was inconsistently detected, whereas NSE was universally detectable, with higher NSE concentrations associated with delirium (risk difference 15.1% comparing 75th and 25th percentiles; 95% CI 2.5 to 27.7; p = 0.026). One-year mortality appeared higher among delirious patients, 12.3% compared with 7.1%, but the difference was not significant (p = 0.28)., Conclusions: Post-operative delirium is common in lung transplant recipients, and several potentially modifiable risk factors deserve further study to determine their associated mechanisms and predictive values., (Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Idiopathic pulmonary fibrosis (IPF), a progressive disease with an unknown pathogenesis, may be due in part to an abnormal response to injurious stimuli by alveolar epithelial cells. Air pollution and particulate inhalation of matter evoke a wide variety of pulmonary and systemic inflammatory diseases. We therefore hypothesized that increased average ambient particulate matter (PM) concentrations would be associated with an accelerated rate of decline in FVC in IPF., Methods: We identified a cohort of subjects seen at a single university referral center from 2007 to 2013. Average concentrations of particulate matter < 10 and < 2.5 μg/m 3 (PM 10 and PM 2.5 , respectively) were assigned to each patient based on geocoded residential addresses. A linear multivariable mixed-effects model determined the association between the rate of decline in FVC and average PM concentration, controlling for baseline FVC at first measurement and other covariates., Results: One hundred thirty-five subjects were included in the final analysis after exclusion of subjects missing repeated spirometry measurements and those for whom exposure data were not available. There was a significant association between PM 10 levels and the rate of decline in FVC during the study period, with each μg/m 3 increase in PM 10 corresponding with an additional 46 cc/y decline in FVC (P = .008)., Conclusions: Ambient air pollution, as measured by average PM 10 concentration, is associated with an increase in the rate of decline of FVC in IPF, suggesting a potential mechanistic role for air pollution in the progression of disease., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Unplanned rehospitalizations (UR) within 30 days of discharge are common after lung transplantation. It is unknown whether UR represents preventable gaps in care or necessary interventions for complex patients. The objective of this study was to assess the incidence, causes, risk factors, and preventability of UR after initial discharge after lung transplantation., Methods: This was a single-center prospective cohort study. Subjects completed a modified short physical performance battery to assess frailty at listing and at initial hospital discharge after transplantation and the State-Trait Anxiety Inventory at discharge. For each UR, a study staff member and the patient's admitting or attending clinician used an ordinal scale (0, not; 1, possibly; 2, definitely preventable) to rate readmission preventability. A total sum score of 2 or higher defined a preventable UR., Results: Of the 90 enrolled patients, 30 (33.3%) had an UR. The single most common reasons were infection (7 [23.3%]) and atrial tachyarrhythmia (5 [16.7%]). Among the 30 URs, 9 (30.0%) were deemed preventable. Unplanned rehospitalization that happened before day 30 were more likely to be considered preventable than those between days 30 and 90 (30.0% versus 6.2%, P = 0.04). Discharge frailty, defined as short physical performance battery less than 6, was the only variable associated with UR on multivariable analysis (odds ratio, 3.4; 95% confidence interval, 1.1-11.8; P = 0.04)., Conclusions: Although clinicians do not rate the majority of UR after lung transplant as preventable, discharge frailty is associated with UR. Further research should identify whether modification of discharge frailty can reduce UR.

Background: Quick and successful vascular access in injured patients arriving in extremis is crucial to enable early resuscitation and rapid OR transport for definitive repair. We hypothesized that intraosseous (IO) access would be faster and have higher success rates than peripheral intravenous (PIV) or central venous catheters (CVCs)., Methods: High-definition video recordings of resuscitations for all patients undergoing emergency department thoracotomy from April 2016 to July 2017 were reviewed as part of a quality improvement initiative. Demographics, mechanism of injury, access type, access location, start and stop time, and success of each vascular access attempt were recorded. Times to completion for access types (PIV, IO, CVC) were compared using Kruskal-Wallis test adjusted for multiple comparisons, while categorical outcomes, such as success rates by access type, were compared using χ test or Fisher's exact test., Results: Study patients had a median age of 30 years (interquartile range [IQR], 25-38 years), 92% were male, 92% were African American, and 93% sustained penetrating trauma. A total of 145 access attempts in 38 patients occurred (median, 3.8; SD, 1.4 attempts per patient). There was no difference between duration of PIV and IO attempts (0.63; IQR, 0.35-0.96 vs. 0.39 IQR, 0.13-0.65 minutes, adjusted p = 0.03), but both PIV and IO were faster than CVC attempts (3.2; IQR, 1.72-5.23 minutes; adjusted p < 0.001 for both comparisons). Intraosseous lines had higher success rates than PIVs or CVCs (95% vs. 42% vs. 46%, p < 0.001)., Conclusion: Access attempts using IO are as fast as PIV attempts but are more than twice as likely to be successful. Attempts at CVC access in patients in extremis have high rates of failure and take a median of over 3 minutes. While IO access may not completely supplant PIVs and CVCs, IO access should be considered as a first-line therapy for trauma patients in extremis., Level of Evidence: Therapeutic, level III.

Rationale: Cigarette smoking is associated with increased risk of acute respiratory distress syndrome (ARDS) in patients after severe trauma; however, the mechanisms underlying this association are unknown., Objectives: To determine whether cigarette smoking contributes to ARDS development after trauma by altering community composition of the lung microbiota., Methods: We studied the lung microbiota of mechanically ventilated patients admitted to the ICU after severe blunt trauma. To do so, we used 16S ribosomal RNA gene amplicon sequencing of endotracheal aspirate samples obtained on ICU admission (n = 74) and at 48 hours after admission (n = 30). Cigarette smoke exposure (quantified using plasma cotinine), ARDS development, and other clinical parameters were correlated with lung microbiota composition., Measurements and Main Results: Smoking status was significantly associated with lung bacterial community composition at ICU admission (P = 0.007 by permutational multivariate ANOVA [PERMANOVA]) and at 48 hours (P = 0.03 by PERMANOVA), as well as with significant enrichment of potential pathogens, including Streptococcus, Fusobacterium, Prevotella, Haemophilus, and Treponema. ARDS development was associated with lung community composition at 48 hours (P = 0.04 by PERMANOVA) and was characterized by relative enrichment of Enterobacteriaceae and of specific taxa enriched at baseline in smokers, including Prevotella and Fusobacterium., Conclusions: After severe blunt trauma, a history of smoking is related to lung microbiota composition, both at the time of ICU admission and at 48 hours. ARDS development is also correlated with respiratory microbial community structure at 48 hours and with taxa that are relatively enriched in smokers at ICU admission. The data derived from this pilot study suggest that smoking-related changes in the lung microbiota could be related to ARDS development after severe trauma.

We report that human conventional CD15 + neutrophils can be isolated in the peripheral blood mononuclear cell (PBMC) layer during Ficoll gradient separation, and that they can impair T cell proliferation in vitro without concomitant neutrophil activation and killing. This effect was observed in a total of 92 patients with organ transplants, lung cancer or anxiety/depression, and in 18 healthy donors. Although such features are typically associated in the literature with the presence of certain myeloid-derived suppressor cell (PMN-MDSC) populations, we found that commercial centrifuge tubes that contained membranes or gels for PBMC isolation led to up to 70% PBMC contamination by CD15 + neutrophils, with subsequent suppressive effects in certain cellular assays. In particular, the suppressive activity of human MDSC should not be evaluated using lectin or microbead stimulation, whereas assays involving soluble or plate-bound antibodies or MLR are unaffected. We conclude that CD15 + neutrophil contamination, and associated effects on suppressor assays, can lead to significant artefacts in studies of human PMN-MDSC.

Primary graft dysfunction (PGD) is acute lung injury within 72 hours of lung transplantation. We hypothesized that cell-free hemoglobin (CFH) contributes to PGD by increasing lung microvascular permeability and tested this in patients, ex vivo human lungs, and cultured human lung microvascular endothelial cells. In a nested case control study of 40 patients with severe PGD at 72 hours and 80 matched controls without PGD, elevated preoperative CFH was independently associated with increased PGD risk (odds ratio [OR] 2.75, 95%CI, 1.23-6.16, P = 0.014). The effect of CFH on PGD was magnified by reperfusion fraction of inspired oxygen (FiO2) ≥ 0.40 (OR 3.41, P = 0.031). Isolated perfused human lungs exposed to intravascular CFH (100 mg/dl) developed increased vascular permeability as measured by lung weight (CFH 14.4% vs. control 0.65%, P = 0.047) and extravasation of Evans blue-labeled albumin dye (EBD) into the airspace (P = 0.027). CFH (1 mg/dl) also increased paracellular permeability of human pulmonary microvascular endothelial cell monolayers (hPMVECs). Hyperoxia (FiO2 = 0.95) increased human lung and hPMVEC permeability compared with normoxia (FiO2 = 0.21). Treatment with acetaminophen (15 μg/ml), a specific hemoprotein reductant, prevented CFH-dependent permeability in human lungs (P = 0.046) and hPMVECs (P = 0.037). In summary, CFH may mediate PGD through oxidative effects on microvascular permeability, which are augmented by hyperoxia and abrogated by acetaminophen.

Rationale: Primary graft dysfunction (PGD) is a form of acute lung injury that occurs after lung transplantation. The definition of PGD was standardized in 2005. Since that time, clinical practice has evolved, and this definition is increasingly used as a primary endpoint for clinical trials; therefore, validation is warranted., Objectives: We sought to determine whether refinements to the 2005 consensus definition could further improve construct validity., Methods: Data from the Lung Transplant Outcomes Group multicenter cohort were used to compare variations on the PGD definition, including alternate oxygenation thresholds, inclusion of additional severity groups, and effects of procedure type and mechanical ventilation. Convergent and divergent validity were compared for mortality prediction and concurrent lung injury biomarker discrimination., Measurements and Main Results: A total of 1,179 subjects from 10 centers were enrolled from 2007 to 2012. Median length of follow-up was 4 years (interquartile range = 2.4-5.9). No mortality differences were noted between no PGD (grade 0) and mild PGD (grade 1). Significantly better mortality discrimination was evident for all definitions using later time points (48, 72, or 48-72 hours; P < 0.001). Biomarker divergent discrimination was superior when collapsing grades 0 and 1. Additional severity grades, use of mechanical ventilation, and transplant procedure type had minimal or no effect on mortality or biomarker discrimination., Conclusions: The PGD consensus definition can be simplified by combining lower PGD grades. Construct validity of grading was present regardless of transplant procedure type or use of mechanical ventilation. Additional severity categories had minimal impact on mortality or biomarker discrimination.

Background: Enoxaparin 30 mg twice daily and dalteparin 5,000 units once daily are two common low-molecular-weight heparin (LMWH) thromboprophylaxis regimens used in the trauma population. Pharmacodynamic studies suggest that enoxaparin provides more potent anticoagulation than does dalteparin., Methods: In 2009, our institution switched its formulary LMWH from enoxaparin to dalteparin followed by a switch back to enoxaparin in 2013. Using a difference in differences design, we contrasted the change in the VTE rate accompanying the LMWH switch with the change in a control group of trauma patients given unfractionated heparin (UFH) during the same period., Results: The study included 5,880 patients: enoxaparin period (enoxaparin, n = 2,371; UFH, n = 1,539) vs the dalteparin period (dalteparin, n = 1,046; UFH, n = 924). The VTE rate was unchanged in the LMWH group: 3.3/1000 days in the enoxaparin period vs 3.8/1000 days in the dalteparin period: rate ratio (RR), 1.16; 95% CI 0.74-1.81. The rate was also unchanged in the UFH control subjects: 5.7/1,000 days in the enoxaparin period vs 5.2/1,000 days in the dalteparin period: RR, 0.92; 95% CI, 0.61-1.38. After confounding adjustment, the ratio of the change in VTE rate between the LMWH and UFH groups was similar: RR, 1.06; 95% CI 0.71-2.00. A secondary analysis excluding patients with delayed or interrupted prophylaxis (or both) altered this estimate nonsignificantly in favor of enoxaparin: RR, 2.39; 95% CI, 0.80-7.09., Conclusions: Our results suggest that dalteparin has an effectiveness similar to that of enoxaparin in real-world trauma patients. Future research should investigate how the timing and consistency of prophylaxis affects LMWH effectiveness., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objective: Plasma interleukin-1 beta may influence sepsis mortality, yet recombinant human interleukin-1 receptor antagonist did not reduce mortality in randomized trials. We tested for heterogeneity in the treatment effect of recombinant human interleukin-1 receptor antagonist by baseline plasma interleukin-1 beta or interleukin-1 receptor antagonist concentration., Design: Retrospective subgroup analysis of randomized controlled trial., Setting: Multicenter North American and European clinical trial., Patients: Five hundred twenty-nine subjects with sepsis and hypotension or hypoperfusion, representing 59% of the original trial population., Interventions: Random assignment of placebo or recombinant human interleukin-1 receptor antagonist × 72 hours., Measurements and Main Results: We measured prerandomization plasma interleukin-1 beta and interleukin-1 receptor antagonist and tested for statistical interaction between recombinant human interleukin-1 receptor antagonist treatment and baseline plasma interleukin-1 receptor antagonist or interleukin-1 beta concentration on 28-day mortality. There was significant heterogeneity in the effect of recombinant human interleukin-1 receptor antagonist treatment by plasma interleukin-1 receptor antagonist concentration whether plasma interleukin-1 receptor antagonist was divided into deciles (interaction p = 0.046) or dichotomized (interaction p = 0.028). Interaction remained present across different predicted mortality levels. Among subjects with baseline plasma interleukin-1 receptor antagonist above 2,071 pg/mL (n = 283), recombinant human interleukin-1 receptor antagonist therapy reduced adjusted mortality from 45.4% to 34.3% (adjusted risk difference, -0.12; 95% CI, -0.23 to -0.01), p = 0.044. Mortality in subjects with plasma interleukin-1 receptor antagonist below 2,071 pg/mL was not reduced by recombinant human interleukin-1 receptor antagonist (adjusted risk difference, +0.07; 95% CI, -0.04 to +0.17), p = 0.230. Interaction between plasma interleukin-1 beta concentration and recombinant human interleukin-1 receptor antagonist treatment was not statistically significant., Conclusions: We report a heterogeneous effect of recombinant human interleukin-1 receptor antagonist on 28-day sepsis mortality that is potentially predictable by plasma interleukin-1 receptor antagonist in one trial. A precision clinical trial of recombinant human interleukin-1 receptor antagonist targeted to septic patients with high plasma interleukin-1 receptor antagonist may be worthy of consideration.

Sepsis-associated acute respiratory distress syndrome (ARDS) is characterized by neutrophilic inflammation and poor survival. Since neutrophil myeloperoxidase (MPO) activity leads to increased plasma 2-chlorofatty acid (2-ClFA) levels, we hypothesized that plasma concentrations of 2-ClFAs would associate with ARDS and mortality in subjects with sepsis. In sequential consenting patients with sepsis, free 2-ClFA levels were significantly associated with ARDS, and with 30-day mortality, for each log increase in free 2-chlorostearic acid. Plasma MPO was not associated with either ARDS or 30-day mortality but was correlated with 2-ClFA levels. Addition of plasma 2-ClFA levels to the APACHE III score improved prediction for ARDS. Plasma 2-ClFA levels correlated with plasma levels of angiopoietin-2, E selectin, and soluble thrombomodulin. Endothelial cells treated with 2-ClFA responded with increased adhesion molecule surface expression, increased angiopoietin-2 release, and dose-dependent endothelial permeability. Our results suggest that 2-ClFAs derived from neutrophil MPO-catalyzed oxidation contribute to pulmonary endothelial injury and have prognostic utility in sepsis-associated ARDS.

The scarcity of suitable organ donors leads to protracted waiting times and mortality in patients awaiting lung transplantation. This study aims to assess the short- and long-term effects of a high emergency organ allocation policy on the outcome of lung transplantation. We developed a simulation model of lung transplantation waiting queues under two allocation strategies, based either on waiting time only or on additional criteria to prioritise the sickest patients. The model was informed by data from the United Network for Organ Sharing. We compared the impact of these strategies on waiting time, waiting list mortality and overall survival in various situations of organ scarcity. The impact of a high emergency allocation strategy depends largely on the organ supply. When organ supply is sufficient (>95 organs per 100 patients), it may prevent a small number of early deaths (1 year survival: 93.7% against 92.4% for waiting time only) without significant impact on waiting times or long-term survival. When the organ/recipient ratio is lower, the benefits in early mortality are larger but are counterbalanced by a dramatic increase of the size of the waiting list. Consequently, we observed a progressive increase of mortality on the waiting list (although still lower than with waiting time only), a deterioration of patients' condition at transplant and a decrease of post-transplant survival times. High emergency organ allocation is an effective strategy to reduce mortality on the waiting list, but causes a disruption of the list equilibrium that may have detrimental long-term effects in situations of significant organ scarcity., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at openres.ersjournals.com

Clinical factors alone poorly explain acute respiratory distress syndrome (ARDS) risk and ARDS outcome. In the search for individual factors that may influence ARDS risk, the past 20 years have witnessed the identification of numerous genes and genetic variants that are associated with ARDS. The field of ARDS genomics has cycled from candidate gene association studies to bias-free approaches that identify new candidates, and increasing effort is made to understand the functional consequences that may underlie significant associations. More recently, methodologies of causal inference are being applied to maximize the information gained from genetic associations. Although challenges of sample size, both recognized and unrecognized phenotypic heterogeneity, and the paucity of early ARDS lung tissue limit some applications of the rapidly evolving field of genomic investigation, ongoing genetic research offers unique contributions to elucidating ARDS pathogenesis and the paradigm of precision ARDS medicine.

Background: Failure to rescue (FTR) is defined as death after an adverse event. The original metric was derived in elective surgical populations and reclassifies deaths not preceded by recorded adverse events as FTR cases under the assumption these deaths resulted from missed adverse events. This approach lacks face validity in trauma because patients often die without adverse events as a direct result of injury. Another common approach simply excludes deaths without recorded adverse events, but this approach reduces the reliability of the FTR metric. We hypothesized that a hybrid metric excluding expected deaths but otherwise including patients without recorded adverse events in FTR analysis would improve face validity and reliability relative to existing methods., Methods: Using 3 years of single-state adult trauma registry data from 30 trauma centers, we constructed 3 FTR metrics: (1) excluding deaths not preceded by adverse events (FTR-E), (2) reclassifying deaths not preceded by adverse events (FTR-R), and (3) including deaths not preceded by adverse events in FTR analysis except those with predicted mortality or greater than 50% (FTR-T). Mortality, adverse event, and FTR rates were calculated under each method, and reliability was tested using Spearman correlation for split-sample center rankings., Results: A total of 89,780 patients were included (median age, 57 years [interquartile range, 26-73 years]; 85% were white; 59% were male; 92% had blunt mechanism of injury; median Injury Severity Score, 9 [interquartile range, 5-14]). The FTR rates varied by metric (FTR-E, 11.2%; FTR-R, 31.2%; FTR-T, 21.4%), as did the proportion of deaths preceded by adverse events (FTR-E, 28%; FTR-R, 100%; FTR-T, 60%). Spit-sample reliability was higher FTR-T than FTR-E (ρ = 0.59 vs. = 0.27, p < 0.001)., Conclusions: A trauma-specific FTR metric increases face validity and reliability relative to other FTR methods that may be used in trauma populations. Future trauma outcomes studies examining FTR rates should use a metric designed for this cohort., Level of Evidence: Retrospective cohort study, outcomes, level III.