Risk Of Acute Lung Injury Research Articles

Novel variants in the PRDX6 Gene and the risk of Acute Lung Injury following major trauma.

BackgroundPeroxiredoxin 6 (PRDX6) is involved in redox regulation of the cell and is thought to be protective against oxidant injury. Little is known about genetic variation within the PRDX6 gene and its association with acute lung injury (ALI). In this study we sequenced the PRDX6 gene to uncover common variants, and tested association with ALI following major trauma.MethodsTo examine the extent of variation in the PRDX6 gene, we performed direct sequencing of the 5' UTR, exons, introns and the 3' UTR in 25 African American cases and controls and 23 European American cases and controls (selected from a cohort study of major trauma), which uncovered 80 SNPs. In silico modeling was performed using Patrocles and Transcriptional Element Search System (TESS). Thirty seven novel and tagging SNPs were tested for association with ALI compared with ICU at-risk controls who did not develop ALI in a cohort study of 259 African American and 254 European American subjects that had been admitted to the ICU with major trauma.ResultsResequencing of critically ill subjects demonstrated 43 novel SNPs not previously reported. Coding regions demonstrated no detectable variation, indicating conservation of the protein. Block haplotype analyses reveal that recombination rates within the gene seem low in both Caucasians and African Americans. Several novel SNPs appeared to have the potential for functional consequence using in silico modeling. Chi2 analysis of ALI incidence and genotype showed no significant association between the SNPs in this study and ALI. Haplotype analysis did not reveal any association beyond single SNP analyses.ConclusionsThis study revealed novel SNPs within the PRDX6 gene and its 5' and 3' flanking regions via direct sequencing. There was no association found between these SNPs and ALI, possibly due to a low sample size, which was limited to detection of relative risks of 1.93 and above. Future studies may focus on the role of PRDX6 genetic variation in other diseases, where oxidative stress is suspected.

Focusing on the Flood

Focusing on the Flood

Genomic investigations into acute inflammatory lung injury.

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome, are complex illnesses involving the interplay of both environmental (such as mechanical ventilation) and genetic factors. To understand better the underlying mechanisms of pathogenesis associated with ALI, we recently identified several candidate genes by global expression profiling in preclinical models of ALI and relevant single-nucleotide polymorphisms. We summarize here several strategies successfully used to identify novel ALI candidate genes and detail the validation of variants in these genes as contributing factors to ALI pathobiology, conclusions based on functional analyses, and specific genetic association studies conducted in ALI cohorts. Continued insights into ALI pathogenesis and identification of genetic variants, which confer ALI risk and severity, promise to reveal novel molecular therapeutic targets that can be translated into personalized treatments to reduce the very high, unacceptable mortality of this disorder.

The Leukocyte Antibody Prevalence Study-II (LAPS-II): a retrospective cohort study of transfusion-related acute lung injury in recipients of high-plasma-volume human leukocyte antigen antibody-positive or -negative components.

We used a multicenter retrospective cohort study design to evaluate whether human leukocyte antigen (HLA) antibody donor screening would reduce the risk of transfusion-related acute lung injury (TRALI) or possible TRALI. In the Leukocyte Antibody Prevalence Study-II (LAPS-II), we evaluated pulmonary outcomes in recipients of 2596 plasma-rich blood components (transfusable plasma and plateletpheresis) sent to participating hospitals; half of the components were collected from anti-HLA-positive donors (study arm) and half from anti-HLA-negative donors (control arm) matched by sex, parity, and blood center. A staged medical record review process was used. Final recipient diagnosis was based on case review by a blinded expert panel of pulmonary or critical care physicians. TRALI incidence was 0.59% (seven cases) in study arm recipients versus 0.16% (two cases) in control arm recipients for an odds ratio (OR) of 3.6 (95% confidence interval [CI], 0.7-17.4; p = 0.10). For possible TRALI cases (nine study arm, eight control arm), the OR was 1.2 (95% CI, 0.4-3.0; p = 0.81), and for TRALI and possible TRALI aggregated together, it was 1.7 (95% CI, 0.7-3.7; p = 0.24). Transfusion-associated circulatory overload incidence was identical in the two arms (1.17 and 1.22%, respectively; OR, 1.0; p = 1.0). TRALI incidence in recipients of anti-HLA-positive components was relatively low for a lookback study (1 in 170) and was higher than in the control arm, but did not reach significance. Based on this trend, the data are consistent with the likelihood that TRALI risk is decreased by selecting high-volume plasma components for transfusion from donors at low risk of having HLA antibodies.

Alloexposed blood donors and transfusion‐related acute lung injury: a case‐referent study

Donor white blood cell (WBC) antibodies are thought to increase the risk of transfusion-related acute lung injury (TRALI). WBC antibodies can be present in blood products from donors who have been alloexposed. Alloexposed donors are increasingly excluded from donating plasma, but can still donate plasma-poor products. We aimed to quantify the contribution of alloexposed donors to the occurrence of TRALI for different blood product types. We performed a case-referent study including all reported TRALI patients and all Dutch blood donors. Data on alloexposure status of donors of all TRALI cases reported between January 2004 and October 2008, in the Netherlands, were compared to information on the total donor population. Alloexposure status of all 223 involved donors was compared to the expected status. The overall percentage of TRALI cases that could have been prevented by the deferral of all alloexposed donors (i.e., population-attributable risk [PAR]) was 51% (95% confidence interval [CI], 14%-88%). In 19 recipients of exclusively plasma-poor products (mostly red blood cells [RBCs]), alloexposure of the donors was not associated with TRALI, while in 28 recipients of both plasma-poor and plasma-rich products (>200 mL plasma), the PAR was 94% (95% CI, 34%-100%). Alloexposed donors conferred an increased risk of TRALI in recipients of plasma-rich products, but not in recipients of plasma-poor products. Although WBC antibodies are an important risk factor for TRALI, among RBC recipients another risk factor must be more important.

Zinc supplementation restores PU.1 and Nrf2 nuclear binding in alveolar macrophages and improves redox balance and bacterial clearance in the lungs of alcohol-fed rats.

Chronic alcohol abuse causes oxidative stress, impairs alveolar macrophage immune function, and increases the risk of pneumonia and acute lung injury. Recently we determined that chronic alcohol ingestion in rats decreases zinc levels and macrophage function in the alveolar space; provocative findings in that zinc is essential for normal immune and antioxidant defenses. Alveolar macrophage immune function depends on stimulation by granulocyte/monocyte colony-stimulating factor, which signals via the transcription factor PU.1. In parallel, the antioxidant response element signals via the transcription factor Nrf2. However, the role of zinc bioavailability on these signaling pathways within the alveolar space is unknown. To determine the efficacy of dietary zinc supplementation on lung bacterial clearance and oxidative stress, we tested 3 different groups of rats: control-fed, alcohol-fed, and alcohol-fed with zinc supplementation. Rats were then inoculated with intratracheal Klebsiella pneumoniae, and lung bacterial clearance was determined 24 hours later. Isolated alveolar macrophages were isolated from uninfected animals and evaluated for oxidative stress and signaling through PU.1 and Nrf2. Alcohol-fed rats had a 5-fold decrease in lung bacterial clearance compared to control-fed rats. Dietary zinc supplementation of alcohol-fed rats normalized bacterial clearance and mitigated oxidative stress in the alveolar space, as reflected by the relative balance of the thiol redox pair cysteine and cystine, and increased nuclear binding of both PU.1 and Nrf2 in alveolar macrophages from alcohol-fed rats. Dietary zinc supplementation prevents alcohol-induced alveolar macrophage immune dysfunction and oxidative stress in a relevant experimental model, suggesting that such a strategy could decrease the risk of pneumonia and lung injury in individuals with alcohol use disorders.

Hepcidin and Anemia of the Critically Ill Patient

A NEMIA occurs frequently in critically ill patients, with 60–66% of them having anemia when admitted to the intensive care unit (ICU), and is associated with worse outcomes (such as increased length of stay and increased mortality). Anemia is only partially corrected during ICU stay because recent recommendations have led to a decrease in transfusion triggers. Today the prevalence of anemia in patients being discharged from the ICU is very high, being found in at least 75% of the patients upon final hemoglobin measurement. This common, and severe anemia at ICU discharge may also be prolonged after the ICU stay. The median time to recovery of anemia is 11 weeks. One observational study reports that more than half of such patients are still anemic at 6 months. Although the impact of anemia on rehabilitation after ICU discharge or quality of life has not been fully evaluated, it is well accepted that anemia is associated with worse outcomes for postoperative rehabilitation and for patients with chronic diseases such as cancer and thus should retain our interest at the bedside and in the research unit. Because blood transfusion is not an option for complete correction of this anemia, one may advocate the use of other treatments, such as erythropoiesis-stimulating agents (ESA) or iron. ESA efficacy has been studied in critically ill patients and has not proven to be indicated, at least according to the design of the studies. Iron is needed for erythropoiesis and thus may be indicated for the treatment of this anemia, but iron is also a toxic compound with the ability to induce oxidative stress or promote bacterial growth. A better understanding of iron metabolism regulation may help to define the place of iron in these indications. The recent discovery of hepcidin (i.e., the master regulator of iron metabolism) has shed new light on the regulation of iron homeostasis and has increased understanding of the physiopathology of anemia in complex clinical situations where several regulatory circuits interfere with iron metabolism, such as anemia of inflammation and anemia of critically ill patients. This article reviews the link between iron metabolism and anemia in critically ill patients and discusses therapeutic perspectives in this area.

Differential effects of plasma and red blood cell transfusions on acute lung injury and infection risk following liver transplantation

Patients with chronic liver disease have an increased risk of developing transfusion-related acute lung injury (TRALI) from plasma-containing blood products. Similarly, red blood cell transfusions have been associated with postoperative and nosocomial infections in surgical and critical care populations. Patients undergoing liver transplantation receive large amounts of cellular and plasma-containing blood components, but it is presently unclear which blood components are associated with these postoperative complications. A retrospective cohort study of 525 consecutive liver transplant patients revealed a perioperative TRALI rate of 1.3% (7/525, 95% confidence interval = 0.6%-2.7%), which was associated with increases in the hospital mortality rate [28.6% (2/7) versus 2.9% (15/518), P = 0.02] and the intensive care unit length of stay [2 (1-11 days) versus 0 days (0-2 days), P = 0.03]. Only high-plasma-containing blood products (plasma and platelets) were associated with the development of TRALI. Seventy-four of 525 patients (14.1%) developed a postoperative infection, and this was also associated with increased in-hospital mortality [10.8% (8/74) versus 2.0% (9/451), P < 0.01] and a prolonged length of stay. Multivariate logistic regression determined that the number of transfused red blood cell units (adjusted odds ratio = 1.08, 95% confidence interval = 1.02-1.14, P < 0.01), the presence of perioperative renal dysfunction, and reoperation were significantly associated with postoperative infection. In conclusion, patients undergoing liver transplantation have a high risk of developing postoperative complications from blood transfusion. Plasma-containing blood products were associated with the development of TRALI, whereas red blood cells were associated with the development of postoperative infections in a dose-dependent manner.

ANGPT2 Genetic Variant Is Associated with Trauma-associated Acute Lung Injury and Altered Plasma Angiopoietin-2 Isoform Ratio

Acute lung injury (ALI) acts as a complex genetic trait, yet its genetic risk factors remain incompletely understood. Large-scale genotyping has not previously been reported for ALI. To identify ALI risk variants after major trauma using a large-scale candidate gene approach. We performed a two-stage genetic association study. We derived findings in an African American cohort (n = 222) using a cardiopulmonary disease-centric 50K single nucleotide polymorphism (SNP) array. Genotype and haplotype distributions were compared between subjects with ALI and without ALI, with adjustment for clinical factors. Top performing SNPs (P < 10(-4)) were tested in a multicenter European American trauma-associated ALI case-control population (n = 600 ALI; n = 2,266 population-based control subjects) for replication. The ALI-associated genomic region was sequenced, analyzed for in silico prediction of function, and plasma was assayed by ELISA and immunoblot. Five SNPs demonstrated a significant association with ALI after adjustment for covariates in Stage I. Two SNPs in ANGPT2 (rs1868554 and rs2442598) replicated their significant association with ALI in Stage II. rs1868554 was robust to multiple comparison correction: odds ratio 1.22 (1.06-1.40), P = 0.0047. Resequencing identified predicted novel splice sites in linkage disequilibrium with rs1868554, and immunoblots showed higher proportion of variant angiopoietin-2 (ANG2) isoform associated with rs1868554T (0.81 vs. 0.48; P = 0.038). An ANGPT2 region is associated with both ALI and variation in plasma angiopoietin-2 isoforms. Characterization of the variant isoform and its genetic regulation may yield important insights about ALI pathogenesis and susceptibility.

Accuracy of waste blood measurement in critically ill patients

Dear Editor, Timely identification and enrollment of critically ill patients into clinical trials is a challenge. Residual blood samples (‘‘waste’’ blood) obtained for routine clinical tests is a precious and potentially underutilized source of biospecimens. The accurate measurement of specific biomarker using waste blood may be compromised due to sample handling, storage, and the quality control of the platform used [1, 2]. We hypothesized that waste blood samples, if appropriately processed, provide accurate results and are comparable to fresh samples. Adults with increased risk for acute lung injury (ALI), using a lung injury prediction score (LIPS) [3], were identified daily within 12 h of hospital admission. EDTA plasma samples were collected and processed within 2 h, and divided in two aliquots, one immediately frozen at -80 C (fresh blood sample), and the other kept at 4 C for 24 h before being frozen at -80 C (waste blood sample). The plasma was used for multiplex cytokine analysis (Procarta Cytokine kit, Affymetrix Panomics, Fremont, CA, USA) and evaluation of soluble receptor for advanced glycation end-products (sRAGE) (R&D Systems, Minneapolis, MN, USA). Bland–Altman analysis [4] was performed by using JMP 8 (SAS Institute Inc., Cary, NC, USA) to determine the agreement between paired comparisons of fresh and waste blood for the cytokines and sRAGE. The study was approved by the Institutional Review Board (09-000881) and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Between May and December 2009, plasma samples of 29 patients were analyzed: median LIPS score of 4 (IQR 3.5–4.5). Sepsis was the most common risk factor (76%). The Bland–Altman plot (mean bias ? SD, limits of agreement) showed good agreement for IL-1ra (-9 ± 79 pg/ml, -166 to 148 pg/ml), IL-6 (0.9 ± 16 pg/ml, -15 to 33 pg/ml), IL-8 (-0.3 ± 1.6 pg/ml, -3.4 to 2.8 pg/ml), IL-12 (p40) (-0.2 ± 1.4 pg/ml, -2.8 to 2.6 pg/ml), MCP-1(-0.2 ± 11 pg/ml, -22.2 to 21.8 pg/ml), and sRAGE (-24 ± 325 pg/ml, -626 to 673 pg/ml) between fresh blood and waste blood samples (Fig. 1). In this prospective study of critically ill patients at risk of ALI, cytokines and sRAGE measurements from fresh and waste blood samples provided comparable results. This observation has important implications for future mechanistic studies allowing for more liberal use of rapidly separated and properly stored clinical ‘‘waste’’ samples. This strategy can increase the time window to obtain informed consent and limit the amount of blood collected, a common cause of anemia in critically ill patients [5]. This study has several limitations including the small sample size of this cohort, the timing of blood collection, and a biomarker panel limited to epithelial injury and inflammation. Nevertheless, the ability to use properly collected and stored blood from clinical samples for investigational use broadens the possibility of obtaining samples that would otherwise be scarce or impossible to collect for research purposes only. However, it remains prudent to evaluate and validate the stability of each biomarker of interest before using stored blood samples for research.

Changes in Plasma Fibronectin Isoform Levels Predict Distinct Clinical Outcomes in Critically Ill Patients

Introduction:Concentrations of the total pool of fibronectin in plasma (TFN), and the subset of this pool that contains the alternatively spliced EDA segment (A+FN), are both affected by disease processes, and the latter pool has gained a reputation as a biomarker for vascular injury. We therefore wished to determine if changes in either FN pool correlate with clinical outcomes in critically ill individuals.Methods:We analyzed a database for 57 patients with major trauma (n = 33) or sepsis syndrome (n = 24) in which plasma levels of TFN and A+FN had been measured at intervals, along with clinical parameters. Logistic regression analysis was performed to detect associations between predictive variables and three clinical outcomes: 1) the acute respiratory distress syndrome (ARDS), 2) milder acute lung injury designated acute hypoxemic respiratory failure (AHRF), and 3) survival to hospital discharge.Results:An increase in plasma TFN during the first 24 hours of intensive care unit (ICU) observation was negatively associated with progression to ARDS (odds ratio 0.98 per 1 microgram (μg)/ml increase, 95% CI (0.97, 1.00)) and AHRF (OR 0.97 per 1 μg/ml increase, (0.95, 0.99)), whereas an increase in A+FN over the first 24 hours was positively associated with progression to AHRF (OR 1.65 per 1 μg/ml increase, (1.04, 2.62)). Additionally, the ratio of the partial pressure of oxygen in arterial blood (PaO2) to the percentage of oxygen in inspired air (FIO2) after 24 hours was positively associated with survival (OR 1.01 per 1 unit increase in ratio, (1.00, 1.03)), along with change in A+FN (OR 1.30 per 1 μg/ml increase, (0.90, 1.88)).Conclusions:Different FN isoforms may constitute predictive covariate markers for distinct clinical outcomes in critically ill patients. The data also suggest that early TFN accumulation in the circulation may confer a clinical benefit to patients at risk for acute lung injury.

Risk-Reduction Strategies for Platelet Transfusion in the United States

Despite bacterial culture of platelets, transfusion-associated bacteremia/sepsis (TABS) may occur with a frequency of approximately 1/60,000 platelet transfusions, while an emerging transfusion-transmitted infection (TTI) could reproduce the epidemic of transfusion-transmitted human immunodeficiency virus (HIV) in the future. As platelet pathogen-reduction (PR) systems licensed in Europe may eventually become licensed in the U.S., three alternative strategies for reducing the residual risks of TTIs and TABS may become available in the U.S. in the future: (1) transfusion of (already-available) non–pathogen-reduced single-donor (as opposed to pooled whole-blood-derived [PWBD]) platelets, (2) transfusion of pathogen-reduced single-donor platelets, or (3) transfusion of pathogen-reduced PWBD platelets (if trials of this component are conducted in the U.S. in the future). PR of platelets will increase the risk of mild and moderate (albeit perhaps not severe) bleeding complications and it cannot protect from all pathogens. Compared to PWBD platelets, single-donor platelets can reduce, by at least twofold, the risk of all known and emerging TTIs, as well as the risk of TABS, without incurring any risk. The fewer donor exposures secured by the use of single-donor platelets – especially if combined with collection of red blood cells and/or plasma from the same donation for transfusion to the same recipient through the use of multicomponent apheresis – may also reduce the risk of transfusion-related acute lung injury. To choose between pathogen-reduced and non–pathogen-reduced single-donor platelets, the increased risks of bleeding complications as well as other possible adverse events secondary to PR need to be quantified precisely and weighed against the competing risks of TABS and emerging TTIs.

Analysis of cutoffs for screening sensitized blood donors for HLA alloantibodies using a cytometric microbead assay

Cytometric-based microbead assays for HLA alloantibodies may be effective tools for transfusion-related acute lung injury (TRALI) risk reduction. However, the optimal cutoff for donor screening is unclear. To optimize the screening test cutoff in sensitized donors, sera were screened with a cytometric microbead assay. Confirmatory testing was performed on samples with a normalized background (NBG) ratio of 2.4 or more. Sera with a NBG of 2.4 to 9.9 had positive predictive values (PPVs) of 78.2% (95% confidence interval [CI], 67.8%-86.0%) and 71.1% (95% CI, 56.5%-82.4%) for Class I and II antibodies, respectively. Sera with a NBG of 10 or more had PPVs of 98.9% (95% CI, 93.3%-100%) and 99.1 (95% CIs, 94.7%-100%) for Class I and II, respectively. The percent panel-reactive antibody (PRA) of confirmed HLA alloantibodies from sera with a NBG of 2.4 to 9.9 was 29.3±17% (mean±standard deviation) for Class I and 22.3±16.7% for Class II, but for antibodies from sera with a NBG of 10 or more the PRAs were 65.3±24.0 and 64.1±25.2% for Class I and II, respectively (p<0.00001). Serial dilution studies comparing the screening test with antiglobulin-enhanced lymphocytotoxicity suggested that NBG correlated with antibody titer. In our center, deferral for prior pregnancy or transfusion would result in loss of 28.8% of apheresis platelet (PLT) donors. Using the screening test at a cutoff of 2.4 or more or 10 or more would reduce the fraction of donors lost to 12.7 or 8.0%, respectively. A screening cutoff of 10 or more predicts HLA alloimmunization in sensitized donors and is associated with higher PRAs and titers. Implementation of this cutoff may reduce TRALI risk while limiting unnecessary deferral of PLT donors.

Effective reduction of transfusion-related acute lung injury risk with male-predominant plasma strategy in the American Red Cross (2006-2008)

Effective reduction of transfusion-related acute lung injury risk with male-predominant plasma strategy in the American Red Cross (2006-2008)

Red blood cell transfusion and outcomes in patients with acute lung injury, sepsis and shock

IntroductionIn this study, we sought to determine the association between red blood cell (RBC) transfusion and outcomes in patients with acute lung injury (ALI), sepsis and shock.MethodsWe performed a secondary analysis of new-onset ALI patients enrolled in the Acute Respiratory Distress Syndrome Network Fluid and Catheter Treatment Trial (2000 to 2005) who had a documented ALI risk factor of sepsis or pneumonia and met shock criteria (mean arterial pressure (MAP) < 60 mmHg or vasopressor use) within 24 hours of randomization. Using multivariable logistic regression, we examined the association between RBC transfusion and 28-day mortality after adjustment for age, sex, race, randomization arm and Acute Physiology and Chronic Health Evaluation III score. Secondary end points included 90-day mortality and ventilator-free days (VFDs). Finally, we examined these end points among the subset of subjects meeting prespecified transfusion criteria defined by five simultaneous indicators: hemoglobin < 10.2 g/dL, central or mixed venous oxygen saturation < 70%, central venous pressure ≥ 8 mmHg, MAP ≥ 65 mmHg, and vasopressor use.ResultsWe identified 285 subjects with ALI, sepsis, shock and transfusion data. Of these, 85 also met the above prespecified transfusion criteria. Fifty-three (19%) of the two hundred eighty-five subjects with shock and twenty (24%) of the subset meeting the transfusion criteria received RBC transfusion within twenty-four hours of randomization. We found no independent association between RBC transfusion and 28-day mortality (odds ratio = 1.49, 95% CI (95% confidence interval) = 0.77 to 2.90; P = 0.23) or VFDs (mean difference = -0.35, 95% CI = -4.03 to 3.32; P = 0.85). Likewise, 90-day mortality and VFDs did not differ by transfusion status. Among the subset of patients meeting the transfusion criteria, we found no independent association between transfusion and mortality or VFDs.ConclusionsIn patients with new-onset ALI, sepsis and shock, we found no independent association between RBC transfusion and mortality or VFDs. The physiological criteria did not identify patients more likely to be transfused or to benefit from transfusion.

Genetic variants in the TIRAP gene are associated with increased risk of sepsis-associated acute lung injury

BackgroundToll like receptors (TLRs) signaling pathways, including the adaptor protein Mal encoded by the TIRAP gene, play a central role in the development of acute lung injury (ALI). Recently, the TIRAP variants have been described association with susceptibility to inflammatory diseases. The aim of this study was to investigate whether genetic variants in TIRAP are associated with the development of ALI.MethodsA case-control collection from Han Chinese of 298 healthy subjects, 278 sepsis-associated ALI and 288 sepsis alone patients were included. Three tag single nucleotide polymorphisms (SNPs) of the TIRAP gene and two additional SNPs that have previously showed association with susceptibility to other inflammatory diseases were genotyped by direct sequencing. The differences of allele, genotype and haplotype frequencies were evaluated between three groups.ResultsThe minor allele frequencies of both rs595209 and rs8177375 were significantly increased in ALI patients compared with both healthy subjects (odds ratio (OR) = 1.47, 95% confidence interval (CI):1.15-1.88, P = 0.0027 and OR = 1.97, 95% CI: (1.38-2.80), P = 0.0001, respectively) and sepsis alone patients (OR = 1.44, 95% CI: 1.12-1.85, P = 0.0041 and OR = 1.82, 95% CI: 1.28-2.57, P = 0.00079, respectively). Haplotype consisting of these two associated SNPs strengthened the association with ALI susceptibility. The frequency of haplotype AG (rs595209A, rs8177375G) in the ALI samples was significantly higher than that in the healthy control group (OR = 2.13, 95% CI: 1.46-3.09, P = 0.00006) and the sepsis alone group (OR = 2.24, 95% CI: 1.52-3.29, P = 0.00003). Carriers of the haplotype CA (rs595209C, rs8177375A) had a lower risk for ALI compared with healthy control group (OR = 0.69, 95% CI: 0.54-0.88, P = 0.0003) and sepsis alone group (OR = 0.71, 95% CI: 0.55-0.91, P = 0.0006). These associations remained significant after adjustment for covariates in multiple logistic regression analysis and for multiple comparisons.ConclusionsThese results indicated that genetic variants in the TIRAP gene might be associated with susceptibility to sepsis-associated ALI in Han Chinese population. However, the association needs to be replicated in independent studies.

S105 Does vitamin D deficiency increase risk of acute lung injury post oesophagectomy?

IntroductionVitamin D has profound effects on the immune system and its deficiency has been implicated in increased risk of diseases such as tuberculosis and pneumonia. We have shown vitamin D...

An Alternative Method of Acute Lung Injury Classification for Use in Observational Studies

In observational studies using acute lung injury (ALI) as an outcome, a spectrum of lung injury and difficult-to-interpret chest radiographs (CXRs) may hamper efforts to uncover risk factor associations. We assessed the impact of excluding patients with difficult-to-classify or equivocal ALI diagnosis on clinical and genetic risk factor associations for ALI after trauma. This study was of a prospective cohort of 280 critically ill trauma patients. The primary outcome was the development of ALI. Patients were classified into one of three groups: (1) definite ALI (patients who fulfilled the American-European Consensus Conference [AECC] criteria for ALI), (2)equivocal ALI (patients who had difficult-to-interpret CXRs), and (3) definite non-ALI. We compared clinical and genetic ALI risk factor associations between two classification schemes: AECC classification (definite ALI vs rest) and alternative classification (definite ALI vs definite non-ALI, excluding equivocal ALI). Ninety-three (35%) patients were classified as definite ALI, 67 (25%) as equivocal, and 104 (39%) as definite non-ALI. Estimates of clinical and genetic ALI risk factor associations were farther from the null using the alternative classification. In a multivariable risk factor model, the C statistic of the alternative classification was significantly higher than that derived from the AECC classification (0.82 vs 0.74; P < .01). The ability to detect ALI risk factors may be improved by excluding patients with equivocal or difficult-to-classify ALI. Such analyses may provide improved ability to detect clinical and genetic risk factor associations in future epidemiologic studies of ALI.

In vitro and in vivo evaluation of apheresis platelets stored for 5 days in 65% platelet additive solution/35% plasma

In the United States, apheresis platelets (PLTs) are suspended in autologous plasma. PLT additive solutions, long used in Europe, decrease recipient allergic reactions and may reduce the risk of transfusion-related acute lung injury. We evaluated Amicus-collected PLTs stored in platelet additive solution (PAS) III (InterSol) for 5 days. In Study 1, 71 subjects donated two products on a single day-one each stored in 100% plasma or 65% PAS III/35% plasma. Products underwent standard in vitro testing on Days 1 and 5. In Study 2, 43 additional subjects provided Amicus products stored for 5 days in 65% PAS III/35% plasma for in vivo radiolabeled recovery and survival determinations. The effect of approximately 2500cGy Day 1 gamma irradiation was evaluated in a subset of products. PAS III PLTs (n=70) had a median Day 5 pH(22°C) of 7.2 (lower 95%, 95% tolerance limit, 6.9). Mean Day 5 recovery and survival of radiolabeled PAS III PLTs (n=33) were, respectively, 80.5 and 72.1%, of fresh autologous PLTs. With 95% confidence, these values were at least 66% of fresh PLT recovery and 58% of survival. All in vitro variables remained within ranges seen in licensed products for irradiated and nonirradiated PAS III PLTs. Leukoreduced Amicus PLTs stored in 65% PAS III/35% plasma in PL-2410 containers maintained pH ≥6.9 throughout 5 days' storage. Radiolabeled PLT recovery and survival values met US Food and Drug Administration statistical criteria. Gamma-irradiated PAS III PLTs demonstrated no significant adverse effects due to irradiation in in vitro testing.

Genetic variation in the FAS gene and associations with acute lung injury.

Fas (CD95) modulates apoptosis and inflammation and is believed to play an important role in lung injury. To determine if common genetic variation in FAS is associated with acute lung injury (ALI) susceptibility, risk of death, and FAS gene expression. We genotyped 14 single nucleotide polymorphisms (tagSNPS) in FAS in samples from healthy white volunteers (control subjects, n = 294) and patients with ALI (cases, n = 324) from the ARDSnet Fluid and Catheter Treatment Trial (FACTT). FAS genotypes associated with ALI in the discovery study were confirmed in a nested case-control validation study of critically ill patients at risk for ALI (n = 657). We also tested for associations between selected tagSNPS and FAS mRNA levels in whole blood from healthy control subjects exposed to media alone or LPS ex vivo. We identified associations between four tagSNPs in FAS (FAS(-11341A>T) [rs17447140], FAS(9325G>A) [rs2147420], FAS(21541C>T) [rs2234978], and FAS(24484A>T) [rs1051070]) and ALI case status. Haplotype-based analyses suggested that three of the tagSNPs (FAS(9325G>A), FAS(21541C>T), and FAS(24484A>T)) function as a unit. The association with this haplotype and ALI was validated in a nested case-control study of at-risk subjects (P = 0.05). This haplotype was also associated with increased FAS mRNA levels in response to LPS stimulation. There was no association between FAS polymorphisms and risk of death among ALI cases. Common genetic variants in FAS are associated with ALI susceptibility. This is the first genetic evidence supporting a role for FAS in ALI.