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The authors previously identified plasma plasminogen activator inhibitor-1 (PAI-1) level as a quantitative lung injury biomarker in primary graft dysfunction (PGD). They hypothesized that plasma levels of PAI-1 used as a quantitative trait could facilitate discovery of genetic loci important in PGD pathogenesis. A two-stage cohort study was performed. In stage 1, they tested associations of loci with PAI-1 plasma level using linear modeling. Genotyping was performed using the Illumina CVD Bead Chip v2. Loci meeting a p < 5 × 10(-4) cutoff were carried forward and tested in stage 2 for association with PGD. Two hundred ninety-seven enrollees were evaluated in stage 1. Six loci, associated with PAI-1, were carried forward to stage 2 and evaluated in 728 patients. rs3168046 (Toll interacting protein [TOLLIP]) was significantly associated with PGD (p = 0.006). The increased risk of PGD for carrying at least one copy of this variant was 11.7% (95% confidence interval 4.9-18.5%). The false-positive rate for individuals with this genotype who did not have PGD was 6.1%. Variants in the TOLLIP gene are associated with higher circulating PAI-1 plasma levels and validate for association with clinical PGD. A protein quantitative trait analysis for PGD risk prioritizes genetic variations in TOLLIP and supports a role for Toll-like receptors in PGD pathogenesis.

Primary graft dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in the Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002 to 2010; with separate validation in 382 subjects accrued from 2011 to 2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 h, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed three prediction models, where low-risk recipients had a normal BMI (18.5-25 kg/m(2) ), chronic obstructive pulmonary disease/cystic fibrosis, and absent or mild pulmonary hypertension (mPAP

Inherent recipient factors, including pretransplant diagnosis, obesity and elevated pulmonary pressures, are established primary graft dysfunction (PGD) risks. We evaluated the relationship between preoperative lung injury biomarkers and PGD to gain further mechanistic insight in recipients. We performed a prospective cohort study of recipients in the Lung Transplant Outcomes Group enrolled between 2002 and 2010. Our primary outcome was Grade 3 PGD on Day 2 or 3. We measured preoperative plasma levels of five biomarkers (CC-16, sRAGE, ICAM-1, IL-8 and Protein C) that were previously associated with PGD when measured at the postoperative time point. We used multivariable logistic regression to adjust for potential confounders. Of 714 subjects, 130 (18%) developed PGD. Median CC-16 levels were elevated in subjects with PGD (10.1 vs. 6.0, p

We hypothesized alterations in gene expression could identify important pathways involved in transplant lung injury. Broncho alveolar lavage fluid (BALF) was sampled from donors prior to procurement and in recipients within an hour of reperfusion as part of the NIAID Clinical Trials in Organ Transplantation Study. Twenty-three patients with Grade 3 primary graft dysfunction (PGD) were frequency matched with controls based on donor age and recipient diagnosis. RNA was analyzed using the Human Gene 1.0 ST array. Normalized mRNA expression was transformed and differences between donor and postreperfusion values were ranked then tested using Gene Set Enrichment Analysis. Three-hundred sixty-two gene sets were upregulated, with eight meeting significance (familywise-error rate, FWER p-value

Early epithelial injury after lung transplantation may contribute to development of bronchiolitis obliterans syndrome (BOS). We evaluated the relationship between early postoperative soluble receptor for advanced glycation end-product (sRAGE) levels, a marker of type I alveolar cell injury and BOS. We performed a cohort study of 106 lung transplant recipients between 2002 and 2006 at the University of Pennsylvania with follow-up through 2010. Plasma sRAGE was measured 6 and 24 h after transplantation. Cox proportional hazards models were used to evaluate the association between sRAGE and time to BOS, defined according to ISHLT guidelines. Sixty (57%) subjects developed BOS. The average time to BOS was 3.4 years. sRAGE levels measured at 6 h (HR per SD of sRAGE: 1.69, 95% CI: 1.11, 2.57, p = 0.02) and 24 h (HR per SD of sRAGE: 1.74, 95% CI: 1.14, 2.65, p = 0.01) were associated with an increased hazard of BOS. Multivariable Cox regression indicated this relationship was independent of potential confounders. Elevated plasma sRAGE levels measured in the immediate postoperative period are associated with the development of BOS. Early epithelial injury after transplantation may contribute to the development of fibrosis in BOS.

Rationale: Cognitive and psychiatric morbidity is common and potentially modifiable after acute lung injury (ALI). However, practical measures of neuropsychological function for use in multicenter trials are lacking.Objectives: To determine whether a validated telephone-based neuropsychological test battery is feasible in a multicenter trial. To determine the frequency and risk factors for long-term neuropsychological impairment.Methods: As an adjunct study to the Acute Respiratory Distress Syndrome Clinical Trials Network Fluid and Catheter Treatment Trial, we assessed neuropsychological function at 2 and 12 months post-hospital discharge.Measurements and Main Results: Of 406 eligible survivors, we approached 261 to participate and 213 consented. We tested 122 subjects at least once, including 102 subjects at 12 months. Memory, verbal fluency, and executive function were impaired in 13% (12 of 92), 16% (15 of 96), and 49% (37 of 76) of long-term survivors. Long-term cognitive impairment was present in 41 of the 75 (55%) survivors who completed cognitive testing. Depression, post-traumatic stress disorder, or anxiety was present in 36% (37 of 102), 39% (40 of 102), and 62% (63 of 102) of long-term survivors. Enrollment in a conservative fluid-management strategy (P = 0.005) was associated with cognitive impairment and lower partial pressure of arterial oxygen during the trial was associated with cognitive (P = 0.02) and psychiatric impairment (P = 0.02).Conclusions: Neuropsychological function can be assessed by telephone in a multicenter trial. Long-term neuropsychological impairment is common in survivors of ALI. Hypoxemia is a risk factor for long-term neuropsychological impairment. Fluid management strategy is a potential risk factor for long-term cognitive impairment; however, given the select population studied and an unclear mechanism, this finding requires confirmation. [ABSTRACT FROM AUTHOR]

Rationale: Obesity has been linked to acute lung injury and is a risk factor for early mortality after lung transplantation.Objectives: To examine the associations of obesity and plasma adipokines with the risk of primary graft dysfunction after lung transplantation.Methods: We performed a prospective cohort study of 512 adult lung transplant recipients with chronic obstructive pulmonary disease or interstitial lung disease enrolled in the Lung Transplant Outcomes Group Study. In a nested case-control study, we measured plasma leptin, adiponectin, and resistin before lung transplantation and 6 and 24 hours after lung transplantation in 40 cases of primary graft dysfunction and 80 control subjects. Generalized linear mixed models and logistic regression were used to estimate risk ratios and odds ratios.Measurements and Main Results: Grade 3 primary graft dysfunction developed within 72 hours of transplantation in 29% participants. Obesity was associated with a twofold increased risk of primary graft dysfunction (adjusted risk ratio 2.1; 95% confidence interval, 1.7-2.6). The risk of primary graft dysfunction increased by 40% (confidence interval, 30–50%) for each 5 kg/m(2) increase in body mass index after accounting for center, diagnosis, cardiopulmonary bypass, and transplant procedure. Higher plasma leptin levels were associated with a greater risk of primary graft dysfunction (sex-adjusted P = 0.02). The associations of both obesity and leptin with primary graft dysfunction tended to be stronger among those who did not undergo cardiopulmonary bypass.Conclusions: Obesity is an independent risk factor for primary graft dysfunction after lung transplantation. [ABSTRACT FROM AUTHOR]

Background: Warfarin is the primary therapy to prevent stroke and venous thromboembolism. Significant periods of nonadherence frequently go unreported by patients and undetected by providers. Currently, no comprehensive screening tool exists to help providers assess the risk of nonadherence at the time of initiation of warfarin therapy.Methods: This article reports on a prospective cohort study of adults initiating warfarin therapy at two anticoagulation clinics (university- and Veterans Affairs-affiliated). Nonadherence, defined by failure to record a correct daily pill bottle opening, was measured daily by electronic pill cap monitoring. A multivariable logistic regression model was used to develop a point system to predict daily nonadherence to warfarin.Results: We followed 114 subjects for a median of 141 days. Median nonadherence of the participants was 14.4% (interquartile range [IQR], 5.8-33.8). A point system, based on nine demographic, clinical, and psychosocial factors, distinguished those demonstrating low vs high levels of nonadherence: four points or fewer, median nonadherence 5.8% (IQR, 2.3-14.1); five points, 9.1% (IQR, 5.9-28.6); six points, 14.5% (IQR, 7.1-24.1); seven points, 14.7% (IQR, 7.0-34.7); and eight points or more, 29.3% (IQR, 15.5-41.9). The model produces a c-statistic of 0.66 (95% CI, 0.61-0.71), suggesting modest discriminating ability to predict day-level warfarin nonadherence.Conclusions: Poor adherence to warfarin is common. A screening tool based on nine demographic, clinical, and psychosocial factors, if further validated in other patient populations, may help to identify groups of patients at lower risk for nonadherence so that intensified efforts at increased monitoring and intervention can be focused on higher-risk patients. [ABSTRACT FROM AUTHOR]

Background: Evidence that continuous positive airway pressure (CPAP) reduces cardiovascular morbidity comes largely from observational studies. This association may be confounded if CPAP adherents are healthier in ways not measured by investigators. We assessed whether patients adhering to lipid-lowering medications were more adherent to CPAP.Methods: This was a retrospective cohort study undertaken at the Philadelphia Veterans Affairs (VA) Medical Center (2005-2006) of consecutive patients on lipid-lowering therapy newly initiating CPAP for obstructive sleep apnea. Adherence to medications dispensed via the VA closed-pharmacy system was measured as the proportion of days covered (>/=80% vs < 80%) in the year prior to CPAP initiation. CPAP adherence was defined as >/= 4 h/d of "mask-on" time, measured electronically daily during the first week of CPAP. We examined the association between medication adherence and CPAP adherence using multivariable logistic regression.Results: Complete data were available for 117 of 142 (81.5%) subjects. After adjustment for age, race, medical comorbidity, and sleep apnea-related clinical factors, subjects with low medication adherence demonstrated a 40.1% (95% CI, 30.0-51.0) probability of using CPAP >/= 4 h/d compared with 55.2% (95% CI, 46.9-63.1) for subjects with adequate (>/=80%) medication adherence (adjusted for comparison, odds ratio (OR) = 1.8 [95% CI, 1.0-3.3], P = .04). Married patients were more adherent to medications and CPAP; inclusion of this factor reduced to nonsignificance the association of medication and CPAP adherence (OR = 1.6 [95% CI, 0.9-2.8], P = .12).Conclusion: Patients consistently refilling lipid-lowering medications were more adherent to CPAP, suggesting that differences in medication adherence or other health-promoting behaviors should be investigated in future nonrandomized, observational studies linking CPAP adherence and cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Rationale: The receptor for advanced glycation end products (RAGE) is an important marker of lung epithelial injury and may be associated with impaired alveolar fluid clearance. We hypothesized that patients with primary graft dysfunction (PGD) after lung transplantation would have higher RAGE levels in plasma than patients without PGD.Objectives: To test the association of soluble RAGE (sRAGE) levels with PGD in a prospective, multicenter cohort study.Methods: We measured plasma levels of sRAGE at 6 and 24 hours after allograft reperfusion in 317 lung transplant recipients at seven centers. The primary outcome was grade 3 PGD (Pa(O(2))/Fi(O(2)) < 200 with alveolar infiltrates) within the first 72 hours after transplantation.Measurements and Main Results: Patients who developed PGD had higher levels of sRAGE than patients without PGD at both 6 hours (median 9.3 ng/ml vs. 7.5 ng/ml, respectively; P = 0.028) and at 24 hours post-transplantation (median 4.3 ng/ml vs. 1.9 ng/ml, respectively; P < 0.001). Multivariable logistic regression analyses indicated that the relationship between levels of sRAGE and PGD was attenuated by elevated right heart pressures and by the use of cardiopulmonary bypass. Median sRAGE levels were higher in subjects with cardiopulmonary bypass at both 6 hours (P = 0.003) and 24 hours (P < 0.001). sRAGE levels at 6 hours were significantly associated with intraoperative red cell transfusion (Spearman's rho = 0.39, P = 0.002 in those with PGD), and in multivariable linear regression analyses this association was independent of confounding variables (P = 0.02).Conclusions: Elevated plasma levels of sRAGE are associated with PGD after lung transplantation. Furthermore, plasma sRAGE levels are associated with blood product transfusion and use of cardiopulmonary bypass. [ABSTRACT FROM AUTHOR]

RATIONALE: General intensive care units (ICUs) provide care across a wide range of diagnoses, whereas specialty ICUs provide diagnosis-specific care. Risk-adjusted outcome differences across such units are unknown. OBJECTIVES: To determine the association between specialty ICU care and the outcome of critical illness. METHODS: We conducted a retrospective cohort study design analyzing patients admitted to 124 ICUs participating in the Acute Physiology and Chronic Health Evaluation IV from January 2002 to December 2005. We examined 84,182 patients admitted to specialty and general ICUs with an admitting diagnosis or procedure of acute coronary syndrome, ischemic stroke, intracranial hemorrhage, pneumonia, abdominal surgery, or coronary-artery bypass graft surgery. ICU type was determined by a local data coordinator at each site. Patients were classified by admission to a general ICU, a diagnosis-appropriate ('ideal') specialty ICU, or a diagnosis-inappropriate ('non-ideal') specialty ICU. The primary outcomes were in-hospital mortality and ICU length of stay. MEASUREMENTS AND MAIN RESULTS: After adjusting for important confounders, there were no significant differences in risk-adjusted mortality between general versus ideal specialty ICUs for all conditions other than pneumonia. Risk-adjusted mortality was significantly greater for patients admitted to non-ideal specialty ICUs. There was no consistent effect of specialization on length of stay for all patients or for ICU survivors. CONCLUSIONS: Ideal specialty ICU care appears to offer no survival benefit over general ICU care for select common diagnoses. Non-ideal specialty ICU care (i.e., 'boarding') is associated with increased risk-adjusted mortality. [ABSTRACT FROM AUTHOR]

Background: Single nucleotide polymorphisms in the myosin light chain kinase (MYLK) gene have been implicated in the risk of sepsis-related acute lung injury and asthma. MYLK encodes protein isoforms involved in multiple components of the inflammatory response, including apoptosis, vascular permeability, and leukocyte diapedesis. We tested the association of MYLK gene variation in the development of acute lung injury in major trauma patients.Methods: We conducted a prospective cohort study of 273 subjects with major trauma (injury severity score > or = 16). All x-rays and clinical data were reviewed by three clinicians for acute lung injury classification. A total of 17 tagging single nucleotide polymorphisms in MYLK were genotyped. Single nucleotide polymorphisms were individually assessed at the genotype level, and multiple logistic regression models were used to adjust for baseline variables. Haplotype analyses of sliding windows including 2-5 single nucleotide polymorphisms were conducted.Results: Ninety-one of the 273 subjects (33%) met criteria for acute lung injury within 5 days of traumatic insult. Three informative MYLK coding single nucleotide polymorphisms were individually associated with acute lung injury, with two informative risk-conferring genotypes His21Pro (CC genotype, odds ratio = 1.87, 95% confidence interval 1.06-3.33; p = 0.022) and Pro147Ser (TT, odds ratio = 2.13, 95% confidence interval 1.14-4.10; p = 0.011) more frequent than the noninformative Thr335Thr CC genotype (odds ratio = 0.42, 95% confidence interval 0.20-0.85; p = 0.010). Each of these genotypic associations was more pronounced in African Americans with trauma. Multivariate analyses demonstrated the association of each MYLK single nucleotide polymorphism with acute lung injury to be independent of age, injury severity score, Acute Physiology and Chronic Health Evaluation III, and the mechanism of trauma. Finally, haplotype analyses revealed strong acute lung injury associations with 2-4 single nucleotide polymorphism haplotypes, all involving His21Pro (p < 0.008).Conclusions: Three MYLK coding single nucleotide polymorphisms previously associated with sepsis-induced acute lung injury and severe asthma in African Americans were associated with acute lung injury development after trauma in African Americans, although effect directions differed. These results confirm our prior studies implicating MYLK as a susceptibility gene in a distinct acute lung injury subset other than sepsis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Both single and bilateral lung transplantation are recognised options for patients who have end-stage chronic obstructive pulmonary disease (COPD); however, which procedure leads to longer survival remains unclear. We aimed to compare survival after each procedure by analysing data from the registry of the International Society for Heart and Lung Transplantation. METHODS: We analysed data for 9883 patients with COPD, 3525 (35.7%) of whom underwent bilateral lung transplantation, and 6358 (64.3%) single lung transplantation, between 1987 and 2006. We accounted for possible selection bias with analysis of covariance, propensity-score risk adjustment, and propensity-based matching. FINDINGS: Median survival after either type of lung transplantation for patients with COPD was 5.0 years (95% CI 4.8-5.2). Survival for patients who had lung transplantation before 1998 was 4.5 years (4.3-4.8), compared with 5.3 years (5.0-5.5) for those who had it after 1998 (p<0.0001). The proportion of patients who had bilateral lung transplantation increased from 101/467 (21.6%) in 1993 to 345/614 (56.2%) in 2006. Median survival time after bilateral lung transplantation was longer than that after single lung transplantation: 6.41 years (6.02-6.88) versus 4.59 years (4.41-4.76) (p<0.0001). Pretransplant characteristics of patients who had single and bilateral lung transplantation differed, but whichever method was used to adjust for baseline differences, bilateral lung transplantation was associated with longer survival than was single lung transplantation; the hazard ratio ranged from 0.83 (0.78-0.92) for analysis of covariance to 0.89 (0.80-0.97) for propensity-based matching. However, bilateral lung transplantation had little benefit compared with single lung transplantation for patients who were 60 years and older (HR 0.95; 0.81-1.13). INTERPRETATION: Bilateral lung transplantation leads to longer survival than single lung transplantation in patients with COPD, especially those who are younger than 60 years. [ABSTRACT FROM AUTHOR]

Background: Acute lung injury is characterized by hypercoagulability and impaired fibrinolysis. We hypothesized that lower protein C and higher type 1 plasminogen activator inhibitor (PAI-1) levels in plasma would be associated with primary graft dysfunction (PGD) after lung transplantation.Design: Prospective, multicenter cohort study.Methods: We measured plasma levels of protein C and PAI-1 before lung transplantation and 6, 24, 48, and 72 h after allograft reperfusion in 128 lung transplant recipients at six centers. The primary outcome was grade 3 PGD (Pa(O(2))/Fi(O(2)) < 200 with alveolar infiltrates) 72 h after transplantation. Biomarker profiles were evaluated using logistic regression and generalized estimating equations.Results: Patients who developed PGD had lower protein C levels 24 h posttransplantation than did patients without PGD (mean +/- SD [relative to control]: 64 +/- 27 vs. 92 +/- 41%, respectively; p = 0.002). Patients with PGD also had PAI-1 levels that were almost double those of patients without PGD at 24 h (213 +/- 144 vs. 117 +/- 89 ng/ml, respectively; p < 0.001). Throughout the 72-h postoperative period, protein C levels were significantly lower (p = 0.007) and PAI-1 levels were higher (p = 0.026) in subjects with PGD than in others. These differences persisted despite adjustment for potential confounders in multivariate analyses. Higher recipient pulmonary artery pressures, measured immediately pretransplantation, were associated with higher PAI-1 levels and increased risk of PGD.Conclusion: Lower postoperative protein C and higher PAI-1 plasma levels are associated with PGD after lung transplantation. Impaired fibrinolysis and enhanced coagulation may be important in PGD pathogenesis. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVES: Sarcoidosis is a granulomatous disorder with heterogeneous clinical manifestations, which are potentially reflective of a syndrome with different etiologies leading to similar histologic findings. We examined the relationship between environmental and occupational exposures, and the clinical phenotype of sarcoidosis. DESIGN: We performed a cross-sectional study of incident sarcoidosis cases that had been identified by A Case Control Etiologic Study of Sarcoidosis. Subjects were categorized into the following two groups: (1) pulmonary-only disease; and (2) systemic disease (with or without pulmonary involvement). Logistic regression was used to examine the associations of candidate exposures with clinical phenotype. SETTING: Ten academic medical centers across the United States. PATIENTS: The current study included 718 subjects in whom sarcoidosis had been diagnosed within 6 months of study enrollment. Patients met the following criteria prior to enrollment: (1) tissue confirmation of noncaseating granulomas on tissue biopsy on one or more organs within 6 months of study enrollment with negative stains for acid-fast bacilli and fungus; (2) clinical signs or symptoms that were consistent with sarcoidosis; (3) no other obvious explanation for the granulomatous disease; and (4) age > 18 years. MEASUREMENTS AND RESULTS: Several exposures were associated with significantly less likelihood of having extrapulmonary disease in multivariate analysis, including agricultural organic dusts and wood burning. The effects of many of these exposures were significantly different in patients of different self-defined race. CONCLUSIONS: The differentiation of sarcoidosis subjects on the basis of clinical phenotypes suggests that these subgroups may have unique environmental exposure associations. Self-defined race may play a role in the determination of the effect of certain exposures on disease phenotypes. [ABSTRACT FROM AUTHOR]

Rationale: Primary graft dysfunction is a severe acute lung injury syndrome after lung transplantation. Long-term outcomes of subjects with primary graft dysfunction have not been studied.Objectives: We sought to test the relationship of primary graft dysfunction with both short- and long-term mortality using a large registry.Methods: We used data collected on 5,262 patients in the United Network for Organ Sharing/International Society of Heart and Lung Transplantation registry between 1994 and 2000. We assessed outcomes in all subjects; to assess potential bias from the effects of early mortality, we also evaluated subjects who survived at least 1 year, using Cox proportional hazards models with time-varying covariates.Main Results: The overall incidence of primary graft dysfunction was 10.2% (95% confidence intervals [CI], 9.2, 10.9). The incidence did not vary by year over the period of observation (p = 0.22). All-cause mortality at 30 days was 42.1% for primary graft dysfunction versus 6.1% in patients without graft dysfunction (relative risk = 6.95; 95% CI, 5.98, 8.08; p < 0.001); among subjects who died by 30 days, 43.6% had primary graft dysfunction. Among patients surviving at least 1 year, those who had primary graft dysfunction had significantly worse survival over ensuing years (hazard ratio, 1.35; 95% CI, 1.07, 1.70; p = 0.011). Adjustment for clinical variables including bronchiolitis obliterans syndrome did not change this relationship.Conclusion: Primary graft dysfunction contributes to nearly half of the short-term mortality after lung transplantation. Survivors of primary graft dysfunction have increased risk of death extending beyond the first post-transplant year. [ABSTRACT FROM AUTHOR]

Background: Patients at the Philadelphia Veterans Affairs Medical Center frequently voice concern that air exposure during lung cancer surgery might cause tumor spread. Several African-American patients asserted that this belief was common in the African-American community.Objective: To assess the prevalence of the belief that air exposure during lung cancer surgery might cause tumor spread and gauge the influence of this belief on the willingness of African-American and white patients to have lung cancer surgery.Design: Prospective questionnaire survey.Setting: Philadelphia Veterans Affairs Medical Center and University of Pennsylvania, Philadelphia, Pennsylvania; Los Angeles Veterans Affairs Medical Center, Los Angeles, California; and Medical University of South Carolina, Charleston, South Carolina.Patients: 626 consecutive patients in pulmonary and lung cancer clinics.Measurements: None.Results: 38% of patients (61% of whom were African American and 29% of whom were white) stated that they believe air exposure at surgery causes tumor spread. The most significant predictor of belief was African-American race (odds ratio, 3.5 [95% CI, 1.9 to 6.5]), even after controlling for other relevant variables in a multivariable analysis. Nineteen percent of African Americans stated that this belief was a reason for opposing surgery, and 14% would not accept their physicians' assertion that the belief is false. These rates were also statistically significantly higher among African-American than white patients.Conclusions: Belief in accelerated tumor spread at surgery is prevalent among general pulmonary outpatients and lung cancer clinic patients facing lung surgery, particularly among African-American patients. Our findings may pertain to key racial disparities in lung cancer surgery and survival rates and suggest that culturally sensitive physician training or outreach programs directed at disparate beliefs and attitudes may help to address racial discrepancies in health care outcomes. [ABSTRACT FROM AUTHOR]

Background: Allergic sensitization to mold is a risk factor for poor asthma outcomes, but whether it accounts for disparities in asthma outcomes according to race or socioeconomic status is not well-studied., Objective: To identify factors associated with allergic sensitization to molds and evaluate associations of sensitization to molds with asthma exacerbations after stratifying by race., Methods: We conducted a retrospective cohort study of adults with asthma who had an outpatient visit to a large health system between January 1, 2017 and June 30, 2023 and received aeroallergen testing to Aspergillus fumigatus, Penicillium, Alternaria, and Cladosporium. We used logistic regression models to evaluate factors associated with mold sensitization and the effect of mold sensitization on asthma exacerbations in the 12 months before testing, overall and then stratified by race., Results: A total of 2732 patients met the inclusion criteria. Sensitization to each mold was negatively associated with being a woman (odds ratios [ORs] ≤ 0.59, P ≤ .001 in 5 models) and positively associated with the Black race (ORs ≥ 2.16 vs White, P < .0005 in 5 models). In the full cohort, sensitization to molds was not associated with asthma exacerbations (ORs = 0.95-1.40, P ≥ .003 in 5 models and all above the corrected P value threshold). Among 1032 Black patients, sensitization to A fumigatus, but not to other molds, was associated with increased odds of asthma exacerbations (OR = 2.04, P < .0005)., Conclusion: Being a man and Black race were associated with allergic sensitization to molds. Sensitization to A fumigatus was associated with asthma exacerbations among Black patients but not the overall cohort, suggesting that A fumigatus allergy is a source of disparities in asthma outcomes according to race., Competing Interests: Disclosures Dr Morales owns stock in Altria Group, Inc, British American Tobacco PLC, and Phillip Morris International, Inc. The remaining authors have no conflicts of interest to report., (Copyright © 2024 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Multiple listing (ML) is a practice used to increase the potential for transplant but is controversial due to concerns that it disproportionately benefits patients with greater access to health care resources., Research Question: Is there disparity in ML practices based on social deprivation in the United States and does ML lead to quicker time to transplant?, Study Design and Methods: A retrospective cohort study of adult (≥ 18 years of age) lung transplant candidates listed for transplant (2005-2018) was conducted. Exclusion criteria included heart only or heart and lung transplant and patients relisted during the observation period. Data were obtained from the United Network for Organ Sharing Standard Transplant Analysis and Research File. The first exposure of interest was the Social Deprivation Index with a primary outcome of ML status, to assess disparities between ML and single listing (SL) participants. The second exposure of interest was ML status with a primary outcome of time to transplant, to assess whether implementation of ML leads to quicker time to transplant., Results: A total of 35,890 patients were included in the final analysis, of whom 791 (2.2%) were ML and 35,099 (97.8%) were SL. ML participants had lower median level of social deprivation (5 units, more often female: 60.0% vs 42.3%) and lower median lung allocation score (35.3 vs 37.3). ML patients were more likely to be transplanted than SL patients (OR, 1.42; 95% CI, 1.17-1.73), but there was a significantly quicker time to transplant only for those whom ML was early (within 6 months of initial listing) (subdistribution hazard ratio, 1.17; 95% CI, 1.04-1.32)., Interpretation: ML is an uncommon practice with disparities existing between ML and SL patients based on several factors including social deprivation. ML patients are more likely to be transplanted, but only if they have ML status early in their transplant candidacy. With changing allocation guidelines, it is yet to be seen how ML will change with the implementation of continuous distribution., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Primary graft dysfunction (PGD) contributes substantially to both short- and long-term mortality after lung transplantation, but the mechanisms that lead to PGD are not well understood. Exposure to ambient air pollutants is associated with adverse events during waitlisting for lung transplantation and chronic lung allograft dysfunction, but its association with PGD has not been studied. We hypothesized that long-term exposure of the lung donor and recipient to high levels of ambient air pollutants would increase the risk of PGD in lung transplant recipients., Methods: Using data from 1428 lung transplant recipients and their donors enrolled in the Lung Transplant Outcomes Group observational cohort study, we evaluated the association between the development of PGD and zip-code-based estimates of long-term exposure to 6 major air pollutants (ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide, particulate matter 2.5, and particulate matter 10) in both the lung donor and the lung recipient. Exposure estimates used daily EPA air pollutant monitoring data and were based on the geographic centroid of each subject's residential zip code. Associations were tested in both univariable and multivariable models controlling for known PGD risk factors., Results: We did not find strong associations between air pollutant exposures in either the donor or the recipient and PGD., Conclusions: Exposure to ambient air pollutants, at the levels observed in this study, may not be sufficiently harmful to prime the donor lung or the recipient to develop PGD, particularly when considering the robust associations with other established PGD risk factors., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Centralizing deceased organ donor management and organ recovery into donor care units (DCUs) may mitigate the critical organ shortage by positively impacting donation and recipient outcomes., Objective: To compare donation and lung transplant outcomes between 2 common DCU models: independent (outside of acute-care hospitals) and hospital-based., Design, Setting, and Participants: This is a retrospective cohort study of Organ Procurement and Transplantation Network deceased donor registry and lung transplant recipient files from 21 US donor service areas with an operating DCU. Characteristics and lung donation rates among deceased donors cared for in independent vs hospital-based DCUs were compared. Eligible participants included deceased organ donors (aged 16 years and older) after brain death, who underwent organ recovery procedures between April 26, 2017, and June 30, 2022, and patients who received lung transplants from those donors. Data analysis was conducted from May 2023 to March 2024., Exposure: Organ recovery in an independent DCU (vs hospital-based DCU)., Main Outcome and Measures: The primary outcome was duration of transplanted lung survival (through December 31, 2023) among recipients of lung(s) transplanted from cohort donors. A Cox proportional hazards model stratified by transplant year and program, adjusting for donor and recipient characteristics was used to compare graft survival., Results: Of 10 856 donors in the starting sample (mean [SD] age, 42.8 [15.2] years; 6625 male [61.0%] and 4231 female [39.0%]), 5149 (primary comparison group) underwent recovery procedures in DCUs including 1466 (28.4%) in 11 hospital-based DCUs and 3683 (71.5%) in 10 independent DCUs. Unadjusted lung donation rates were higher in DCUs than local hospitals, but lower in hospital-based vs independent DCUs (418 donors [28.5%] vs 1233 donors [33.5%]; P < .001). Among 1657 transplant recipients, 1250 (74.5%) received lung(s) from independent DCUs. Median (range) duration of follow-up after transplant was 734 (0-2292) days. Grafts recovered from independent DCUs had shorter restricted mean (SE) survival times than grafts from hospital-based DCUs (1548 [27] days vs 1665 [50] days; P = .04). After adjustment, graft failure remained higher among lungs recovered from independent DCUs than hospital-based DCUs (hazard ratio, 1.85; 95% CI, 1.28-2.65)., Conclusions and Relevance: In this retrospective analysis of national donor and transplant recipient data, although lung donation rates were higher from deceased organ donors after brain death cared for in independent DCUs, lungs recovered from donors in hospital-based DCUs survived longer. These findings suggest that further work is necessary to understand which factors (eg, donor transfer, management, or lung evaluation and acceptance practices) differ between DCU models and may contribute to these differences.

Some United States organ procurement organizations transfer deceased organ donors to donor care units (DCUs) for recovery procedures. We used Organ Procurement and Transplantation Network data, from April 2017 to June 2021, to describe the proximity of adult deceased donors after brain death to DCUs and understand the impact of donor service area (DSA) boundaries on transfer efficiency. Among 19 109 donors (56.1% of the cohort) in 25 DSAs with DCUs, a majority (14 593 [76.4%]) were in hospitals within a 2-hour drive. In areas with DCUs detectable in the study data set, a minority of donors (3582 of 11 532 [31.1%]) were transferred to a DCU; transfer rates varied between DSAs (median, 27.7%, range, 4.0%-96.5%). Median hospital-to-DCU driving times were not meaningfully shorter among transferred donors (50 vs 51 minutes for not transferred, P < .001). When DSA boundaries were ignored, 3241 cohort donors (9.5%) without current DCU access were managed in hospitals within 2 hours of a DCU and thus potentially eligible for transfer. In summary, approximately half of United States deceased donors after brain death are managed in hospitals in DSAs with a DCU. Transfer of donors between DSAs may increase DCU utilization and improve system efficiency., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose, as described by the American Journal of Transplantation. Emily Vail, Vicky Tam, and Vishnu Potluri acknowledge investigator-initiated grant support to their institutions from the Transplant Foundation, which supported the current work. Emily Vail acknowledges sponsor-initiated support to her institution from eGenesis, which is unrelated to the current work. She also serves on the Editorial Board of the British Journal of Anaesthesia Open. Niels Martin is Medical Director of the Gift of Life Donor Program at Penn Medicine donor care unit (Philadelphia, PA), which operates under contract from the Gift of Life Donor Program organ procurement organization. Peter Abt is an Associate Editor of the American Journal of Transplantation. Peter Reese acknowledges investigator-initiated grant support to his institution from Merck, Gilead, and eGenesis, all unrelated to the current work. He is also an Associate Editor of the American Journal of Kidney Diseases., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Inflammation induced by lung infection is a double-edged sword, moderating both anti-viral and immune pathogenesis effects; the mechanism of the latter is not fully understood. Previous studies suggest the vasculature is involved in tissue injury. Here, we report that expression of Sparcl1, a secreted matricellular protein, is upregulated in pulmonary capillary endothelial cells (EC) during influenza-induced lung injury. Endothelial overexpression of SPARCL1 promotes detrimental lung inflammation, with SPARCL1 inducing 'M1-like' macrophages and related pro-inflammatory cytokines, while SPARCL1 deletion alleviates these effects. Mechanistically, SPARCL1 functions through TLR4 on macrophages in vitro, while TLR4 inhibition in vivo ameliorates excessive inflammation caused by endothelial Sparcl1 overexpression. Finally, SPARCL1 expression is increased in lung ECs from COVID-19 patients when compared with healthy donors, while fatal COVID-19 correlates with higher circulating SPARCL1 protein levels in the plasma. Our results thus implicate SPARCL1 as a potential prognosis biomarker for deadly COVID-19 pneumonia and as a therapeutic target for taming hyperinflammation in pneumonia., (© 2024. The Author(s).)

BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS).METHODSIn a single-center prospective cohort of intubated pediatric patients with ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage-associated molecular patterns (DAMPs) were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models.RESULTSIn 279 patients (64 [23%] nonsurvivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in nonsurvivors. Survivors and nonsurvivors showed different biomarker trajectories. IL-1α, soluble tumor necrosis factor receptor 1, angiopoietin 2 (ANG2), and surfactant protein D increased in nonsurvivors, while DAMPs remained persistently elevated. ANG2 and procollagen type III N-terminal peptide were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality.CONCLUSIONSPediatric ARDS survivors and nonsurvivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in nonsurvivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS.FUNDINGNIH (K23HL-136688, R01-HL148054).

Background: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Accurate prediction of PGD risk could inform donor approaches and perioperative care planning. We sought to develop a clinically useful, generalizable PGD prediction model to aid in transplant decision-making., Methods: We derived a predictive model in a prospective cohort study of subjects from 2012 to 2018, followed by a single-center external validation. We used regularized (lasso) logistic regression to evaluate the predictive ability of clinically available PGD predictors and developed a user interface for clinical application. Using decision curve analysis, we quantified the net benefit of the model across a range of PGD risk thresholds and assessed model calibration and discrimination., Results: The PGD predictive model included distance from donor hospital to recipient transplant center, recipient age, predicted total lung capacity, lung allocation score (LAS), body mass index, pulmonary artery mean pressure, sex, and indication for transplant; donor age, sex, mechanism of death, and donor smoking status; and interaction terms for LAS and donor distance. The interface allows for real-time assessment of PGD risk for any donor/recipient combination. The model offers decision-making net benefit in the PGD risk range of 10% to 75% in the derivation centers and 2% to 10% in the validation cohort, a range incorporating the incidence in that cohort., Conclusion: We developed a clinically useful PGD predictive algorithm across a range of PGD risk thresholds to support transplant decision-making, posttransplant care, and enrich samples for PGD treatment trials., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Obesity at the time of lung transplant is associated with decreased survival. How providers manage obesity after lung transplantation is unknown. We performed an international survey of lung transplant providers to assess beliefs and practices regarding post-transplant obesity management. Eighty-one providers initiated the survey and 73 (90%) completed the full survey. Respondents were primarily North American-based pulmonary physicians. Nearly all providers believe treating obesity improves quality of life (99%) and survival (95%) after lung transplantation, but that only 41% of patients attempting weight loss are successful. While respondents nearly always recommend diet (96%), exercise (92%), and dietician consultation (89%), they less frequently recommend prescription weight loss medications (29%) or bariatric surgery (11%). Lung transplant providers are motivated to treat obesity in transplant recipients. However, there is a gap between general obesity treatment guidelines and lung transplant practice. Additional training, education, and trials in this population could address this gap.

Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation. Prior studies implicated proxy-defined donor smoking as a risk factor for PGD and mortality. Objectives: We aimed to more accurately assess the impact of donor smoke exposure on PGD and mortality using quantitative smoke exposure biomarkers. Methods: We performed a multicenter prospective cohort study of lung transplant recipients enrolled in the Lung Transplant Outcomes Group cohort between 2012 and 2018. PGD was defined as grade 3 at 48 or 72 hours after lung reperfusion. Donor smoking was defined using accepted thresholds of urinary biomarkers of nicotine exposure (cotinine) and tobacco-specific nitrosamine (4-[methylnitrosamino]-1-[3-pyridyl]-1-butanol [NNAL]) in addition to clinical history. The donor smoking-PGD association was assessed using logistic regression, and survival analysis was performed using inverse probability of exposure weighting according to smoking category. Measurements and Main Results: Active donor smoking prevalence varied by definition, with 34-43% based on urinary cotinine, 28% by urinary NNAL, and 37% by clinical documentation. The standardized risk of PGD associated with active donor smoking was higher across all definitions, with an absolute risk increase of 11.5% (95% confidence interval [CI], 3.8% to 19.2%) by urinary cotinine, 5.7% (95% CI, -3.4% to 14.9%) by urinary NNAL, and 6.5% (95% CI, -2.8% to 15.8%) defined clinically. Donor smoking was not associated with differential post-lung transplant survival using any definition. Conclusions: Donor smoking associates with a modest increase in PGD risk but not with increased recipient mortality. Use of lungs from smokers is likely safe and may increase lung donor availability. Clinical trial registered with www.clinicaltrials.gov (NCT00552357).

Background: Whether functional status is associated with survival to pediatric lung transplant is unknown. We hypothesized that completely dependent functional status at waitlist registration, defined using Lansky Play Performance Scale (LPPS), would be associated with worse outcomes., Methods: Retrospective cohort study of pediatric lung transplant registrants utilizing United Network for Organ Sharing's Standard Transplant Analysis and Research files (2005-2020). Primary exposure was completely dependent functional status, defined as LPPS score of 10-40. Primary outcome was waitlist removal for death/deterioration with cause-specific hazard ratio (CSHR) regression. Subdistribution hazard regression (SHR, Fine and Gray) was used for the secondary outcome of waitlist removal due to transplant/improvement with a competing risk of death/deterioration. Confounders included: sex, age, race, diagnosis, ventilator dependence, extracorporeal membrane oxygenation, year, and listing center volume., Results: A total of 964 patients were included (63.5% ≥ 12 years, 50.2% cystic fibrosis [CF]). Median waitlist days were 95; 20.1% were removed for death/deterioration and 68.2% for transplant/improvement. Completely dependent functional status was associated with removal due to death/deterioration (adjusted CSHR 5.30 [95% CI 2.86-9.80]). This association was modified by age (interaction p = 0.0102), with a larger effect for age ≥12 years, and particularly strong for CF. In the Fine and Gray model, completely dependent functional status did not affect the risk of removal due to transplant/improvement with a competing risk of death/deterioration (adjusted SHR 1.08 [95% CI 0.77-1.49])., Conclusions: Pediatric lung transplant registrants with the worst functional status had worse pretransplant outcomes, especially for adolescents and CF patients. Functional status at waitlist registration may be a modifiable risk factor to improve survival to lung transplant., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)