Lung Transplantation from hepatitis C+ donor lungs: Reassuring midterm outcomes.

BACKGROUND: The development of modern antiviral therapy for hepatitis C virus (HCV) has allowed for the transplantation of HCV nucleic acid amplification testing-positive (NAT+) donor lungs with acceptable short-term outcomes. We sought to evaluate trends and midterm outcomes of lung transplant recipients of HCV NAT+ donor allografts. METHODS: All adults undergoing isolated lung transplantation in the United Network for Organ Sharing database from January 2016 to December 2022 were included in the study. Lung transplant recipients were stratified based on donor HCV status (HCV NAT+ vs NAT-). Propensity score matching was used to adjust for differences between groups. Several outcomes, including acute rejection by 1 year, early (30-day and in-hospital) mortality, and both 1- and 3-year survival, were compared between matched groups. RESULTS: A total of 16,725 patients underwent lung transplantation during the study period, with 489 (3%) receiving HCV NAT+ donor lungs. Regions 1 (18%) and 6/8 (both 0%) had the highest and lowest proportions, respectively, of HCV NAT+ donor transplants. Utilization of HCV NAT+ donors increased throughout the study period from 2 (0.1%) in 2016 to a peak of 117 (5%) in 2019. Donors who were HCV NAT+ were younger (34 vs 36 years, p < 0.001), more often female (44% vs 39%, p < 0.01), and more commonly died due to drug intoxication (56% vs 15%, p < 0.001). Recipients of HCV NAT+ donor lungs were similar in age (62 vs 62 years, p = 0.69) and female gender (43% vs 39%, p = 0.15) but had lower lung allocation scores (38 vs 41, p < 0.001) compared to others. Rates of acute rejection (13% vs 17%, p = 0.09), early mortality (30-day: 2% vs 1%, p = 0.59, in-hospital: 3% vs 4%, p = 0.38), as well as 1-year (90% vs 92%, p = 0.29) and 3-year survival (69% vs 75%, p = 0.13) were not significantly different between matched groups. CONCLUSIONS: Lung transplant recipients of HCV NAT+ donor allografts experience similar rates of acute rejection, early mortality, and 3-year survival compared to all other lung recipients. Increased use of HCV NAT+ donor allografts may help to expand the donor pool and alleviate donor shortages.

Implementation of a prospective screening strategy to identify adults with a telomere biology disorder among those undergoing lung transplant evaluation for interstitial lung disease.

INTRODUCTION: Patients with interstitial lung disease (ILD) secondary to telomere biology disorders (TBD) experience increased morbidity after lung transplantation. Identifying patients with TBD may allow for personalized management to facilitate better outcomes. However, establishing a TBD diagnosis in adults is challenging. METHODS: A TBD screening questionnaire was introduced prospectively into the lung transplant evaluation. Patients with ILD screening positive were referred for comprehensive TBD phenotyping and concurrent telomere length measurement and germline genetic testing. RESULTS: Of 98 patients, 32 (33%) screened positive. Eight patients (8% of total; 25% of patients with a positive screen) met strict TBD diagnostic criteria, requiring either critically short lymphocyte telomeres (<1st percentile) (n = 4), a pathogenic variant in a TBD-associated gene (n = 1), or both (n = 3) along with a TBD clinical phenotype. Additional patients not meeting strict diagnostic criteria had histories consistent with TBD along with telomere lengths <10th percentile and/or rare variants in TBD-associated genes, highlighting a critical need to refine TBD diagnostic criteria for this patient population. CONCLUSION: A TBD phenotype screening questionnaire in patients with ILD undergoing lung transplant evaluation has a diagnostic yield of 25%. Additional gene discovery, rare variant functional testing, and refined TBD diagnostic criteria are needed to realize the maximum benefit of testing for TBD in patients undergoing lung transplantation.

Evaluating the evolutionary mechanisms maintaining alternative mating strategies in a simulated bull trout (Salvelinus confluentus) population.

The coexistence of distinct alternative mating strategies (AMS) is often explained by mechanisms involving trade-offs between reproductive traits and lifetime fitness; yet their relative importance remains poorly understood. Here, we used an established individual-based, spatially explicit model to simulate bull trout (Salvelinus confluentus) in the Skagit River (Washington, USA) and investigated the influence of female mating preference, sneaker-specific mortality, and variation in age-at-maturity on AMS persistence using global sensitivity analyses and boosted regression trees. We assumed that two genetically fixed AMS coexisted within the population: sneaker males (characterized by younger age-at-maturity, greater AMS-specific mortality, and lower reproductive fitness) and territorial males. After 300 years, variation in relative sneaker success in the system was explained by sneaker males' reproductive fitness (72%) and, to a lesser extent, the length of their reproductive lifespan (21%) and their proportion in the initial population (8%). However, under a wide range of parameter values, our simulated scenarios predicted the extinction of territorial males or their persistence in small, declining populations. Although these results do not resolve the coexistence of AMS in salmonids, they reinforce the importance of mechanisms reducing sneaker's lifetime reproductive success in favoring AMS coexistence within salmonid populations but also limit the prediction that, without any other selective mechanisms at play, strong female preference for mating with territorial males and differences in reproductive lifespan allow the stable coexistence of distinct AMS.

Risks of mining to salmonid-bearing watersheds.

Mining provides resources for people but can pose risks to ecosystems that support cultural keystone species. Our synthesis reviews relevant aspects of mining operations, describes the ecology of salmonid-bearing watersheds in northwestern North America, and compiles the impacts of metal and coal extraction on salmonids and their habitat. We conservatively estimate that this region encompasses nearly 4000 past producing mines, with present-day operations ranging from small placer sites to massive open-pit projects that annually mine more than 118 million metric tons of earth. Despite impact assessments that are intended to evaluate risk and inform mitigation, mines continue to harm salmonid-bearing watersheds via pathways such as toxic contaminants, stream channel burial, and flow regime alteration. To better maintain watershed processes that benefit salmonids, we highlight key windows during the mining governance life cycle for science to guide policy by more accurately accounting for stressor complexity, cumulative effects, and future environmental change.

Internal and External Validation of an Alcohol Biomarker for Screening in Trauma.

OBJECTIVE: We aimed to examine biomarkers for screening unhealthy alcohol use in the trauma setting. SUMMARY AND BACKGROUND DATA: Self-report tools are the practice standard for screening unhealthy alcohol use; however, their collection suffers from recall bias and incomplete collection by staff. METHODS: We performed a multi-center prospective clinical study of 251 adult patients who arrived within 24 hours of injury with external validation in another 60 patients. The Alcohol Use Disorders Identification Test served as the reference standard. The following biomarkers were measured: (1) PEth; (2) ethyl glucuronide; (3) ethyl sulfate; (4) gamma-glutamyl-transpeptidase; (5) carbohydrate deficient transferrin; and (6) blood alcohol concentration (BAC). Candidate single biomarkers and multivariable models were compared by considering discrimination (AUROC). The optimal cutpoint for the final model was identified using a criterion for setting the minimum value for specificity at 80% and maximizing sensitivity. Decision curve analysis was applied to compare to existing screening with BAC. RESULTS: PEth alone had an AUROC of 0.93 [95% confidence interval (CI): 0.92-0.93] in internal validation with an optimal cutpoint of 25 ng/mL. A 4- variable biomarker model and the addition of any single biomarker to PEth did not improve AUROC over PEth alone ( P > 0.05). Decision curve analysis showed better performance of PEth over BAC across most predicted probability thresholds. In external validation, sensitivity and specificity were 76.0% (95% CI: 53.0%-92.0%) and 73.0% (95% CI: 56.0%-86.0%), respectively.Conclusion and Relevance: PEth alone proved to be the single best biomarker for screening of unhealthy alcohol use and performed better than existing screening systems with BAC. PEth may overcome existing screening barriers.

A Case Report of Cystic Fibrosis Plus Tuberous Sclerosis: A Cautionary Tale Regarding Lung Transplantation.

BACKGROUND: Cystic fibrosis (CF) and tuberous sclerosis complex (TSC) are 2 rare genetic diseases that often affect the lungs. Pulmonary compromise in TSC or CF can be severe enough to require lung transplantation. In rare instances patients with CF undergo pneumonectomy to control recurrent lung infections and lung necrosis affecting one lung more than the other. Lung transplantation in these patients is exceedingly rare because preexistent pneumonectomy increases the risk of lung transplant-associated morbidity and mortality. CASE PRESENTATION: We present the case of a young woman with co-occurrence of TSC and CF, who underwent left-sided pneumonectomy and, approximately 2 years later, right-sided single lung transplant. The posttransplant clinical course was complicated by phrenic nerve injury, ventilator dependency, Aspergillus endocarditis with embolic shower, and death. Pretransplant pneumonectomy, Aspergillus colonization, and posttransplant phrenic nerve injury contributed to the complex postoperative course, ventilatory dependence, and poor outcome. CONCLUSION: This cautionary case should alert physicians on the challenges associated with single lung transplant in patients with preexistent pneumonectomy.

Cystic fibrosis foundation consensus statements for the care of cystic fibrosis lung transplant recipients.

Cystic fibrosis (CF) is the indication for transplantation in approximately 15% of recipients worldwide, and Cystic Fibrosis Lung Transplant Recipients (CFLTRs) have excellent long-term outcomes. Yet, CFLTRs have unique comorbidities that require specialized care. The objective of this document is to provide recommendations to CF and lung transplant clinicians for the management of perioperative and underlying comorbidities of CFLTRs and the impact of transplantation on these comorbidities. The Cystic Fibrosis Foundation (CFF) organized a multidisciplinary committee to develop CF Lung Transplant Clinical Care Recommendations. Three workgroups were formed to develop focused questions. Following a literature search, consensus recommendations were developed by the committee members based on literature review, committee experience and iterative revisions, and in response to public comment. The committee formulated 32 recommendation statements in the topics related to infectious disease, endocrine, gastroenterology, pharmacology, mental health and family planning. Broadly, the committee recommends close coordination of care between the lung transplant team, the cystic fibrosis care center, and specialists in other disciplines with experience in the care of CF and lung transplant recipients. These consensus statements will help lung transplant providers care for CFLTRs in order to improve post-transplant outcomes in this population.

Self-reported alcohol use in the cystic fibrosis community.

INTRODUCTION: Excessive alcohol use (EAU), a harmful pattern of drinking that includes binge drinking and heavy use, occurs in 25% (binge) and 6% (heavy use) of the US population, respectively. Little is known about alcohol use in individuals with cystic fibrosis (CF). The objective of this investigation is to examine alcohol consumption patterns in individuals with CF using a health survey administered from a social media platform. METHODS: Individuals with CF, 18 years of age or older, were recruited for participation through social media and internet-based platforms. RESULTS: 1135 individuals initially participated in the survey and 84% (n = 952) were eligible and completed the survey. Of the respondents, 77% (n = 729) currently consume alcohol, 18% (n = 171) formerly consumed alcohol, and 5% (n = 52) never consumed alcohol. Amongst the people with CF who currently consume alcohol, 54% (N = 391) met criteria for EAU. Thirty percent of current drinkers experienced symptoms of harmful alcohol use. Of those who met criteria for EAU, 7% wore oxygen, 6% had a lung transplant, 10% had liver disease and 32% had diabetes. Those with EAU reported more hospitalizations than those without EAU [244 (62%) vs 182 (54%), p = .034]. Characteristics associated with EAU after multivariable adjustment included younger age, unmarried status, male gender and younger age at initiation of drinking. CONCLUSION: EAU is occurring at a much higher proportion in individuals with CF. A substantial percentage of CF individuals with EAU also have medical co-morbidities. Screening, brief intervention, and referral to treatment for EAU in CF clinics is warranted.

Association between diverticular disease requiring surgical intervention and mortality in the postlung transplant population - a retrospective cohort study.

Lung Transplant recipients are at increased risk of complicated diverticular disease. We aim to assess the rate of diverticular surgery in a postlung transplantation population and identify risk factors for surgery. We performed a retrospective cohort study of lung transplant recipients from 2007 to 2011. Demographic variables were evaluated with the Mann-Whitney U and chi-squared tests. Cox regression was performed to evaluate 1- and 2-year landmark survival, assess predictor variables of diverticular surgery and evaluate impact of surgery on CLAD development. Of 17 of 158 patients (10.7%) underwent diverticular-related surgery. Surgical patients had significantly worse survival than nonsurgical patients at 1 year [aHR 2.93 (1.05-8.21), P = 0.041] and 2 year [aHR 4.17 (1.26-13.84), P = 0.020] landmark analyses. Transplant indication of alpha-1 antitrypsin disease and cystic fibrosis were significantly associated with the need for diverticular surgery. Emergent surgery was associated with poorer survival [aHR 5.12(1.00-26.27), P = 0.050]. Lung transplant patients requiring surgery for complicated diverticular disease have significantly poorer survival than those who do not require surgery. Surgery was more common in patients transplanted for A1AT and CF. Optimal assessment and risk stratification of diverticular disease is necessary to prevent excessive morbidity and mortality following transplantation.

Use of alcohol biomarkers to identify alcohol misuse in organ donors.

Phosphatidylethanol is a direct alcohol biomarker for identifying alcohol misuse. It carries several advantages over other alcohol biomarkers, including a detection half-life of several weeks and little confounding by patient characteristics or organ dysfunction. The aim of this study is to derive an optimal phosphatidylethanol cut point to identify organ donors with alcohol misuse, and to assess the impact of alcohol misuse on organ allocation. Discrimination of phosphatidylethanol was evaluated using the area under the ROC curve from a mixed effects logistic regression model. Phosphatidylethanol had an area under the ROC curve of 0.89 (95% CI 0.80-0.98). A phosphatidylethanol cut point of ≥84 ng/mL provided optimal discrimination for the identification of alcohol misuse with a sensitivity of 75% (95% CI 52.9%-89.4%) and a specificity of 97% (95% CI 91%-99%), a positive predictive value of 82% (95% CI 59%-94%), and a negative predictive value of 95% (95% CI 89%-98%). In deceased organ donors who had been critically ill, phosphatidylethanol had good test characteristics to discriminate alcohol misuse. Other alcohol biomarkers performed poorly in deceased organ donors. Liver allocation was decreased in donors with alcohol misuse by proxy history, but not in those with phosphatidylethanol >84 ng/mL, revealing possible information bias in liver allocation.

Recent alcohol use prolongs hospital length of stay following lung transplant.

Little is known about the alcohol habits of people with advanced lung disease. Following lung transplantation, patients are asked to abstain from or minimize alcohol use. The aim of this investigation was to assess alcohol use in a cohort of patients with advanced lung disease undergoing evaluation for lung transplant. This is a prospective observational investigation comparing patient self-report of alcohol use with their responses on the Alcohol Use Disorders Identification Test (AUDIT), and alcohol biomarkers collected at the time of transplant. There were 86 included in the cohort, 34% currently using alcohol, 13% had AUDIT scores >3, and 10% had positive results for alcohol biomarkers at the time of transplantation. Patients with evidence of recent alcohol use prior to lung transplant surgery had a 1.5-fold increase in hospital length of stay following lung transplant (P = .028), spent 3 times as long on mechanical ventilation after transplant, and required intensive care unit monitoring nearly 3 times longer than those without recent alcohol use (P = .008). There were no differences in primary graft dysfunction, although several patients with recent alcohol use had post-transplant atrial arrhythmias, acute kidney injury, and acute cellular rejection. Abstaining from alcohol use may optimize outcomes following lung transplant.

Cut-Point Levels of Phosphatidylethanol to Identify Alcohol Misuse in a Mixed Cohort Including Critically Ill Patients.

BACKGROUND: Although alcohol misuse is associated with deleterious outcomes in critically ill patients, its detection by either self-report or examination of biomarkers is difficult to obtain consistently. Phosphatidylethanol (PEth) is a direct alcohol biomarker that can characterize alcohol consumption patterns; however, its diagnostic accuracy in identifying misuse in critically ill patients is unknown. METHODS: PEth values were obtained in a mixed cohort comprising 122 individuals from medical and burn intensive care units (n = 33), alcohol detoxification unit (n = 51), and healthy volunteers (n = 38). Any alcohol misuse and severe misuse were referenced by Alcohol Use Disorders Identification Test (AUDIT) and AUDIT-C scores separately. Mixed-effects logistic regression analysis was performed, and the discrimination of PEth was evaluated using the area under the receiver-operating characteristic (ROC) curve. RESULTS: The area under the ROC curve for PEth was 0.927 (95% CI: 0.877, 0.977) for any misuse and 0.906 (95% CI: 0.850, 0.962) for severe misuse defined by AUDIT. By AUDIT-C, the area under the ROC curves was 0.948 (95% CI: 0.910, 0.956) for any misuse and 0.913 (95% CI: 0.856, 0.971) for severe misuse. The PEth cut-points of ≥250 and ≥400 ng/ml provided optimal discrimination for any misuse and severe misuse, respectively. The positive predictive value for ≥250 ng/ml was 88.7% (95% CI: 77.5, 95.0), and the negative predictive value was 86.7% (95% CI: 74.9, 93.7). PEth ≥ 400 ng/ml achieved similar values, and similar results were shown for AUDIT-C. In a subgroup analysis of critically ill patients only, test characteristics were similar to the mixed cohort. CONCLUSIONS: PEth is a strong predictor and has good discrimination for any and severe alcohol misuse in a mixed cohort that includes critically ill patients. Cut-points at 250 ng/ml for any, and 400 ng/ml for severe, are favorable. External validation will be required to establish these cut-points in critically ill patients.

Increased risk of PTLD in lung transplant recipients with cystic fibrosis.

BACKGROUND: Post-transplant lymphoproliferative disease (PTLD) is an important cause of morbidity and mortality following lung transplantation. Recipients with cystic fibrosis (CF) may have an increased risk of PTLD although the literature is limited to single center cohorts. Our primary aim is to examine PTLD in an adult lung transplant population by utilizing the International Society for Heart and Lung Transplantation Registry. METHODS: We studied 30,598 adult recipients of lung transplants performed between 1999 and 2011. The primary outcome was development of and time to PTLD. In addition to indication for transplant, other predictors examined included Epstein-Barr virus (EBV) and cytomegalovirus (CMV) serostatus, gender, and age. Outcomes were assessed with univariable and multivariable Cox proportional hazard models to obtain hazard ratios (HR). RESULTS: 17% of the cohort had a diagnosis of CF. PTLD developed in 2% of CF recipients compared to 1% for non-CF recipients (p<0.001). Compared to non-CF recipients, CF recipients had higher prevalence of EBV and CMV seronegativity and higher prevalences of high risk EBV and CMV mismatch (D+/R-). There is a significant association between CF and the development of PTLD [HR 1.66 (95% CI 1.30-2.12)]. Stratified multivariable analysis controlling for age revealed EBV negative non-CF recipients have an almost 2 fold increased risk of developing PTLD, whereas EBV negative CF recipients had an almost 6.5 fold increased risk. CONCLUSIONS: CF recipients have a higher risk for PTLD compared to non-CF recipients. Further studies are needed to account for additional risk factors and management in this population post-transplant.

Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans.

Hyperammonemia syndrome is a fatal complication affecting immunosuppressed patients. Frequently refractory to treatment, it is characterized by progressive elevations in serum ammonia of unknown etiology, ultimately leading to cerebral edema and death. In mammals, ammonia produced during amino acid metabolism is primarily cleared through the hepatic production of urea, which is eliminated in the kidney. Ureaplasma species, commensals of the urogenital tract, are Mollicutes dependent on urea hydrolysis to ammonia and carbon dioxide for energy production. We hypothesized that systemic infection with Ureaplasma species might pose a unique challenge to human ammonia metabolism by liberating free ammonia resulting in the hyperammonemia syndrome. We used polymerase chain reaction, specialized culture, and molecular resistance profiling to identify systemic Ureaplasma infection in lung transplant recipients with hyperammonemia syndrome, but did not detect it in any lung transplant recipients with normal ammonia concentrations. Administration of Ureaplasma-directed antimicrobials to patients with hyperammonemia syndrome resulted in biochemical and clinical resolution of the disorder. Relapse in one patient was accompanied by recurrent Ureaplasma bacteremia with antimicrobial resistance. Our results provide evidence supporting a causal relationship between Ureaplasma infection and hyperammonemia, suggesting a need to test for this organism and provide empiric antimicrobial treatment while awaiting microbiological confirmation.

Heavy alcohol use in lung donors increases the risk for primary graft dysfunction.

BACKGROUND: Heavy alcohol use is known to increase the risk of acute lung injury and the acute respiratory distress syndrome. This is in part due to increased production of reactive oxygen species. We hypothesized that recipients of lungs from heavy drinkers would be more susceptible to lung injury following transplantation. METHODS: In this retrospective cohort study, donor histories and transplant outcomes were reviewed in 192 consecutive lung transplant recipients. Donors were classified as No Alcohol Use, Moderate Alcohol Use, or Heavy Alcohol Use based on documented donor histories. RESULTS: Freedom from mechanical ventilation took longer in the lung transplant recipients whose donors had Heavy Alcohol Use, compared with those whose donors had No Alcohol Use or Moderate Alcohol Use (p = 0.01). At admission to the intensive care unit, the Heavy Alcohol Use group had median PaO2 /FiO2 ratio 219 (interquartile range [IQR]: 162 to 382), compared with 305 (IQR: 232 to 400) in the Moderate Alcohol Use group and 314 (IQR: 249 to 418) in the No Alcohol Use group (p = 0.005). The odds of developing severe primary graft dysfunction (PGD) in the Heavy Alcohol Use group versus the No Alcohol Use group were 8.7 times greater (95% confidence interval 1.427 to 53.404, p = 0.019) after controlling for factors known to be associated with PGD. CONCLUSIONS: Recipients of donors with a heavy alcohol use history had an over 8 times greater risk of developing severe PGD following lung transplant. The increase in PGD resulted in poorer gas exchange in the recipients of donor lungs from heavy alcohol users, and these recipients subsequently required mechanical ventilation for a longer time following transplant. Further investigation into lung donors with heavy alcohol use histories is necessary to determine those at highest risk for PGD following transplant.

The aging lung.

There are many age-associated changes in the respiratory and pulmonary immune system. These changes include decreases in the volume of the thoracic cavity, reduced lung volumes, and alterations in the muscles that aid respiration. Muscle function on a cellular level in the aging population is less efficient. The elderly population has less pulmonary reserve, and cough strength is decreased in the elderly population due to anatomic changes and muscle atrophy. Clearance of particles from the lung through the mucociliary elevator is decreased and associated with ciliary dysfunction. Many complex changes in immunity with aging contribute to increased susceptibility to infections including a less robust immune response from both the innate and adaptive immune systems. Considering all of these age-related changes to the lungs, pulmonary disease has significant consequences for the aging population. Chronic lower respiratory tract disease is the third leading cause of death in people aged 65 years and older. With a large and growing aging population, it is critical to understand how the body changes with age and how this impacts the entire respiratory system. Understanding the aging process in the lung is necessary in order to provide optimal care to our aging population. This review focuses on the nonpathologic aging process in the lung, including structural changes, changes in muscle function, and pulmonary immunologic function, with special consideration of obstructive lung disease in the elderly.

Pepsin concentrations are elevated in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis after lung transplantation.

BACKGROUND: Aspiration of gastroesophageal refluxate has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and the progression of bronchiolitis obliterans syndrome after lung transplantation. The goals of the present study were to identify lung transplant patients at the greatest risk of aspiration and to investigate the causative factors. MATERIALS AND METHODS: From September 2009 to November 2011, 252 bronchoalveolar lavage fluid (BALF) samples were collected from 100 lung transplant patients. The BALF pepsin concentrations and the results of transbronchial biopsy, esophageal function testing, barium swallow, and gastric emptying scan were compared among those with the most common end-stage lung diseases requiring lung transplantation: IPF, chronic obstructive pulmonary disease, cystic fibrosis, and α1-antitrypsin deficiency. RESULTS: Patients with IPF had higher BALF pepsin concentrations and a greater frequency of acute rejection than those with α1-antitrypsin deficiency, cystic fibrosis, or chronic obstructive pulmonary disease (P = 0.037). Moreover, the BALF pepsin concentrations correlated negatively with a lower esophageal sphincter pressure and distal esophageal amplitude; negatively with distal esophageal amplitude and positively with total esophageal acid time, longest reflux episode, and DeMeester score in those with chronic obstructive pulmonary disease; and negatively with the upright acid clearance time in those with IPF. CONCLUSIONS: Our results suggest that patients with IPF after lung transplantation are at increased risk of aspiration and a greater frequency of acute rejection episodes, and that the risk factors for aspiration might be different among those with the most common end-stage lung diseases who have undergone lung transplantation. These results support the role of evaluating the BALF for markers of aspiration in assessing lung transplant patients as candidates for antireflux surgery.

Aspiration, localized pulmonary inflammation, and predictors of early-onset bronchiolitis obliterans syndrome after lung transplantation.

BACKGROUND: We hypothesized that immune mediator concentrations in the bronchoalveolar fluid (BALF) are predictive of bronchiolitis obliterans syndrome (BOS) and demonstrate specific patterns of dysregulation, depending on the presence of acute cellular rejection, BOS, aspiration, and timing of lung transplantation. STUDY DESIGN: We prospectively collected 257 BALF samples from 105 lung transplant recipients. The BALF samples were assessed for absolute and differential white blood cell counts and 34 proteins implicated in pulmonary immunity, inflammation, fibrosis, and aspiration. RESULTS: There were elevated BALF concentrations of interleukin (IL)-15, IL-17, basic fibroblast growth factor, tumor necrosis factor-α, and myeloperoxidase, and reduced concentrations of α1-antitrypsin, which were predictive of early-onset BOS. Patients with BOS had an increased percentage of BALF lymphocytes and neutrophils, with a reduced percentage of macrophages (p < 0.05). The BALF concentrations of IL-1ß; IL-8; interferon-γ-induced protein 10; regulated upon activation, normal T-cell expressed and secreted; neutrophil elastase; and pepsin were higher in patients with BOS (p < 0.05). Among those with BOS, BALF concentrations of IL-1RA; IL-8; eotaxin; interferon-γ-induced protein 10; regulated upon activation, normal T-cell expressed and secreted; myeloperoxidase; and neutrophil elastase were positively correlated with time since transplantation (p < 0.01). Those with worse grades of acute cellular rejection had an increased percentage of lymphocytes in their BALF (p < 0.0001) and reduced BALF concentrations of IL-1ß, IL-7, IL-9, IL-12, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-γ, and vascular endothelial growth factor (p ≤ 0.001). Patients with aspiration based on detectable pepsin had increased percentage of neutrophils (p < 0.001) and reduced BALF concentrations of IL-12 (p < 0.001). CONCLUSIONS: The BALF levels of IL-15, IL-17, basic fibroblast growth factor, tumor necrosis factor-α, myeloperoxidase, and α1-antitrypsin at 6 to 12 months after lung transplantation are predictive of early-onset BOS, and those with BOS and aspiration have an augmented chemotactic and inflammatory balance of pulmonary leukocytes and immune mediators. These data justify the surgical prevention of aspiration and argue for the refinement of antirejection regimens.

Cellular basis of tissue regeneration by omentum.

The omentum is a sheet-like tissue attached to the greater curvature of the stomach and contains secondary lymphoid organs called milky spots. The omentum has been used for its healing potential for over 100 years by transposing the omental pedicle to injured organs (omental transposition), but the mechanism by which omentum helps the healing process of damaged tissues is not well understood. Omental transposition promotes expansion of pancreatic islets, hepatocytes, embryonic kidney, and neurons. Omental cells (OCs) can be activated by foreign bodies in vivo. Once activated, they become a rich source for growth factors and express pluripotent stem cell markers. Moreover, OCs become engrafted in injured tissues suggesting that they might function as stem cells.Omentum consists of a variety of phenotypically and functionally distinctive cells. To understand the mechanism of tissue repair support by the omentum in more detail, we analyzed the cell subsets derived from the omentum on immune and inflammatory responses. Our data demonstrate that the omentum contains at least two groups of cells that support tissue repair, immunomodulatory myeloid derived suppressor cells and omnipotent stem cells that are indistinguishable from mesenchymal stem cells. Based on these data, we propose that the omentum is a designated organ for tissue repair and healing in response to foreign invasion and tissue damage.