Limited Effect of Prevention Strategies on Incidence of Clinically Detectable Venous Thromboembolism After Lung Transplantation.

BACKGROUND: Thromboembolic complications are common post-lung transplant, leading to significant morbidity. We instituted multiple interventions because of an observed 36.8% incidence of venous thromboembolism (VTE) (Incidence rate (IR) 5.74/1000 pt days) in our recipients. METHODS: Our initiative commenced January 2015 with enoxaparin initiation within 6-8 hours of intensive care unit arrival and continuation for 4-6 weeks. We evaluated the IR of VTE in lung transplant recipients within 90 days of transplant. In 2017, the protocol was modified to extend the time to initiation of prophylaxis to within 72 hours of ICU arrival. In 2019, we further amended our intraoperative vascular access strategy. RESULTS: Eighteen of 26 lung transplant recipients (LTR) met inclusion criteria in the 2015 cohort. Six of 18 (33.3%) developed VTE, 50% of which were upper extremity (UE), line associated. Fifty two of 75 LTR were eligible for enoxaparin prophylaxis in the 2017 cohort. Fifteen of 52 subjects (28.8%) developed VTE, 77.8% of which were UE and line associated. Despite improved adherence in 2017, there was little change in VTE IR (3.90/1000 pt days compared with 3.85/1000 pt days). Twenty six of 43 LTR met protocol inclusion criteria in the 2019 cohort. Ten subjects (38.5%) developed VTE, 67% of which were UE and line associated (IR 5.18/1000 pt days). CONCLUSION: Our prospective study found that LTR remain at high risk for VTE despite aggressive prophylaxis with 4-6 weeks of enoxaparin and adjustment of vascular access approach. Alternative interventions should be investigated to minimize VTE development in this vulnerable population.

Decreased IDO1-dependent tryptophan metabolism in aged lung during influenza.

Influenza epidemics remain a leading cause of morbidity and mortality worldwide. In the current study, we investigated the impact of chronological ageing on tryptophan metabolism in response to influenza infection.Examination of metabolites present in plasma collected from critically ill patients identified tryptophan metabolism as an important metabolic pathway utilised specifically in response to influenza. Using a murine model of influenza infection to further these findings illustrated that there was decreased production of kynurenine in aged lung in an indoleamine-pyrrole 2,3-dioxygenase-dependent manner that was associated with increased inflammatory and diminished regulatory responses. Specifically, within the first 7 days of influenza, there was a decrease in kynurenine pathway mediated metabolism of tryptophan, which resulted in a subsequent increase in ketone body catabolism in aged alveolar macrophages. Treatment of aged mice with mitoquinol, a mitochondrial targeted antioxidant, improved mitochondrial function and restored tryptophan metabolism.Taken together, our data provide additional evidence as to why older persons are more susceptible to influenza and suggest a possible therapeutic to improve immunometabolic responses in this population.

Impact of Influenza on Pneumococcal Vaccine Effectiveness during Streptococcus pneumoniae Infection in Aged Murine Lung.

Changes in innate and adaptive immune responses caused by viral imprinting can have a significant direct or indirect influence on secondary infections and vaccine responses. The purpose of our current study was to investigate the role of immune imprinting by influenza on pneumococcal vaccine effectiveness during Streptococcus pneumoniae infection in the aged murine lung. Aged adult (18 months) mice were vaccinated with the pneumococcal polyvalent vaccine Pneumovax (5 mg/mouse). Fourteen days post vaccination, mice were instilled with PBS or influenza A/PR8/34 virus (3.5 × 102 PFU). Control and influenza-infected mice were instilled with PBS or S. pneumoniae (1 × 103 CFU, ATCC 6303) on day 7 of infection and antibacterial immune responses were assessed in the lung. Our results illustrate that, in response to a primary influenza infection, there was diminished bacterial clearance and heightened production of pro-inflammatory cytokines, such as IL6 and IL1ß. Vaccination with Pneumovax decreased pro-inflammatory cytokine production by modulating NFÒ¡B expression; however, these responses were significantly diminished after influenza infection. Taken together, the data in our current study illustrate that immune imprinting by influenza diminishes pneumococcal vaccine efficacy and, thereby, may contribute to increased susceptibility of older persons to a secondary infection with S. pneumoniae.

Targeted antioxidants as therapeutics for treatment of pneumonia in the elderly.

Community acquired pneumonia is a leading cause of mortality in the United States. Along with predisposing comorbid health status, age is an independent risk factor for determining the outcome of pneumonia. Research over the last few decades has contributed to better understanding the underlying immunodysregulation and imbalanced redox homeostasis tied to this aged population group that increases susceptibility to a wide range of pathologies. Major approaches include targeting oxidative stress by reducing ROS generation at its main sources of production which includes the mitochondrion. Mitochondria-targeted antioxidants have a number of molecular strategies that include targeting the biophysical properties of mitochondria, mitochondrial localization of catalytic enzymes, and mitigating mitochondrial membrane potential. Results of several antioxidant studies both in vitro and in vivo have demonstrated promising potential as a therapeutic in the treatment of pneumonia in the elderly. More human studies will need to be conducted to evaluate its efficacy in this clinical setting.

Epigenetic maturation in colonic mucosa continues beyond infancy in mice.

Monozygotic twin and other epidemiologic studies indicate that epigenetic processes may play an important role in the pathogenesis of inflammatory bowel diseases that commonly affect the colonic mucosa. The peak onset of these disorders in young adulthood suggests that epigenetic changes normally occurring in the colonic mucosa shortly before adulthood could be important etiologic factors. We assessed developmental changes in colitis susceptibility during the physiologically relevant period of childhood in mice [postnatal day 30 (P30) to P90] and concurrent changes in DNA methylation and gene expression in murine colonic mucosa. Susceptibility to colitis was tested in C57BL/6J mice with the dextran sulfate sodium colitis model. Methylation specific amplification microarray (MSAM) was used to screen for changes in DNA methylation, with validation by bisulfite pyrosequencing. Gene expression changes were analyzed by microarray expression profiling and real time RT-PCR. Mice were more susceptible to chemically induced colitis at P90 than at P30. DNA methylation changes, however, were not extensive; of 23 743 genomic intervals interrogated, only 271 underwent significant methylation alteration during this developmental period. We found an excellent correlation between the MSAM and bisulfite pyrosequencing at 11 gene associated intervals validated (R(2) = 0.89). Importantly, at the genes encoding galectin-1 (Lgals1), and mothers against decapentaplegic homolog 3 or Smad3, both previously implicated in murine colitis, developmental changes in DNA methylation from P30 to P90 were inversely correlated with expression. Colonic mucosal epigenetic maturation continues through early adulthood in the mouse, and may contribute to the age-associated increase in colitis susceptibility. Transcript Profiling: Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/), accession numbers: GSE18031 (DNA methylation arrays), GSE19506 (gene expression arrays).