Presence Of Systemic Inflammation Research Articles

Inhibition of HDAC1 and 3 in the Presence of Systemic Inflammation Reduces Retinal Degeneration in a Model of Dry Age-Related Macular Degeneration.

Purpose: Previously, we identified increased retinal degeneration and cytokine response in a mouse model of dry age-related macular degeneration (AMD) in the presence of systemic inflammation from rheumatoid arthritis (RA). Histone deacetylases (HDACs) regulate cytokine production by reducing acetylation and are found to be dysregulated in inflammatory diseases, including RA and AMD. Therefore, this current study investigates the effect of HDAC inhibition on AMD progression in the presence of systemic inflammation. Methods: Collagen induced arthritis (CIA) was induced in C57BL6J mice, followed by sodium iodate (NaIO3)-induced retinal degeneration. Mice were treated with a selective HDAC class I inhibitor, MS-275, and retinal structure [optical coherence tomography (OCT)], function (electroretinography), and molecular changes quantitative real-time polymerase chain reaction (RT-qPCR, Western Blot) were assessed. Results: NaIO3 retinal damage was diminished in CIA mice treated with MS-275 (P ≤ 0.05). While no significant difference was observed in retinal pigment epithelium (RPE) function, a trend in increased c-wave amplitude was detected in CIA + NaIO3 mice treated with MS-275. Finally, we identified decreased Hdac1, Hdac3, and Cxcl9 expression in CIA + NaIO3 mouse RPE/choroid when treated with MS-275 (P ≤ 0.05). Conclusions: Our data demonstrate that HDAC inhibition can reduce the additive effect of NaIO3-induced retinal degeneration in the presence of systemic inflammation by CIA as measured by OCT analysis. In addition, HDAC inhibition in CIA + NaIO3 treated mice resulted in reduced cytokine production. These findings are highly innovative and provide additional support to the therapeutic potential of HDAC inhibitors for dry AMD treatment.

New-onset organ dysfunction as a screening tool for the identification of sepsis and outcome prediction in dogs with systemic inflammation.

Sepsis in people is defined as a life-threatening organ dysfunction (OD) caused by a dysregulated host response to infection. In veterinary medicine, sepsis is still defined by the presence of systemic inflammation plus the evidence of infection. Based on recent veterinary studies, multiorgan dysfunction syndrome (MODS) has been associated with a worse outcome in sepsis. Thus, the screening for OD is warranted to identify the most critically ill patients. The aim of this study was to investigate the diagnostic value of new-onset OD for the prediction of sepsis and outcome in a population of critically ill dogs with systemic inflammation. Dogs admitted to the Emergency Room and/or the Intensive Care Unit with systemic inflammation, defined by a serum C-reactive protein concentration > 1.6 mg/dL, were retrospectively included. Enrolled dogs were categorized according to the presence of sepsis or non-infectious systemic inflammation. The presence of newly diagnosed OD was assessed based on criteria adapted from human literature and previously reported canine criteria. 275 dogs were included: 128 had sepsis and 147 had non-infectious systemic inflammation. The frequency of new-onset OD was not different between these groups. Only the presence of fluid-refractory hypotension was significantly associated with a diagnosis of sepsis (OR 10.51, 3.08-35.94; p < 0.0001). The frequency of at least two ODs was significantly higher in non-survivors compared to survivors, according to both the human and the veterinary criteria considered for the study (p = 0.0001 and p = 0.0004, respectively). Specifically, the presence of acute kidney injury, stupor or coma, prolonged Prothrombin Time and decreased Base Excess were associated with a higher risk of death in the multivariate binary logistic regression. In this population of critically ill dogs with systemic inflammation, the detection of newly diagnosed ODs was not able to predict sepsis diagnosis, other than the presence of fluid-refractory hypotension. However, given the strong prognostic significance associated with ODs, our results support the early screening for ODs in any severe inflammatory critical care condition to identify high-risk patients and optimize their management.

Serum ferritin/C-reactive protein ratio is a simple and effective biomarker for diagnosing iron deficiency in the context of systemic inflammation.

Diagnosing iron deficiency is challenging in the presence of systemic inflammation. To investigate the relationship between plasma C-reactive protein (CRP), serum ferritin (SF) and transferrin saturation (TS), with the objective of establishing a straightforward ratio applicable in the presence of inflammatory syndrome. Test prospective cohort and validation retrospective cohort. A prospective cohort of inpatients (n = 140) assessed the correlation between CRP and SF/TS levels. The diagnostic performance of a determined ratio was evaluated for identifying iron deficiency (ID) using different definitions and in the presence of inflammation and/or chronic heart and/or kidney failure. A large validation cohort (n = 795) further assessed the predictive power of this ratio. In a training cohort (median age 76 years [57-84]), a linear relation was observed between SF (µg/l) and CRP (mg/l), unlike with TS. The SF/CRP ratio accurately predicted ID, with receiver operating characteristic-area under the curve (ROC-AUC) values ranging from 0.85 to 0.92 for different ID definitions. A threshold of ≤6 demonstrated the highest Youden index (0.61). In the validation cohort (age 72 years [57-84]), the SF/CRP ratio exhibited an ROC-AUC of 0.88 [95% CI: 0.85-0.90], with an odds ratio of 37.9 [95% CI: 20.3-68.9] for the threshold of ≤6. In this study, we demonstrated that the SF/CRP ratio, with a threshold of ≤6, is a simple and effective biomarker for ID, even in the presence of systemic inflammation or comorbidities. This ratio could potentially replace the complex set of criteria currently recommended by learned societies.

Limitations of PLX3397 as a microglial investigational tool: peripheral and off-target effects dictate the response to inflammation.

Microglia, the resident macrophages of the central nervous system (CNS), play a critical role in CNS homeostasis and neuroinflammation. Pexidartinib (PLX3397), a colony-stimulating factor 1 (CSF1) receptor inhibitor, is widely used to depletemicroglia, offering flexible options for both long-term depletion andhighly versatile depletion-repopulation cycles. However, the potential impact of PLX3397 on peripheral (immune) cells remains controversial. Until now, the microglia-specificity of this type of compounds has not been thoroughly evaluated, particularly in the context of peripherally derived neuroinflammation. Our study addresses this gap by examining the effects of PLX3397 on immune cells in the brain, liver, circulation and bone marrow, both in homeostasis and systemic inflammation models. Intriguingly, we demonstrate that PLX3397 treatment not only influences the levels of tissue-resident macrophages, but also affects circulating and bone marrow immune cells beyond the mononuclear phagocyte system (MPS). These alterations in peripheral immune cells disrupt the response to systemic inflammation, consequently impacting the phenotype irrespective of microglial depletion. Furthermore, we observed that a lower dose of PLX3397, which does not deplete microglia, demonstrates similar (non-)MPS effects, both in the periphery and the brain, but fails to fully replicate the peripheral alterations seen in the higher doses, questioning lower doses as a 'peripheral control' strategy. Overall, our data highlight the need for caution when interpreting studies employing this compound, as it may not be suitable for specific investigation of microglial function in the presence of systemic inflammation.

The Relationship between Eosinophil Density in the Colonic Mucosa and Eosinophil Blood Count in Children: A Cross-Sectional Study.

Eosinophils are found in the mucosa of the healthy gastrointestinal tract, but they also often accompany gastrointestinal diseases. We hypothesized that a positive correlation exists between blood eosinophil count and colonic eosinophil mucosal density in children. Electronic health records regarding 181 colonoscopies, performed with biopsy in the years 2019-2022, were screened for information on blood and colonic eosinophil count, age, sex, diagnoses, weight, height, white blood cell (WBC) count, serum C-reactive protein (CRP), and total IgE concentration. The median age (IQR) of the 107 included children (109 colonoscopies) was 12.4 years (8.1-15.5); 32 presented with blood eosinophilia (29.3%). The median eosinophil density/high-power field in the colonic mucosa was 22.5 (9-31). We found a weak correlation between colonic mucosal eosinophil density and blood eosinophil count (r = 0.295, 95% CI 0.108-0.462, p = 0.0018). This association was more pronounced in patients with elevated CRP (r = 0.529, 95% CI 0.167-0.766, p = 0.0054) and older than 12.4 years (r = 0.448, 95% CI 0.197-0.644, p = 0.00068). Peripheral blood eosinophilia might hint at increased mucosal colonic eosinophil density, especially in older children and in the presence of systemic inflammation. However, it seems unlikely that blood and colonic eosinophilia are strongly linked in younger children. Studies in adults are warranted.

Bronchiectasis: A pulmonary disease with systemic consequences.

The pathophysiology of bronchiectasis is currently interpreted in terms of two main processes: bronchial inflammation (predominantly neutrophilic, but also with a known mononuclear and sometimes eosinophilic component) and bronchial infection due to pathogenic microorganisms. The latter is usually the primary factor driving airway inflammation and can temporarily intensify acute conditions (exacerbations) or even become chronic, causing a parallel increase in airway inflammation and, consequently, a chronic worsening of a patient's symptoms. Chronic infection with Pseudomonas aeruginosa (PA) and severe exacerbations have a significant impact on clinical outcomes and constitute a specific bronchiectasis phenotype. These events occur at the pulmonary level and are related to a local response. However, regardless of the systemic nature of some diseases that cause, or are associated with, bronchiectasis, it may also have clear systemic repercussions.1 Systemic inflammation in bronchiectasis has been recently evaluated in several studies, which have demonstrated an increase in the peripheral levels of mediators and cells associated with a pro-inflammatory state, oxidative stress and various nutritional deficiencies.2 Moreover, this systemic inflammation increases temporarily during exacerbations and is highly heterogeneous in nature, as shown by Saleh et al.2 In this study, some 31 different biomarkers related to systemic inflammation were grouped into five components: mononuclear chemotaxis, immune regulation, acute phase response, immune activation and polymorphonuclear chemotaxis. However, around half of the molecules analysed could not be assigned to any of these five groups. Several mediators or groups of mediators were associated with different etiologies, and fibrinogen levels were associated with bronchiectasis severity and poorer quality of life. These findings indicate the large number of different pathophysiological mechanisms (endotypes) related to inflammation or regulation of the immune system, and they probably explain, at least in part, the great phenotypic diversity of bronchiectasis.2 Moreover, various studies have related the presence of systemic inflammation to a greater severity of bronchiectasis, based on higher multidimensional scale scores, a greater number and severity of exacerbations, a faster decline in lung function, a greater bronchial bacterial load or a higher probability of chronic pulmonary infection by pathogenic microorganisms (especially PA), poorer quality of life and mortality.3 Systemic inflammation in bronchiectasis could have significant systemic consequences, such as an increased incidence of metabolic or cardiovascular disease (Figure 1). This hypothesis is supported by various findings. On the one hand, other airway diseases closely related to bronchiectasis, such as COPD with chronic bronchial infection, present extrapulmonary manifestations such as an increased incidence of cardiovascular disease. On the other hand, two of the most studied mediators in systemic inflammation in bronchiectasis—fibrinogen and C-reactive protein (CRP)4—have also been directly related to an increased incidence of cardiovascular events. Moreover, some nutritional and metabolic alterations, as well as muscular dysfunctions, have been associated with an excess of systemic inflammation in bronchiectasis.5 Finally, there have been reports of coronary arterial calcification, aortic stiffness, endothelial dysfunction and subclinical atherosclerosis in bronchiectasis patients, all of which are known cardiovascular risk factors.6, 7 Gao et al.7 performed a brachial-ankle pulse wave velocity (baPWV) test (a measure of arterial stiffness) in 80 bronchiectasis patients and 80 well-matched controls, and found a difference between the groups of 1.62 m/s. This difference is clinically significant, since a recent meta-analysis showed that a baPWV increase of merely 1 m/s could lead to an increase of approximately 20% in cardiovascular morbidity and mortality. These findings could explain the excess incidence of cardiovascular events observed across various bronchiectasis cohorts.8, 9 However, this finding could not be related to the presence of systemic inflammation (measured by peripheral levels of fibrinogen, CRP, IL-8 and IL-6) but it was associated with an increase in both the number and severity of exacerbations, as well as the presence of a chronic bronchial infection, especially with PA. Accordingly, either there are mechanisms other than systemic inflammation that could explain this finding or, given the great heterogeneity of the systemic inflammation mentioned above, the molecules potentially related to this finding were not analysed. The results of several studies suggest that, of all these mechanisms, the number and severity of exacerbations could play a crucial role,6 while Huang et al. observed that an increased serum concentration of desmosine (as part of systemic inflammation in bronchiectasis) was associated with an increased adjusted cardiovascular mortality in bronchiectasis patients.10 The future therapeutic implications of this situation could be highly significant. Some authors have observed that both non-pharmacological treatments (such as muscle rehabilitation and nutritional programs) and pharmacological treatments (such as statins, neutrophil elastase inhibitors, CXCR2 inhibitors, antibiotics and other immunomodulatory treatments)11 can reduce the level of some systemic proinflammatory molecules. However, no beneficial effect on bronchiectasis has been demonstrated from treatment of systemic inflammation, and, consequently, international guidelines do not recommend such interventions. Finally, some markers of systemic inflammation could also be used to predict treatment response. For example, the number or percentage of peripheral eosinophils could predict the response to biological or inhaled steroid treatments in bronchiectasis (as in the case of COPD), as already suggested by various authors.12 In conclusion, systemic inflammation in bronchiectasis patients has been demonstrated in the past decade, and it could cause extrapulmonary damage, especially in terms of an increased risk of cardiovascular and metabolic/nutritional diseases. As highlighted by the EMBARC (European Multicentre Bronchiectasis Audit and Research Collaboration) taskforce on research priorities, further studies are needed to identify biomarkers that can assist in risk stratification, targeted interventions and monitoring strategies, as well as the confirmation of a causal relationship between the presence of systemic inflammation (directly or through an increase in exacerbations of bronchial infection) and damage to several target organs. None declared.

Clinical Significance of the Relationship Between D-dimer and Erythrocyte Distribution Width in Covid-19 Patients

Introduction: Red cell distribution width (RDW) is a marker that can be used in the presence of systemic inflammation and evaluating thromboembolic condition.We aimed to evaluate the relationship between RDW and the level of D-dimer known as related to adverse events in Coronavirus disease 2019 (COVID-19) in this study. Methods: One hundred twenty two patients with COVID-19 and 62 healthy individuals with age and sex-matched were enrolled in the present study. The patients were divided into two groups based on evaluating their D-dimer level. The first group contained 45 patients with higher D-dimer level whereas the second group contained 77 patients with normal D-dimer level. Results: RDWvalues were found to be higher in patients with COVID-19 and higher D-dimer level than patients with normal D-dimer level and control group. These results were found to be statistically significant (P=0.006 and P=0.013, respectively). Among patients with COVID-19, a positive correlation was observed between RDW and D-dimer level (r=0.270, P=0.003). Among the various variables associated with higher D-dimer in multivariate logistic regression analyses, RDW detected an independent predictor of higher D-dimer in COVID-19 patients (95% CI: CI:0.322-0.979, P=0.042). Conclusion: The results indicated that high RDW values in patients with COVID-19 disease could be used as a marker in clinical follow-up of patients as D-dimer.

Hematological biomarkers of systemic inflammation in genuine (physiologic and pathologic) halitosis

Halitosis is an unpleasant odor discharged through the oral cavity with a prevalence as high as 30%–50% of the general population. Conventional diagnostic methods have been focused on mouth air analysis measuring the amount of sulfur compounds which does not directly reflect the cause of halitosis. Also, the possible role of halitosis as an indicator of general health status has been steadily suggested and inflammation has been constantly associated with aversive body odor. Therefore, this study aimed to search for inter-relationships between hematologic indicators, clinical characteristics, and halitosis measurement that can predict the presence of pathologic halitosis and its intensity. Furthermore, the tentative relationship between halitosis and the presence of systemic inflammation was investigated. A total of 125 patients were divided into 103 patients in the genuine halitosis group (value ⩾80 ppb) and 22 patients in the pseudo halitosis group (value <80 ppb) based on portable sulfide monitor measurements. Clinical examination and hematological indices including inflammatory prognostic factors and halitosis measurements including organoleptic testing, portable sulfide monitor, and gas chromatography were evaluated. The genuine halitosis group showed a significantly higher white blood cell (WBC) count (p< 0.01) compared to the pseudo halitosis group. Erythrocyte sedimentation rate (ESR, β = 0.341, p < 0.05) values and duration of halitosis (β= 0.353, p < 0.05) showed a significant association with halitosis intensity and neutrophil to lymphocyte ratio (NLR) values (β = 3.859, p < 0.05) were significantly related to genuine halitosis diagnosis. A new WBC cut-off value of 5575 μl−1 showed near to fair discriminative power in predicting genuine halitosis (area under the curve 0.661, p < 0.05). The results of this study showing an increased WBC count in genuine halitosis and its strong association with hematologic indices of subclinical inflammation including ESR and NLR suggest inflammatory hematologic markers as potential diagnostic tools in the diagnosis of genuine halitosis.

Systemic inflammation May limit the effect of protein supplement on nutritional status in peritoneal dialysis.

Malnutrition and inflammation are highly prevalent and associated with poor outcomes in continuous ambulatory peritoneal dialysis (CAPD). Nutritional supplements are commonly used; however, presence of systemic inflammation could limit their effect. To evaluate the impact of systemic inflammation on nutritional status of CAPD patients receiving an oral protein supplement. Prospective observational study; 34 malnourished patients (subjective global assessment; SGA) received both nutritional counseling and oral egg albumin-based protein supplement. During 6-month of follow-up, patients had monthly clinical, and quarterly biochemical and inflammation [interleukin 6 and high sensitivity C-reactive protein (hsCRP)] evaluations. According to baseline hsCRP, patients were classified in two groups: Inflammation (>3mg/L) and No-inflammation (≤3mg/L). Comparing baseline vs final, macronutrient intake and SGA increased in both groups, however, improvement of SGA was more marked in the No-inflammation group at the end of the study: 70% improved, 25% no change and 5% worsened (p=0.001); whereas in the Inflammation group results were: 50% improved, 36% no change and 14% worsened (p=0.03). Additionally, at final evaluation, serum albumin tended to increase more in the No-inflammation (3.0±0.9 vs 3.4±1.1g/dL, p=0.08) than in Inflammation group (2.8±0.6 vs 3.0±0.9g/dL, p=0.66), and body mass index significantly increased in No-inflammation group (20.3±3.0 vs 21.6±3.3kg/m2, p<0.001) but not in Inflammation group (21.9±3.0 vs 22.5±3.3kg/m2, p=0.09). The presence of systemic inflammation in malnourished CAPD patients seemed to limit the trend for improvement on nutritional status observed with counseling and oral egg albumin-based protein supplement in patients without inflammation.

Circulating markers of endothelial activation in canine parvoviral enteritis

Canine parvovirus (CPV) is a common cause of enteritis, immune suppression and systemic inflammation in young dogs. Endothelial markers, such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), and molecules that upregulate their expression, such as high mobility group box 1 protein (HMGB-1), provide insight into the state of the endothelium during inflammation. This study aimed to determine if circulating concentrations of ICAM-1, VCAM-1 and HMGB-1 were altered in CPV enteritis compared to healthy controls, and whether a correlation existed between these molecules and the degree of inflammation. Thirty dogs with naturally occurring CPV enteritis and ten control dogs were included. Physical examinations, complete blood count and C-reactive protein (CRP) measurements were performed on all dogs at presentation. The concentrations of ICAM-1, VCAM-1 and HMGB-1 were measured using commercially available canine-specific enzyme-linked immunosorbent assay (ELISA) kits. In dogs with CPV enteritis, ICAM-1 concentrations were significantly lower (median: 5.9 [IQR: 4.3-8.3]) and CRP higher (134 [IQR: 85-195]) compared to controls (8.0 [IQR: 6.9-10.3], p = 0.008; 1 [IQR: 0-7], p < 0.001). No significant difference was found for VCAM- 1 and HMGB-1. A strong correlation was identified between VCAM-1 and segmented neutrophil count (r = 0.612, p < 0.001). Despite the presence of systemic inflammation in CPV enteritis, evidenced by high CRP concentrations, our results suggest circulating concentrations of ICAM-1, VCAM-1 and HMGB-1 failed to show an increase. Endothelial activation with subsequent leukocyte adhesion and transmigration through the endothelium may be affected in CPV enteritis and these findings require further investigation.

Role of fluid status markers as risk factors for suboptimal vancomycin concentration during continuous infusion in neonates: an observational study.

Vancomycin C24h was underdosed in 60% of patients and factors linked to changes in vancomycin pharmacokinetic such as volume of distribution and clearance, linked to creatinine level, inflammation, or weight gain, were identified. •Adjustment of vancomycin regimen remains difficult due to inter- and intra-individual variability of vancomycin pharmacokinetics. • Impact of fluid status on vancomycin concentration in critically ill neonates is incompletely studied. •Proportion of patients with adequate vancomycin concentration using a target adapted to nosocomial gram-positive bacteria MIC is low. • We confirmed the role of creatinine level and report two new factors associated with low vancomycin concentration: presence of systemic inflammation and weight gain.

Understanding Aberrant Signaling to Elude Therapy Escape Mechanisms in Myeloproliferative Neoplasms.

Simple SummaryMyeloproliferative neoplasms are a group of rare disorders characterized by genetic mutations in hematopoietic stem cells and by the presence of systemic inflammation. The main driver mutations causing these diseases converge in activating the JAK2 signal transduction pathway, which plays a major role in disease onset and maintenance. Treatments based on JAK2 inhibitors ameliorate symptoms without suppressing the disease. This depends on the reactivation of JAK2 signaling and on the emergence of alternative pathways also sustained by inflammatory mediators. Molecular mechanisms at the basis of disease persistence and new therapeutic attempts to overcome them are discussed in the review.Aberrant signaling in myeloproliferative neoplasms may arise from alterations in genes coding for signal transduction proteins or epigenetic regulators. Both mutated and normal cells cooperate, altering fragile balances in bone marrow niches and fueling persistent inflammation through paracrine or systemic signals. Despite the hopes placed in targeted therapies, myeloid proliferative neoplasms remain incurable diseases in patients not eligible for stem cell transplantation. Due to the emergence of drug resistance, patient management is often very difficult in the long term. Unexpected connections among signal transduction pathways highlighted in neoplastic cells suggest new strategies to overcome neoplastic cell adaptation.

Abstract P2-08-14: Effect of markers of systemic inflammation on tumor infiltrating lymphocytes in patients with non-metastatic triple negative and HER2+ breast cancer: A single center retrospective study

Abstract Background: Tumor infiltrating lymphocytes (TILs) are increasingly being recognized as a vital component of the tumor immune microenvironment. TILs have also been established as a predictive biomarker for response to neoadjuvant therapy in triple negative (TNBC) and HER2+ breast cancer. The relationship between TILs and the systemic immune environment remains poorly understood. Metabolic syndrome and other states of inflammation create dynamic changes in systemic immunity. We hypothesize that the presence of systemic inflammation as measured by hematologic markers and features of metabolic syndrome affects the quantity of TILs in non-metastatic TNBC and HER2+ breast cancer. Methods: A retrospective chart review was conducted in the Harris County Health System to examine the correlation of baseline markers of systemic inflammation to quantity of TILs at the time of breast cancer diagnosis. 141 patients with TNBC and HER2+ breast cancer with evaluable TILs were identified between 2018 and 2020. Body mass index (BMI), Hemoglobin A1C (HgbA1C), low density lipoprotein (LDL), neutrophil lymphocyte ratio (NLR), and platelet lymphocyte ratio (PLR) were collected as markers of metabolic syndrome and inflammation within ≤ 6 months prior to diagnosis. TILs were categorized as low (0-10%), moderate (10-60%), and high (greater than 60%) and measured by one expert pathologist at our center. Results: The average age at diagnosis was 51.9 years (range 32-74). 64 (45.3%) patients had TNBC while 77 (54.6%) had HER2+ disease, of these patients, 46 (59.7%) were also estrogen receptor (ER) positive. 97 (68.8%) patients were Hispanic, 38 (26.9%) were African American. 46 (32.6%) patients had stage II disease, 79 (56%) patients had stage III disease. In measurement of TILs, 73 (57.8%) patients were categorized as low, 56 (39.7%) as moderate, and 12 (8.5%) as high. Diabetes mellitus as measured by HgbA1C ≥ 6.5% or fasting glucose ≥ 200 (adjusted odds ratio (OR) 1.32 95% CI 0.5-3.4), hyperlipidemia as measured by LDL ≥ 129 (OR 1.27 95% CI 0.55-2.9), and elevated BMI ≥ 25 (OR 1.08 95% CI 0.35 - 3.6) were associated with increased TILs. PLR ≥ 130 was most strongly associated with increased TILs (OR 1.93 95% CI 0.87 - 4.35, p-value 0.11). NLR ≥ 2.5 did not correlate with amount of TILs (OR 1.01 95% CI 0.44 - 2.29). None of the odds ratios were statistically significant, with p values ≥ 0.05. Discussion: Overall, markers of inflammation correlated with increased amount of TILs. Metabolic syndrome, as measured by elevated BMI, presence of diabetes mellitus, and presence of hyperlipidemia as well as hematologic marker of inflammation PLR, demonstrated varying degrees of correlation to increasing TILs without statistical significance. PLR ≥ 130 demonstrated the strongest correlation with increased TILs with a p value of 0.11. This retrospective study is limited by the small patient population, however these results suggest that systemic inflammation as measured by metabolic syndrome and hematologic markers may correlate with higher TILs and thus these patients may demonstrate improved response to neoadjuvant therapy. Larger patient samples may be needed to reach statistical significance and continued data collection is underway. Citation Format: Nan Chen, Shaun Bulsara, Susan Hilsenbeck, Valentina Hoyos. Effect of markers of systemic inflammation on tumor infiltrating lymphocytes in patients with non-metastatic triple negative and HER2+ breast cancer: A single center retrospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-14.

Systemic Inflammation During the Episode of Acute Variceal Bleeding Determines Clinical Outcomes Independent of Severity of Liver Disease: A Proof of Concept Study

Background: Development of post-bleeding acute decompensations (AD), infections and rebleeding are the major determinants of 6-week mortality after an episode of acute variceal bleeding(AVB). While the portal pressure driven pathogenesis of outcomes is extensively studied, little is known about the presence of systemic inflammation and endotoxemia across different strata of severity of liver disease in AVB. and its prognostic relevance in determining the outcomes. Aim: To study the role of systemic inflammation and endotoxemia in AVB as relevant predictors of outcomes. Methods: In this prospective observational study, during hospitalisation serum levels of interleukin-1(IL-1), interleukin-6(IL-6), tumor necrosis factor alpha(TNFα), C reactive protein (CRP) and IgM anti-endotoxin levels were estimated at baseline in consecutive patients of cirrhosis presenting with AVB. The patients were followed up for 6-week outcomes like mortality, new onset/worsening AD. Results: Patients presenting with AVB (n=89) (mean age-46±11 years, 77% males) with baseline MELD score-15.5±5.1, and Child class (A/B/C)- (38%/32%/30%) were included. The incidence of 6-week mortality, new onset/worsening AD and infection was 20.2%, 34.8% and 15.7%, respectively. IL-6[AUROC-0.877(0.78-0.974)] and TNFα[0.732(0.58-0.884)] outperformed MELD score[0.737(0.632-0.841)] (P=0.001) for predicting 6-week mortality. IL-6[AUROC-0.902(0.836-0.967)] emerged as the most accurate marker for predicting 6-week new onset/worsening AD and infections with performance better than TNFα [0.635 (0.511- 0.76)] and MELD score[0.69(0.577-0.803)]. On multivariate analysis, IL-6 levels [HR:1.017(1.012-1.022), P<0.001] and ascites [HR: 2.815(1.086-7.485), P=0.033] emerged as independent predictors of 6-week AD, whereas MELD (0.987) was not significant. Among predictors of systemic inflammation, except for correlation of TNFα with active alcohol use (P=0.013) and endotoxemia with active bleed on endoscopy (P<0.001) none of the markers correlated with alcohol use, recent AD, hypotension and active bleeding. Distinct phenotypes were identified by IL-6 levels within the same child class with different course of disease and outcomes. Conclusions: Systemic inflammation particularly IL-6 potentially predicts outcomes in AVB independent of severity of liver disease by identifying distinct clinical phenotypes.

Central nervous system and systemic oxidative stress interplay with inflammation in a bile duct ligation rat model of type C hepatic encephalopathy

The role and coexistence of oxidative stress (OS) and inflammation in type C hepatic encephalopathy (C HE) is a subject of intense debate. Under normal conditions the physiological levels of intracellular reactive oxygen species are controlled by the counteracting antioxidant response to maintain redox homeostasis. Our previous in-vivo1H-MRS studies revealed the longitudinal impairment of the antioxidant system (ascorbate) in a bile-duct ligation (BDL) rat model of type C HE.Therefore, the aim of this work was to examine the course of central nervous system (CNS) OS and systemic OS, as well as to check for their co-existence with inflammation in the BDL rat model of type C HE. To this end, we implemented a multidisciplinary approach, including ex-vivo and in-vitro electron paramagnetic resonance spectroscopy (EPR) spin-trapping, which was combined with UV–Vis spectroscopy, and histological assessments. We hypothesized that OS and inflammation act synergistically in the pathophysiology of type C HE.Our findings point to an increased CNS- and systemic-OS and inflammation over the course of type C HE progression. In particular, an increase in the CNS OS was observed as early as 2-weeks post-BDL, while the systemic OS became significant at week 6 post-BDL. The CNS EPR measurements were further validated by a substantial accumulation of 8-Oxo-2′-deoxyguanosine (Oxo-8-dG), a marker of oxidative DNA/RNA modifications on immunohistochemistry (IHC). Using IHC, we also detected increased synthesis of antioxidants, glutathione peroxidase 1 (GPX-1) and superoxide dismutases (i.e.Cu/ZnSOD (SOD1) and MnSOD (SOD2)), along with proinflammatory cytokine interleukin-6 (IL-6) in the brains of BDL rats. The presence of systemic inflammation was observed already at 2-weeks post-surgery. Thus, these results suggest that CNS OS is an early event in type C HE rat model, which seems to precede systemic OS. Finally, our results suggest that the increase in CNS OS is due to enhanced formation of intra- and extra-cellular ROS rather than due to reduced antioxidant capacity, and that OS in parallel with inflammation plays a significant role in type C HE.

Transdermal auricular vagus stimulation for the treatment of postural tachycardia syndrome.

Postural Tachycardia Syndrome (POTS) is a chronic disorder characterized by symptoms of orthostatic intolerance such as fatigue, lightheadedness, dizziness, palpitations, dyspnea, chest discomfort and remarkable tachycardia upon standing. Non-invasive transdermal vagal stimulators have been applied for the treatment of epilepsy, anxiety, depression, headache, and chronic pain syndromes. Anti-inflammatory and immunomodulating effects after transdermal vagal stimulation raised interest for applications in other diseases. Patients with sympathetic overactivity, reduced cardiac vagal drive and presence of systemic inflammation like POTS may benefit from tVNS. This article will address crucial methodological aspects of tVNS and provide preliminary results of its acute and chronic use in POTS, with regards to its potential effectiveness on autonomic symptoms reduction and heart rate modulation.

Psoriasis is a systemic disease: A proposed approach for inflammation scale calculation

Background: Psoriasis is a skin disease affecting 2.3% of the Iraqi population and begins as a local disease with subsequent systemic comorbidities. Aim: The aim was to clarify whether psoriasis is a local or systemic disease. Materials and Methods: A total of 211 subjects with psoriasis and 163 sex- and age-matched controls were included in the study. Serum adiponectin, interleukin-6, interleukin-8, interleukin-10 (IL-10), interleukin-23 (IL-23), interleukin-18 (IL-18), paraoxonase, lipoprotein (a), osteopontin, chemerin, tumor necrosis factor-a (TNF-a), high-sensitivity C- reactive protein (hs-CRP), bilirubin, D-dimer, and creatinine were determined using commercial kits. Results: There was no significant difference in the mean age and BMI between psoriasis and the control groups. However, there was significantly higher mean serum values of IL-6, IL-8, IL-10, IL-23, lipoprotein (a), chemerin, TNF-a, hs-CRP, osteopontin, D-dimer, troponin I, creatinine, bilirubin, and platelet counts in psoriatic patients than in the controls. Meanwhile, the serum mean values of adiponectin, paraoxonase, and cortisol were significantly lower in psoriasis subjects than in the controls. The mathematical model was proposed to clarify whether psoriasis is a systemic or local disease. The application of the model to our data of biomarkers indicated the presence of systemic inflammation in psoriasis. Conclusion: The present study finding suggests that psoriasis is a systemic disease rather than a local skin disease. However, there is a need for the application of the model in a large-scale study.

The Preoperative Neutrophil Lymphocyte Ratio and Platelet Lymphocyte Ratio Predicts Disease-Free Survival in Resectable Esophageal Squamous Cell Carcinoma.

BackgroundRecent studies have revealed that the presence of systemic inflammation is associated with poor survival for esophageal squamous cell carcinoma. We aimed to investigate prognostic values of preoperative neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) in resectable esophageal squamous cell carcinoma.MethodsA cohort of 167 resectable ESCC patients was retrospectively reviewed between January 2017 and September 2020. The best cut-off value of NLR and PLR was selected by plotting the receiver operating characteristic curve. All reviewed patients were divided into high NLR/PLR or low NLR/PLR group to evaluate prognostic factors.ResultsAmong the 167 patients, 34 (20.36%) were women and 133 (79.64%) were men. The mean age was 62.64 ±7.91 years, with an age range from 44 to 85 years. All patients were divided into low NLR (<2.20) or high NLR (≥2.20) group (AUC=62.5% with the sensitivity of 61.8% and specificity 60.9%, P=0.025), low PLR (<110) or high PLR (≥110) group (AUC=59.6% with the sensitivity of 82.4% and specificity 35.3%, P=0.083). High NLR and PLR were associated with a larger tumor diameter (P<0.05), while high NLR was also associated with poor tumor classification (P=0.022). There was a positive correlation between NLR and PLR (r = 0.614, P < 0.001). High NLR and PLR were significantly associated with poor disease-free survival. Multivariate analyses identified NLR as a prognostic factor in resectable ESCC.ConclusionThe NLR and PLR predict disease-free survival in resectable esophageal squamous cell carcinoma.

COVID-19 associated coagulopathy is correlated with increased age and markers of inflammation response

Abstract Background: The severe manifestations of the coronavirus disease 2019 (COVID-19) are linked to viral hyper-inflammation, cytokine release syndrome and subsequent coagulation disturbances. The most common coagulation abnormality observed in COVID-19 patients is the elevation of the plasma levels of D-dimers. The aim of this study was to evaluate the characteristics of COVID-19-associated inflammatory syndrome and coagulopathy, in correlation with disease severity. Methods: We performed a cross-sectional study, enrolling all consecutive COVID-19 patients treated in the Adulti 3 Department of the Prof. Dr. Matei Bals National Institute of Infectious Diseases, Bucharest, Romania, between 1st march and 30th September 2020. We recorded clinical and epidemiological characteristics, inflammatory markers, coagulation abnormalities and lymphocyte count. The severity of lung involvement was assessed using native Computed Tomography examination. Results: We included 106 patients with SARS-COV2 infection, 50 males (47.2%) and 56 females (52.8%), age range 14-91 years. All markers of inflammation were increased in our study in patients with severe disease, as were lactate dehydrogenase, monocyte distribution width, and neutrophil-to-lymphocyte ratio. An elevated level of serum D-dimers was observed in approximately half of our subjects and was associated with disease severity. Our best linear regression model for predicting COVID-19 coagulopathy (manifested as abnormal D-dimer levels) included age, fibrinogen, and lymphocyte count. Conclusion: Our findings emphasize the association between COVID-19 coagulopathy and the presence of systemic inflammation. A significant proportion of patients with moderate and severe disease had coagulation abnormalities and these were linked with the presence of inflammation and older age..

Tocilizumab for the treatment of non‐critical COVID‐19 pneumonia: an overview of the rationale and clinical evidence to date

ABSTRACT Introduction: Tocilizumab is one of the main repurposed therapies investigated for COVID-19 pneumonia since the start of the pandemic, but there has been conflicting evidence for its use. Areas covered: This review covers the physiology of interleukin-6 and its role in the pathophysiology of COVID-19. We discuss the use of tocilizumab in other diseases and the rationale for its use in COVID-19. We summarize the design, contrasting results, and implications of the clinical trials of tocilizumab in COVID-19 to date and discuss the current guidance for its use. Expert opinion: The evidence to date suggests benefit with the use of tocilizumab in some but not all patients with COVID-19. Benefit seems to be greatest when given early after clinical deterioration with the presence of systemic inflammation. However, questions remain around the optimal timing, patient selection, and concomitant treatments.