Extent Of Systemic Inflammation Research Articles

Effects of inflammation on thrombosis and outcomes in COVID-19: secondary analysis of the ATTACC/ACTIV-4a trial

BackgroundPatients hospitalized for COVID-19 are at high risk of thrombotic complications and organ failure, and often exhibit severe inflammation, which may contribute to hypercoagulability. ObjectivesTo determine whether patients hospitalized for COVID-19 experience differing frequencies of thrombotic and organ failure complications and derive variable benefits from therapeutic-dose heparin dependent on the extent of systemic inflammation and whether observed benefit from therapeutic-dose anticoagulation varies depending on the degree of systemic inflammation. MethodsWe analyzed data from 1346 patients hospitalized for COVID-19 enrolled in the ATTACC and ACTIV-4a platforms who were randomized to therapeutic-dose heparin or usual care for whom levels of C-reactive protein (CRP) were reported at baseline. ResultsIncreased CRP was associated with worse patient outcomes, including a >98% posterior probability of increased organ support requirement, hospital length of stay, risk of 28-day mortality, and incidence of major thrombotic events or death (patients with CRP 40-100 mg/L or ≥100 mg/L compared to patients with CRP <40 mg/L). Patients with CRP 40 to 100 mg/L experienced the greatest degree of benefit from treatment with therapeutic doses of unfractionated or low molecular weight heparin compared with usual-care prophylactic doses. This was most significant for an increase in organ support-free days (odds ratio: 1.63; 95% confidence interval, 1.09-2.40; 97.9% posterior probability of beneficial effect), with trends toward benefit for other evaluated outcomes. ConclusionModerately ill patients hospitalized for COVID-19 with CRP between 40 mg/L and 100 mg/L derived the greatest benefit from treatment with therapeutic-dose heparin.

Delirium: The Next Vital Sign in the PICU?*

Delirium: The Next Vital Sign in the PICU?*

Systemic inflammation and oxidative stress contribute to acute kidney injury after transcatheter aortic valve implantation.

BackgroundAcute kidney injury (AKI) is a frequent complication of transcatheter aortic valve implantation (TAVI) and has been linked to preexisting comorbidities, peri-procedural hypotension, and systemic inflammation. The extent of systemic inflammation after TAVI is not fully understood. Our aim was to characterize the inflammatory response after TAVI and evaluate its contribution to the mechanism of post-procedural AKI.MethodsOne hundred and five consecutive patients undergoing TAVI at our institution were included. We analyzed the peri-procedural inflammatory and oxidative stress responses by measuring a range of biomarkers (including C-reactive protein [hsCRP], cytokine levels, and myeloperoxidase [MPO]), before TAVI and 6, 24, and 48 hours post-procedure. We correlated this with changes in renal function and patient and procedural characteristics.ResultsWe observed a significant increase in plasma levels of pro-inflammatory cytokines (hsCRP, interleukin 6, tumor necrosis factor alpha receptors) and markers of oxidative stress (MPO) after TAVI. The inflammatory response was significantly greater after transapical (TA) TAVI compared to transfemoral (TF). This was associated with a higher incidence of AKI in the TA cohort compared to TF (44% vs. 8%, respectively, p < 0.0001). The incidence of AKI was significantly lower when N-acetylcysteine (NAC) was given peri-procedurally (12% vs. 38%, p < 0.005). In multivariate analysis, only the TA approach and no use of NAC before the procedure were independent predictors of AKI.ConclusionsTAVI creates a significant post-procedural inflammatory response, more so with the TA approach. Mechanisms of AKI after TAVI are complex. Inflammatory response, hypoperfusion, and oxidative stress may all play a part and are potential therapeutic targets to reduce/prevent AKI.

New insights into sex differences in primary biliary cholangitis. Gender difference in primary biliary cholangitis.

To highlight the clinical characteristics of primary biliary cholangitis on the basis of gender in terms of the extent of liver injury and extra-liver autoimmune expressions. The retrospective study was conducted at the Tri-Service General Hospital, Taiwan, and comprised data of patients aged >20 years diagnosed with primary biliary cholangitis between January 2000 and December 2018. Patients in the control group were randomly selected from the health examination centre. Liver injury manifestations and susceptibilities were analysed along gender lines. The gene expression microarray data from the National Centre for Biotechnology Information Gene Expression Omnibus database was also used to explore the relationship between autoimmune-induced inflammation and androgen response expression. Statistical analysis was done using Graph-Pad Prism 7.0. Of the 75 cases, 63(84%) were females with a mean age of 64.6±1.78 years, and 12(16%%) were males with a mean age of 46.6±5.6 years. Of the 66 controls, 55(83.3%) were females with a mean age of 51.67 years, and 11(16.6%) were males with a mean age of 45.9 years. There were no significant differences in terms of liver profiles related to gender in the control group (p>0.05). Among the cases, male patients showed fewer extrahepatic autoimmune disorders and more severe liver injuries before or after ursodeoxycholic acid treatment (p<0.05). There was a positive correlation between androgen receptor response and the extent of systemic inflammation (p<0.05). Conclusion: The association between androgen receptor responses and inflammation was linked to gender-related hepatic injuries, which may explain why liver inflammation in male patients is generally more severe compared to the female patients. The association between androgen receptor responses and inflammation was linked to gender-related hepatic injuries, which may explain why liver inflammation in male patients is generally more severe compared to the female patients.

Should COVID-19 take advice from rheumatologists?

Should COVID-19 take advice from rheumatologists?

Circulating Senescent T Cells Are Linked to Systemic Inflammation and Lesion Size During Human Cutaneous Leishmaniasis.

Leishmania (Viannia) braziliensis induces American tegumentary leishmaniasis that ranges in severity from the milder form, cutaneous (CL) to severe disseminated cutaneous leishmaniasis. Patients with CL develop a cell-mediated Th1 immune response accompanied by production of inflammatory cytokines, which contribute to parasite control and pathogenesis of disease. Here, we describe the accumulation of circulating T cells with multiple features of telomere dependent-senescence including elevated expression of CD57, KLRG-1, and γH2AX that have short telomeres and low hTERT expression during cutaneous L. braziliensis infection. This expanded population of T cells was found within the CD45RA+CD27− (EMRA) subset and produced high levels of inflammatory cytokines, analogous to the senescence-associated secretory profile (SASP) that has been described in senescent non-lymphoid cells. There was a significant correlation between the accumulation of these cells and the extent of systemic inflammation, suggesting that they are involved in the inflammatory response in this disease. Furthermore, these cells expressed high level of the skin homing receptor CLA and there was a highly significant correlation between the number of these cells in the circulation and the size of the Leishmania-induced lesions in the skin. Collectively our results suggest that extensive activation during the early stages of leishmaniasis drives the senescence of T cells with the propensity to home to the skin. The senescence-related inflammatory cytokine secretion by these cells may control the infection but also contribute to the immunopathology in the disease.

Positive Association Between Neutrophil-Lymphocyte Ratio and Presence of Panoramically Imaged Carotid Atheromas Among Men

Heightened levels of systemic inflammation documented by increased neutrophil-to-lymphocyte ratios (NLRs) characterize a robust atherosclerosis processes evidenced by carotid and coronary artery plaques at ultrasound and angiography with associated strokes and myocardial infarctions (MIs). Therefore, this study investigated whether calcified carotid artery plaques (CCAPs) on panoramic images (PIs), known to herald future stroke and MI, are associated with increased NLRs. Using a cross-sectional study design, electronic medical records and PIs of non-Hispanic white men at least 55years old who were treated by the dental service (January 1, 2017 to December 31, 2017) were retrieved. Two groups of patients (n=50 per group) with plaque (CCAP+) and without plaque (CCAP-) were constituted. The predictor variable was CCAP+ and the outcome variable was the NLR. A t test analyzed the differences in mean NLRs between groups. Other variables of interest, that is, atherogenic risk factors (hypertension, hyperlipidemia, and diabetes mellitus), were included in a logistic regression analysis to assess their influence on the association of CCAP with the NLR. Significance was set at .05 for all tests. The study group of 50 men with CCAP+ (mean age, 71.7±7.47yr) evidenced a mean NLR of 3.07±1.43. The control group of 50 men with CCAP- (mean age, 69.8±9.29yr) evidenced a mean NLR of 2.13±0.68. A t test analysis comparison showed a significant (P=.00007) difference (95% confidence interval, 0.49-1.39). Logistic regression failed to show any relevant relation of the NLR with the covariate and other variables of interest. There is a strong association between CCAP+ in older non-Hispanic white men and extent of systemic inflammation as evidenced by increased NLRs. These plaques are "risk factors or indicators" for future stroke and MI. Therefore, maxillofacial surgeons providing care for patients with CCAP+should consider referring them for a comprehensive cerebrovascular and cardiovascular workup.

Chronic Systemic Inflammation Moderates the Relationship Between Adiposity and Behavioral and Neuroelectric Indices of Attention

PURPOSE: Two-thirds of the US population today is living with overweight or obesity, signifying a serious public health concern. One co-morbidity of obesity is chronic inflammation, which contributes to cardiovascular and metabolic disease, and is often indicated by elevated plasma C-reactive protein (CRP) concentrations. Further, adiposity has been linked to decrements in selective aspects of cognitive function. However, the potential interactive effects of adiposity and inflammation on cognitive function are limited. This study aimed to examine the relationships among plasma CRP concentrations, cognitive function, and adiposity. METHODS: 36 adults (25-45 years) underwent a fasted venous blood draw for measurement of CRP and a dual x-ray absorptiometry (DXA) scan for quantification of whole body adiposity. Cognitive function was assessed using a two-stimulus visual oddball paradigm while underlying event-related brain potentials were recorded. Specifically, the latency of the P3 waveform in a central-parietal region of interest (ROI) was used to index attentional resource allocation and information processing speed, respectively. RESULTS: According to bivariate correlations, plasma CRP was positively associated with whole body percent fat (r=0.55, p<0.001). Whole body percent fat and CRP were negatively correlated with target accuracy (r=-0.28, p=0.048; r=-0.44, p=0.003; respectively). Whole body percent fat was correlated with lower peak latency difference (target peak latency - non-target peak latency) in the ROI (r=-0.38, p=0.01), signifying poorer modulation in cognitive processing speed. Yet, adjustment of plasma CRP using partial correlations revealed that the relationship between adiposity and target accuracy (r=-0.13, p=0.23), and P3 peak latency difference (r=-0.24, p=0.09) was mitigated (All, P>0.05). CONCLUSIONS: The cross-sectional relationship between adiposity and cognitive function was moderated by the extent of systemic inflammation in overweight and obese adults. Future studies are needed to determine whether reducing chronic systemic inflammation via exercise and nutritional manipulations prevents the negative implications of adiposity for cognitive function.

Neutrophil to lymphocyte ratio as the main predictor of peripheral artery disease in regular hemodialysis patients

Cardiovascular disease is the most inducer of morbidity and mortality of chronic kidney disease (CKD) patients who have undergone dialysis. Today, neutrophil to lymphocyte ratio (NLR) is considered an indicator of the severity and extent of systemic inflammation and atherosclerosis in patients with renal and cardiovascular disorders. To examine the relationship between NLR with PAD in regular hemodialysis patients, a cross-sectional study, Ankle- Brachial Index (ABI) measurement and peripheral blood examination was on 72 regular hemodialysis patients ≥6 months. The ABI value ≤0.9 is considered PAD. NLR≥ 3.5 is considered abnormal based on some pre-existing research. Prevalence of PAD is 29.16%. Chi- square test showed significant correlation between NLR with PAD (p = 0.0001), multiplication of Calcium and Phosphorus (p = 0.0001), and type 2 Diabetes Mellitus (T2DM) (p = 0.039), multivariate analysis showed that NLR was an independent predictor for PAD in regular hemodialysis patients (RR = 2.271 p = 0.027). In conclusion, NLR, a new inflammatory marker of peripheral blood examination may serve as a marker of PAD in a regular hemodialysis patient, in addition to the multiplication of Calcium and Phosphorus as well as T2DM.

Serum Vascular Endothelial Growth Factor and Angiopoietin-2 Are Associated with the Severity of Systemic Inflammation Rather than the Presence of Hemoptysis in Patients with Inflammatory Lung Disease

PurposeVascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) are major mediators of angiogenesis and are induced by tissue inflammation and hypoxia. The purpose of this study was to investigate whether serum VEGF and Ang-2 are associated with the presence of hemoptysis and the extent of systemic inflammation in patients with inflammatory lung diseases.Materials and MethodsWe prospectively enrolled 52 patients with inflammatory lung disease between June 2008 and October 2009.ResultsThe median values of VEGF and Ang-2 were 436 pg/mL and 2383 pg/mL, respectively. There was a significant positive correlation between serum Ang-2 and VEGF levels. VEGF levels were not significantly different according to the presence of hemoptysis. C-reactive protein (CRP) and Ang-2 level were significantly higher in patients without hemoptysis (n=26) than in those with hemoptysis (n=26; p<0.001 and p<0.001, respectively). CRP and arterial oxygen tension (PaO2) were significantly correlated with both serum VEGF (p=0.032 and p=0.016, respectively) and Ang-2 levels (p<0.001 and p=0.041, respectively), after adjusting for other factors. Age and the absence of hemoptysis were factors correlated with serum Ang-2 levelsConclusionOur study suggests that serum VEGF and Ang-2 levels are associated with PaO2 and the severity of inflammation rather than the presence of hemoptysis in patients with inflammatory lung diseases. Thus, hemoptysis may not be mediated by increased serum levels of VEGF and Ang-2 in patients with inflammatory lung diseases, and further studies are required to determine the mechanisms of hemoptysis.

Serum neutrophil gelatinase-associated lipocalin at inception of renal replacement therapy predicts survival in critically ill patients with acute kidney injury

IntroductionNeutrophil gelatinase-associated lipocalin (NGAL) is a promising novel biomarker that correlates with the severity and outcome of acute kidney injury (AKI). However, its prognostic utility during the late course of AKI, especially in patients that require renal replacement therapy (RRT) remains unknown. The aim of this study was to evaluate the predictive value of serum NGAL in patients with established AKI at inception of RRT in the intensive care unit (ICU).MethodsSerum NGAL (ELISA methodology) was measured in 109 critically ill patients with AKI at inception of RRT in 7 ICUs of a tertiary care university hospital. The primary outcome studied was 28-day mortality. Secondary outcome measures were ICU length of stay, ventilator-free days, and renal recovery at day 28.ResultsThere was a significant difference in serum NGAL between healthy subjects (median [interquartile range] 39.0 [37.5-42.75] ng/mL), critically ill patients with systemic inflammatory response syndrome (SIRS) (297 [184-490] ng/mL), and critically ill patients with sepsis (708 [365-1301] ng/mL; P < 0.0001), respectively. Multiple linear regression showed that NGAL levels were independently related to the severity of AKI and the extent of systemic inflammation. NGAL levels were higher in non-survivors (430 [303-942] ng/mL) compared to survivors (298 [159-506] ng/mL; P = 0.004). Consistently, Cox proportional hazards regression analysis identified NGAL as a strong independent predictor for 28-day survival (hazard ratio 1.6 (95% confidence interval [CI] 1.15 - 2.23), P = 0.005).ConclusionsThis is the first prospective evaluation of serum NGAL as an outcome-specific biomarker in critically ill patients at initiation of RRT. The results from this study indicate that serum NGAL is as an independent predictor of 28-day mortality in ICU patients with dialysis-dependent AKI.

Syndecan-1 shedding facilitates the resolution of neutrophilic inflammation by removing sequestered CXC chemokines

Heparan sulfate binds to and regulates many inflammatory mediators in vitro, suggesting that it serves an important role in directing the progression and outcome of inflammatory responses in vivo. Here, we evaluated the role of syndecan-1, a major heparan sulfate proteoglycan, in modulating multiorgan host injury responses in murine endotoxemia. The extent of systemic inflammation was similar between endotoxemic syndecan-1-null and wild-type mice. However, high levels of CXC chemokines (KC and MIP-2), particularly at later times after LPS, were specifically sustained in multiple organs in syndecan-1-null mice and associated with exaggerated neutrophilic inflammation, organ damage, and lethality. Syndecan-1 shedding was activated in several organs of endotoxemic wild-type mice, and this associated closely with the removal of tissue-bound CXC chemokines and resolution of accumulated neutrophils. Moreover, administration of a shedding inhibitor exacerbated disease by impeding the removal of CXC chemokines and neutrophils, whereas administration of heparan sulfate inhibited the accumulation of CXC chemokines and neutrophils in tissues and attenuated multiorgan injury and lethality. These data show that syndecan-1 shedding is a critical endogenous mechanism that facilitates the resolution of neutrophilic inflammation by aiding the clearance of proinflammatory chemokines in a heparan sulfate-dependent manner.

Care of the Caregiver: Stress and Dysregulation of Inflammatory Control in Cancer Caregivers

Care of the Caregiver: Stress and Dysregulation of Inflammatory Control in Cancer Caregivers

Relationships Among Regional Arterial Inflammation, Calcification, Risk Factors, and Biomarkers

Background— Fluorodeoxyglucose positron-emission tomography (FDG PET) imaging of atherosclerosis has been used to quantify plaque inflammation and to measure the effect of plaque-stabilizing drugs. We explored how atherosclerotic plaque inflammation varies across arterial territories and how it relates to arterial calcification. We also tested the hypotheses that the degree of local arterial inflammation measured by PET is correlated with the extent of systemic inflammation and presence of risk factors for vascular disease. Methods and Results— Forty-one subjects underwent vascular PET/computed tomography imaging with FDG. All had either vascular disease or multiple risk factors. Forty subjects underwent carotid imaging, 27 subjects underwent aortic, 24 subjects iliac, and 13 subjects femoral imaging. Thirty-three subjects had a panel of biomarkers analyzed. We found strong associations between FDG uptake in neighboring arteries (left versus right carotid, r =0.91, P &lt;0.001; ascending aorta versus aortic arch, r =0.88, P &lt;0.001). Calcification and inflammation rarely overlapped within arteries (carotid artery FDG uptake versus calcium score, r =−0.42, P =0.03). Carotid artery FDG uptake was greater in those with a history of coronary artery disease (target-to-background ratio, 1.83 versus 1.61, P &lt;0.01) and in males versus females (target-to-background ratio, 1.83 versus 1.63, P &lt;0.05). Similar findings were also noted in the aorta and iliac arteries. Subjects with the highest levels of FDG uptake also had the greatest concentrations of inflammatory biomarkers (descending aorta target-to-background ratio versus matrix metalloproteinase 3, r =0.53, P =0.01; carotid target-to-background ratio versus matrix metalloproteinase 9, r =0.50, P =0.01). Nonsignificant positive trends were seen between FDG uptake and levels of interleukin-18, fibrinogen, and C-reactive protein. Finally, we found that the atheroprotective biomarker adiponectin was negatively correlated with the degree of arterial inflammation in the descending aorta ( r =−0.49, P =0.03). Conclusions— This study shows that FDG PET imaging can increase our knowledge of how atherosclerotic plaque inflammation relates to calcification, serum biomarkers, and vascular risk factors. Plaque inflammation and calcification rarely overlap, supporting the theory that calcification represents a late, burnt-out stage of atherosclerosis. Inflammation in one arterial territory is associated with inflammation elsewhere, and the degree of local arterial inflammation is reflected in the blood levels of several circulating biomarkers. We suggest that FDG PET imaging could be used as a surrogate marker of both atherosclerotic disease activity and drug effectiveness. Prospective, event-driven studies are now underway to determine the role of this technique in clinical risk prediction.

Calcitonin precursors: early markers of gut barrier dysfunction in patients with acute pancreatitis.

Severe acute pancreatitis is associated with an early increase in intestinal permeability and endotoxemia. Endotoxin is a potent stimulator for the production and release of procalcitonin and its components (calcitonin precursors; [CTpr]). The aim of this study is to evaluate the role of plasma CTpr as an early marker for gut barrier dysfunction in patients with acute pancreatitis. Intestinal permeability to macromolecules (polyethylene glycol 3350), serum endotoxin and antiendotoxin core antibodies, plasma CTpr, and serum C-reactive protein (CRP) were measured on admission in 60 patients with acute pancreatitis. Attacks were classified as mild (n = 48) or severe (n = 12) according to the Atlanta criteria. Compared with mild attacks of acute pancreatitis, severe attacks were significantly associated with an increase in intestinal permeability index (median: 0.02 vs. 0.006, P < 0.001), the frequency of endotoxemia (73% vs. 41%, P = 0.04), and the extent of depletion of serum IgM antiendotoxin antibodies (median: 43 MMU vs. 100 MMU, P = 0.004). Plasma CTpr levels were significantly elevated in patients with severe attacks compared with mild attacks on both the day of admission and on day 3 (median: 64 vs. 22 fmol/mL, P = 0.03; and 90 vs. 29 fmol/mL, P = 0.003 respectively). A positive and significant correlation was observed between the admission serum endotoxin and plasma CTpr levels on admission (r = 0.7, P < 0.0001) and on day 3 (r = 0.96, P < 0.0001), and between plasma CTpr on day 7 and the intestinal permeability index (r = 0.85, P = 0.0001). In contrast, only a weak positive correlation was observed between peak serum levels of CRP and plasma CTpr on admission (r = 0.3, P = 0.017) and on day 7 (r = 0.471, P = 0.049), as well as between CRP and each of the admission serum endotoxin (r = 0.3, P = 0.03) and the intestinal permeability index (r = 0.375, P = 0.007). In patients with acute pancreatitis, plasma concentrations of CTpr appear to reflect more closely the derangement in gut barrier function rather than the extent of systemic inflammation.