Higher Interleukin-6 Research Articles

TNF-α versus IL-6 Genes Expression levels in Active Rheumatoid Arthritis: Clinical and Laboratory Determinants

This study intended to compare the expression levels of tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) genes in active rheumatoid arthritis (RA) patients who were receiving conventional synthetic disease-modifying drugs (csDMARDs) and to find the clinical and laboratory determinants affecting TNF-α and IL-6 genes expression levels among active RA patients. This was a cross sectional study that included 108 active RA patients who were receiving csDMARDs. A detailed history was reviewed for all patients in addition to a complete physical examination and assessment of the 28-joint disease activity score (DAS28). Some laboratory measures were recorded as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and serum rheumatoid factor (RF). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure expression levels of TNF- α and IL-6 genes. In active RA patients, TNF-α and IL-6 genes expression levels were significantly correlated to each other (p<0.001, r=0.788). Also, both had positive correlations with the age and DAS28 among RA patients (p<0.001). IL-6 and TNF-α expression levels were significantly higher in RA patients with high DAS28 scores (p<0.001). Most RA patients (81.5%) had relatively higher IL-6 gene expression levels than TNF-α. RA patients with relatively high IL-6 expression levels were younger in age and had shorter disease duration and less DAS28 than RA patients with relatively high TNF-α gene expression levels. In addition, they had higher CRP and RF levels. Young age was detected as a significant predictor for relatively higher IL-6 gene expression levels than TNF-α. In conclusion, most active RA patients had higher IL-6 gene expression levels than TNF-α. Young age could be considered a significant predictor for relatively high IL-6 gene expression levels among active RA patients.

Large Right Ventricular Hemangioma Presented as Acute Pulmonary Embolism at Two Weeks Post-COVID19 Vaccination: A Case Report

Background: Right ventricular hemangioma is very rare. Corona Virus disease (COVID-19) and vaccination were documented to cause diverse thromboembolic phenomena. Case presentation: We report a large right ventricular hemangioma presented as acute pulmonary embolism two weeks after COVID-19 vaccination associated with acute kidney injury and significantly elevated Interleukin-6 (IL-6). There was no thrombocytopenia; therefore, the diagnosis of vaccine-induced immune thrombotic thrombocytopenia (VIIT) was deemed unlikely. The patient underwent emergency cardiac surgery. The mass was excised through a right atriotomy, and tricuspid annuloplasty was done. IL-6 normalized after six days with resolution of acute kidney injury. Conclusions: Pulmonary embolism is a rare presentation of the right ventricular hemangioma, and COVID-19 vaccination could play a role in this presentation. Cardiac hemangioma could be associated with high IL-6 that resolves with excision.

Association between aging-related biomarkers and longitudinal trajectories of intrinsic capacity in older adults.

Intrinsic capacity (IC), the composite of physical and mental capacities, declines with age at different rates and patterns between individuals. We aimed to investigate the association between longitudinal IC trajectories and plasma biomarkers of two hallmarks of aging-chronic inflammation and mitochondrial dysfunction-in older adults. From the Multidomain Alzheimer Preventive Trial (MAPT), we included 1271 community-dwelling older people (mean [SD] age = 76.0 [4.3] years) with IC data over four years. Group-based multi-trajectory modeling was performed to identify clusters of the participants with similar longitudinal patterns across four IC domains: cognition, locomotion, psychology, and vitality. Five IC multi-trajectory groups were determined: low in all domains (8.4%), low locomotion (24.6%), low psychological domain (16.7%), robust (i.e., high in all domains except vitality; 28.3%), and robust with high vitality (22.0%). Compared to the best trajectory group (i.e., robust with high vitality), elevated levels of plasma interleukin-6 (IL-6), tumor necrosis factor receptor-1 (TNFR-1), and growth differentiation factor-15 (GDF-15) were associated with a higher risk of belonging to the "low in all domains" group (IL-6: relative risk ratio (RRR) [95% CI] = 1.42 [1.07 - 1.88]; TNFR-1: RRR = 1.46 [1.09 - 1.96]; GDF-15: RRR = 1.99 [1.45 - 2.73]). Higher IL-6 and GDF-15 also increased the risk of being in the "low locomotion" group. GDF-15 outperformed other biomarkers by showing the strongest associations with IC trajectory groups. Our findings found that plasma biomarkers reflecting inflammation and mitochondrial impairment distinguished older people with multi-impaired IC trajectories from those with high-stable IC.

PM2.5-bound metals and blood metals are associated with pulmonary function and Th17/Treg imbalance: A panel study of asthmatic adults

Growing research has demonstrated that exposure to fine particulate matter (PM2.5) was associated with decreased pulmonary function and obvious inflammatory response. However, few pieces of research focus on the effects of PM2.5-bound metals on people with asthma. Here, we assessed whether PM2.5 and PM2.5-bound metals exposure could worsen pulmonary function in asthmatic patients and further elucidate the possible mechanisms. Thirty-four asthmatic patients were recruited to follow up for one year with eight visits in 2019–2020 in Taiyuan City, China. The index of pulmonary function was detected and blood and nasal epithelial lining fluid (ELF) samples were acquired for biomarkers measurement at each follow-up. Linear mixed-effect (LME) models were used to evaluate the relations between PM2.5, PM2.5-bound metals, and blood metals with lung function and biomarkers of Th17/Treg balance. The individual PM2.5 exposure concentration varied from 37 μg/m3 to 194 μg/m3 (mean: 59.63 μg/m3) in the present study. An interquartile range (IQR) increment of PM2.5 total mass was associated with a faster decline in maximal mid-expiratory flow (MMEF) and higher interleukin-23 (IL-23). PM2.5-bound metals [e.g. copper (Cu), nickel (Ni), manganese (Mn), titanium (Ti), and zinc (Zn)] were significantly associated with IL-23 (Cu: 5.1126%, 95% CI: 9.3708, 0.8544; Mn: 14.7212%, 95% CI: 27.926, 1.5164; Ni: 1.0269%, 95% CI: 2.0273, 0.0264; Ti: 16.7536%, 95% CI: 31.6203, 1.8869; Zn: 24.5806%, 95% CI: 46.609, 2.5522). Meanwhile, blood lead (Pb) and Cu were associated with significant declines of 0.382–3.895% in MMEF and maximum ventilatory volume (MVV). Blood Pb was associated with descending transforming growth factor β (TGF-β). In conclusion, exposure to PM2.5-bound metals and blood metals is a risk factor for decreased pulmonary function, especially in small airways. These alterations might be partially attributed to the imbalance of Th17/Treg.

Preventive effects of sodium hyaluronate combined with pelvic floor neuromuscular electrical stimulation on the intrauterine adhesions in women after abortion.

The aim of this study was to investigate the clinical efficacy of combining pelvic floor neuromuscular stimulation treatment (NMES) with sodium hyaluronate in preventing intrauterine adhesions (IUA) following abortion. A total of 140 women who underwent artificial abortion were enrolled. The control group received only an intrauterine injection of sodium hyaluronate post-surgery, while the observation group received both the injection and daily pelvic floor NMES treatments, beginning on the day after the abortion. Monthly follow-ups on menstrual conditions were conducted for six months post-surgery. Fasting venous blood samples from both groups were collected on the second day post-abortion and the day after treatment. Transvaginal color Doppler ultrasound was used on the second day post-abortion and the 15th day post the first menstrual cycle to measure endometrial thickness, and the pulsatility and resistance indices of the endometrial spiral arteries. Over the six-month follow-up, the combination therapy group exhibited a notably lower IUA incidence compared to the control group (2.8% vs. 15.7%). Furthermore, combined treatment significantly expedited post-abortion menstrual recovery, reduced vaginal bleeding volume and duration (P < 0.001). It also increased endometrial thickness and reduced the endometrial spiral artery's pulsatility and resistance indices (P < 0.05). In addition, lower serum tumor necrosis factor alpha (TNF-α) and higher interleukin-10 (IL-10) were found in the observation group compared to the control group (P < 0.05). The combination therapy offers significant advantages in preventing and reducing IUA after abortion, resulting in a substantial reduction in IUA occurrence.

Effect of Non-Surgical Periodontal Therapy on Renal Function Among Pre-Dialysis Chronic Kidney Disease Patients

Background: Association between chronic kidney disease (CKD) and periodontitis has been established. The aim of this study was to determine the effect of non-surgical periodontal therapy (NSPT) on renal function among pre-dialysis CKD patients. Methods: This is an intervention study involving 120 CKD participants. 60 CKD participants constituted the intervention group while 60 CKD participants constituted the control group. Blood samples were collected from all participants at baseline and after 3 months for the measurement of high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and serum creatinine for the estimation of glomerular filtration rate (eGFR). Periodontal clinical examination was performed in all participants at six sites per tooth by the researcher for the measurement of Probing Pocket Depth (PPD) and Clinical Attachment Loss (CAL). The intervention group received NSPT (scaling and root planning) and oral hygiene motivation while the control group received only oral hygiene motivation only. Re-evaluation was done after 3 months. Results: In this study, three months post NSPT, PPD reduced from 5.44mm to 3.17mm (P &lt; 0.01) and CAL from 6.29mm to 4.29mm (P &lt; 0.01) in the intervention group. There was also a statistically significant reduction in the mean values of hsCRP and IL-6 at 3 months post NSPT in the intervention group (p&lt;0.01). However, there was no reduction observed in the control group (p=0.59 and 0.66) respectively. Estimated GFR (eGFR) for the intervention group improved from 40.55 mL/min/1.73m2 to 43.22 mL/min/1.73m2 three months post NSPT (P &lt; 0.01). Conclusion: This study demonstrates the potential beneficial effects of NSPT on renal function among pre-dialysis CKD participants as estimated by improvement in eGFR.

Transcriptomic and proteomic assessment of tocilizumab response in a randomized controlled trial of patients hospitalized with COVID-19

High interleukin (IL)-6 levels are associated with greater COVID-19 severity. IL-6 receptor blockade by tocilizumab (anti-IL6R; Actemra) is used globally for the treatment of severe COVID-19, yet a molecular understanding of the therapeutic benefit remains unclear. We characterized the immune profile and identified cellular and molecular pathways modified by tocilizumab in peripheral blood samples from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial of the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19. We identified markers of inflammation, lymphopenia, myeloid dysregulation, and organ injury that predict disease severity and clinical outcomes. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab and identified novel pharmacodynamic biomarkers. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysregulation associated with severe COVID-19, indicating greater anti-inflammatory activity relative to placebo and potentially leading to faster recovery in patients hospitalized with COVID-19.

Exploring the role of tryptophanyl-tRNA synthetase and associations with inflammatory markers and clinical outcomes in COVID-19 patients: A case-control study

Tryptophanyl-tRNA synthetase (WRS) is a critical enzyme involved in protein synthesis, responsible for charging tRNA with the essential amino acid tryptophan. Recent studies have highlighted its novel role in stimulating innate immunity against bacterial and viral infections. However, the significance of WRS in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains elusive. In this study, we aimed to investigate the complex interplay between WRS, inflammatory markers, Toll-like receptor-4 (TLR-4), and clinical outcomes in coronavirus disease 19 (COVID-19) patients. A case-control investigation comprised 127 COVID-19 patients, carefully classified as severe or moderate upon admission, and 112 healthy individuals as a comparative group. Blood samples were meticulously collected before treatment initiation, and WRS, interleukin-6 (IL-6), and C-reactive protein (CRP) concentrations were quantified using a well-established commercial ELISA kit. Peripheral blood mononuclear cells (PBMCs) were isolated from the blood samples, and RNA was extracted for cDNA synthesis. Semi-quantitative real-time polymerase chain reaction (PCR) was employed to assess the relative expression of TLR-4. COVID-19 patients exhibited elevated levels of WRS, IL-6, CRP, and TLR-4 expression compared to healthy individuals, with the severe group displaying significantly higher levels than the moderate group. Notably, severe patients demonstrated substantial fluctuations in CRP, IL-6, and WRS levels over time, a pattern not observed in their moderate counterparts. Although no significant distinctions were observed in the dynamic alterations of WRS, IL-6, CRP, and TLR-4 expression between deceased and surviving patients, a trend emerged indicating higher IL-6_1 levels in deceased patients and elevated lactate dehydrogenase (LDH) levels in severe patients who succumbed to the disease. This pioneering research highlights the dynamic alterations of WRS in COVID-19 patients, providing valuable insights into the correlation between WRS, inflammatory markers, and disease severity within this population. Understanding the role of WRS in SARS-CoV-2 infection may open new avenues for therapeutic interventions targeting innate immunity to combat COVID-19.

Plasma Interleukin-6 (IL-6), Angiopoietin-2, and C-Reactive Protein Levels Predict Subsequent Type 1 Myocardial Infarction in Persons With Treated HIV Infection.

HIV infection leads to endothelial activation, promoting platelet adhesion, and accelerating atherosclerosis. Our goal was to determine whether biomarkers of endothelial activation and hemostasis/thrombosis were elevated in people with treated HIV (PWH) before myocardial infarction (MI). In a case-control study nested within the CFAR Network of Integrated Clinical Systems (CNICS) cohort, we compared 69 adjudicated cases with type 1 MI with 138 controls matched for antiretroviral therapy regimen. We measured angiopoietin-1, angiopoietin-2 (ANG-2), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), von Willebrand factor, C-reactive protein (CRP), interleukin-6 (IL-6), plasminogen activation inhibitor-1, P-selectin, serum amyloid-A, soluble CD14, and apolipoprotein A1 in stored plasma. Conditional logistic regression identified associations with subsequent MI, with and without adjustment for Atherosclerotic Cardiovascular Disease (ASCVD) and Veterans Aging Cohort Study (VACS) scores. Higher IL-6 was associated with MI after adjustment for ASCVD score (adjusted odds ratio [AOR] 1.51, 95% confidence interval [95% CI]: 1.05 to 2.17 per standard-deviation-scaled log 2 increment). In a separate model adjusting for VACS score, higher ANG-2 (AOR 1.49, 95% CI: 1.04 to 2.14), higher CRP (AOR 1.45, 95% CI: 1.06 to 2.00), and higher IL-6 (AOR 1.68, 95% CI: 1.17 to 2.41) were associated with MI. In a sensitivity analysis excluding PWH with viral load ≥400 copies/mL, higher IL-6 remained associated with MI after adjustment for ASCVD score and after adjustment for VACS score. Among PWH, higher levels of plasma IL-6, CRP, and ANG-2 predict subsequent type 1 MI, independent of conventional risk scores. IL-6 had the most consistent associations with type 1 MI, regardless of viral load suppression.

High expression of IL6 and decrease in immune cells in COVID-19 patients combined with myocardial injury.

Myocardial injury, as a serious complication of coronavirus disease-2019 (COVID-19), increases the occurrence of adverse outcomes. Identification of key regulatory molecules of myocardial injury may help formulate corresponding treatment strategies and improve the prognosis of COVID-19 patients. Gene Set Enrichment Analysis (GSEA) was conducted to identify co-regulatory pathways. Differentially expressed genes (DEGs) in GSE150392 and GSE169241 were screened and an intersection analysis with key genes of the co-regulatory pathway was conducted. A protein-protein interaction (PPI) network was constructed to screen for key regulatory genes. Preliminarily screened genes were verified using other datasets to identify genes with consistent expression. Based on the hierarchical cluster, we divided the patients from GSE177477 into high- and low-risk groups and compared the proportion of immune cells. A total of 267 COVID-19 patients from the Zhejiang Provincial Hospital of Chinese Medicine from December 26, 2022, to January 11, 2023, were enrolled to verify the bioinformatics results. Univariate and multivariate analyses were performed to analyze the risk factors for myocardial injury. According to high-sensitivity troponin (hsTnI) levels, patients with COVID-19 were divided into high- and low-sensitivity groups, and interleukin 6 (IL6) expression and lymphocyte subsets were compared. Patients were also divided into high and low groups according to the IL6 expression, and hsTnI levels were compared. Interleukin signaling pathway and GPCR ligand binding were shown to be co-regulatory pathways in myocardial injury associated with COVID-19. According to the hierarchical cluster analysis of seven genes (IL6, NFKBIA, CSF1, CXCL1, IL1R1, SOCS3, and CASP1), patients with myocardial injury could be distinguished from those without myocardial injury. Age, IL6 levels, and hospital stay may be factors influencing myocardial injury caused by COVID-19. Compared with COVID-19 patients without myocardial injury, the levels of IL6 in patients with myocardial injury increased, while the number of CD4+ T cells, CD8+ T cells, B cells, and NK cells decreased (P<0.05). The hsTnI levels in COVID-19 patients with high IL6 levels were higher than those in patients with low IL6 (P<0.05). The COVID-19 patients with myocardial injury had elevated IL6 expression and decreased lymphocyte counts. IL6 may participate in myocardial injury through the interleukin signaling pathway.

Ectodomain Shedding by ADAM17 Increases the Release of Soluble CD40 from Human Endothelial Cells under Pro-Inflammatory Conditions.

Homozygosity for the C allele of the -1T>C single nucleotide polymorphism (SNP) of the CD40 gene (rs1883832) is associated with susceptibility to coronary heart disease (CHD), enhanced CD40 expression, and shedding. The disintegrin metalloprotease ADAM17 can cleave various cell surface proteins. This study investigates an association between ADAM17-mediated CD40 shedding and inflammation in CC genotype human endothelial cells. Human umbilical vein endothelial cells (HUVEC) carrying the CC genotype were stimulated with soluble CD40 ligand (sCD40L) or tumor necrosis factor-α (TNFα). Messenger RNA and protein expression were determined with standard methods. Levels of high sensitive c-reactive protein (hs-CRP), interleukin-6 (IL-6), and sCD40 in plasma samples from patients with CHD were assessed using ELISA. ADAM17 surface abundance was elevated following stimulation with CD40L and TNFα just as its regulator iRhom2. Inhibition of ADAM17 prevented TNFα-induced sCD40 and soluble vascular cell adhesion molecule-1 release into the conditioned medium and reinforced CD40 surface abundance. Secondary to inhibition of ADAM17, stimulation with CD40L or TNFα upregulated monocyte chemoattractant protein-1 mRNA and protein. Levels of sCD40 and the inflammatory biomarkers hs-CRP and IL-6 were positively correlated in the plasma of patients with CHD. We provide a mechanism by which membrane-bound CD40 is shed from the endothelial cell surface by ADAM17, boosting sCD40 formation and limiting downstream CD40 signaling. Soluble CD40 may represent a robust biomarker for CHD, especially in conjunction with homozygosity for the C allele of the -1T>C SNP of the CD40 gene.

Expression of the readthrough transcript CiDRE in alveolar macrophages boosts SARS-CoV-2 susceptibility and promotes COVID-19 severity

Lung infection during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the angiotensin-I-converting enzyme 2 (ACE2) receptor induces a cytokine storm. However, the precise mechanisms involved in severe COVID-19 pneumonia are unknown. Here, we showed that interleukin-10 (IL-10) induced the expression of ACE2 in normal alveolar macrophages, causing them to become vectors for SARS-CoV-2. The inhibition of this system in hamster models attenuated SARS-CoV-2 pathogenicity. Genome-wide association and quantitative trait locus analyses identified a IFNAR2-IL10RB readthrough transcript, COVID-19 infectivity-enhancing dual receptor (CiDRE), which was highly expressed in patients harboring COVID-19 risk variants at the IFNAR2 locus. We showed that CiDRE exerted synergistic effects via the IL-10-ACE2 axis in alveolar macrophages and functioned as a decoy receptor for type I interferons. Collectively, our data show that high IL-10 and CiDRE expression are potential risk factors for severe COVID-19. Thus, IL-10R and CiDRE inhibitors might be useful COVID-19 therapies.

High serum interleukin-6 concentration upon admission is predictive of disease severity in paediatric trauma patients.

Trauma is the leading cause of death among children worldwide. The inflammatory response of paediatric patients to multiple injuries can be monitored using serum interleukin-6 (IL-6) levels. This study aimed to assess the value of IL-6 levels in predicting the severity of paediatric trauma and its clinical association with disease activity. We prospectively tested serum IL-6 levels and evaluated the Paediatric Trauma Score (PTS) and other clinical data among 106 paediatrics trauma patients from January 2022 to May 2023 at the Emergency Department of the Xi'an Children's Hospital in China. The relationship between IL-6 and trauma severity levels by PTS was analyzed statistically. IL-6 levels were elevated in 76 (71.70%) of the 106 paediatric patients with trauma. Spearman's test showed a significant negative linear correlation between IL-6 and PTS (rs = -0.757, p < 0.001). IL-6 levels were moderate positively correlated with alanine aminotransferase, aspartate aminotransferase, white blood cells, blood lactic acid and interleukin 10 (rs = 0.513, 0.600, 0.503, 0.417, 0.558, p < 0.01). IL-6 levels were positively correlated with hypersensitive C-reactive protein and glucose (rs = 0.377, rs = 0.389, respectively, p < 0.001). IL-6 levels were negatively correlated with fibrinogen and PH (rs = -0.434, p < 0.001; rs = -0.382, respectively, p < 0.001). Binary scatter plots further demonstrated higher levels of IL-6 correlated with lower PTS scores. Serum IL-6 levels significantly increased with increasing severity of paediatric trauma. Serum levels of IL-6 can function as important indicators for predicting disease severity and activity in paediatric trauma patients.

Increased serum IL-12 levels are associated with adverse IVF outcomes

Interleukin-12 (IL-12) is involved in the occurrence and development of many diseases, such as preeclampsia, intrauterine growth restriction, preterm labor, and recurrent pregnancy losses. This study aimed to determine whether a high serum level of IL-12 was associated with adverse in vitro fertilization (IVF) outcomes. Included infertile women with high serum IL-12 levels who underwent IVF cycles and infertile controls with pure tubal etiology. The impact of serum IL-12 on baseline and clinical characteristics, immune-related indicators, IVF laboratory, and pregnancy outcomes were compared. In addition, the correlation of follicular fluid IL-12 and serum IL-12 level and the role of IL-12 in apoptosis of granulosa cells (GCs) was investigated. Women with high serum IL-12 levels had lower numbers of retrieved oocytes, embryos, perfect and available embryos, lower rates of perfect and available embryos, and blastocyst formation. Additionally, significantly higher levels of serum Th1, Th2, and Th17-related cytokines were observed in women with high serum IL-12 levels than in the controls. Meanwhile, the follicular fluid IL-12 levels were positively correlated with serum IL-12 levels, and IL-12 promoted apoptosis of GCs in vitro. We concluded that women with serum high IL-12 levels may have adverse IVF outcomes, partly by promoting apoptosis of GCs. Therefore, early screening for cytokines, especially IL-12, and appropriate consultation for couples receiving IVF-ET should be considered. In addition, specific immune and inflammatory mechanisms associated with high serum IL-12 levels should be further explored.

Circulating Biomarkers, Fraction of Exhaled Nitric Oxide, and Lung Function in Patients With Human Immunodeficiency Virus and Tuberculosis.

Identification of proinflammatory factors responding to Mycobacterium tuberculosis is important to reduce long-term sequelae of pulmonary tuberculosis (TB). We examined the association between plasma biomarkers, the fraction of exhaled nitric oxide (FeNO), and lung function among a prospective cohort of 105 adults newly diagnosed with TB/human immunodeficiency virus (HIV) in South Africa. Participants were followed for 48 weeks from antiretroviral therapy (ART) initiation with serial assessments of plasma biomarkers, FeNO, lung function, and respiratory symptoms. Linear regression and generalized estimating equations were used to examine the associations at baseline and over the course of TB treatment, respectively. At baseline, higher FeNO levels were associated with preserved lung function, whereas greater respiratory symptoms and higher interleukin (IL)-6 plasma levels were associated with worse lung function. After ART and TB treatment initiation, improvements in lung function were associated with increases in FeNO (rate ratio [RR] = 86 mL, 95% confidence interval [CI] = 34-139) and decreases in IL-6 (RR = -118 mL, 95% CI = -193 to -43) and vascular endothelial growth factor ([VEGF] RR = -178 mL, 95% CI = -314 to -43). Circulating IL-6, VEGF, and FeNO are associated with lung function in adults being treated for TB/HIV. These biomarkers may help identify individuals at higher risk for post-TB lung disease and elucidate targetable pathways to modify the risk of chronic lung impairment among TB survivors.

Systemic pro- and anti-inflammatory profiles in acute non-specific low back pain: An exploratory longitudinal study of the relationship to six-month outcome.

Pro-inflammatory molecules are thought to underpin the development of chronic low back pain (LBP). Although research has begun to explore the association between pro-inflammatory molecules in acute LBP and long-term outcome, no study has explored the role of anti-inflammatory molecules. We aimed to explore whether levels of systemic pro- and anti-inflammatory molecules 1) changed over a period of six months from the onset of acute LBP; 2) differed between people who were recovered (N = 11) and unrecovered (N = 24) from their episode of LBP at six months; 3) baseline psychological factors were related to inflammatory molecule serum concentrations at baseline, three and six months. We retrospectively included participants with acute LBP included from a larger prospective trial and examined blood samples for the measurement of pro- and anti-inflammatory molecules and measures of pain, disability, and psychological factors at baseline, three and six months. The serum concentrations of pro- and anti-inflammatory molecules did not differ over time when compared between participants who recovered and those who did not recover at six-month follow-up. At three months, the unrecovered group had higher interleukin (IL)-8 and IL-10 serum concentrations than the recovered group. Baseline psychological factors were not related to inflammatory molecules at any time point. This exploratory study showed that levels of systemic inflammatory molecules did not change over the course of LBP, irrespective of whether people were recovered or unrecovered at six months. There was no relationship between acute-stage psychological factors and systemic inflammatory molecules. Further investigation is needed to elucidate the contribution of pro- and anti-inflammatory molecules to long-term LBP outcome.

Generation of IL-2-Fc-antibody conjugates by click chemistry.

Immunocytokines (ICKs) are antibody directed cytokines produced by genetic fusion of an antibody to a cytokine. We now show that antibodies conjugated by click chemistry to interleukin-2 (IL-2)-Fc form fully active conjugates, and in one example, equivalent activity to a genetically produced ICK. An IL-2-Fc fusion protein was optimized for click chemistry at hinge cysteines using protein stabilizing IL-2 mutations at Lys35 and Cys125 and Fc hinge mutations at Cys142 and Cys148. The IL-2-Fc fusion protein with K35E and C125S mutations with 3 intact hinge cysteines, designated as IL-2-Fc Par, was selected based on its minimal tendency to aggregate. IL-2-Fc-antibody clicked conjugates retained high IL-2 activity and bound target antigens comparable to parent antibodies. An IL-2-Fc-anti-CEA click conjugate showed comparable anti-tumor activity to an anti-CEA-IL-2 ICK in immunocompetent CEA transgenic mice bearing CEA positive orthotopic breast tumors. Significant increases in IFNγ+ /CD8+ and decreases in FoxP3+ /CD4+ T-cells were found for the clicked conjugate and ICK therapies, suggesting a common mechanism of tumor reduction. The production of antibody targeted IL-2 therapy via a click chemistry approach is feasible with comparable activity to genetically produced ICKs with the added advantage of multiplexing with other monoclonal antibodies.

#5655 NEUTROPHIL TO LYMPHOCYTE RATIO, TOTAL IRON BINDING CAPACITY, SERUM ALBUMIN AND SYSTEMIC INFLAMMATION IN CHILDREN WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims Chronic kidney disease (CKD) is widely linked to chronic inflammation, with a higher incidence in the advanced stages of the disease. Recognition of systemic inflammation may be useful for prompt diagnosis and management of various CKD related disorders and may open the door towards the development and application of anti-inflammatory strategy treatments. This case-control and cross-sectional study investigates the association of neutrophil to lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), total iron binding capacity (TIBC) and serum albumin with high serum interleukin-6 (IL-6) in children with chronic kidney disease (CKD). Method NLR and PLR were measured in 53 patients (median age: 12.9 years) and 25 healthy controls, stratified by age and sex. Lipid and iron profile, glucose tolerance parameters, serum albumin, uric acid and IL-6 were measured in the patient group. Results Compared to controls, NLR and PLR were higher in patients (p = 0.004 and p = 0.032 respectively), and particularly in those with CKD on dialysis (CKD 5D) (17 patients) (p&amp;lt;0.001 and p = 0.001). LnIL-6 was correlated to NLR (rs = 0.344, p = 0.014), albumin (rs = -0.350, p = 0.011) and TIBC (rs = -0.345, p = 0.012) after adjustment for CKD stage, while the correlation between lnIL-6 and PLR was not significant (rs = 0.206, p = 0.151). Patients with NLR ≥1.7, TIBC ≤300 μg/dl and albumin ≤3.8 g/dl presented a higher risk for increased IL-6 (15 patients) regardless CKD stage (OR 5.499, 95% CI 1.272-22.017, p = 0.016, OR 9.818, 95% CI 2.311-41.706, p = 0.002 and OR 7.543, 95% CI 1.891-30.083, p = 0.004). NLR ≥1.7 and TIBC≤ 300 μg/dl predicted high IL-6 with the highest sensitivity (73.3%), while NLR ≥1.7, TIBC≤ 300 μg/dl and serum albumin ≤ 3.8 g/dl with the highest specificity (97.4%). Conclusion Both NLR and PLR increase in pediatric CKD, especially in CKD 5D. NLR rather than PLR may serve as diagnostic marker of systemic inflammation in pediatric CKD, along with TIBC and serum albumin.

#3437 THE ASSOCIATION OF INTERLEUKIN-6 TO ALBUMIN RATIO WITH MORTALITY IN PATIENTS WITH KIDNEY FAILURE

Abstract Background and Aims Systemic inflammation - characterized by high interleukin-6 (IL-6) and low albumin circulating concentrations - associates with worse outcomes in patients with kidney failure (KF). We examined the value of IL-6 to albumin ratio (IAR) to stratify risk of death in KF patients. Method In 435 incident dialysis patients (median age 56 years, 61.8% male, 31% diabetes mellitus (DM), 38.4% cardiovascular (CV) disease (CVD)), plasma IL-6 and albumin were measured at baseline to calculate IAR. We performed receiver operating characteristic curve (ROC) to compare the discriminatory performance of albumin, IL-6 and IAR for predicting all-cause and CV mortality. We divided patients into IAR tertiles and analysed: 1) cumulative incidence of all-cause mortality and CV mortality censored for renal transplantation during follow up of up to 60 months; 2) the association of IAR and all-cause and CV mortality risk according to Fine-Gray analysis taking renal transplantation as competing risk; and 3) the restricted mean survival time (RMST) and differences of RMST (∆RMST) between IAR tertiles to describe quantitative differences of survival time. Results Among 435 patients, 146 patients (33.6%) died, and 175 (40.2%) patients underwent renal transplantation during median 24.9 months of follow-up; 83 (56.8%) of the 146 deaths were due to CVD. The area under the ROC curve (AUC) of IAR (0.696 for all-cause mortality; 0.657 for CV mortality) was higher than that of both albumin and IL-6. As shown in Fig. 1 A and B: 1) the cumulative incidence of all-cause and CV mortality of patients in middle and high IAR tertiles was significantly higher than in low IAR tertile; 2) higher IAR associated with higher risk of all-cause (sub-hazard ratio (sHR) 1.93, 95% confidence interval (CI) 1.22-3.06 for high IAR tertile) and CV mortality (sHR 1.99, 95% CI 1.03-3.87 for middle IAR tertile) risk after adjusting for age, sex, DM, CVD, and smoking; and 3) ∆RMST at 59 months showed shorter survival time in middle and high IAR tertiles compared with low IAR tertile for all-cause (∆RMST -6.21 months for middle vs low tertile; ∆RMST -11.4 months for high vs low tertile) and CV mortality (∆RMST -4.73 months for middle vs low tertile; ∆RMST -7.49 months for high vs low tertile). Conclusion Higher IAR was independently associated with significantly higher all-cause and CV mortality risk in KF patients. These results suggest that IAR may provide useful prognostic information in patients with KF.

#3195 PATIENTS ON HD WITH CENTRAL CATHETERS LOCKED WITH TAUROLIDINE HAVE A SIMILAR INFLAMMATORY PROFILE TO SUBJECTS WITH NATIVE ARTERIOVENOUS FISTULA

Abstract Background and Aims Inflammation is a near-universal condition in haemodialysis (HD) patients, which contributes to increased complications, morbidity and mortality. The inflammatory profile is enhanced in subjects who need a central venous catheter (CVC) as vascular access in comparison with patients with native arteriovenous fistula (AVF), the optimal vascular access for HD. The aim of the present study was to analyse the inflammatory profile of HD patients according to their vascular access (CVC vs AVF), and to evaluate whether Taurolidine-citrate-heparin lock solution (TCH; taurolidine 1.35%, citrate 4% and heparin 500 IU) is able to modulate the inflammatory state of patients with CVC towards an inflammatory profile similar to that observed in subjects with AVF. Method A total of 109 patients with AVF or tunneled CVC under regular haemodialysis for more than 6 months were screened. Exclusion criteria included intercurrent infections in the previous 3 months, active inflammatory or immunologic diseases, and treatment with antibiotics or drugs affecting the immune system. Finally, 85 patients were included in the study and classified according to the vascular access: 25 patients with AVF and 60 with CVC. Subsequently, two subgroups were formed from the group of patients with tunneled CVC according to a heparin-containing catheter lock solution with (CVC-TCH) and without taurolidine-citrate (CVC-Hep). Subsequently, high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) concentrations in serum and messenger ribonucleic acid (mRNA) gene expression levels of IL-6 and TNF-alpha in peripheral blood mononuclear cells (PBMC) were measured at inclusion and after three months follow-up. Results Altogether eighty-five subjects (42 males and 43 females; mean age 61 ± 9 yrs; 39% diabetics) were initially included in the study. In 25 subjects the vascular access was AVF, while the rest used tunneled CVC; of these 31 used standard CVC-Hep and 29 used CVC-TCH. Five patients dropped out the study and thus 80 patients completed the 3-month follow-up and were finally evaluated. At inclusion, patients with CVC had significantly higher serum and expression levels of inflammatory parameters compared to subjects with AVF. After 3 months, there were no significant changes in inflammatory markers in subjects with AVF compared to baseline, whereas in subjects with CVC-Hep a significant increase in serum and gene expression of IL-6 could be observed. On the contrary, subjects with CVC-TCH experienced a decrease of all parameters compared to baseline, of which differences in serum IL-6 and gene expression levels of IL-6 and TNF-alpha were significant. After 3 months of follow-up there was no significant difference in any inflammatory parameter when comparing patients with CVD-TCH with those with AVF (Table). Conclusion In patients under HD with cuffed tunneled CVC, the use of TCH lock solution after each HD session is associated with a significant improvement in the inflammatory serum and gene expression state. Thus, the inflammatory profile of patients with CVC using TCH does not differ from that of patients with native AVF after at least three months of CVC-TCH use.