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IL-6 antagonists to replace systemic corticosteroids as the preferred anti-inflammatory therapy in patients with COVID-19?
Kow, CS, Zaihan, AF, Ramachandram, DS, Hasan, SS
Cytokine. 2022;:155730
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Beneficial effects of novel aureobasidium pullulans strains produced beta-1,3-1,6 glucans on interleukin-6 and D-dimer levels in COVID-19 patients; results of a randomized multiple-arm pilot clinical study.
Raghavan, K, Dedeepiya, VD, Suryaprakash, V, Rao, KS, Ikewaki, N, Sonoda, T, Levy, GA, Iwasaki, M, Senthilkumar, R, Preethy, S, et al
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022;:112243
Abstract
OBJECTIVE In this pilot clinical study, we report the beneficial effects of beta glucans derived from two strains AFO-202 and N-163 of a black yeast Aureobasidium pullulans on the biomarkers for cytokine storm and coagulopathy in COVID-19 patients. METHODS A total of 24 RT-PCR positive COVID-19 patients were recruited and randomly divided into three groups (Gr): Gr. 1 control (n = 8) - Standard treatment; Gr. 2: Standard treatment + AFO-202 beta glucan (n = 8); and Gr. 3, Standard treatment + combination of AFO-202 and N-163 beta glucans (n = 8) for 30 days. RESULTS There was no mortality or requirement of ventilation of the subjects in any of the groups. There was a decrease in D-Dimer values (751 ng/ml to 143.89 ng/ml) and IL-6 values (7.395-3.16 pg/ml) in Gr. 1 in 15 days but the levels increased to abnormal levels on day 30 (D-Dimer: 202.5 ng/ml; IL-6 55.37 pg/ml); which steadily decreased up to day 30 in groups 2 (D-dimer: 560.99 ng/dl to 79.615; IL-6: 26.18-3.41 pg/ml) and 3 (D-dimer: 1614 ng/dl to 164.25 ng/dl; IL-6: 6.25-0.5 pg/ml). The same trend was observed with ESR. LCR and LeCR increased while NLR decreased significantly in Gr. 3. CD4 + and CD8 + T cell count showed relatively higher increase in Gr.3. There was no difference in CRP within the groups. CONCLUSION As these beta glucans are well known food supplements with a track record for safety, larger multi-centric clinical studies are recommended to validate their use as an adjunct in the management of COVID-19 and the ensuing long COVID-19 syndrome.
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Baseline Interleukin-6 and -8 predict response and survival in patients with advanced hepatocellular carcinoma treated with sorafenib monotherapy: an exploratory post hoc analysis of the SORAMIC trial.
Öcal, O, Schütte, K, Kupčinskas, J, Morkunas, E, Jurkeviciute, G, de Toni, EN, Ben Khaled, N, Berg, T, Malfertheiner, P, Klümpen, HJ, et al
Journal of cancer research and clinical oncology. 2022;(2):475-485
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Abstract
PURPOSE To explore the potential correlation between baseline interleukin (IL) values and overall survival or objective response in patients with hepatocellular carcinoma (HCC) receiving sorafenib. METHODS A subset of patients with HCC undergoing sorafenib monotherapy within a prospective multicenter phase II trial (SORAMIC, sorafenib treatment alone vs. combined with Y90 radioembolization) underwent baseline IL-6 and IL-8 assessment before treatment initiation. In this exploratory post hoc analysis, the best cut-off points for baseline IL-6 and IL-8 values predicting overall survival (OS) were evaluated, as well as correlation with the objective response. RESULTS Forty-seven patients (43 male) with a median OS of 13.8 months were analyzed. Cut-off values of 8.58 and 57.9 pg/mL most effectively predicted overall survival for IL-6 and IL-8, respectively. Patients with high IL-6 (HR, 4.1 [1.9-8.9], p < 0.001) and IL-8 (HR, 2.4 [1.2-4.7], p = 0.009) had significantly shorter overall survival than patients with low IL values. Multivariate analysis confirmed IL-6 (HR, 2.99 [1.22-7.3], p = 0.017) and IL-8 (HR, 2.19 [1.02-4.7], p = 0.044) as independent predictors of OS. Baseline IL-6 and IL-8 with respective cut-off values predicted objective response rates according to mRECIST in a subset of 42 patients with follow-up imaging available (IL-6, 46.6% vs. 19.2%, p = 0.007; IL-8, 50.0% vs. 17.4%, p = 0.011). CONCLUSION IL-6 and IL-8 baseline values predicted outcomes of sorafenib-treated patients in this well-characterized prospective cohort of the SORAMIC trial. We suggest that the respective cut-off values might serve for validation in larger cohorts, potentially offering guidance for improved patient selection.
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Whole Grain Consumption and Inflammatory Markers: A Systematic Literature Review of Randomized Control Trials.
Milesi, G, Rangan, A, Grafenauer, S
Nutrients. 2022;(2)
Abstract
Whole grain foods are rich in nutrients, dietary fibre, a range of antioxidants, and phytochemicals, and may have potential to act in an anti-inflammatory manner, which could help impact chronic disease risk. This systematic literature review aimed to examine the specific effects of whole grains on selected inflammatory markers from human clinical trials in adults. As per the Preferred Reporting Items for Systematic Reviews (PRISMA) protocol, the online databases MEDLINE, Embase, Cochrane, CINAHL, and Scopus were searched from inception through to 31 August 2021. Randomized control trials (RCTs) ≥ 4 weeks in duration, reporting ≥1 of the following: C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor (TNF), were included. A total of 31 RCTs were included, of which 16 studies recruited overweight/obese individuals, 12 had pre-existing conditions, two were in a healthy population, and one study included participants with prostate cancer. Of these 31 RCTs, three included studies with two intervention arms. A total of 32 individual studies measured CRP (10/32 were significant), 18 individual studies measured IL-6 (2/18 were significant), and 13 individual studies measured TNF (5/13 were significant). Most often, the overweight/obese population and those with pre-existing conditions showed significant reductions in inflammatory markers, mainly CRP (34% of studies). Overall, consumption of whole grain foods had a significant effect in reducing at least one inflammatory marker as demonstrated in 12/31 RCTs.
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A prospective observational study of urinary cytokines and inflammatory response in patients with Overactive Bladder Syndrome.
Gill, K, Horsley, H, Swamy, S, Khasriya, R, Malone-Lee, J
BMC urology. 2021;(1):39
Abstract
BACKGROUND Contemporary studies have discredited the methods used to exclude urinary tract infection (UTI) when treating overactive bladder (OAB). Thus we must revisit the OAB phenotype to check that UTI has not been overlooked. AIMS To examine the differences in urinary cytokines IL6 and lactoferrin in OAB patients compared to controls, with references to microscopy of urine and enhanced quantitative urine culture. METHODS A blinded, prospective cohort study with normal controls using six repeated measures, achieved two-monthly, over 12 months. RESULTS The differences between patients and controls in urine IL6 (F = 49.0, p < .001) and lactoferrin (F = 228.5, p < .001) were significant and of a magnitude to have clinical implications. These differences were for lactoferrin correlated to symptoms (9.3, p = .003); for both to pyuria (IL6 F = 66.2, p < .001, Lactoferrin F = 73.9, p < .001); and for IL6 microbial abundance (F = 5.1, p = .024). The pathological markers had been missed by urinary dipsticks and routine MSU culture. CONCLUSION The OAB phenotype may encompass patients with UTI that is being overlooked because of the failure of standard screening methods.
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The acute effect of incorporating lettuce or watercress into a moderately high-fat meal on postprandial lipid, glycemic response, and plasma inflammatory cytokines in healthy young men: a randomized crossover trial.
Shokraei, S, Khandouzi, N, Sina, Z, Nasrollahzadeh, J
Lipids in health and disease. 2021;(1):66
Abstract
BACKGROUND Postprandial responses to food mostly depend on the composition of the meal and the consumption of vegetables may modulate this postprandial state. In this study, the effects of lettuce or watercress consumption with a moderately high-fat meal (40% kcal from fat) on postprandial lipemia, glycemia, and inflammatory cytokines were determined in healthy men. METHODS This randomized, 3-arm, crossover study was conducted in sixteen healthy young men with a mean ± SEM age and body mass index (in kg/m2) of 22.8 ± 0.5 years old and 23.7 ± 1.16, respectively. Lettuce and watercress were added to the test meal in portions of 100 g and cellulose was added to the control meal. Thereafter, blood samples were collected by passing 0, 1, 2, 3, and 4 h for analysis. The postprandial response was measured in plasma glucose, triglycerides (TG), total cholesterol, high-density-lipoproteins cholesterol (HDL-C), and low-density-lipoproteins cholesterol (LDL-C), as the area under the postprandial curve (AUC). Moreover, plasma tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were determined once before and once 4 h after the meal's consumption. RESULTS The 0-4-h AUCs for glucose (385.7, 361.9, and 382.3 mg/dL for the control, lettuce, and watercress meals, respectively) were calculated to be lower when meal was consumed with lettuce compared to the control (P < 0.05) and watercress (P < 0.01) meals. The maximum values of insulin were obtained as 43.8 ± 18.8, 33.5 ± 19.5, and 42.8 ± 17.7 μIU/mL for the control, lettuce, and watercress meals, respectively. As well, the lettuce-containing meal more reduced the AUC for insulin compared with the control (P < 0.05), but not watercress. Notably, plasma TG, total cholesterol, HDL-C, and LDL-C had no significant differences among the meals. Moreover, the levels of plasma IL-6 and TNF-α did not differ among the meals. CONCLUSION In this study on healthy men, the addition of lettuce to a moderately high-fat meal delayed the postprandial glycemic response. However, the effect of the consumption of these vegetables on postprandial responses in subjects with cardiometabolic risk factors remains to be elucidated yet. This clinical trial was registered at the Iran Clinical Trials Registration Office (IRCT) on March 3, 2018, with an ID of IRCT20160702028742N4 ( https://www.irct.ir/user/trial/23233/view ).
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Effects of long-term vitamin D and n-3 fatty acid supplementation on inflammatory and cardiac biomarkers in patients with type 2 diabetes: secondary analyses from a randomised controlled trial.
Limonte, CP, Zelnick, LR, Ruzinski, J, Hoofnagle, AN, Thadhani, R, Melamed, ML, Lee, IM, Buring, JE, Sesso, HD, Manson, JE, et al
Diabetologia. 2021;(2):437-447
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Abstract
AIMS/HYPOTHESIS Interventions that reduce inflammation may delay progression of microvascular and macrovascular complications in diabetes. We examined the effects of vitamin D3 and/or n-3 fatty acid supplementation vs placebo on 5 year changes in serum inflammatory and cardiac biomarkers in adults with type 2 diabetes. METHODS This study reports pre-specified secondary outcomes of the Vitamin D and Omega-3 Trial to Prevent and Treat Diabetic Kidney Disease, in which 1312 US adults with type 2 diabetes and without known cardiovascular disease, malignancy, or end-stage kidney disease were randomised using computer-generated random numbers in blocks of eight to vitamin D3 (2000 IU/day) vs placebo and n-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]; 1 g/day) vs placebo in a 2 × 2 factorial design. Participants, examiners, and researchers assessing outcomes were blinded to intervention assignment. We measured serum IL-6, high-sensitivity C-reactive protein (hsCRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and after 2 and 5 years. RESULTS A total of 333 participants were randomised to vitamin D3 and placebo n-3 fatty acids, 289 to n-3 fatty acids and placebo vitamin D3, 370 to vitamin D3 and n-3 fatty acids, and 320 to 2 placebos; 989 (75%) and 934 (71%) participants returned blood samples at 2 and 5 years, respectively. Participants had a mean age of 67.6 years (46% women). Overall, baseline geometric means of IL-6, hsCRP and NT-proBNP were 1.2 pg/ml, 1.9 mg/l and 262 ng/l, respectively. After 5 years, mean IL-6 and hsCRP remained within 6% of their baseline values while mean NT-proBNP increased by 55% overall. Compared with placebo, participants assigned to vitamin D3 had a 1.24-fold greater increase in NT-proBNP over 5 years (95% CI 1.09, 1.41; p = 0.003), while IL-6 and hsCRP did not have a significant difference in change. Comparing n-3 fatty acids with placebo, there was no significant difference in change in IL-6, hsCRP or NT-proBNP. No heterogeneity was observed in subgroup analyses accounting for baseline eGFR, urine albumin to creatinine ratio, initial biomarker concentration, 25-hydroxyvitamin D level or EPA+DHA index. CONCLUSIONS/INTERPRETATION Among adults with type 2 diabetes, supplementation with vitamin D3 or n-3 fatty acids did not reduce IL-6, hsCRP or NT-proBNP over 5 years. TRIAL REGISTRATION ClinicalTrials.gov NCT01684722 FUNDING The study was funded by grant R01DK088762 from the National Institute of Diabetes and Digestive and Kidney Diseases. Graphical abstract.
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Tocilizumab for treating COVID-19: a systemic review and meta-analysis of retrospective studies.
Zhao, M, Lu, J, Tang, Y, Dai, Y, Zhou, J, Wu, Y
European journal of clinical pharmacology. 2021;(3):311-319
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Abstract
OBJECTIVES COVID-19 has become a global epidemic, and effective therapies have not been discovered up to now. We conducted this study to explore the effectiveness and safety of tocilizumab recently used for treating COVID-19. METHOD A comprehensive search was conducted (up to September 27, 2020), and 19 eligible records were identified according to the inclusion and exclusion criteria. The data of the studies were extracted by 2 independent reviewers and were analyzed to evaluate the safety and availability of tocilizumab for treating COVID-19. RESULTS Thirteen retrospective case-control studies (n = 2285 patients) and 6 retrospective single-armed studies (n = 208) were retrieved in this study. In the comparison of tocilizumab treatment group (TCZ) and standard treatment group (ST), significant associations with a lower risk of admission to ICU, use of ventilation, and mortality (OR, 95% CI: 0.53, 0.26~1.09; 0.66, 0.46~0.94; 0.44, 0.36~0.55) were found in the tocilizumab treatment group. What is more, patients treated with tocilizumab had better clinical improvement compared with the patients treated with ST (OR, 1.24; 95% CI, 0.96~1.62). After taking tocilizumab, the patients had lower C-reactive protein (CRP), white blood cell count (WBC), aspartate aminotransferase (AST) (WMD, 95% CI: - 99.66, - 156.24~- 43.09; - 0.95, - 1.8~- 0.11; - 12.58, - 18.88~-6.29) but higher troponin (WMD, 7.61; 95% CI, 3.06~12.15) than before. In addition, tocilizumab did not have significant influence on patients' neutrophil count (Neut), lymphocyte count (Lymp), platelet count (Plt), alanine aminotransferase (ALT), and creatine (WMD, 95% CI: - 0.29, - 2.91~2.33; 0.42, - 0.23~1.07; 5.2, - 2.85~13.25; 22.49, - 2.73~47.7; - 44.78, - 93.37~3.81). CONCLUSION Tocilizumab may have potential effectiveness to treat COVID-19 according to the results of this study. However, more large-scale studies are needed for more accurate conclusions.
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The role of IL-6-174 G/C polymorphism and intraocular IL-6 levels in the pathogenesis of ocular diseases: a systematic review and meta-analysis.
Ulhaq, ZS, Soraya, GV, Budu, , Wulandari, LR
Scientific reports. 2020;(1):17453
Abstract
Interleukin-6 (IL-6) is one of the key regulators behind the inflammatory and pathological process associated with ophthalmic diseases. The role of IL-6-174 G/C polymorphism as well as intraocular IL-6 levels among various eye disease patients differ across studies and has not been systematically reviewed. Thus, this study aims to provide a summary to understand the relationship between IL-6 and ophthalmic disease. In total, 8,252 and 11,014 subjects for IL-6-174 G/C and intraocular levels of IL-6, respectively, were retrieved from PubMed, Scopus and Web of Science. No association was found between IL-6-174 G/C polymorphisms with ocular diseases. Subgroup analyses revealed a suggestive association between the GC genotype of IL-6-174 G/C with proliferative diabetic retinopathy (PDR). Further, the level of intraocular IL-6 among ocular disease patients in general was found to be higher than the control group [standardized mean difference (SMD) = 1.41, 95% confidence interval (CI) 1.24-1.58, P < 0.00001]. Closer examination through subgroup analyses yielded similar results in several ocular diseases. This study thus indicates that the IL-6-174 G/C polymorphism does not predispose patients to ocular disease, although the GC genotype is likely to be a genetic biomarker for PDR. Moreover, intraocular IL-6 concentrations are related to the specific manifestations of the ophthalmic diseases. Further studies with larger sample sizes are warranted to confirm this conclusion.
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The impact of a randomized dietary and physical activity intervention on chronic inflammation among obese African-American women.
Babatunde, OA, Arp Adams, S, Truman, S, Sercy, E, Murphy, AE, Khan, S, Hurley, TG, Wirth, MD, Choi, SK, Johnson, H, et al
Women & health. 2020;(7):792-805
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Lifestyle interventions may reduce inflammation and lower breast cancer (BrCa) risk. This randomized trial assessed the impact of the Sistas Inspiring Sistas Through Activity and Support (SISTAS) study on plasma C-reactive protein (CRP), interleukin-6 (IL-6) and Dietary Inflammatory Index (DII). This unblinded, dietary and physical activity trial was implemented in 337 obese (body mass index [BMI] ≥30 kg/m2) African American (AA) women recruited between 2011 and 2015 in South Carolina through a community-based participatory approach with measurements at baseline, 3 months, and 12 months. Participants were randomized into either intervention (n = 176) or wait-list control group (n = 161). Linear mixed-effect models were used for analyses of CRP and IL-6. Baseline CRP was significantly higher in those with greater obesity, body fat percentage, and waist circumference (all p <.01). No difference was observed between groups for CRP or IL-6 at 3 or 12 months; however, improvements in diet were observed in the intervention group compared to the control group (p = .02) at 3 months but were not sustained at 12 months. Although the intervention was not successful at reducing levels of CRP or IL-6, a significant decrease was observed in DII score for the intervention group, indicating short-term positive dietary change.