Higher Interleukin-6 Levels Research Articles

Waist-to-height ratio cut-off points to predict obesity in adolescents and associa-tion with inflammatory markers.

Introduction: obesity increases inflammatory molecules and cardiovascular risk even in young populations. New indicators are being investigated, including the waist-to-height ratio (WHtR) to predict obesity and the relationship with inflammatory markers in childhood and adolescence. Objective: to identify the cut-off points of the WHtR to determine obesity and its association with inflammatory markers in adolescents in São Luís, state of Maranhão, Brazil. Methods: this is a cross-sectional study, with 2,209 adolescents aged 18 and 19, belonging to the third phase of the birth cohort entitled "RPS", carried out in 2016. The total area under the ROC curve (AUC) was identified to assess the predictive capacity of WHtR in relation to body fat percentage (%BF), obtained by air displacement plethysmography (ADP). The association of WHtR with inflammatory markers interleukin-6 (IL-6), tumor necrosis factor (TNF-α) and c-reactive protein (CRP) was evaluated. Results: prevalence of obesity by the %BF was 10.3 % in males and 40.4 % in females. The cut-off points for the WHtR were 0.50 for females and 0.51 for males, with an AUC of 0.90 (95 % CI: 0.88-0.92) and 0.93 (95 % CI: 0.90-0.97). There was an association of elevated WHtR with higher levels of IL-6 and CRP (p < 0.05). Conclusion: the predictive capacity of WHtR for obesity was excellent. Elevated values of the WHtR were associated with early inflammatory markers. This study contributed to the identification of cut-off points for simple and low-cost anthropometric indicators.

INTERLEUKIN-6 AND C-REACTIVE PROTEIN AS INDICATORS OF LATE-LIFE COGNITIVE DECLINE IN DEMENTIA

Background: Patients with dementia have higher levels of peripheral inflammatory markers. We investigated whether midlife levels of interleukin-6 (IL-6) and C-reactive protein (CRP) predicted concurrently evaluated intelligence and eventual cognitive impairment in order to determine their causal function. Method: In the cohort study, the mean values of IL-6 and CRP were measured in 100 individuals taking irregular supplements of vitamins (27.8% of whom were women) between Oct 2019 and May 2020 and June 2020 and Oct 2020. These values were then divided into tertiles to examine a 1-year decline in the mean (mean = 1, SD = 2) standardised scores of verbal fluency, memory, and reasoning. Logistic regression was used to model declines greater than 2 points. For the baseline age, sex, and education, as well as for subsequent analyses, adjustments were made to the analyses. Result: In cross-sectional research, participants with high IL-6 levels had poorer reasoning scores (0.08 SD; 95% [CI] 20.13, 20.02). In a retrospective study, participants with high IL-6 had a 1-year reduction in reasoning that was larger (p-value = 0.02) than that of those with low IL-6 (20.28; 90% CI 20.30, 20.26) (20.34; 90% CI 20.36, 20.32). In none of the tests, CRP was connected to deterioration. Conclusion: The overall cross-sectional and long term impacts across the 1-year observation time approximated to an age effect of 2.5 months; elevated IL-6 but not CRP in midlife indicates cognitive deterioration.

Electrocardiographic abnormalities in patients with COVID-19 pneumonia and raised interleukin-6.

Cardiac injury is associated with high mortality in patients with COVID-19 infection. Electrocardiographic changes can give clues to the underlying cardiovascular abnormalities. Raised inflammatory markers like raised interleukin-6 (IL-6) are associated with arrhythmia, heart failure, and coronary artery disease. However, past studies have not highlighted the electrocardiographic abnormalities in patients with COVID-19 infection with raised IL- 6 levels. This study compared the electrocardiogram (ECG) changes in COVID-19 patients with high and normal IL-6 levels. A retrospective analysis of ECG of 306 patients with COVID-19 infection was done, out of which 250 patients had normal IL- 6 levels, whereas 56 patients had raised IL-6 levels. IL-6 levels were measured in all the patients. Detailed clinicodemographic profile of all the serial COVID-19 patients admitted with moderate to severe COVID-19 pneumonia was noted from the hospital record section. Electrocardiographic findings and biochemical parameters of all the patients were noted. Out of 56 patients with raised IL-6 levels, 41 (73.2%) patients had ECG abnormalities compared to 177 (70.8%) patients with normal IL-6 levels. This difference was not statistically significant. However, ECG abnormality such as sinus tachycardia was significantly more common in patients with raised IL-6 levels than those with normal levels. Among patients with raised IL-6 levels who were discharged, 5 (16.6%) had sinus tachycardia, 2 (6.6%) had ST/T wave changes as compared to 15 (57.6%), and 10 (38.4%) who had tachycardia and ST/T wave change respectably succumbed to death. This difference was statistically significant. Sinus tachycardia followed by atrial fibrillation and right bundle branch block are common ECG changes in patients with COVID-19 infection with raised IL-6. The possible association of cardiac injury in patients with COVID-19 infection with coexisting raised IL-6 levels should be explored further.

Evaluation of oral mucositis in pediatric cancer patients in Hiwa Hospital in Sulaymaniyah city, Kurdistan Region, Iraq

Background and objective: Oral mucositis is caused by the destruction of the oral mucosal epithelium and suppression of its growth secondary to antineoplastic treatment in the form of chemotherapeutic drugs, substances, or radiotherapy. This study aimed to evaluate oral mucositis in pediatric cancer patients because it is one of the common side effects of cancer therapy that influences the outcome. Methods: This is a cross-sectional study that enrolled 100 pediatric patients with both hematological and non-hematological cancer. The age of the patients ranged from 1-18 years, involving both genders. Cases admitted to Hiwa hospital were clinically evaluated for oral mucositis, and ethical permission was taken from parents. Risk factors were assessed, including age, sex, cancer type, type of chemotherapy, radiotherapy, number of cycles, complete blood count, interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and tumor necrosis factor-beta. Results: Baseline serum cytokines levels showed significant correlation between Interleukin-6 and intensity of the oral mucositis (P = 0.003, rho = 0.314) and no correlation between severity of oral mucositis with tumor necrosis factor-alpha, tumor necrosis factor-beta nor interleukin-1 beta (P = 0.140 and rho = 0.258, P = 0.463 and rho = -0.079, and P = 0.706 and rho = -0.041, respectively). There was significant relationship between Hemoglobin level, neutropenia and type of non-hematological cancer with the intensity of oral mucositis respectively (P ≤0.001 and rho = -0.352, P = 0.027 and rho = -0.221, and P = 0.035 and rho = 0.095, respectively). Correlation between age, gender, white blood cell count, platelet count, type of hematological malignancy and past history with the intensity of the oral mucositis did not show significant result. Conclusion: Intensity of oral mucositis increased with anemia, neutropenia, high interleukin-6 level, and the type of non-hematological cancer. It is recommended to treat anemic, neutropenic patients as soon as possible before exacerbating the mucositis. Methotrexate is the most aggressive drug alone and in combined chemotherapy agents, which may cause mucositis and needs prophylaxis like topical nystatin suspension or other methods. Keywords: Oral mucositis; Pediatric cancer; Non-hematological; Hematological; Sulaymaniyah.

Exploring interleukin-6, lipopolysaccharide-binding protein and brain-derived neurotrophic factor following 12 weeks of adjunctive minocycline treatment for depression.

This study aimed to explore effects of adjunctive minocycline treatment on inflammatory and neurogenesis markers in major depressive disorder (MDD). Serum samples were collected from a randomised, placebo-controlled 12-week clinical trial of minocycline (200 mg/day, added to treatment as usual) for adults (n = 71) experiencing MDD to determine changes in interleukin-6 (IL-6), lipopolysaccharide binding protein (LBP) and brain derived neurotrophic factor (BDNF). General Estimate Equation modelling explored moderation effects of baseline markers and exploratory analyses investigated associations between markers and clinical outcomes. There was no difference between adjunctive minocycline or placebo groups at baseline or week 12 in the levels of IL-6 (week 12; placebo 2.06 ± 1.35 pg/ml; minocycline 1.77 ± 0.79 pg/ml; p = 0.317), LBP (week 12; placebo 3.74 ± 0.95 µg/ml; minocycline 3.93 ± 1.33 µg/ml; p = 0.525) or BDNF (week 12; placebo 24.28 ± 6.69 ng/ml; minocycline 26.56 ± 5.45 ng/ml; p = 0.161). Higher IL-6 levels at baseline were a predictor of greater clinical improvement. Exploratory analyses suggested that the change in IL-6 levels were significantly associated with anxiety symptoms (HAMA; p = 0.021) and quality of life (Q-LES-Q-SF; p = 0.023) scale scores. No other clinical outcomes were shown to have this mediation effect, nor did the other markers (LBP or BDNF) moderate clinical outcomes. There were no overall changes in IL-6, LBP or BDNF following adjunctive minocycline treatment. Exploratory analyses suggest a potential role of IL-6 on mediating anxiety symptoms with MDD. Future trials may consider enrichment of recruitment by identifying several markers or a panel of factors to better represent an inflammatory phenotype in MDD with larger sample size.

Inflammatory Glycoprotein 130 Signaling Links Changes in Microtubules and Junctophilin-2 to Altered Mitochondrial Metabolism and Right Ventricular Contractility.

Right ventricular dysfunction (RVD) is the leading cause of death in pulmonary arterial hypertension (PAH), but no RV-specific therapy exists. We showed microtubule-mediated junctophilin-2 dysregulation (MT-JPH2 pathway) causes t-tubule disruption and RVD in rodent PAH, but the druggable regulators of this critical pathway are unknown. GP130 (glycoprotein 130) activation induces cardiomyocyte microtubule remodeling in vitro; however, the effects of GP130 signaling on the MT-JPH2 pathway and RVD resulting from PAH are undefined. Immunoblots quantified protein abundance, quantitative proteomics defined RV microtubule-interacting proteins (MT-interactome), metabolomics evaluated the RV metabolic signature, and transmission electron microscopy assessed RV cardiomyocyte mitochondrial morphology in control, monocrotaline, and monocrotaline-SC-144 (GP130 antagonist) rats. Echocardiography and pressure-volume loops defined the effects of SC-144 on RV-pulmonary artery coupling in monocrotaline rats (8-16 rats per group). In 73 patients with PAH, the relationship between interleukin-6, a GP130 ligand, and RVD was evaluated. SC-144 decreased GP130 activation, which normalized MT-JPH2 protein expression and t-tubule structure in the monocrotaline RV. Proteomics analysis revealed SC-144 restored RV MT-interactome regulation. Ingenuity pathway analysis of dysregulated MT-interacting proteins identified a link between microtubules and mitochondrial function. Specifically, SC-144 prevented dysregulation of electron transport chain, Krebs cycle, and the fatty acid oxidation pathway proteins. Metabolomics profiling suggested SC-144 reduced glycolytic dependence, glutaminolysis induction, and enhanced fatty acid metabolism. Transmission electron microscopy and immunoblots indicated increased mitochondrial fission in the monocrotaline RV, which SC-144 mitigated. GP130 antagonism reduced RV hypertrophy and fibrosis and augmented RV-pulmonary artery coupling without altering PAH severity. In patients with PAH, higher interleukin-6 levels were associated with more severe RVD (RV fractional area change 23±12% versus 30±10%, P=0.002). GP130 antagonism reduces MT-JPH2 dysregulation, corrects metabolic derangements in the RV, and improves RVD in monocrotaline rats.

Peripheral Cytokine Levels as a Prognostic Indicator in Gastric Cancer: A Review of Existing Literature.

Although strong connections exist between the carcinogenesis of gastric cancer and chronic inflammation, gastric cancer is unique in that the chronic gastritis which frequently precedes carcinogenesis is strongly associated with H. pylori infection. The interplay between H. pylori virulence factors and host immune cells is complex but culminates in the activation of inflammatory pathways and transcription factors such as NF-κB, STAT3, and AP-1, all of which upregulate cytokine production. Due to the key role of cytokines in modulating the immune response against tumour cells as well as possibly stimulating tumour growth and proliferation, different patterns of cytokine secretion may be associated with varying patient outcomes. In relation to gastric cancer, interleukin-6, 8, 10, 17A, TNF, and IFN-γ may have pro-tumour properties, although interleukin-10, TNF, and IFN-γ may have anti-tumour effects. However, due to the lack of studies investigating patient outcomes, only a link between higher interleukin-6 levels and poorer prognosis has been demonstrated. Further investigations which link peripheral cytokine levels to patient prognosis may elucidate important pathological mechanisms in gastric cancer which adversely impact patient survival and allow treatments targeting these processes to be developed.

Intake of Vitamin D in Patients with Multiple Sclerosis in the Valencian Region and Its Possible Relationship with the Pathogenesis of the Disease.

(1) Background: Multiple sclerosis (MS) is a neurodegenerative disease characterized by pronounced inflammation. Interleukin 6 (IL-6) is an accurate marker for the state of inflammation, due to the high levels of this cytokine linked to the pathogenesis of the disease. These IL-6 levels could be lowered with an adequate dietary intake of vitamin D. The objective of the study was to determine the level of vitamin D ingested in a sample of patients with MS in the Valencian region (Spain), to establish the vitamin sources, and the possible link between the intake of vitamin D and the pathogenesis of the disease through a relationship with the level of IL-6. (2) Materials and Methods: A descriptive pilot study was carried out with 39 patients with MS in the Valencian region. The dietary-nutritional anamnesis was gained through the food frequency questionnaire (FFQ) and a food diary. Diet and eating habits were analyzed through the Easy Diet (version: 2.0.1)—Consultation Management Program® software, and IL-6 levels in blood by ELISA technique. (3) Results: The results show a low intake of vitamin D, which is significantly and negatively related to the intake of proteins of vegetable origin, which are consumed in less quantity than proteins of animal origin, and significantly and negatively related with the high blood levels of IL-6, possibly as a consequence of the high intake of fats, mainly unsaturated. (4) Conclusions: MS patients in the Valencian region ingest little vitamin D related to low intake of vegetable protein, which would explain the high levels of IL-6 linked to the high intake of mainly saturated fats.

317 Aldosterone and interleukin-6: the synergic effect in COVID-19

AimsSeveral evidence have identified the role of Interleukin-6 (IL-6) in the cytokine storm induced by COVID-19. Interestingly, the correlation between the serum levels of IL-6 and the plasma aldosterone has already been demonstrated in patients affected by primary aldosteronism (PA). Thus, we suppose that hyperaldosteronism may increase IL-6 levels in COVID-19.Methods and resultsWe report a case of 47-year-old female Covid-19 patient who had developed severe pneumonia complicated by Guillain–Barreé syndrome (GBS). Blood test revealed high levels of IL-6 (serum IL-6: 402 pg/ml) and of its soluble receptor (soluble IL-6 receptor >1900 pg/ml) and she required mechanical ventilation for severe hypoxaemia. Furthermore, the evidence of right adrenal adenoma, resistant hypertension, severe hypokalaemia, and high serum levels of aldosterone with high aldosterone/renin ratio were also consistent with diagnosis of PA. Thus, Spironolactone was administered with rapid improvements in clinical condition. Finally, she was diagnosed with acute motor sensitive neuropathy and started the rehabilitation phase.ConclusionsElevated aldosterone levels in PA may stimulate IL-6 production, inducing more severe forms of COVID-19 with the development of serious complications such as GBS. Hyperaldosteronism may also contribute to the poorest prognosis of patients with secondary aldosteronism such as heart failure and COVID-19, in which elevated IL-6 levels could exert its detrimental effects, mostly on the progression of ventricular dysfunction. Further studies are necessary to evaluate therapy with mineralocorticoid receptors antagonists such as spironolactone in COVID-19.

High levels of interleukin-6 are associated with final infarct size and adverse clinical events in patients with STEMI

ObjectiveInflammation has emerged as a new treatment target in patients with coronary artery disease and inflammation seems to play an important role in ischaemia/reperfusion injury that follows ST-elevation myocardial infarction...

Serum MicroRNA Expression Patterns in Subjects After the 5-km Exercise Are Strongly Associated With Cardiovascular Adaptation.

Circulating microRNAs (miRNAs) have been reported dysregulated during exercise. However, the changes of specific serum miRNAs during the 5-km run test with intensity of 51–52% maximum oxygen uptake (V̇O2max) and their association with traditional cardiovascular-related indicators remain well-characterized. Levels of miR-1, miR-21, miR-146a, miR-155, miR-181, and miR-210 were detected in 120 young subjects before and after the exercise training by quantitative reverse-transcription PCR (RT-qPCR). Besides, the levels of cardiac troponin I (cTNI), myoglobin (Myo), creatine kinase (CK), creatine kinase-MB (CK-MB), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), ischemia-modified albumin (IMA), interleukin-6 (IL-6), and C-reactive protein (CRP) were measured and the correlation between levels of serum miRNAs and biochemical parameters was also analyzed. Compared with resting state, the serum levels of miR-1, miR-146a, miR-155, miR-181, and miR-210 were significantly increased after exercise training. Serum levels of miR-146a, miR-155, and miR-210 after exercise training were positively correlated with Myo, CK-MB, and LDH, respectively, while miR-1, miR-146a, miR-181, and miR-155 were positively correlated with the levels of IL-6. Additionally, all the five miRNAs were negatively correlated with IMA levels. The multivariate logistic regression analysis showed that high levels of miR-146a, AST, LDH, and IL-6 in serum were risk factors, while low IMA contents were a protective factor for cardiovascular adaptation during exercise. In conclusion, the dynamic changes of miRNAs under the condition of the 5-km continuous running contribute to the adaptive regulation of the cardiovascular function of the body.

Abstract 13873: Ischemic Time and Interleukin 6 Levels in Acute Myocardial Infarction

Introduction: Increased levels of the inflammatory cytokine interleukin 6 (IL-6) after percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) are associated with larger infarct size and decreased cardiac function. Early treatment with the IL-6 receptor inhibitor tocilizumab in STEMI patients resulted in less myocardial damage, especially in patients treated &gt;3 hours after symptom onset. However, the specific window of opportunity for IL-6 inhibition in STEMI patients remains to be investigated. Therefore, we studied IL-6 levels in STEMI patients varying in ischemic time (i.e. time from symptom onset to PCI), and its association with infarct size. Methods: In 369 STEMI patients IL-6 levels were measured at 24 hours post-PCI. Patients were categorized according to ischemic time (&lt;2 hours, 2-3 hours, 3-4 hours, 4-5 hours, &gt;5 hours). At 4 months, infarct size was assessed by magnetic resonance imaging. IL-6 levels were log transformed for statistical analysis. Results: IL-6 levels at 24 hours post-PCI increased from 9.2 ng/ml (IQR 5.2-16.7 ng/ml) in patients with symptom onset &lt;2 hours to 13.2 ng/ml (IQR 9.0-20.2 ng/ml) in patients with symptom onset between 4-5 hours (P trend =0.036), stabilizing in patients with symptom onset &gt;5 hours ( Figure 1A ). Higher IL-6 levels at 24 hours post-PCI were associated with larger infarct size in patients with symptom onset &lt;4 hours (&lt;2 hours: β 1.9, 95% CI 0.6-3.1, P=0.004; 2-3 hours: β 1.9, 95% CI 0.3-3.4, P=0.019; 3-4 hours: β 3.0, 95% CI 1.6-4.5, P&lt;0.001) ( Figure 1B ). Conclusions: IL-6 levels at 24 hours post-PCI are related to ischemic time. Moreover, higher IL-6 levels are associated with larger infarct size in patients with ischemic time shorter than 4 hours, suggesting a time dependent role of IL-6. This suggests that the window of opportunity for IL-6 inhibition in STEMI patients is within 4 hours of symptom onset. Randomized controlled trials are necessary to further establish this relationship.

Abstract 14181: Subclinical Left Ventricular Dysfunction in COVID-19 Recovered Patients Using Speckle Tracking Echocardiography

Introduction: Myocardial injury during active coronavirus disease-2019 (COVID-19) infection is well described however, its persistence during recovery is unclear. We assessed left ventricle (LV) global longitudinal strain (GLS) using speckle tracking echocardiography (STE) in COVID-19 recovered patients and studied its correlation with various parameters. Methods: A total of 134 subjects within 30-45 days post recovery from COVID-19 infection and normal LV ejection fraction were enrolled. Routine blood investigations, inflammatory markers (on admission) and comprehensive echocardiography including STE were done for all subjects. Results: Of the 134 subjects, 121 (90.3%) were symptomatic during COVID-19 illness and were categorized into mild: 61 (45.5%), moderate: 50 (37.3%) and severe: 10 (7.5%) COVID-19 illness groups. Asymptomatic COVID-19 infection was reported in 13 (9.7%) patients. Subclinical LV and right ventricle (RV) dysfunction were seen in 40 (29.9%) and 14 (10.5%) patients respectively. Impaired LVGLS was reported in 1 (7.7%), 8 (13.1%), 22 (44%) and 9 (90%) subjects with asymptomatic, mild, moderate and severe disease respectively. LVGLS was significantly lower in patients recovered from severe illness (mild: -21 ± 3.4%; moderate: -18.1 ± 6.9%; severe: -15.5 ± 3.1%; P &lt; 0.0001). Subjects with reduced LVGLS had significantly high interleukin-6 (P &lt; 0.0001), C-reactive protein (P = 0.001), lactate dehydrogenase (P = 0.009) and serum ferritin (P = 0.03) levels during index admission. Conclusions: Subclinical LV dysfunction was seen in nearly a third of recovered COVID-19 patients while 10.5% had RV dysfunction. Our study suggests a need of close follow-up among COVID-19 recovered subjects to elucidate long-term cardiovascular outcomes.

Interleukin-6 as surrogate marker for imaging-based hypoxia dynamics in patients with head-and-neck cancers undergoing definitive chemoradiation—results from a prospective pilot trial

PurposeIntratumoral hypoxia increases resistance of head-and-neck squamous cell carcinoma (HNSCC) to radiotherapy. [18F]FMISO PET imaging enables noninvasive hypoxia monitoring, though requiring complex logistical efforts. We investigated the role of plasma interleukin-6 (IL-6) as potential surrogate parameter for intratumoral hypoxia in HNSCC using [18F]FMISO PET/CT as reference.MethodsWithin a prospective trial, serial blood samples of 27 HNSCC patients undergoing definitive chemoradiation were collected to analyze plasma IL-6 levels. Intratumoral hypoxia was assessed in treatment weeks 0, 2, and 5 using [18F]FMISO PET/CT imaging. The association between PET-based hypoxia and IL-6 was examined using Pearson’s correlation and multiple regression analyses, and the diagnostic power of IL-6 for tumor hypoxia response prediction was determined with receiver-operating characteristic analyses.ResultsMean IL-6 concentrations were 15.1, 19.6, and 31.0 pg/mL at baseline, week 2 and week 5, respectively. Smoking (p=0.050) and reduced performance status (p=0.011) resulted in higher IL-6 levels, whereas tumor (p=0.427) and nodal stages (p=0.334), tumor localization (p=0.439), and HPV status (p=0.294) had no influence. IL-6 levels strongly correlated with the intratumoral hypoxic subvolume during treatment (baseline: r=0.775, p<0.001; week 2: r=0.553, p=0.007; week 5: r=0.734, p<0.001). IL-6 levels in week 2 were higher in patients with absent early tumor hypoxia response (p=0.016) and predicted early hypoxia response (AUC=0.822, p=0.031). Increased IL-6 levels at week 5 resulted in a trend towards reduced progression-free survival (p=0.078) and overall survival (p=0.013).ConclusionPlasma IL-6 is a promising surrogate marker for tumor hypoxia dynamics in HNSCC patients and may facilitate hypoxia-directed personalized radiotherapy concepts.Trial registrationThe prospective trial was registered in the German Clinical Trial Register (DRKS00003830). Registered 20 August 2015

Interleukin-6 in SARS-CoV-2 induced disease: Interactions and therapeutic applications.

Interleukin-6 (IL-6) is a multi-tasking cytokine that represents high activity in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and cancer. High concentration of this pleiotropic cytokine accounts for hyperinflammation and cytokine storm, and is related to multi-organ failure in patients with SARS-CoV-2 induced disease. IL-6 promotes lymphopenia and increases C-reactive protein (CRP) in such cases. However, blockade of IL-6 is not a full-proof of complete response. Hypoxia, hypoxemia, aberrant angiogenesis and chronic inflammation are inter-related events occurring as a response to the SARS-CoV-2 stimulatory effect on high IL-6 activity. Taking both pro- and anti-inflammatory activities will make complex targeting IL-6 in patient with SARS-CoV-2 induced disease. The aim of this review was to discuss about interactions occurring within the body of patients with SARS-CoV-2 induced disease who are representing high IL-6 levels, and to determine whether IL-6 inhibition therapy is effective for such patients or not. We also address the interactions and targeted therapies in cancer patients who also have SARS-CoV-2 induced disease.

Correlation between Serum Interleukin-6 Levels and Clinical Response to Anthracycline-Based Neoadjuvant Chemotherapy Regimen in Locally Advanced Breast Cancer Patients

Background: Neoadjuvant chemotherapy is the initial therapy and the main pillar of treatment for locally advanced breast cancer (LABC). Currently, there is marker that widely accepted as a predictive factor for chemotherapy response in LABC. Elevated serum interleukin-6 (IL-6) levels and tumor sites have been proposed as prognostic markers for breast cancer. In this study, we aimed to examine the association between serum IL-6 levels with clinical response after the administration of neoadjuvant chemotherapy. Methods: This study is an observational analytic study with a cohort prospective character to determine the relationship between IL-6 serum levels and clinical response to anthracycline-based neoadjuvant chemotherapy in locally advanced breast cancer (LABC) patients at Dr. Soetomo General Hospital during April 2021 to September 2021 with a total sample of 38 patients. Results: Fourteen patients (77.8%) had a positive response in the low IL-6 level group and 4 patients (22.2%) had a negative response. In high IL-6 level group, 4 patients (40%) had a positive response and 16 patients (80%) had a negative response. The cut off of 15.495 pg/mL was used as cut off value for IL-6 to predict the clinical response to chemotherapy. The sensitivity, specificity, PPV, NPV, and accuracy of IL-6 to predict the clinical response after chemotherapy were 80.0%, 77.8%, 80.0%, 77.8%, and 78.9%, respectively. Conclusion: There is a relationship between serum IL-6 levels and clinical response to anthracycline-based neoadjuvant chemotherapy regimens in locally advanced breast cancer (LABC) patients. Keywords: interleukin-6, clinical response, locally advanced breast cancer.

Prognostic Role of IL-6 in POEMS Syndrome

Prognostic Role of IL-6 in POEMS Syndrome

Clinical and Immunological Assessment of Patients with Sars-Cov-2 Infections

▪Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced coronavirus disease-2019 (COVID-19) has presented humanity with unprecedented challenges. Severe disease is associated with acute respiratory distress syndrome (ARDS), use of mechanical ventilation, ICU stay and prolonged hospitalization, The role of the immune system in the pathogenesis of COVID-19 disease is still unclear, which imposes limitations on identifying potential immunotherapy that can improve care for acute and chronic phases of COVID-19 in conjunction with current therapies. Research efforts are ongoing for more than 1 year to identify key immunological mechanisms involved in the disease process. While insightful, this knowledge is still incomplete and can be complemented with the assessment of immune response kinetics. Such assessment will help with the identification of early interventional modalities of immune cell regulation. With these considerations in mind, we aimed to assess several parameters of immune system regulation during the current medical care of patients with COVID-19.Methods: This is a pre-clinical prospective cohort study which involved laboratory-based assessments of blood samples obtained from COVID-19 patients and healthy volunteers. The study population was divided into three cohorts. Our first cohort included 18 years and older COVID-19 patients with respiratory complaints, oxygen (O2) saturations of less than or equal to 92 and pulmonary infiltrates on an imaging study or who were critically ill and required ventilatory support. Second cohort included 18 years and older COVID-19 patients who were hospitalized and did not require ventilatory support. Third cohort included participants with no prior diagnosis of COVID-19, or any recent viral respiratory symptoms including fever, cough or shortness of breath for the last 2 weeks. Patients with an established diagnosis of cancer or immunologic disorders were excluded. Blood specimens were collected over the period of hospitalization: specimen number 1 on day 1-3 of hospitalization, specimen number 2 on days 3-4 of hospitalization, specimen number 3 on days 5-7 of hospitalization, and specimen number 4 on 7-30 days after discharge. We performed capillary electrophoresis for serology and automated ELISA for cytokine measurement. We collected clinical data on patient demographic, clinical characteristics such as presence of any acute and chronic comorbidities and serum inflammatory markers C-Reactive Protein, D-Dimer and Ferritin.Results: We had 15 patients in cohort 1, 10 in cohort 2 and 15 in cohort 3. Patients in cohort 1 were older and had higher comorbidities. Males constituted a substantially high percentage of patients in cohort 1 and 2 (60% and 70% respectively). Patients had similar BMI in cohort 1 and 2. Total antibody levels were highest in cohort 1 but an upward trend over the course of hospitalization was noted in all cohorts. Most interesting pattern was noted in the context of antibodies against spike protein S1 receptor-binding domain (S1RBD) where patients in cohort 2 developed minimal S1RBD antibodies. Cohort 1 on average had higher levels of Interleukin 6(IL-6), Interleukin 8(IL-8), C-X-C motif chemokine ligand 10 (CXCL10) and other inflammatory cytokines except Interferon gamma (IFN-gamma) compared to Cohort 2. Remarkable difference in CXCL-10 levels was noted between the groups and healthy volunteers had the lowest levels. No significant difference in IFN-gamma was noted between cohorts and the levels quickly depleted over the course of the infection.Conclusion: Our analysis confirms that neutralizing antibodies do not correlate with lessened COVID-19 disease severity. Severe COVID-19 infection is secondary to ineffective innate immunity associated with immune overshoot. CXCL10 serves as a major component in triggering the cytokine storm that is a hallmark of SARS-CoV-2 infections. Our findings show an association between high levels of CXCL10 and more severe COVID-19 infection. There does not seem to be any significant correlation with disease severity and IFN-gamma levels. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

AMV564 Depletes Myeloid-Derived Suppressor Cells and Expands T Cells: Potential to Address Key Limitations of Cellular Therapies

BackgroundMyeloid-derived suppressor cells (MDSC) contribute to an immunosuppressive tumor environment and are a barrier to immune therapeutic approaches, including cell-based therapies such as chimeric antigen receptor T cells (CAR T). Despite good overall response rates with certain subsets of B cell leukemias and lymphomas, a significant percentage of patients treated with CAR T therapy do not respond or subsequently relapse. Poor CAR T expansion, poor persistence of infused cells, and clinical treatment failure are associated with tumor and systemic immune dysregulation including high blood levels of peripheral blood monocytic MDSC (M-MDSCs) and interleukin-6, both of which are associated with lack of durable responses 1. In addition, CAR T therapy has been limited by the occurrence of severe cytokine release syndrome (CRS), which is associated with high IL-6 production 2 by myeloid cells such as MDSC.AMV564 is a potent T cell engager that selectively depletes MDSC while promoting T cell activation and proliferation without significant IL-6 induction 3. In phase 1 studies in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors, AMV564 has been demonstrated to be clinically safe and active with some patients achieving complete remissions.MethodsCell lines, primary human cells, and patient samples were analyzed using flow cytometry with appropriate marker panels. T cell activation and cytotoxicity assays were conducted using primary human T cells from healthy donors and target cells (3:1 ratio) for 72 hours. T cell activation using ImmunoCult Human CD3/CD28 served as an assay reference.ResultsAnalysis of patients treated with AMV564 demonstrated statistically significant selective depletion of M-MDSC by cycle 2 (Fig. 1A). While on AMV564 therapy, median IL-6 levels remained below 100 pg/mL despite robust T cell activation and expansion. Granzyme B production by CD8 T cells increased significantly between Cycle 1 and Cycle 2 in patients on therapy, and effector CD8 T cells expand over the course of treatment (Fig. 1B-C). These data collectively support the finding that AMV564 both removes a key source of immune suppression and is a potent agonist of T cell function and differentiation in patients.AMV564 potently activates and expands primary T cells ex vivo. Across donors, peak proliferation was significantly higher with AMV564 than with the CD3/CD28 reference (Fig. 2A). Importantly, T cell viability remained significantly higher with AMV564 when compared to reference control (CD3/CD28), and there was no evidence of activation-induced cell death (AICD) in AMV564-treated samples (Fig. 2B).ConclusionsAMV564 depletes MDSC and stimulates expansion and longevity of T cells without significant IL-6 induction, suggesting a possible strategy for improvement in efficacy of cell-based therapy such as CAR T approaches. As circulating M-MDSC both at baseline and after CAR T infusion correlate with poor clinical efficacy 4, AMV564 may have beneficial effects during the conditioning phase of cell therapy, after re-infusion of CAR T products into patients, or both. Ex vivo studies using donor T cells and ongoing in vitro studies using CAR T molecules suggest that AMV564 may provide dual benefit with respect to both depletion of MDSC and T cell agonism.

Hypovitaminosis D Is Associated with Higher Levels of Inflammatory Cytokines and with HAM/TSP in HTLV-Infected Patients.

Recent studies have shown the effects of vitamin D on host response to infectious diseases. Some studies detected a high prevalence of hypovitaminosis D in HIV-infected patients, but scarce information exists for HTLV-1 infection. We conducted a cross-sectional study to evaluate the frequency of hypovitaminosis D in HTLV-1 patients and its relationship with their immune response in HTLV-infected patients and in age- and gender-matched controls at a Brazilian rehabilitation hospital. We compared vitamin D, interleukin-6 (IL-6), tumoral necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) levels across groups. Logistic regression was utilized to assess the association between hypovitaminosis D and cytokine levels. We enrolled 161 HTLV-infected subjects (129 HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, 32 asymptomatic HTLV carriers) and equal number of HTLV-negative controls. We observed a significantly higher prevalence of hypovitaminosis D in patients with HAM/TSP than in HTLV asymptomatic carriers (p < 0.001), or controls (p < 0.001). HAM/TSP patients also had higher levels of IL-6 and IFN-γ than asymptomatic carriers. Patients with HAM/TSP and hypovitaminosis D had higher levels of TNF-α than asymptomatic HTLV carriers. These findings suggest hypovitaminosis D plays a role in HAM/TSP pathogenesis, and it needs to be evaluated in further studies.