Selenium is inversely associated with interleukin-6 in the elderly.

Abstract BACKGROUND:
Selenium is an essential trace element with antioxidant property. Decreased serum selenium concentration with aging had been found in previous report. In this study, we aim to investigate the association between serum selenium and the inflammatory cytokine interleukin-6 in the elderly living in long-term care facilities in Taiwan.

MATERIALS AND METHODS:
A total of 336 subjects aged 65 years and older (range of age: 65 - 101 years) were recruited from eight long-term care facilities in 2002-2003. Baseline characteristics, anthropometric indices, and biochemical data were obtained. Selenium deficiency was defined as serum selenium concentration < 80 μg/L. Multiple logistic and linear regression analyses were used to examine the relationships between selenium deficiency and interleukin-6 (divided into quartiles).

RESULTS:
The prevalence of selenium deficiency was 35.6% in men and 43.2% in women, respectively. After adjusting for potential confounders using multiple logistic regression analysis, interleukin-6 quartiles were significantly associated with selenium deficiency. Compared to the interleukin-6 quartile I, the adjusted odds ratios of having selenium deficiency for interleukin-6 quartile II, III, IV were 1.00(0.50~2.01), 1.24 (0.62~2.50), and 2.35(1.15~4.83), respectively. The increasing odds ratios for selenium deficiency in higher interleukin-6 quartiles revealed dose-response effects (p < 0.05). Moreover, multiple linear regression analysis showed that serum selenium was significantly inversely associated with interleukin-6 after adjusting for potential confounders.

CONCLUSIONS:
Serum selenium was inversely associated with inflammatory cytokine interleukin-6 among elderly living in long-term care facilities in Taiwan. Monitoring serum selenium should be considered in these institutionalized elderly.


The protagonist of this [cytokine] storm is interleukin 6 (IL-6)

According to the World Health Organization (WHO), viral diseases continue to emerge and represent a serious issue to public health. In the last twenty years, several viral epidemics such as the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 to 2003, and H1N1 influenza in 2009, have been recorded. Most recently, the Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified in Saudi Arabia in 2012.

In a timeline that reaches the present day, an epidemic of cases with unexplained low respiratory infections detected in Wuhan, the largest metropolitan area in China's Hubei province, was first reported to the WHO Country Office in China, on December 31, 2019. Published literature can trace the beginning of symptomatic individuals back to the beginning of December 2019. As they were unable to identify the causative agent, these first cases were classified as "pneumonia of unknown etiology." The Chinese Center for Disease Control and Prevention (CDC) and local CDCs organized an intensive outbreak investigation program. The etiology of this illness is now attributed to a novel virus belonging to the coronavirus (CoV) family.

On February 11, 2020, the WHO Director-General, Dr. Tedros Adhanom Ghebreyesus, announced that the disease caused by this new CoV was a "COVID-19," which is the acronym of "coronavirus disease 2019". In the past twenty years, two additional coronavirus epidemics have occurred. SARS-CoV provoked a large-scale epidemic beginning in China and involving two dozen countries with approximately 8000 cases and 800 deaths, and the MERS-CoV that began in Saudi Arabia and has approximately 2,500 cases and 800 deaths and still causes as sporadic cases.

This new virus seems to be very contagious and has quickly spread globally. In a meeting on January 30, 2020, per the International Health Regulations (IHR, 2005), the outbreak was declared by the WHO a Public Health Emergency of International Concern (PHEIC) as it had spread to 18 countries with four countries reporting human-to-human transmission. An additional landmark occurred on February 26, 2020, as the first case of the disease, not imported from China, was recorded in the United States.

Initially, the new virus was called 2019-nCoV. Subsequently, the task of experts of the International Committee on Taxonomy of Viruses (ICTV) termed it the SARS-CoV-2 virus as it is very similar to the one that caused the SARS outbreak (SARS-CoVs).

The CoVs have become the major pathogens of emerging respiratory disease outbreaks. They are a large family of single-stranded RNA viruses (+ssRNA) that can be isolated in different animal species.[1] For reasons yet to be explained, these viruses can cross species barriers and can cause, in humans, illness ranging from the common cold to more severe diseases such as MERS and SARS. Interestingly, these latter viruses have probably originated from bats and then moving into other mammalian hosts — the Himalayan palm civet for SARS-CoV, and the dromedary camel for MERS-CoV — before jumping to humans. The dynamics of SARS-Cov-2 are currently unknown, but there is speculation that it also has an animal origin.

The potential for these viruses to grow to become a pandemic worldwide seems to be a serious public health risk. Concerning COVID-19, the WHO raised the threat to the CoV epidemic to the "very high" level, on February 28, 2020. Probably, the effects of the epidemic caused by the new CoV has yet to emerge as the situation is quickly evolving. On March 11, as the number of COVID-19 cases outside China has increased 13 times and the number of countries involved has tripled with more than 118,000 cases in 114 countries and over 4,000 deaths, WHO declared the COVID-19 a pandemic.

World governments are at work to establish countermeasures to stem possible devastating effects. Health organizations coordinate information flows and issues directives and guidelines to best mitigate the impact of the threat. At the same time, scientists around the world work tirelessly, and information about the transmission mechanisms, the clinical spectrum of disease, new diagnostics, and prevention and therapeutic strategies are rapidly developing. Many uncertainties remain with regard to both the virus-host interaction and the evolution of the epidemic, with specific reference to the times when the epidemic will reach its peak.

At the moment, the therapeutic strategies to deal with the infection are only supportive, and prevention aimed at reducing transmission in the community is our best weapon. Aggressive isolation measures in China have led to a progressive reduction of cases in the last few days. In Italy, in geographic regions of the north, initially, and subsequently throughout the peninsula, political and health authorities are making incredible efforts to contain a shock wave that is severely testing the health system.

In the midst of the crisis, the authors have chosen to use the "Statpearls" platform because, within the PubMed scenario, it represents a unique tool that may allow them to make updates in real-time. The aim, therefore, is to collect information and scientific evidence and to provide an overview of the topic that will be continuously updated.


Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis

Coronaviruses may activate dysregulated host immune responses. As exploratory studies have suggested that interleukin-6 (IL-6) levels are elevated in cases of complicated COVID-19 and that the anti-IL-6 biologic tocilizumab may be beneficial, we undertook a systematic review and meta-analysis to assess the evidence in this field. Methods: We systematically searched MEDLINE and EMBASE for studies investigating the immunological response in COVID-19 or its treatment with tocilizumab; additional grey literature searches were undertaken. Meta-analysis was undertaken using random effects models. Results: Eight published studies, three pre-prints, and five registered trials were eligible. Meta-analysis of mean IL-6 concentrations demonstrated 2.9-fold higher levels in patients with complicated COVID-19 compared with patients with non-complicated disease (six studies; n=1302; 95%CI, 1.17-7.19; I2=100%). A single non-randomized, single-arm study assessed tocilizumab in patients with severe COVID-19, demonstrating decreased oxygen requirements, resolution of radiographic abnormalities, and clinical improvement. No adverse events or deaths were observed. Conclusions: In patients with COVID-19, IL-6 levels are significantly elevated and associated with adverse clinical outcomes. While inhibition of IL-6 with tocilizumab appears to be efficacious and safe in preliminary investigation, the results of several ongoing clinical trials should be awaited to better define the role of tocilizumab in COVID-19 prior to routine clinical application.


Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients

The pandemic Coronavirus-disease 19 (COVID-19) is characterized by a heterogeneous clinical course. While most patients experience only mild symptoms, a relevant proportion develop severe disease progression with increasing hypoxia up to acute respiratory distress syndrome. The substantial number of patients with severe disease have strained intensive care capacities to an unprecedented level. Owing to the highly variable course and lack of reliable predictors for deterioration, we aimed to identify variables that allow the prediction of patients with a high risk of respiratory failure and need of mechanical ventilation Patients with PCR proven symptomatic COVID-19 infection hospitalized at our institution from 29th February to 27th March 2020 (n=40) were analyzed for baseline clinical and laboratory findings. Patients requiring mechanical ventilation 13/40 (32.5%) did not differ in age, comorbidities, radiological findings, respiratory rate or qSofa score. However, elevated interleukin-6 (IL-6) was strongly associated with the need for mechanical ventilation (p=1.2.10-5). In addition, the maximal IL-6 level (cutoff 80 pg/ml) for each patient during disease predicted respiratory failure with high accuracy (p=1.7.10-8, AUC=0.98). The risk of respiratory failure for patients with IL-6 levels of ≥ 80 pg/ml was 22 times higher compared to patients with lower IL-6 levels. In the current situation with overwhelmed intensive care units and overcrowded emergency rooms, correct triage of patients in need of intensive care is crucial. Our study shows that IL-6 is an effective marker that might be able to predict upcoming respiratory failure with high accuracy and help physicians correctly allocate patients at an early stage.


TNF-a, IL-1b, and IL-6

Severe COVID-19 Dysregulated SI
Laboratory markers 1
❑ Inflammation: ▲ ▲ TNF-a, IL-1b, and IL-6 …
➢ similar to SARS, 2 MERS, 2 and non-viral ARDS3
❑ Acute phase response: C-reactive protein, ferritin
❑ Endothelial injury-Coagulation: D-dimer, INR, platelet count Clinical outcome
❑ ARF similar to ARDS ► MV - leading cause of death

1. Henry BM et al. Hematologic, biochemical a- immune biomarker abnormalities in COVID-19 meta-analysis. Clinical Chem and Lab MediCCLM) 2020 (on line)

2. Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020 3. Meduri GU et al. Activation and regulation of systemic inflammation in ARDS: Rationale for prolonged glucocorticoid therapy. Chest. 2009;136:1631-43


Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes

Highlights:
• Of several cytokines tested, only synergism of TNF-α and IFN-γ induces PANoptosis

• TNF-α and IFN-γ-mediated PANoptosis perpetuates cytokine storm

• TNF-α and IFN-γ shock mirrors cytokine storm syndromes, including COVID-19

• Neutralizing TNF-α and IFN-γ protects against SARS-CoV-2, HLH, and sepsis in mice


Fructose reprogrammes glutamine-dependent oxidative metabolism to support LPS-induced inflammation

Fructose intake has increased substantially throughout the developed world and is associated with obesity, type 2 diabetes and non-alcoholic fatty liver disease. Currently, our understanding of the metabolic and mechanistic implications for immune cells, such as monocytes and macrophages, exposed to elevated levels of dietary fructose is limited. Here, we show that fructose reprograms cellular metabolic pathways to favour glutaminolysis and oxidative metabolism, which are required to support increased inflammatory cytokine production in both LPS-treated human monocytes and mouse macrophages. A fructose-dependent increase in mTORC1 activity drives translation of pro-inflammatory cytokines in response to LPS. LPS-stimulated monocytes treated with fructose rely heavily on oxidative metabolism and have reduced flexibility in response to both glycolytic and mitochondrial inhibition, suggesting glycolysis and oxidative metabolism are inextricably coupled in these cells. The physiological implications of fructose exposure are demonstrated in a model of LPS-induced systemic inflammation, with mice exposed to fructose having increased levels of circulating IL-1β after LPS challenge. Taken together, our work underpins a pro-inflammatory role for dietary fructose in LPS-stimulated mononuclear phagocytes which occurs at the expense of metabolic flexibility.




2013 Tseng: Selenium is inversely associated with interleukin-6 in the elderly.
https://www.ncbi.nlm.nih.gov/pubmed/23459983


2020 Cascella: The protagonist of this [cytokine] storm is interleukin 6 (IL-6)
https://www.ncbi.nlm.nih.gov/books/NBK554776/


2020 Coomes: Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis
https://www.medrxiv.org/content/10.1101/2020.03.30.20048058v1


2020 Herold: Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients
https://www.medrxiv.org/content/10.1101/2020.04.01.20047381v2


2020 Umbertos: TNF-a, IL-1b, and IL-6
https://uthsc.edu/coronavirus/documents/vit-c-rx-covid-19-4-21-20-ro.pdf


2020 Karki: Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes
https://www.sciencedirect.com/science/article/pii/S0092867420315427


2021 Blagih: Fructose reprogrammes glutamine-dependent oxidative metabolism to support LPS-induced inflammation
https://www.nature.com/articles/s41467-021-21461-4