key: cord-1010334-5uyudoz7
authors: Pincemail, Joël; Cavalier, Etienne; Charlier, Corinne; Cheramy–Bien, Jean-Paul; Brevers, Eric; Courtois, Audrey; Fadeur, Marjorie; Meziane, Smail; Goff, Caroline Le; Misset, Benoît; Albert, Adelin; Defraigne, Jean-Olivier; Rousseau, Anne-Françoise
title: Oxidative Stress Status in COVID-19 Patients Hospitalized in Intensive Care Unit for Severe Pneumonia. A Pilot Study
date: 2021-02-07
journal: Antioxidants (Basel)
DOI: 10.3390/antiox10020257
sha: 4bc47a0e6c42d9bc003eef04f9c26b791fe2c988
doc_id: 1010334
cord_uid: 5uyudoz7

Background: A key role of oxidative stress has been highlighted in the pathogenesis of COVID-19. However, little has been said about oxidative stress status (OSS) of COVID-19 patients hospitalized in intensive care unit (ICU). Material and Methods: Biomarkers of the systemic OSS included antioxidants (9 assays), trace elements (3 assays), inflammation markers (4 assays) and oxidative damage to lipids (3 assays). Results: Blood samples were drawn after 9 (7–11) and 41 (39–43) days of ICU stay, respectively in 3 and 6 patients. Vitamin C, thiol proteins, reduced glutathione, γ-tocopherol, β-carotene and PAOT(®) score were significantly decreased compared to laboratory reference values. Selenium concentration was at the limit of the lower reference value. By contrast, the copper/zinc ratio (as a source of oxidative stress) was higher than reference values in 55% of patients while copper was significantly correlated with lipid peroxides (r = 0.95, p < 0.001). Inflammatory biomarkers (C-reactive protein and myeloperoxidase) were significantly increased when compared to normals. Conclusions: The systemic OSS was strongly altered in critically ill COVID-19 patients as evidenced by increased lipid peroxidation but also by deficits in some antioxidants (vitamin C, glutathione, thiol proteins) and trace elements (selenium).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was responsible for Coronavirus disease 2019 (COVID- 19) , the first cases having been reported in Wuhan, China, in December 2019 [1] . Due to fast transmission and pathogenicity, the coronavirus has spread across all countries, provoking a pandemic [2] . COVID-19 is characterized by aberrant host immune response, leading to excessive inflammatory responses (or cytokine storm)-as evidenced by high blood levels of cytokines, chemokines and C-reactive protein-and is associated with severe damage to the respiratory system and multi-organ failure, contributing to fatal outcomes of infected patients [3] [4] [5] . Post-mortem analysis of COVID-19 lungs showed infiltration of inflammatory mononuclear cells and macrophages in the air spaces, which may induce diffuse remodeling of the alveolar wall [6] .

In a large number of pathologies, inflammation is known to be closely related to oxidative stress, one process being easily induced by the other [7] [8] [9] . Oxidative stress (OS) is defined as an imbalance between toxic reactive oxygen species (ROS) and antioxidants in favor of oxidants, leading to a disruption of redox signaling and/or irreversible oxidative damage to lipids, deoxyribonucleic acid (DNA) or proteins [10] . Oxidative damages are involved in the development of different pathologies including cancer, cardiovascular, neurodegenerative and lung diseases [11] . Besides inflammation, other pathophysiological mechanisms in relationship with increased OS have been advocated to explain the pathogenesis of COVID-19 [12] : inhibition of angiotensin converting enzyme 2 (ACE-2) activity [13] [14] [15] [16] , denaturation of hemoglobin leading to iron metabolism dysregulation with release of toxic free iron ion [17] [18] [19] [20] [21] , disseminated intravascular coagulation due to hypoxia [12] and endothelial dysfunction [22] [23] [24] [25] [26] .

Despite recent papers highlighting the key role of oxidative stress and inflammation duo in the development of COVID-19 [12, 27, 28] , little information is available about the systemic oxidative stress status (OSS) of COVID-19 patients hospitalized in intensive care unit (ICU) for severe pneumonia. The present study aimed to specifically identify blood biomarkers of OS including antioxidants, trace elements, and oxidative damages to lipids in such COVID-19 patients and to analyze their relationship with inflammation as a major source of ROS production.

This study was conducted during the first wave of the COVID-19 pandemic in May 2020 in the 50-bed Intensive Care Unit (ICU) of the University Hospital of Liège in Belgium. Due to the particular context of the pandemic, we received first a written agreement from the President of local Ethical Committee on 29 April 2020. The study protocol was then formally approved under national reference B707202000035, Local reference 2020-201, on 5 June 2020. All legal representatives of the patients were instructed on the study objectives and signed informed consent.

The study was conducted on a convenience sample of critically ill adult patients hospitalized for severe COVID-19 pneumonia. Patients were excluded if they were weaned from mechanical ventilation and if they were on continuous veno-venous hemofiltration (CVVH) during the 7 days before blood sampling. In total, nine patients were included.

All the patients received medical nutrition following the local nutritional practices. According to the nutritional guidelines that were available at the time of the study, weightbased formulas were used to estimate energy and protein targets (Table 1) . Enteral nutrition was administered continuously using a volumetric pump. Gastric residual volume was monitored every 6 h: in case of volume ≥250 mL, feeding rate was reduced and prokinetics (metoclopramide or erythromycin) were considered at the intensivist's discretion. The different industrial enteral solutions were: Nutrison Protein Plus, Nutrison Energy Multi Fibre, (Nutricia ® , Brussels, Belgium) and Peptamen AF (Nestlé Health Science ® , Brussels, Belgium). In case of insufficient or contraindicated enteral nutrition, respectively supplemental or total parenteral nutrition was initiated using a ternary mixture (Smofkabiven, Fresenius Kabi ® , Schelle, Belgium). Parenteral nutrition was administered continuously via a central venous line, using a volumetric pump. Patients on parenteral nutrition or continuous veno-venous hemofiltration were supplemented with micronutrients (Addaven ® , Soluvit ® Novum, Vitalipid ® Novum Adult (Frésénius Kabi ® , Schelle, Belgium)).

Demographic data (age, sex, weight, height, body mass index (BMI), medical history, severity scores, organ support duration, route of nutrition, length of stay (LOS), survival) were collected for all patients from the electronic medical record. Blood samples drawn from a venous central line on tubes containing EDTA and citrate were immediately centrifuged at 3000× g during 10 min. Serum gel was allowed to clot during 30 min before being centrifuged. Plasma and sera samples were then frozen at −80 • C until analysis of OS biomarkers. Blood determination of antioxidants, respectively vitamins C and E (γ-and α-tocopherols), vitamin E standardized to cholesterol (Vit E/cholesterol), β-carotene, glutathione (GSH), thiol proteins (PSH), glutathione peroxidase (GPx), trace elements (selenium (Se), copper (Cu), zinc (Zn), copper/zinc ratio), biomarkers of oxidative damages to lipids (lipid peroxides (ROOH), oxidized LDL (ox-LDL), and antibodies IgG against oxidized LDL (Ab-ox-LDL) has been described in detail [29, 30] . C-reactive protein (CRP) concentration was determined on a COBAS ® 8000 analyzer (Roche Diagnostics, Machelen, Belgium). Myeloperoxidase (MPO) was assessed using MPO ELISA kit (Immun Diagnostik, Bensheim, Germany). Cholesterol was measured using an enzymatic method with cholesterol oxidase on Abbott Alinity C (Abbott, Chicago, IL, USA). Albumin was assessed by spectrophotometry using Alinity C kit (Abbott, Chicago, IL, USA). White blood cells and neutrophils were determined by flow fluorocytometry on Sysmex-SN device (Ontario, Canada). The total antioxidant capacity (TAC) of plasma was evaluated by using the PAOT ® (Pouvoir AntiOxydant Total, Institut Européen des Antioxydants, Nancy, France) score as previously described [31] . Briefly, the measurement was carried out in a reaction medium (1 mL physiological solution at pH ranging from 6.7 to 7.2, temperature 24-27 • C) containing a molecule in a free radical state called mediator (M•). Two microelectrodes, one being the working electrode and the second one the reference electrode, were then immersed in the medium. After addition of 20 µL of plasma, the PAOT activity was estimated by registering electrochemical potential modifications in the reaction medium. Blood concentrations of all OS biomarkers were compared to the reference values applicable in the central laboratory of the CHU of Liège [29, 30] .

Patients were divided in two groups according to the ICU stay duration. Patients with an ICU stay ≤10 days (short stayers, N = 3 patients) or >10 days (long stayers, N = 6 patients) before blood sampling were arbitrarily defined as short or long stayers, respectively.

Quantitative data were expressed as median and range while numbers and percent were used for categorical findings. To compare the distribution of biological parameters of COVID-19 patients with the laboratory reference intervals, we used the sign test based on the binomial distribution. Specifically, according to the sign test, when all COVID-19 patient values fell below (or above) the middle of the reference interval, we concluded that the biological test was significantly lowered (or increased) in COVID-19 patients (p = 0.004) and likewise for eight COVID-19 patients (p = 0.040); otherwise, COVID-19 patients were not statistically different from presumably healthy subjects. Comparison of OSS between short and long stayers was made using the nonparametric Mann-Whitney U test. Results were considered significant at the 5% critical level (p < 0.05). The Spearman correlation coefficient was calculated to measure the association between biological parameters. A p-value < 0.05 was considered as statistically significant.

The characteristics of the nine study patients are described in Table 2 . Most of the patients were overweight and/or presented pathologies such as type 2 diabetes (64%) or arterial hypertension (66%). All the patients were on enteral feeding and one patient received supplemental parenteral nutrition during the 7 days before blood sampling. During the entire ICU stay before blood sampling, 3/9 patients received temporary supplemental parenteral nutrition in addition to insufficient enteral nutrition, and 3/9 patients had been temporarily on CVVH. These patients received an intravenous supplementation in vitamins and trace elements. Mean daily macro-and micronutrients intakes from ICU admission to blood sampling are described in Table 3 .

As shown in Table 4 , the median concentration of vitamin C, γ-tocopherol, β-carotene, PSH, GSH and PAOT ® score was statistically lower than the reference interval when considering all patients. By contrast, those of GPx, MPO, neutrophils count and CRP was significantly higher than the standards. Figures S1-S3 (see Supplementary Material) show all the individual OS biomarkers values when compared to the reference interval. Vitamin C, PSH and GSH concentrations were below the lower normal value (LNV) in almost all patients. By contrast, elevated levels in GPX ROOH, copper/zinc ratio and CRP being higher than the upper normal value were found in a large majority of patients. Table 5 displays the main significant correlations observed between OS biomarkers. Copper correlated positively with ROOH, Cu/Zn ratio and CRP but negatively with γtocopherol. Cu/Zn ratio tended to positively correlate with ROOH and similarly for Cu and CRP. By contrast, γ-tocopherol tended to correlate negatively with ROOH, ox-LDL and CRP. MPO negatively correlated with albumin and, to a lesser extent, with PSH. No correlation was found between PSH and albumin (data not shown).

As blood samples were taken after different times in the ICU, we investigated if differences could occur in OS biomarkers concentration between short and long stayers (Table S1, see Supplementary Material). Only a significant increase in vitamin C, β-carotene and selenium was observed in long stayers when compared to short stayers. Nevertheless, the median value of both antioxidants always remained below the INV. By contrast, those of selenium has changed from 51 µg/L in short stayers to 97.5 (73-105) µg/L in long stayers, this last value being in the reference interval. GSH concentration decreased in a non-significant way from 794 µM in short stayers to 598 µM in long stayers, a value largely below the INV. As shown in Table S2 (see Supplementary Material) , abnormal values in vitamin C, PSH, GSH, GPx, copper/zinc ratio, ROOH, neutrophils and CRP were frequent (≥50%) in both groups. Low selenium levels were mostly observed in short stayers ( Figure S2 , see Supplementary Material). 

To the best of our knowledge, this is the first report showing a deep alteration of systemic OSS using an analysis of a large number of biomarkers in COVID-19 patients hospitalized for severe pneumonia. Of interest to note is that results were homogenous despite a different timing (short and long stayers) in the blood collection.

An important collapse in antioxidant defenses was detected in the COVID-19 patients as evidenced by levels of vitamin C, GSH, PSH, γ-tocopherol and β-carotene that were largely below the reference interval.

When considering all the nine COVID-19 patients, their median value in vitamin C corresponds to the definition of a hypovitaminosis C [32] . Despite a significant increase when compared to short stayers, vitamin C level in long stayers remained below the inferior normal value. In a recent paper, Chiscano-Camón et al. [33] reported that undetectable vitamin C levels were observed in 94.4% of COVID-19 patients 17.5 days after ICU hospitalization. In our study, such a vitamin C deficiency indicated that intakes of this antioxidant given at nutritional doses as recommended by ESPEN guidelines [34] were therefore not sufficient to maintain vitamin C concentration in the reference interval, as already observed in other critically ill patients [35] . In fact, intravenous (IV) administration only has been able to restore high-level ascorbic acid plasma concentration [36] . Even if always being a matter of controversy [37, 38] , high doses (several grams) of IV vitamin C could help reducing the "cytokines storm" [39] and could have immunosuppressive effects [40] . When compared to a placebo group, Zhang et al. [41] recently demonstrated in a preprint paper without peer-reviewing that high-doses of IV vitamin C (12 g every 12 h) for 7 days improved oxygenation in COVID-19 critically ill patients. Moreover, blood interleukin-6 levels were significantly reduced after 7 days of treatment. Unfortunately, the authors did not monitor serum vitamin C concentration before and after IV injection.

Glutathione, a crucial antioxidant, is well known to modulate the behavior of many cells including the cells of the immune system, augmenting the innate and the adaptive immunity as well as conferring protection against microbial, viral and parasitic infections [42, 43] . Interaction between GSH metabolism and several diseases were also well described [44] . For example, low glutathione has been associated with abnormalities in the lung surfactant system, while normal levels of intracellular glutathione may exert a critical negative control on the elaboration of pro-inflammatory cytokines [45] . Our study revealed that the GSH status was significantly altered downwards in our COVID-19 patients, particularly in the long stayers. Recently, Polinokov [46] concluded that blood deficiency in GSH exacerbated COVID-19 illness. In two COVID-19 patients, Horowitz et al. [47] observed that the 2 g per os or IV glutathione improved their dyspnea within 1 h of use. Repeated use of 2 g was effective in further relieving respiratory symptoms. Recently, Poe and Corn, Rangel-Mendez et al. and De Flora et al. [48] [49] [50] hypothesized that N-acetyl-Lcysteine (NAC) as a precursor of glutathione could act as a potential therapeutic agent in the treatment of COVID-19 through a variety of potential mechanisms, including increasing glutathione, improving T cell response, and modulating inflammation. Interestingly, we also observed in parallel a deep depletion in PSH. By its large amount in plasma, albumin dotted of -SH groups represents around 75% of the thiol pool [51] . Infectious and inflammatory states are known to alter the serum concentration of albumin [52] , as observed in the present study. Nevertheless, we found no correlation between PSH and albumin.

The determination of the total antioxidant capacity (TAC) has been proposed as a global measure of non-enzymatic antioxidant efficiency despite the problem of inference with uric acid [53, 54] . Using an original electrochemical methodology developed by us [31] , we showed that the TAC as evaluated by the PAOT ® score was logically decreased in COVID-19 patients most probably because of their very low levels in vitamin C and GSH. Nevertheless, no correlation could be evidenced between both antioxidants and TAC as also shown in the EPIC Granada-Gipuzkoa study [55] . Nevertheless, it was interesting to note the positive correlation of PAOT ® score and the Vit E/cholesterol. More investigations are required to better understand and evaluate the real role and place of TAC in the OSS.

Adequate levels of Se are important for initiating immunity, but they are also involved in regulating excessive immune responses and chronic inflammation [56] . In the present study, selenium was close to the inferior normal value, and an important deficit was detected in the three short stayers. Moghaddam et al. [57] analyzed the selenium status in a cohort of 33 COVID-19 patients providing a set of four consecutive serum samples taken from ICU admission to ICU discharge (median: 19 (3-46) days) or death (median: 10 (2-32) days). When compared to reference data issued from a European cross-sectional analysis, these authors found, in agreement with us, a pronounced deficit with a very low selenium concentration in 43.4% of the samples, more particularly in those of short stayers ( Figure S2 , see Supplementary Material). By contrast, all our long stayers exhibited individual values being within the reference interval, significantly higher than those of short stayers. This could suggest that the nutritional intakes in selenium could have been adequate to compensate initial deficits.

In their paper, Moghaddam et al. [57] also analyzed glutathione peroxidase (GPx), an antioxidant enzyme requiring glutathione (GSH) and selenium as co-factors to eliminate lipid peroxides (ROOH). Unlike the present results, these authors found a significant correlation between selenium and GPx. Even if the GPx level was elevated in all our patients, it should be surprising that its activity was optimal given the low level in its co-factor GSH but also the elevated concentration in ROOH.

Copper exhibits, at non-physiological concentration, pro-oxidant activities by inducing free radical formation through Fenton-like reaction [58] . The potential pro-oxidant effect of copper was suggested in our study by both its strong positive correlation with ROOH and negative correlation with γ-tocopherol, a major antioxidant acting as lipid peroxidation inhibitor. Besides an important role in immunity [59] , zinc also had antioxidant properties [60] as main co-factor of superoxide dismutase (SOD) but also as inhibitor of free radical reaction induced by copper. As shown in Figure S2 (see Supplementary Material), Cu/Zn ratio values higher than the UNV were found in half of the patients. As part of an OS assessment, some authors suggested that the Cu/Zn ratio should be considered as a better indicator of OS presence than copper alone [61, 62] . Such a ratio is rarely analyzed in critically ill patients. The strong relationship between health status and Cu/Zn ratio has, however, been extensively reviewed by Malavolta [63] . So, human studies have well evidenced that inflammatory stimuli modify serum concentration of Cu and Zn by increasing the former and decreasing the latter through a hepatic organized mechanism [64] . In our study, we effectively observed that the Cu/Zn ratio was positively correlated with CRP. Moreover, the ratio also tended to be positively correlated with ROOH (Table 5 ). This is in agreement with previous papers reporting that increased copper/zinc ratio was correlated with heightened systemic oxidant load in aging-related degenerative diseases [65] , patients undergoing renal dialysis [66] or women taking oral contraceptive [30] .

Even if the elevated level of lipid peroxides was not statistically different from the reference interval, a majority of COVID-19 patients (63.6%) exhibited higher levels than the upper reference value ( Figure S2 , see Supplementary Material). The strong correlation observed between ROOH and copper highlighted the important role of this last trace element in the development of the lipid peroxidation process. By contrast, ox-LDL, as another form of lipid peroxidation [67] , did not confirm the presence of increased oxidative damages to lipids. However, ox-LDL elicited the production of both IgG and IgM ox-LDL antibodies. It is accepted that IgG ox-LDL antibodies had pro-inflammatory effect while IgM were anti-atherogenic [68] . Surprisingly, we observed in our study two distinct profiles in IgG values ( Figure S2 , see Supplementary Material). We have no clear explanation related to such discrepancy.

In COVID-19 patients as well as in critically ill patients, increased plasma inflammatory markers such as CRP have been well described [69] . In our study, we confirmed such inflammatory process (Table 4 ) as especially evidenced by elevated levels in MPO, an enzyme specifically localized in neutrophils. This reflects the activation of these cells probably by cytokines leading to the release in the extracellular medium of ROS in high amount [70] . MPO can also catalyze the formation of toxic hypochlorous acid (HOCl), able to oxidize albumin [71] . Oxidation of -SH groups of albumin is known to occur in pathophysiological processes associated with increased inflammation and oxidative stress [51] and potentially in COVID-19 patients [72] . This could explain why we have observed a negative correlation between MPO and albumin in our patients.

Our observational study did not allow us to conclude if increased OS and antioxidant depletion could be directly attributed to the COVID-19 disease by itself or by its complications and the delivered organ supports [73] [74] [75] . Nevertheless, significant alterations in vitamin C, GSH and selenium concentrations, all molecules playing a key role in the immunity, raise questions in the particular framework of the COVID-19 pathogenesis. Associated to increased lipid peroxidation, these observations should therefore create opportunities to explore potential approaches for prevention or treatment by antioxidants, as observed in COVID-19 patients [76] [77] [78] [79] [80] . As recently suggested for vitamin C and glutathione [33, 47, 81] , monitoring of OSS should be implemented in COVID-19 critically ill patients, including vitamin C, GSH in association with PSH, and, finally, ROOH in association with the Cu/Zn ratio and CRP.

First, only a few number of patients have been studied and blood sampling timing was not standardized. Second, some clinical data, such as the number of septic complications, were not taken into account in the present analysis. Moreover, OSS status of our patients at ICU admission was unfortunately unknown. Our patients were overweight (median value: 29 kg/m 2 ) and some of them had pre-existing medical conditions such as diabetes (64%) and/or arterial hypertension (55%), all conditions being potentially associated with basal increased OS [82] [83] [84] . If focusing on vitamin C, the literature review indicated, however, that these pathological situations by themselves could not be responsible for hypovitaminosis C [85] [86] [87] [88] . Finally, nutritional support varied between patients and their average energy and protein intakes was lower than recommended. This could have influenced the observed OS status.

The systemic OSS was strongly altered in critically ill COVID-19 patients as evidenced by increased lipid peroxidation but also by deficits in some antioxidants (vitamin C, glutathione, thiol proteins) and trace elements (selenium). Strong positive correlations between lipid peroxides and Cu and the negative correlation between γ-tocopherol and Cu highlighted the role played by copper in increased OS in COVID-19 patients. These observations need to be confirmed on a larger population.

Supplementary Materials: The following are available online at https://www.mdpi.com/2076-392 1/10/2/257/s1, Figure S1 : Individual plasma values in antioxidants observed in COVID-19 patients (N = 9). Figure S2 : Individual plasma values in trace elements and markers of lipid peroxidation observed in COVID-19 patients (N = 9). Figure S3 : Individual plasma or blood values in inflammatory biomarkers observed in COVID-19 patients (N = 9)., Table S1 : Statistical comparison of median values for all investigated OS biomarkers between short and long stayers., Table S2 Institutional Review Board Statement: The study protocol was formally approved by the Ethics committee of University-CHU Liège, Belgium under national reference B707202000035, Local reference 2020-201, on 5 June 2020.

Informed Consent Statement: All legal representatives of the patients were instructed on the study objectives and signed informed consent.

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

The authors declare no conflict of interest.

A Novel Coronavirus from Patients with Pneumonia in China

A novel coronavirus emerging in China-key questions for impact assessment

The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system

Cytokine Storm in COVID-19: When You Come Out of the Storm, You Won't Be the Same Person Who Walked in

Immune response in COVID-19: Addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2

Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: A two-centre descriptive study

Vascular Inflammation and Oxidative Stress: Major Triggers for Cardiovascular Disease

Inflammaging and oxidative stress in human diseases: From molecular mechanisms to novel treatments

Inflammatory and oxidative stress in rotavirus infection

Redefining oxidative stress

Measurement and Clinical Significance of Lipid Peroxidation as a Biomarker of Oxidative Stress: Oxidative Stress in Diabetes, Atherosclerosis, and Chronic Inflammation

SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression

Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: Molecular mechanisms and potential therapeutic target

Clinical implications of SARS-CoV-2 interaction with renin angiotensin system JACC review topic of the week

ACE2-angiotensin-(1-7)-Mas axis and oxidative stress in cardiovascular disease

Oxidative stress-mediated effects of angiotensin II in the cardiovascular system

Hemoglobin value may be decreased in patients with severe coronavirus disease 2019

Protein aggregation as a cellular response to oxidative stress induced by heme and iron

COVID-19: Hemoglobin, iron, and hypoxia beyond inflammation. A narrative review

Revisiting the putative role of heme as a trigger of inflammation

COVID-19 cytokine storm and novel truth

Endothelial cell dysfunction: A major player in SARS-CoV-2 infection (COVID-19)?

Endothelial dysfunction in Coronavirus disease 2019 (COVID-19): Gender and age influences

Central Role of eNOS in the Maintenance of Endothelial Homeostasis

Oxidative stress and endothelial dysfunction in hypertension

Oxidative Stress and New Pathogenetic Mechanisms in Endothelial Dysfunction: Potential Diagnostic Biomarkers and Therapeutic Targets

Oxidative stress as key player in severe acute respiratory syndrome coronaivirus (SARS-COV) infection

Oxidative stress associated SARS-CoV-2 (COVID-19) increases the severity of lung disease-A systematic review

On the potential increase of the oxidative stress status in patients with abdominal aortic aneurysm

Effect of different contraceptive methods on the oxidative stress status in women aged 40-48 years from the ELAN study in the province of Liège

Electrochemical Methodology for Evaluating Skin Oxidative Stress Status (SOSS). Diseases

Regulation of Vitamin C Homeostasis during Deficiency

Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome

ESPEN guideline on clinical nutrition in the intensive care unit

Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes

Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use

Vitamin C in the critically ill-Indications and controversies

Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis

Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome

High-dose Intravenous Vitamin C Treatment for COVID-19

High-dose vitamin C infusion for the treatment of critically ill COVID-19

Glutathione and immune function

The importance of glutathione in human disease

Significance of Glutathione in Lung Disease and Implications for Therapy

Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients

Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases

A potential therapeutic agent for SARS-CoV-2

N-acetylcysteine as a potential treatment for COVID-19

Rationale for the use of N -acetylcysteine in both prevention and adjuvant therapy of COVID-19

The thiol pool in human plasma: The central contribution of albumin to redox processes

Hanouneh, I. Malnutrition vs nutritional assessment

Understanding the association between dietary antioxidants, redox status and disease: Is the Total Antioxidant Capacity the right tool? Redox Rep

Non-enzymatic antioxidant capacity assays: Limitations of use in biomedicine

Plasma Non-Enzymatic Antioxidant Capacity (NEAC) in Relation to Dietary NEAC

The Role of Selenium in Inflammation and Immunity: From Molecular Mechanisms to Therapeutic Opportunities

Selenium Deficiency Is Associated with Mortality Risk from COVID-19

Copper toxicity, oxidative stress and antioxidant nutrients

Zinc in Human Health: Effect of Zinc on Immune Cells

Antioxidant and anti-inflammatory effects of zinc. Zincdependent NF-κB signaling

Cu/Zn ratios are associated with nutritional status, oxidative stress, inflammation, and immune abnormalities in patients on peritoneal dialysis

Copper/zinc and copper/selenium ratios, and oxidative stress as biochemical markers in recurrent aphthous stomatitis

Serum copper to zinc ratio: Relationship with aging and health status

Copper and zinc body levels in inflammation: An overview of the data obtained from animal and human studies

Copper/zinc ratio and systemic oxidant load: Effect of aging and aging-related degenerative diseases

Effects of Zinc Supplementation on Plasma Copper/Zinc Ratios, Oxidative Stress, and Immunological Status in Hemodialysis Patients

Increased Serum ox-LDL Levels Correlated with Lung Function, Inflammation, and Oxidative Stress

Antibodies to oxidized LDL in atherosclerosis development-clinical and animal studies

SARS-CoV-2 antibodies, serum inflammatory biomarkers and clinical severity of hospitalized COVID-19 patients

A New Biomarker of Inflammation in Ischemic Heart Disease and Acute Coronary Syndromes

Myeloperoxidase-Induced Oxidation of Albumin and Ceruloplasmin: Role of Tyrosines

Measurement of oxidized albumin: An opportunity for diagnoses or treatment of COVID-19

Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients

Antioxidant status in patients with acute respiratory distress syndrome

Zinc and selenium status in critically ill patients according to severity stratification

Current status of potential therapeutic candidates for the COVID-19 crisis

Micronutrient status of COVID-19 patients: A critical consideration

An anti-oxidative therapy for ameliorating cardiac injuries of critically ill COVID-19-infected patients

COVID-19 and cardiovascular injury: A role for oxidative stress and antioxidant treatment?

Defective Anti-oxidant System: An Aggravating Factor for COVID-19 Patients Outcome?

Potential interventions for novel coronavirus in China: A systematic review

Oxidative Stress in Obesity: A Critical Component in Human Diseases

Type 2 diabetes mellitus, oxidative stress and inflammation: Examining the links

Essential hypertension and oxidative stress: New insights

Plasma ascorbic acid concentrations and fat distribution in 19 068 British men and women in the European Prospective Investigation into Cancer and Nutrition Norfolk cohort study

Low Plasma Ascorbate Levels in Patients with Type 2 Diabetes Mellitus Consuming Adequate Dietary Vitamin C

Inadequate Vitamin C Status in Prediabetes and Type 2 Diabetes Mellitus: Associations with Glycaemic Control, Obesity, and Smoking

Plasma Vitamin C Modifies the Association Between Hypertension and Risk of Stroke