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      COVID-19 infection and oxidative stress: an under-explored approach for prevention and treatment?

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          Abstract

          To the editors of Pan African Medical Journal Oxidative stress is the result of an imbalance in the body between the oxidizing system, consisting mainly of free radicals, reactive oxygen species (ROS) and reactive nitrogen species (RNS) [1], and antioxidant systems that neutralize these free radicals capable of multiple deleterious effects. This oxidative stress is involved in aging [2] and is found in certain chronic pathologies such as diabetes mellitus, cancers, hypertension, coronary heart disease, etc. [3] and certain infections, particularly by the RNA viruses [4], a family to which belong corona viruses [5]. The objective of this work is to explain the role of oxidative stress in RNA virus infections and probably also in Covid 19 infection, in order to propose measures for prevention and treatment of this deadly infection which has already caused more than 118000 deaths worldwide [6]. This is an analysis of literature about oxidative stress, ways to counteract it, known links with certain RNA viruses and possible links with the new Corona virus. Oxidative stress and reactive oxygen and nitrogen species (RONS): reactive Oxygen and Nitrogen Species (RONS) are molecules characterized by the presence of unpaired valence electrons, which cause them to react with various biological molecules [7,8]. Main ROS are hydroxyl radical (OHº), superoxide anion (O2º-), singlet oxygen (¹O2), oxygen peroxide (H2O2) and ozone (O3), a powerful oxidant formed by endothermic reaction from O2 [8]. For RNS it is nitric oxide (NO) peroxynitrite (ONOO-), the nitrosyl cation (NO+), the nitrosyl anion (NO-), nitrous acid (NH2O2) .... [1,8] These free radicals are natural byproducts of various cellular processes and the functioning of structures such as mitochondria and the endoplasmic reticulum [4]. Under physiological conditions these reactive species play an important role in cell signalling, regulation of cytokines, growth factors, as immunomodulators, etc [1] and are involved in the natural aging of the human organism [2]. But when the balance is broken between oxidizing agents and antioxidant systems, which characterizes oxidative stress, these free radicals will have deleterious effects on all biomolecules [7,8]. The most reactive, hydroxyl radical can oxidize various molecules in its proximity, including DNA, phospholipids, and proteins. The superoxide can generate other free radicals and come into contact with nitric oxide (NO) to give the peroxynitrite radical (ONOO-), a powerful oxidant with NO depletion. Hydrogen peroxide is converted to hydroxyl and can cross cell membranes. Ozone is a powerful oxidant of lipid chains, it can generate other free radicals, and interact with a large number of organic and inorganic compounds [8]. Damage caused by these free radicals will affect cell membranes through the phenomenon of lipid peroxidation, oxidation and denaturation of proteins, DNA damage which can induce inflammatory immune responses, mutations and tumorigenesis risk, apoptosis [4]. So oxidative stress is involved in the occurrence of certain pathologies such as cancers, autoimmune diseases, cataract, Alzheimer’s and neurodegenerative diseases, diabetes mellitus, cardiovascular diseases, chronic kidney disease etc [2,3,8]. What are the situations promoting oxidative stress? about our subject, it is known that oxidative stress is triggered by a wide variety of viral infections [4,7] including HIV 1, viral hepatitis B,C,D viruses, herpes viruses, respiratory viruses, most of the RNA viruses [7] probably also corona viruses belonging to this family. Let us remind that corona viruses are encapsulated RNA viruses with different types: the classic coronaviruses, responsible for moderate respiratory infections in general, the SARS-CoV and MERS-CoV involved in epidemics of more severe respiratory infections [5] and the new coronavirus (SARS-CoV2) discovered in January 2020 responsible for infectious disease called COVID-19 which is currently experiencing a worldwide outbreak [6]. Generally, viral infections lead to an increase in production of free radicals and a depletion of antioxidants [1]. The mode of action varies according to the viruses as demonstrated by the analysis of the oxidative stress induced by different viruses of the flaviviridae family [4] but we find these two phenomena increasing the oxidative stress in these RNA viruses infections and for Ivanov [7] one of the sources of production of these ROS could be the mitochondrial dysfunction caused by the penetration of the virus into the cell. A “cytokine storm” with release of Il-2, Il-6, Il-7, TNF α etc. as been described in COVID-19 [9]. These authors described a cytokine shock with hyperinflammation accompanied by cytopenia, hyperferritinemia, [1,8] which is known to generate by the Fenton reaction (Fe²+ + H2O2→ Fe³+ + HO‾ + HO‾) the production of ROS [7,8]. In addition, cytokines and endotoxins will stimulate one of the isoforms of nitric oxide synthetase (NOs), the inducible isoform iNOs, which will stimulate the production of nitric oxide NO which will react with the superoxide ion to give the powerful oxidizing peroxynitrite radical (ONOO‾) [1,8]. Other factors can promote the endogenous production of free radicals, such as intense physical activity, high blood pressure, tissue ischemia, the action of certain metals (lead, arsenic, cesium, mercury) counteracting the co-factors of antioxidant enzymes, notably superoxide dismutase, NADPH oxidase, myeloperoxidase which will lead to the production of the superoxide radical. Physical agents (ionizing radiation, UV), solvents, various pollutants, an anesthetic agent halotane and even paracetamol have also been incriminated in this genesis of free radicals [8]. Several techniques can be used to evaluate the state of oxidative stress such as electron paramagnetic resonance, direct evaluation of oxidative stress markers such as oxidized glutathione, malonyl aldehyde, quantification of total antioxidant status etc [7]. How are these free radicals neutralized? there are multiple mechanisms to neutralize these free radicals: glutathione a natural antioxydant which has also an effect on viral replication [10], certain vitamins such as vitamin E and C, carotenoids and polyphenol with scavenging effect, [8] the glutathione peroxidase| glutathione reductase system allowing reduced glutathione (GSH) to bind to free radicals giving oxidized glutathione which will be regenerated into GSH through this system, super oxide dismutase (SOD) neutralizing superoxide anion (O2o‾), catalase eliminating H2O2, the peroxyredoxin system that neutralizes the peroxidation of lipids, protecting them from oxidative damage. Some trace elements such as Zinc and Selenium have an anti-oxidant effect as co-factors of anti-oxidant enzymes [1,7,8]. What about covid-19 and oxidative stress? SARS-CoV2, probably like other RNA viruses [4] can trigger an oxidative stress. This hypothesis can easily be checked by the dosage of oxidative stress markers [7] in the blood of sick people of COVID-19. A cytokin storm with hyper inflammation had been found in these patients [9] but researchers should also chek for a possible oxidative storm with all he deleterious effects of RONS, notably lipid peroxydation and proteins oxidation of membranes which can contribute to the transformation, hyalinization of pulmonary alveolar membranes [11] with letal respiratory distress. As elders and people suffering of diabetes, hypertension and cardiovascular diseases have already a state of oxidative stress [2,3], viral infection will increasae this stress, giving us one possible explanation of the severity of COVID-19 in these categories of patients [12]. Suggestions for prevention and treatment of covid-19 infection: in frail people, we propose to reduce their level of oxidative stress by providing them with substances that increase their antioxidant system [2] such as Glutathione, some trace elements like Zinc and Selenium, vitamin E and C, carotenoids and polyphenols [1]. Glutathione has analogues and precursors such as N acetyl cysteine. Indeed, cysteine is one of the three constituent amino acids of the major natural antioxidant Glutathione which also has an immunomodulating effect and destructive action on viruses such as herpes, influenza etc. by blocking viral replication [10]. There are also many antioxidants food, and even food additives such as butylated hydroxyanisole, quercetin and curcumin [1] could also be tested. In sick people, in addition to the various used treatments, we suggest to add antioxidants mentionned above and especially, injectable N acetyl cysteine [10] which has shown its effectiveness in hemorrhagic dengue fever [13] another RNA virus infection [4]. Various antioxidant which have been experimentally used successfully as melatonin, minocycline [1], can also be tested. Conclusion In the fight against Covid-19 infection, all the possible treatments deserve to be taken into account. Relying on the complex pathophysiology of this viral infection, we suggest tu use also antioxydants agents in the treatment. Competing interests The authors declare no competing interests.

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          Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

          Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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            COVID-19: consider cytokine storm syndromes and immunosuppression

            As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
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              Pathological findings of COVID-19 associated with acute respiratory distress syndrome

              Since late December, 2019, an outbreak of a novel coronavirus disease (COVID-19; previously known as 2019-nCoV)1, 2 was reported in Wuhan, China, 2 which has subsequently affected 26 countries worldwide. In general, COVID-19 is an acute resolved disease but it can also be deadly, with a 2% case fatality rate. Severe disease onset might result in death due to massive alveolar damage and progressive respiratory failure.2, 3 As of Feb 15, about 66 580 cases have been confirmed and over 1524 deaths. However, no pathology has been reported due to barely accessible autopsy or biopsy.2, 3 Here, we investigated the pathological characteristics of a patient who died from severe infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by postmortem biopsies. This study is in accordance with regulations issued by the National Health Commission of China and the Helsinki Declaration. Our findings will facilitate understanding of the pathogenesis of COVID-19 and improve clinical strategies against the disease. A 50-year-old man was admitted to a fever clinic on Jan 21, 2020, with symptoms of fever, chills, cough, fatigue and shortness of breath. He reported a travel history to Wuhan Jan 8–12, and that he had initial symptoms of mild chills and dry cough on Jan 14 (day 1 of illness) but did not see a doctor and kept working until Jan 21 (figure 1 ). Chest x-ray showed multiple patchy shadows in both lungs (appendix p 2), and a throat swab sample was taken. On Jan 22 (day 9 of illness), the Beijing Centers for Disease Control (CDC) confirmed by reverse real-time PCR assay that the patient had COVID-19. Figure 1 Timeline of disease course according to days from initial presentation of illness and days from hospital admission, from Jan 8–27, 2020 SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. He was immediately admitted to the isolation ward and received supplemental oxygen through a face mask. He was given interferon alfa-2b (5 million units twice daily, atomisation inhalation) and lopinavir plus ritonavir (500 mg twice daily, orally) as antiviral therapy, and moxifloxacin (0·4 g once daily, intravenously) to prevent secondary infection. Given the serious shortness of breath and hypoxaemia, methylprednisolone (80 mg twice daily, intravenously) was administered to attenuate lung inflammation. Laboratory tests results are listed in the appendix (p 4). After receiving medication, his body temperature reduced from 39·0 to 36·4 °C. However, his cough, dyspnoea, and fatigue did not improve. On day 12 of illness, after initial presentation, chest x-ray showed progressive infiltrate and diffuse gridding shadow in both lungs. He refused ventilator support in the intensive care unit repeatedly because he suffered from claustrophobia; therefore, he received high-flow nasal cannula (HFNC) oxygen therapy (60% concentration, flow rate 40 L/min). On day 13 of illness, the patient's symptoms had still not improved, but oxygen saturation remained above 95%. In the afternoon of day 14 of illness, his hypoxaemia and shortness of breath worsened. Despite receiving HFNC oxygen therapy (100% concentration, flow rate 40 L/min), oxygen saturation values decreased to 60%, and the patient had sudden cardiac arrest. He was immediately given invasive ventilation, chest compression, and adrenaline injection. Unfortunately, the rescue was not successful, and he died at 18:31 (Beijing time). Biopsy samples were taken from lung, liver, and heart tissue of the patient. Histological examination showed bilateral diffuse alveolar damage with cellular fibromyxoid exudates (figure 2A, B ). The right lung showed evident desquamation of pneumocytes and hyaline membrane formation, indicating acute respiratory distress syndrome (ARDS; figure 2A). The left lung tissue displayed pulmonary oedema with hyaline membrane formation, suggestive of early-phase ARDS (figure 2B). Interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were seen in both lungs. Multinucleated syncytial cells with atypical enlarged pneumocytes characterised by large nuclei, amphophilic granular cytoplasm, and prominent nucleoli were identified in the intra-alveolar spaces, showing viral cytopathic-like changes. No obvious intranuclear or intracytoplasmic viral inclusions were identified. Figure 2 Pathological manifestations of right (A) and left (B) lung tissue, liver tissue (C), and heart tissue (D) in a patient with severe pneumonia caused by SARS-CoV-2 SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. The pathological features of COVID-19 greatly resemble those seen in SARS and Middle Eastern respiratory syndrome (MERS) coronavirus infection.4, 5 In addition, the liver biopsy specimens of the patient with COVID-19 showed moderate microvesicular steatosis and mild lobular and portal activity (figure 2C), indicating the injury could have been caused by either SARS-CoV-2 infection or drug-induced liver injury. There were a few interstitial mononuclear inflammatory infiltrates, but no other substantial damage in the heart tissue (figure 2D). Peripheral blood was prepared for flow cytometric analysis. We found that the counts of peripheral CD4 and CD8 T cells were substantially reduced, while their status was hyperactivated, as evidenced by the high proportions of HLA-DR (CD4 3·47%) and CD38 (CD8 39·4%) double-positive fractions (appendix p 3). Moreover, there was an increased concentration of highly proinflammatory CCR6+ Th17 in CD4 T cells (appendix p 3). Additionally, CD8 T cells were found to harbour high concentrations of cytotoxic granules, in which 31·6% cells were perforin positive, 64·2% cells were granulysin positive, and 30·5% cells were granulysin and perforin double-positive (appendix p 3). Our results imply that overactivation of T cells, manifested by increase of Th17 and high cytotoxicity of CD8 T cells, accounts for, in part, the severe immune injury in this patient. X-ray images showed rapid progression of pneumonia and some differences between the left and right lung. In addition, the liver tissue showed moderate microvesicular steatosis and mild lobular activity, but there was no conclusive evidence to support SARS-CoV-2 infection or drug-induced liver injury as the cause. There were no obvious histological changes seen in heart tissue, suggesting that SARS-CoV-2 infection might not directly impair the heart. Although corticosteroid treatment is not routinely recommended to be used for SARS-CoV-2 pneumonia, 1 according to our pathological findings of pulmonary oedema and hyaline membrane formation, timely and appropriate use of corticosteroids together with ventilator support should be considered for the severe patients to prevent ARDS development. Lymphopenia is a common feature in the patients with COVID-19 and might be a critical factor associated with disease severity and mortality. 3 Our clinical and pathological findings in this severe case of COVID-19 can not only help to identify a cause of death, but also provide new insights into the pathogenesis of SARS-CoV-2-related pneumonia, which might help physicians to formulate a timely therapeutic strategy for similar severe patients and reduce mortality. This online publication has been corrected. The corrected version first appeared at thelancet.com/respiratory on February 25, 2020
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                Author and article information

                Journal
                Pan Afr Med J
                Pan Afr Med J
                PAMJ
                The Pan African Medical Journal
                The African Field Epidemiology Network
                1937-8688
                29 April 2020
                2020
                : 35
                : Suppl 2
                : 12
                Affiliations
                [1 ]d´Endocrinologie, Métabolisme, Faculté de Médecine de Libreville, Libreville, Gabon
                Author notes
                [& ] Corresponding author: Marie-Pierrette Ntyonga-Pono, d´Endocrinologie, Métabolisme, Faculté de Médecine de Libreville, Libreville, Gabon
                Article
                PAMJ-SUPP-35-2-12
                10.11604/pamj.2020.35.2.22877
                7266475
                32528623
                e18a08db-5a24-41ed-ac17-1696e7f80b0d
                © Marie-Pierrette Ntyonga-Pono et al.

                The Pan African Medical Journal - ISSN 1937-8688. This is an Open Access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 15 April 2020
                : 21 April 2020
                Categories
                Letter to the Editors

                Medicine
                oxidative stress,covid-19,antioxidants,glutathione
                Medicine
                oxidative stress, covid-19, antioxidants, glutathione

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