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1.
Rev Med Virol ; 31(5): 1-13, 2021 09.
Article in English | MEDLINE | ID: covidwho-1574052

ABSTRACT

Anti-tumour necrosis factor (TNF) biologicals, Dexamethasone and rIL-7 are of considerable interest in treating COVID-19 patients who are in danger of, or have become, seriously ill. Yet reducing sepsis mortality by lowering circulating levels of TNF lost favour when positive endpoints in earlier simplistic models could not be reproduced in well-conducted human trials. Newer information with anti-TNF biologicals has encouraged reintroducing this concept for treating COVID-19. Viral models have had encouraging outcomes, as have the effects of anti-TNF biologicals on community-acquired COVID-19 during their long-term use to treat chronic inflammatory states. The positive outcome of a large scale trial of dexamethasone, and its higher potency late in the disease, harmonises well with its capacity to enhance levels of IL-7Rα, the receptor for IL-7, a cytokine that enhances lymphocyte development and is increased during the cytokine storm. Lymphoid germinal centres required for antibody-based immunity can be harmed by TNF, and restored by reducing TNF. Thus the IL-7- enhancing activity of dexamethasone may explain its higher potency when lymphocytes are depleted later in the infection, while employing anti-TNF, for several reasons, is much more logical earlier in the infection. This implies dexamethasone could prove to be synergistic with rIL-7, currently being trialed as a COVID-19 therapeutic. The principles behind these COVID-19 therapies are consistent with the observed chronic hypoxia through reduced mitochondrial function, and also the increased severity of this disease in ApoE4-positive individuals. Many of the debilitating persistent aspects of this disease are predictably susceptible to treatment with perispinal etanercept, since they have cerebral origins.


Subject(s)
COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Dexamethasone/administration & dosage , Interleukin-17/administration & dosage , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , COVID-19/genetics , COVID-19/immunology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/immunology , Humans , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
2.
Life Sci ; 284: 119201, 2021 Nov 01.
Article in English | MEDLINE | ID: covidwho-1574805

ABSTRACT

BACKGROUND: Cytokine storm is the exaggerated immune response often observed in viral infections. It is also intimately linked with the progression of COVID-19 disease as well as associated complications and mortality. Therefore, targeting the cytokine storm might help in reducing COVID-19-associated health complications. The number of COVID-19 associated deaths (as of January 15, 2021; https://www.worldometers.info/coronavirus/) in the USA is high (1199/million) as compared to countries like India (110/million). Although the reason behind this is not clear, spices may have some role in explaining this difference. Spices and herbs are used in different traditional medicines, especially in countries such as India to treat various chronic diseases due to their potent antioxidant and anti-inflammatory properties. AIM: To evaluate the literature available on the anti-inflammatory properties of spices which might prove beneficial in the prevention and treatment of COVID-19 associated cytokine storm. METHOD: A detailed literature search has been conducted on PubMed for collecting information pertaining to the COVID-19; the history, origin, key structural features, and mechanism of infection of SARS-CoV-2; the repurposed drugs in use for the management of COVID-19, and the anti-inflammatory role of spices to combat COVID-19 associated cytokine storm. KEY FINDINGS: The literature search resulted in numerous in vitro, in vivo and clinical trials that have reported the potency of spices to exert anti-inflammatory effects by regulating crucial molecular targets for inflammation. SIGNIFICANCE: As spices are derived from Mother Nature and are inexpensive, they are relatively safer to consume. Therefore, their anti-inflammatory property can be exploited to combat the cytokine storm in COVID-19 patients. This review thus focuses on the current knowledge on the role of spices for the treatment of COVID-19 through suppression of inflammation-linked cytokine storm.


Subject(s)
COVID-19/pathology , Cytokines/metabolism , Inflammation/pathology , Spices , COVID-19/epidemiology , COVID-19/virology , Cytokine Release Syndrome/pathology , Humans , SARS-CoV-2/physiology
3.
J Clin Med ; 10(8)2021 Apr 07.
Article in English | MEDLINE | ID: covidwho-1526819

ABSTRACT

COVID-19 is currently considered an inflammatory disease affecting the entire organism. In severe forms, an augmented inflammatory response leads to the fulminant "cytokine storm", which may result in severe multisystemic end-organ damage. Apart from the acute inflammatory response, it seems that chronic inflammation also plays a major role in the clinical evolution of COVID-19 patients. Pre-existing inflammatory conditions, such as those associated with chronic coronary diseases, type 2 diabetes mellitus or obesity, may be associated with worse clinical outcomes in the context of COVID-19 disease. These comorbidities are reported as powerful predictors of poor outcomes and death following COVID-19 disease. Moreover, in the context of chronic coronary syndrome, the cytokine storm triggered by SARS-CoV-2 infection may favor vulnerabilization and rupture of a silent atheromatous plaque, with consequent acute coronary syndrome, leading to a sudden deterioration of the clinical condition of the patient. This review aims to present the current status of knowledge regarding the link between COVID-19 mortality, systemic inflammation and several major diseases associated with poor outcomes, such as cardiovascular diseases, diabetes and obesity.

4.
Curr Pharm Des ; 27(41): 4223-4231, 2021.
Article in English | MEDLINE | ID: covidwho-1502208

ABSTRACT

Coronavirus disease-2019 (COVID-19) is a respiratory tract infection accompanied by severe or fatal pneumonia-like symptoms and sometimes death. It has posed to be an ongoing global health emergency caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to a sudden outbreak and a large number of infections and deaths, it became a major concern all over the world. The options available as effective therapeutics should be urgently exercised to handle this pandemic. So far, no specific and accurate anti- SARS-CoV-2 treatment is recommended because of the absence of sufficient clinical evidence. In such cases, the clinical use of available drugs is always considered to be on top priority. A broad-spectrum antiviral agent, remdesivir, is found effective in many cases and recommended by many clinicians in many countries. This drug acts as a potential inhibitor of viral RNA-dependent RNA polymerase protein and thus likely to be efficacious in SARS-CoV-2 infection. Tocilizumab is currently recommended by many hospitals as an alternative treatment for critically ill COVID-19 patients. Tocilizumab has been administered to control cytokine storms that occur due to the release of proinflammatory cytokine, including interleukin 6. Chloroquine and hydroxychloroquine are also used in hospitals to handle severe COVID-19 patients. Currently, plasma therapy has been exercised as a therapeutic alternative, especially to handle severe COVID-19 patients. In addition, herbal medicines are expected to play a significant role in the control and prevention of COVID-19. All these therapeutic options have their advantages and limitations. This review highlights the therapeutic potential of these available drugs, along with their mechanism of action and shortcomings. We have provided detailed information on available therapeutic options, which have proved to be effective in improving clinical symptoms of severe COVID-19 patients.


Subject(s)
Antiviral Agents , COVID-19 , Antiviral Agents/therapeutic use , COVID-19/therapy , Cytokine Release Syndrome , Humans , Hydroxychloroquine , Immunization, Passive , Pandemics , Phytotherapy
5.
Anaesthesist ; 70(2): 121-126, 2021 Feb.
Article in German | MEDLINE | ID: covidwho-1453674

ABSTRACT

A 59-year-old male patient was admitted to hospital diagnosed with moderate pneumonia associated with COVID-19. Upfront treatment with hydroxychloroquine and azithromycin was started. Due to a clinical deterioration (ARDS, circulatory shock) and greatly increased inflammation markers 6 days after admission, a cytokine storm was suspected and off-label treatment with the IL­6 receptor antagonist tocilizumab was initiated. Subsequently there was a dramatic rise of D­dimers indicating pulmonary intravascular coagulopathy and respiratory insufficiency worsened. After a second dose of tocilizumab was administered severe perimyocarditis with cardiac arrhythmia, hemodynamic instability and ST elevation occurred. Shortly afterwards the patient died due to multiorgan failure. From our experience, exacerbation of COVID-19 following treatment with tocilizumab cannot be ruled out. Randomized controlled studies are necessary to further investigate the efficacy, safety and patient selection criteria for tocilizumab treatment in COVID-19.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Blood Coagulation Disorders/etiology , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Myocarditis/etiology , Receptors, Interleukin-6/antagonists & inhibitors , Fatal Outcome , Humans , Male , Middle Aged , Multiple Organ Failure/etiology , Off-Label Use , Respiratory Distress Syndrome/etiology , Respiratory Insufficiency , Treatment Outcome
6.
Int J Environ Res Public Health ; 18(6)2021 03 17.
Article in English | MEDLINE | ID: covidwho-1389362

ABSTRACT

There is growing literature about the SARS-CoV-2 pathogenetic effects exerted during pregnancy and whether vertical transmission or premature birth is possible. It is not well known whether changes in the immune system of pregnant women may lead to a marked susceptibility to infectious processes and the risk of adverse maternal and neonatal complications such as preterm birth, spontaneous abortion, hospitalization in an intensive care unit, transmission to the fetus or newborns, and fetal mortality are poorly understood. Along with this ongoing debate, it is not well defined whether, during pregnancy, the role of host susceptibility in producing a specific inflammatory response to SARS-CoV-2 may represent distinctive markers of risk of vertical transmission. Furthermore, SARS-CoV-2 impact on the vaginal microbiome has not yet been described, despite mounting evidence on its possible effect on the gastrointestinal microbiome and its influence on infectious diseases and preterm labor. This report describes the impact of SARS-CoV-2 on a twin pregnancy diagnosed with infection at the third trimester of gestation including tissue infections, inflammatory response, antibody production, cytokine concentration, and vaginal microbiome composition. We identified a pattern of cytokines including IL1-Ra, IL-9 G-CSF, IL-12, and IL-8 differently expressed, already associated with previously infected patients. We detected a similar concentration of almost all the cytokines tested in both twins, suggesting that the SARS-CoV-2-induced cytokine storm is not substantially impaired during the placental passage. The analysis of the vaginal microbiome did not show relevant signs of dysbiosis, similar to other healthy pregnant women and twin healthy pregnancies. The aim of this report was to analyze the immunological response against SARS-CoV-2 infection and virus tissue tropism in a twin pregnancy.


Subject(s)
COVID-19 , Pregnancy Complications, Infectious , Premature Birth , Female , Humans , Infant, Newborn , Infectious Disease Transmission, Vertical , Pregnancy , Pregnancy Outcome , Pregnancy, Twin , SARS-CoV-2
7.
CNS Neurosci Ther ; 27(1): 36-47, 2021 01.
Article in English | MEDLINE | ID: covidwho-1388231

ABSTRACT

The blood-brain barrier (BBB) is an important physiological barrier that separates the central nervous system (CNS) from the peripheral circulation, which contains inflammatory mediators and immune cells. The BBB regulates cellular and molecular exchange between the blood vessels and brain parenchyma. Normal functioning of the BBB is crucial for the homeostasis and proper function of the brain. It has been demonstrated that peripheral inflammation can disrupt the BBB by various pathways, resulting in different CNS diseases. Recently, clinical research also showed CNS complications following SARS-CoV-2 infection and chimeric antigen receptor (CAR)-T cell therapy, which both lead to a cytokine storm in the circulation. Therefore, elucidation of the mechanisms underlying the BBB disruption induced by peripheral inflammation will provide an important basis for protecting the CNS in the context of exacerbated peripheral inflammatory diseases. In the present review, we first summarize the physiological properties of the BBB that makes the CNS an immune-privileged organ. We then discuss the relevance of peripheral inflammation-induced BBB disruption to various CNS diseases. Finally, we elaborate various factors and mechanisms of peripheral inflammation that disrupt the BBB.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , COVID-19/metabolism , Inflammation Mediators/metabolism , Animals , Blood-Brain Barrier/immunology , Blood-Brain Barrier/pathology , Brain/immunology , Brain/pathology , COVID-19/immunology , COVID-19/pathology , Endothelial Cells/immunology , Endothelial Cells/metabolism , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Inflammation Mediators/immunology
8.
BMC Infect Dis ; 21(1): 398, 2021 Apr 29.
Article in English | MEDLINE | ID: covidwho-1327867

ABSTRACT

BACKGROUND: Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory event and a fatal complication of viral infections. Whether sHLH may also be observed in patients with a cytokine storm induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still uncertain. We aimed to determine the incidence of sHLH in severe COVID-19 patients and evaluate the underlying risk factors. METHOD: Four hundred fifteen severe COVID-19 adult patients were retrospectively assessed for hemophagocytosis score (HScore). A subset of 7 patients were unable to be conclusively scored due to insufficient patient data. RESULTS: In 408 patients, 41 (10.04%) had an HScore ≥169 and were characterized as "suspected sHLH positive". Compared with patients below a HScore threshold of 98, the suspected sHLH positive group had higher D-dimer, total bilirubin, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, serum creatinine, triglycerides, ferritin, interleukin-6, C-reactive protein, procalcitonin, lactate dehydrogenase, creatine kinase isoenzyme, troponin, Sequential Organ Failure Assessment (SOFA) score, while leukocyte, hemoglobin, platelets, lymphocyte, fibrinogen, pre-albumin, albumin levels were significantly lower (all P < 0.05). Multivariable logistic regression revealed that high ferritin (>1922.58 ng/mL), low platelets (<101 × 109/L) and high triglycerides (>2.28 mmol/L) were independent risk factors for suspected sHLH in COVID-19 patients. Importantly, COVID-19 patients that were suspected sHLH positive had significantly more multi-organ failure. Additionally, a high HScore (>98) was an independent predictor for mortality in COVID-19. CONCLUSIONS: HScore should be measured as a prognostic biomarker in COVID-19 patients. In particular, it is important that HScore is assessed in patients with high ferritin, triglycerides and low platelets to improve the detection of suspected sHLH.


Subject(s)
COVID-19/complications , Lymphohistiocytosis, Hemophagocytic/etiology , Adult , Aged , Aspartate Aminotransferases/blood , COVID-19/epidemiology , COVID-19/therapy , China/epidemiology , Comorbidity , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/virology , Female , Ferritins/blood , Humans , Incidence , Lymphocyte Count , Lymphohistiocytosis, Hemophagocytic/epidemiology , Lymphohistiocytosis, Hemophagocytic/mortality , Male , Middle Aged , Mortality , Retrospective Studies , Risk Factors
9.
Antioxidants (Basel) ; 10(4)2021 Apr 06.
Article in English | MEDLINE | ID: covidwho-1173679

ABSTRACT

As human life expectancy is rising, the incidence of age-associated diseases will also increase. Scientific evidence has revealed that healthy diets, including good fats, vitamins, minerals, or polyphenolics, could have antioxidant and anti-inflammatory activities, with antiaging effects. Recent studies demonstrated that vitamin K is a vital cofactor in activating several proteins, which act against age-related syndromes. Thus, vitamin K can carboxylate osteocalcin (a protein capable of transporting and fixing calcium in bone), activate matrix Gla protein (an inhibitor of vascular calcification and cardiovascular events) and carboxylate Gas6 protein (involved in brain physiology and a cognitive decline and neurodegenerative disease inhibitor). By improving insulin sensitivity, vitamin K lowers diabetes risk. It also exerts antiproliferative, proapoptotic, autophagic effects and has been associated with a reduced risk of cancer. Recent research shows that protein S, another vitamin K-dependent protein, can prevent the cytokine storm observed in COVID-19 cases. The reduced activation of protein S due to the pneumonia-induced vitamin K depletion was correlated with higher thrombogenicity and possibly fatal outcomes in COVID-19 patients. Our review aimed to present the latest scientific evidence about vitamin K and its role in preventing age-associated diseases and/or improving the effectiveness of medical treatments in mature adults ˃50 years old.

10.
Acta Neuropsychiatr ; 33(4): 165-177, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1297283

ABSTRACT

Neuropsychiatric sequalae to coronavirus disease 2019 (COVID-19) infection are beginning to emerge, like previous Spanish influenza and severe acute respiratory syndrome episodes. Streptococcal infection in paediatric patients causing obsessive compulsive disorder (PANDAS) is another recent example of an infection-based psychiatric disorder. Inflammation associated with neuropsychiatric disorders has been previously reported but there is no standard clinical management approach established. Part of the reason is that it is unclear what factors determine the specific neuronal vulnerability and the efficacy of anti-inflammatory treatment in neuroinflammation. The emerging COVID-19 data suggested that in the acute stage, widespread neuronal damage appears to be the result of abnormal and overactive immune responses and cytokine storm is associated with poor prognosis. It is still too early to know if there are long-term-specific neuronal or brain regional damages associated with COVID-19, resulting in distinct neuropsychiatric disorders. In several major psychiatric disorders where neuroinflammation is present, patients with abnormal inflammatory markers may also experience less than favourable response or treatment resistance when standard treatment is used alone. Evidence regarding the benefits of co-administered anti-inflammatory agents such as COX-2 inhibitor is encouraging in selected patients though may not benefit others. Disease-modifying therapies are increasingly being applied to neuropsychiatric diseases characterised by abnormal or hyperreactive immune responses. Adjunct anti-inflammatory treatment may benefit selected patients and is definitely an important component of clinical management in the presence of neuroinflammation.


Subject(s)
Autoimmune Diseases/psychology , COVID-19/psychology , Obsessive-Compulsive Disorder/psychology , Streptococcal Infections/psychology , Anti-Inflammatory Agents/therapeutic use , Autoimmune Diseases/epidemiology , Autoimmune Diseases/immunology , COVID-19/complications , COVID-19/diagnosis , COVID-19/epidemiology , Cyclooxygenase 2 Inhibitors/therapeutic use , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Female , Humans , Inflammation/complications , Inflammation/immunology , Inflammation/psychology , Obsessive-Compulsive Disorder/epidemiology , Obsessive-Compulsive Disorder/etiology , Obsessive-Compulsive Disorder/immunology , SARS-CoV-2/genetics , Streptococcal Infections/complications , Streptococcal Infections/epidemiology , Streptococcal Infections/immunology
11.
J Biol Regul Homeost Agents ; 35(2): 423-427, 2021.
Article in English | MEDLINE | ID: covidwho-1298274

ABSTRACT

Acute severe respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causes coronavirus disease-2019 (COVID-19) which is associated with inflammation, thrombosis edema, hemorrhage, intra-alveolar fibrin deposition, and vascular and pulmonary damage. In COVID-19, the coronavirus activates macrophages by inducing the generation of pro-inflammatory cytokines [interleukin (IL)-1, IL-6, IL-18 and TNF] that can damage endothelial cells, activate platelets and neutrophils to produce thromboxane A2 (TxA2), and mediate thrombus generation. In severe cases, all these phenomena can lead to patient death. The binding of SARS-CoV-2 to the Toll Like Receptor (TLR) results in the release of pro-IL-1ß that is cleaved by caspase-1, followed by the production of active mature IL-1ß which is the most important cytokine in causing fever and inflammation. Its activation in COVID-19 can cause a "cytokine storm" with serious biological and clinical consequences. Blockade of IL-1 with inhibitory and anti-inflammatory cytokines represents a new therapeutic strategy also for COVID-19. Recently, very rare allergic reactions to vaccines have been reported, with phenomena of pulmonary thrombosis. These side effects have raised substantial concern in the population. Highly allergic subjects should therefore be vaccinated under strict medical supervision. COVID-19 has accelerated vaccine therapy but also the use of drugs and monoclonal antibodies (mABs) which have been used in COVID-19 therapy. They are primarily adopted to treat high-risk mild-to-moderate non-hospitalized patients, and it has been noted that the administration of two mABs gave better results. mABs, other than polyclonal plasma antibodies from infected subjects with SARS-CoV-2, are produced in the laboratory and are intended to fight SARS-CoV-2. They bind specifically to the antigenic determinant of the spike protein, inhibiting the pathogenicity of the virus. The most suitable individuals for mAB therapy are people at particular risk, such as the elderly and those with serious chronic diseases including diabetics, hypertension and obesity, including subjects suffering from cardiovascular diseases. These antibodies have a well-predetermined target, they bind mainly to the protein S (formed by the S1A, B, C and D subtypes), located on the viral surface, and to the S2 protein that acts as a fuser between the virus and the cell membrane. Since mABs are derived from a single splenic immune cell, they are identical and form a cell clone which can neutralize SARS-CoV-2 by binding to the epitope of the virus. However, this COVID-19 therapy may cause several side effects such as mild pain, bleeding, bruising of the skin, soreness, swelling, thrombotic-type episodes, arterial hypertension, changes in heart activity, slowed bone marrow activity, impaired renal function, diarrhea, fatigue, nausea, vomiting, allergic reaction, fever, and possible subsequent infection may occur at the site of injection. In conclusion, the studies promoting mAB therapy in COVID-19 are very promising but the results are not yet definitive and more investigations are needed to certify both their good neutralizing effects of SARS-CoV-2, and to eliminate, or at least mitigate, the harmful side effects.


Subject(s)
COVID-19 , SARS-CoV-2 , Aged , Antibodies, Monoclonal , Cytokine Release Syndrome , Endothelial Cells , Humans
12.
Int J Mol Sci ; 22(8)2021 Apr 17.
Article in English | MEDLINE | ID: covidwho-1298166

ABSTRACT

The virus responsible for the current COVID-19 pandemic is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): a new virus with high infectivity and moderate mortality. The major clinical manifestation of COVID-19 is interstitial pneumonia, which may progress to acute respiratory distress syndrome (ARDS). However, the disease causes a potent systemic hyperin-flammatory response, i.e., a cytokine storm or macrophage activation syndrome (MAS), which is associated with thrombotic complications. The complexity of the disease requires appropriate intensive treatment. One of promising treatment is statin administration, these being 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that exert pleiotropic anti-inflammatory effects. Recent studies indicate that statin therapy is associated with decreased mortality in COVID-19, which may be caused by direct and indirect mechanisms. According to literature data, statins can limit SARS-CoV-2 cell entry and replication by inhibiting the main protease (Mpro) and RNA-dependent RNA polymerase (RdRp). The cytokine storm can be ameliorated by lowering serum IL-6 levels; this can be achieved by inhibiting Toll-like receptor 4 (TLR4) and modulating macrophage activity. Statins can also reduce the complications of COVID-19, such as thrombosis and pulmonary fibrosis, by reducing serum PAI-1 levels, attenuating TGF-ß and VEGF in lung tissue, and improving endothelial function. Despite these benefits, statin therapy may have side effects that should be considered, such as elevated creatinine kinase (CK), liver enzyme and serum glucose levels, which are already elevated in severe COVID-19 infection. The present study analyzes the latest findings regarding the benefits and limitations of statin therapy in patients with COVID-19.


Subject(s)
COVID-19/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Animals , COVID-19/complications , Endothelium/drug effects , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Inflammation/complications , Inflammation/drug therapy , Lipid Metabolism/drug effects , Macrophage Activation/drug effects , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/drug therapy , SARS-CoV-2/drug effects , Thrombosis/complications , Thrombosis/drug therapy
13.
Int J Clin Pract ; 75(9): e14452, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1273092

ABSTRACT

BACKGROUND: A growing body of evidence supports the intestinal trophism of SARS-CoV-2, with ciliated cells and intestinal enterocytes being target cells because of the high expression of ACE2 and TMPRSS2. Indeed, COVID-19 promotes a "cytokine storm" in the intestinal mucosa: the resulting epithelial damage leads to increased barrier permeability, allowing the passage of gliadin in the intestinal lamina. METHODS: Based on current literature, we hypothesize the role of COVID-19 as a potential trigger factor for celiac disease in predisposed patients. CONCLUSIONS: Genetically predisposed patients could be more likely to develop celiac disease following SARS-CoV-2 infection, making COVID-19 a candidate culprit for a potential outbreak of celiac disease in the forthcoming future.


Subject(s)
COVID-19 , Celiac Disease , Celiac Disease/epidemiology , Disease Outbreaks , Gliadin , Humans , SARS-CoV-2
14.
Front Pharmacol ; 12: 640040, 2021.
Article in English | MEDLINE | ID: covidwho-1266675

ABSTRACT

The evolution of SARS-CoV-2 pneumonia to acute respiratory distress syndrome is linked to a virus-induced "cytokine storm", associated with systemic inflammation, coagulopathies, endothelial damage, thrombo-inflammation, immune system deregulation and disruption of angiotensin converting enzyme signaling pathways. To date, the most promising therapeutic approaches in COVID-19 pandemic are linked to the development of vaccines. However, the fight against COVID-19 pandemic in the short and mid-term cannot only rely on vaccines strategies, in particular given the growing proportion of more contagious and more lethal variants among exposed population (the English, South African and Brazilian variants). As long as collective immunity is still not acquired, some patients will have severe forms of the disease. Therapeutic perspectives also rely on the implementation of strategies for the prevention of secondary complications resulting from vascular endothelial damage and from immune system deregulation, which contributes to acute respiratory distress and potentially to long term irreversible tissue damage. While the anti-inflammatory effects of low dose irradiation have been exploited for a long time in the clinics, few recent physiopathological and experimental data suggested the possibility to modulate the inflammatory storm related to COVID-19 pulmonary infection by exposing patients to ionizing radiation at very low doses. Despite level of evidence is only preliminary, these preclinical findings open therapeutic perspectives and are discussed in this article.

15.
J Investig Med High Impact Case Rep ; 9: 23247096211019557, 2021.
Article in English | MEDLINE | ID: covidwho-1262488

ABSTRACT

An outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2, initially in December 2019 at Wuhan, China, subsequently spread around the world. We describe a case series of COVID-19 patients treated at our academic medical center with focus on cytokine storm and potential therapeutic role of tocilizumab. A 59-year-old female admitted for shortness of breath (SOB), productive cough, fever, and nausea in the setting of COVID-19 pneumonia. Oxygen saturation was 81% necessitating supplemental oxygen. She was transferred to intensive care unit (ICU) for worsening hypoxia; intubated and received tocilizumab following which her oxygen requirements improved. A 52-year-old female admitted from an outside hospital with SOB, intubated for worsening hypoxia, in the setting of COVID-19 pneumonia. She received tocilizumab 400 mg intravenous for 2 doses on ICU admission, with clinical improvement. A 56-year-old female hospitalized with worsening SOB, fever, and cough for 8 days saturating 88% on room air in the setting of COVID-19 pneumonia. Worsening hypoxia necessitated high flow nasal cannula. She was transferred to the ICU where she received 2 doses of tocilizumab 400 mg intravenous. She did not require intubation and was transitioned to nasal cannula. A hyperinflammatory syndrome may cause a life-threatening acute respiratory distress syndrome in patients with COVID-19 pneumonia. Tocilizumab is the first marketed interleukin-6 blocking antibody, and through targeting interleukin-6 receptors likely has a role in treating cytokine storm. We noted clinical improvement of patients treated with tocilizumab.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/complications , Cytokine Release Syndrome/drug therapy , Receptors, Interleukin-6/antagonists & inhibitors , Respiratory Distress Syndrome/drug therapy , COVID-19/diagnostic imaging , COVID-19/drug therapy , Critical Care , Cytokine Release Syndrome/diagnostic imaging , Cytokine Release Syndrome/etiology , Female , Humans , Lung/diagnostic imaging , Middle Aged , Oxygen Inhalation Therapy , Pennsylvania , Respiratory Distress Syndrome/diagnostic imaging , SARS-CoV-2 , Trauma Centers
16.
EClinicalMedicine ; 36: 100926, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1261877

ABSTRACT

BACKGROUND: Hyperimmune anti-COVID-19 Intravenous Immunoglobulin (C-IVIG) is an unexplored therapy amidst the rapidly evolving spectrum of medical therapies for COVID-19 and is expected to counter the three most life-threatening consequences of COVID-19 including lung injury by the virus, cytokine storm and sepsis. METHODS: A single center, phase I/II, randomized controlled, single-blinded trial was conducted at Dow University of Health Sciences, Karachi, Pakistan. Participants were COVID-19 infected individuals, classified as either severely or critically ill with Acute Respiratory Distress Syndrome (ARDS). Participants were randomized through parallel-group design with sequential assignment in a 4:1 allocation to either intervention group with four C-IVIG dosage arms (0.15, 0.20, 0.25, 0.30 g/kg), or control group receiving standard of care only (n = 10). Primary outcomes were 28-day mortality, patient's clinical status on ordinal scale and Horowitz index (HI), and were analysed in all randomized participants that completed the follow-up period (intention-to-treat population). The trial was registered at clinicaltrials.gov (NCT04521309). FINDINGS: Fifty participants were enrolled in the study from June 19, 2020 to February 3, 2021 with a mean age of 56.54±13.2 years of which 22 patients (44%) had severe and 28 patients (56%) had critical COVID-19. Mortality occurred in ten of 40 participants (25%) in intervention group compared to six of ten (60%) in control group, with relative risk reduction in intervention arm I (RR, 0.333; 95% CI, 0.087-1.272), arm II (RR, 0.5; 95% CI, 0.171-1.463), arm III (RR, 0.167; 95% CI, 0.024-1.145), and arm IV (RR, 0.667; 95% CI, 0.268-1.660). In intervention group, median HI significantly improved to 359 mmHg [interquartile range (IQR) 127-400, P = 0.009)] by outcome day, while the clinical status of intervention group also improved as compared to control group, with around 15 patients (37.5%) being discharged by 7th day with complete recovery. Additionally, resolution of chest X-rays and restoration of biomarkers to normal levels were also seen in intervention groups. No drug-related adverse events were reported during the study. INTERPRETATION: Administration of C-IVIG in severe and critical COVID-19 patients was safe, increased the chance of survival and reduced the risk of disease progression. FUNDING: Higher Education Commission (HEC), Pakistan (Ref no. 20-RRG-134/RGM/R&D/HEC/2020).

17.
Regen Ther ; 18: 152-160, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1260854

ABSTRACT

The Covid-19 disease has recently become one of the biggest challenges globally, and there is still no specific medication. Findings showed the immune system in severe Covid-19 patients loses regulatory control of pro-inflammatory cytokines, especially IL-6 production, called the "Cytokine storm" process. This process can cause injury to vital organs, including lungs, kidneys, liver, and ultimately death if not inhibited. While many treatments have been proposed to reduce cytokine storm, but the safety and effectiveness of each of them are still in doubt. Mesenchymal stem cells (MSCs) are multipotent cells with self-renewal potential capable of suppressing overactive immune responses and leading to tissue restoration and repair. These immuno-modulatory properties of MSCs and their derivatives (like exosomes) can improve the condition of Covid-19 patients with serious infectious symptoms caused by adaptive immune system dysfunction. Many clinical trials have been conducted in this field using various MSCs around the world. Some of these have been published and summarized in the present article, while many have not yet been completed. Based on these available data, MSCs can reduce inflammatory cytokines, increase oxygen saturation, regenerate lung tissue and improve clinical symptoms in Covid-19 patients. The review article aims to collect available clinical data in more detail and investigate the role of MSCs in reducing cytokine storms as well as improving clinical parameters of Covid-19 patients for use in future clinical studies.

18.
Pharmgenomics Pers Med ; 14: 621-629, 2021.
Article in English | MEDLINE | ID: covidwho-1256179

ABSTRACT

INTRODUCTION: The renin-angiotensin-aldosterone system (RAAS), a metabolic cascade regulating pressure and circulating blood volume, has been considered the main system involved in the pathogenesis of severe lung injury and organs decline in COVID-19 patients. The angiotensin I-converting enzyme (ACE1), angiotensin-converting enzyme 2 (ACE2), angiotensinogen (AGT) and receptors angiotensin II receptor type 1 (AGTR1) are key factors for SARS-CoV-2 entering in the cells, sodium and water retention with an increase blood pressure, promotion of fibrotic and inflammatory phenomena resulting in a cytokine storm. METHODS: In this pilot study, the frequencies of six polymorphisms in the ACE1, ACE2, AGT and AGTR1 genes were analysed in symptomatic patients affected by COVID-19 and compared with the results obtained from asymptomatic subjects. RESULTS: Thus, we have identified that rs2074192 (ACE2), rs1799752 (ACE1) and rs699 (AGT) SNPs could potentially be a valuable tool for predicting the clinical outcome of SARS-CoV-2 infected patients. A genetic predisposition may be prospected for severe internal organ damages and poor prognosis in patients with COVID-19 disease, as observed in symptomatic vs asymptomatic. CONCLUSION: This study provides evidence that analysis of RAAS polymorphisms could be considered the key point in understanding and predicting the SARS-CoV-2 course infection.

19.
Scand J Clin Lab Invest ; 81(4): 255-263, 2021 07.
Article in English | MEDLINE | ID: covidwho-1242057

ABSTRACT

Coronaviruses belonging to the Coronaviridae family are single-stranded RNA viruses. The entry of SARS-CoV-2 is accomplished via ACE-2 receptors. SARS-CoV-2 infection coactivates both innate and adaptive immune responses. Although SARS-CoV-2 stimulates antibody production with a typical pattern of IgM/IgG, cellular immunity is also impaired. In severe cases, low CD4 + and CD8 + T cell counts are associated with impaired immune functions, and high neutrophil/lymphocyte ratios accompanying low lymphocyte subsets have been demonstrated. Recently, high IFN -α/γ ratios with impaired T cell responses, and increased IL-1, IL-6, TNF-α, MCP-1, IP-10, IL-4, IL-10 have been reported in COVID-19 infection. Increased proinflammatory cytokines and chemokines in patients with severe COVID-19 may cause the suppression of CD4 + and CD8 + T cells and regulatory T cells, causing excessive inflammatory responses and fatal cytokine storm with tissue and organ damage. Consequently, novel therapeutics to be developed against host immune system, including blockade of cytokines (IL-6, IL-1, IFN) themselves, their receptors or signaling pathways- JAK inhibitors- could be effective as potential therapeutics.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/immunology , COVID-19/physiopathology , Adrenal Cortex Hormones/therapeutic use , Animals , Antiviral Agents/therapeutic use , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/virology , Cytokines/antagonists & inhibitors , Cytokines/metabolism , Glucocorticoids/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Immunotherapy/methods , Macrophages/immunology , Macrophages/pathology , Macrophages/virology
20.
Am J Pathol ; 191(8): 1374-1384, 2021 08.
Article in English | MEDLINE | ID: covidwho-1240148

ABSTRACT

Patients with coronavirus disease 2019 (COVID-19) who are critically ill develop vascular complications characterized by thrombosis of small, medium, and large vessels. Dysfunction of the vascular endothelium due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been implicated in the pathogenesis of the COVID-19 vasculopathy. Although initial reports suggested that endothelial injury was caused directly by the virus, recent studies indicate that endothelial cells do not express angiotensin-converting enzyme 2, the receptor that SARS-CoV-2 uses to gain entry into cells, or express it at low levels and are resistant to the infection. These new findings, together with the observation that COVID-19 triggers a cytokine storm capable of injuring the endothelium and disrupting its antithrombogenic properties, favor an indirect mechanism of endothelial injury mediated locally by an augmented inflammatory reaction to infected nonendothelial cells, such as the bronchial and alveolar epithelium, and systemically by the excessive immune response to infection. Herein we review the vascular pathology of COVID-19 and critically discuss the potential mechanisms of endothelial injury in this disease.


Subject(s)
COVID-19/metabolism , Cytokine Release Syndrome/metabolism , Endothelium, Vascular/injuries , Endothelium, Vascular/metabolism , SARS-CoV-2/metabolism , Thrombosis/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Bronchi/metabolism , Bronchi/pathology , COVID-19/complications , COVID-19/pathology , COVID-19/therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/therapy , Endothelium, Vascular/pathology , Humans , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/pathology , Respiratory Mucosa/metabolism , Respiratory Mucosa/pathology , Thrombosis/etiology , Thrombosis/pathology , Thrombosis/therapy
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