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1.
BMC Infect Dis ; 21(1): 1277, 2021 Dec 22.
Article in English | MEDLINE | ID: covidwho-1638012

ABSTRACT

BACKGROUND: Several anti-cytokine therapies were tested in the randomized trials in hospitalized patients with severe acute respiratory syndrome coronavirus 2 infection (COVID-19). Previously, dexamethasone demonstrated a reduction of case-fatality rate in hospitalized patients with respiratory failure. In this matched control study we compared dexamethasone to a Janus kinase inhibitor, ruxolitinib. METHODS: The matched cohort study included 146 hospitalized patients with COVID-19 and oxygen support requirement. The control group was selected 1:1 from 1355 dexamethasone-treated patients and was matched by main clinical and laboratory parameters predicting survival. Recruitment period was April 7, 2020 through September 9, 2020. RESULTS: Ruxolitinib treatment in the general cohort of patients was associated with case-fatality rate similar to dexamethasone treatment: 9.6% (95% CI [4.6-14.6%]) vs 13.0% (95% CI [7.5-18.5%]) respectively (p = 0.35, OR = 0.71, 95% CI [0.31-1.57]). Median time to discharge without oxygen support requirement was also not different between these groups: 13 vs. 11 days (p = 0.13). Subgroup analysis without adjustment for multiple comparisons demonstrated a reduced case-fatality rate in ruxolitnib-treated patients with a high fever (≥ 38.5 °C) (OR 0.33, 95% CI [0.11-1.00]). Except higher incidence of grade 1 thrombocytopenia (37% vs 23%, p = 0.042), ruxolitinib therapy was associated with a better safety profile due to a reduced rate of severe cardiovascular adverse events (6.8% vs 15%, p = 0.025). For 32 patients from ruxolitinib group (21.9%) with ongoing progression of respiratory failure after 72 h of treatment, additional anti-cytokine therapy was prescribed (8-16 mg dexamethasone). CONCLUSIONS: Ruxolitinib may be an alternative initial anti-cytokine therapy with comparable effectiveness in patients with potential risks of steroid administration. Patients with a high fever (≥ 38.5 °C) at admission may potentially benefit from ruxolitinib administration. Trial registration The Ruxolitinib Managed Access Program (MAP) for Patients Diagnosed With Severe/Very Severe COVID-19 Illness NCT04337359, CINC424A2001M, registered April, 7, 2020. First participant was recruited after registration date.


Subject(s)
COVID-19 , Adult , COVID-19/drug therapy , Cohort Studies , Dexamethasone/therapeutic use , Humans , Nitriles , Pyrazoles , Pyrimidines , SARS-CoV-2 , Treatment Outcome
2.
Trials ; 23(1): 35, 2022 Jan 15.
Article in English | MEDLINE | ID: covidwho-1635071

ABSTRACT

BACKGROUND: Since December 2019, SARS-CoV-2 virus has infected millions of people worldwide. In patients with COVID-19 pneumonia in need of oxygen therapy or mechanical ventilation, dexamethasone 6 mg per day is currently recommended. However, the dose of 6 mg of dexamethasone is currently being reappraised and may miss important therapeutic potential or may prevent potential deleterious effects of higher doses of corticosteroids. METHODS: REMED is a prospective, open-label, randomised controlled trial testing the superiority of dexamethasone 20 mg (dexamethasone 20 mg on days 1-5, followed by dexamethasone 10 mg on days 6-10) vs 6 mg administered once daily intravenously for 10 days in adult patients with moderate or severe ARDS due to confirmed COVID-19. Three hundred participants will be enrolled and followed up for 360 days after randomization. Patients will be randomised in a 1:1 ratio into one of the two treatment arms. The following stratification factors will be applied: age, Charlson Comorbidity Index, CRP levels and trial centre. The primary endpoint is the number of ventilator-free days (VFDs) at 28 days after randomisation. The secondary endpoints are mortality from any cause at 60 days after randomisation; dynamics of the inflammatory marker, change in WHO Clinical Progression Scale at day 14; and adverse events related to corticosteroids and independence at 90 days after randomisation assessed by the Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days. The study will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. DISCUSSION: We aim to compare two different doses of dexamethasone in patients with moderate to severe ARDS undergoing mechanical ventilation regarding efficacy and safety. TRIAL REGISTRATION: EudraCT No. 2020-005887-70. ClinicalTrials.gov NCT04663555. Registered on December 11, 2020.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Adult , COVID-19/drug therapy , Dexamethasone/adverse effects , Humans , Multicenter Studies as Topic , Prospective Studies , Quality of Life , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2 , Treatment Outcome
3.
PLoS One ; 16(12): e0261707, 2021.
Article in English | MEDLINE | ID: covidwho-1623660

ABSTRACT

The objective of this retrospective cohort study was to describe pre-treatment characteristics, treatment patterns, health resource use, and clinical outcomes among adults hospitalized with COVID-19 in the United States (US) who initiated common treatments for COVID-19. The Optum® COVID-19 electronic health records database was used to identify patients >18 years, diagnosed with COVID-19, who were admitted to an inpatient setting and received treatments of interest for COVID-19 between September 2020 and January 2021. Patients were stratified into cohorts based on index treatment use. Patient demographics, medical history, care setting, medical procedures, subsequent treatment use, patient disposition, clinical improvement, and outcomes were summarized descriptively. Among a total of 26,192 patients identified, the most prevalent treatments initiated were dexamethasone (35.4%) and dexamethasone + remdesivir (14.9%), and dexamethasone was the most common subsequent treatment. At day 14 post-index, <10% of patients received any treatments of interest. Mean (standard deviation [SD]) patient age was 65.6 (15.6) years, and the most prevalent comorbidities included hypertension (44.8%), obesity (35.4%), and diabetes (25.7%). At the end of follow-up, patients had a mean (SD) 8.1 (6.6) inpatient days and 1.4 (4.1) days with ICU care. Oxygen supplementation, non-invasive, or invasive ventilation was required by 4.5%, 3.0%, and 3.1% of patients, respectively. At the end of follow-up, 84.2% of patients had evidence of clinical improvement, 3.1% remained hospitalized, 83.8% were discharged, 4% died in hospital, and 9.1% died after discharge. Although the majority of patients were discharged alive, no treatments appeared to alleviate the inpatient morbidity and mortality associated with COVID-19. This highlights an unmet need for effective treatment options for patients hospitalized with COVID-19.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Dexamethasone/therapeutic use , Hypertension/epidemiology , Obesity/epidemiology , Patient Discharge , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Adenosine Monophosphate/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Alanine/therapeutic use , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/virology , Comorbidity , Drug Therapy, Combination/methods , Female , Follow-Up Studies , Humans , Male , Middle Aged , RNA, Viral/genetics , Retrospective Studies , Treatment Outcome , United States/epidemiology , Young Adult
4.
Trials ; 22(1): 172, 2021 Mar 01.
Article in English | MEDLINE | ID: covidwho-1622253

ABSTRACT

OBJECTIVES: The primary objective of this study is to test the hypothesis that administration of dexamethasone 20 mg is superior to a 6 mg dose in adult patients with moderate or severe ARDS due to confirmed COVID-19. The secondary objective is to investigate the efficacy and safety of dexamethasone 20 mg versus dexamethasone 6 mg. The exploratory objective of this study is to assess long-term consequences on mortality and quality of life at 180 and 360 days. TRIAL DESIGN: REMED is a prospective, phase II, open-label, randomised controlled trial testing superiority of dexamethasone 20 mg vs 6 mg. The trial aims to be pragmatic, i.e. designed to evaluate the effectiveness of the intervention in conditions that are close to real-life routine clinical practice. PARTICIPANTS: The study is multi-centre and will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. INCLUSION CRITERIA: Subjects will be eligible for the trial if they meet all of the following criteria: 1. Adult (≥18 years of age) at time of enrolment; 2. Present COVID-19 (infection confirmed by RT-PCR or antigen testing); 3. Intubation/mechanical ventilation or ongoing high-flow nasal cannula (HFNC) oxygen therapy; 4. Moderate or severe ARDS according to Berlin criteria: • Moderate - PaO2/FiO2 100-200 mmHg; • Severe - PaO2/FiO2 < 100 mmHg; 5. Admission to ICU in the last 24 hours. EXCLUSION CRITERIA: Subjects will not be eligible for the trial if they meet any of the following criteria: 1. Known allergy/hypersensitivity to dexamethasone or excipients of the investigational medicinal product (e.g. parabens, benzyl alcohol); 2. Fulfilled criteria for ARDS for ≥14 days at enrolment; 3. Pregnancy or breastfeeding; 4. Unwillingness to comply with contraception measurements from enrolment until at least 1 week after the last dose of dexamethasone (sexual abstinence is considered an adequate contraception method); 5. End-of-life decision or patient is expected to die within next 24 hours; 6. Decision not to intubate or ceilings of care in place; 7. Immunosuppression and/or immunosuppressive drugs in medical history: a) Systemic immunosuppressive drugs or chemotherapy in the past 30 days; b) Systemic corticosteroid use before hospitalization; c) Any dose of dexamethasone during the present hospital stay for COVID-19 for ≥5 days before enrolment; d) Systemic corticosteroids during present hospital stay for conditions other than COVID-19 (e.g. septic shock); 8. Current haematological or generalized solid malignancy; 9. Any contraindication for corticosteroid administration, e.g. • intractable hyperglycaemia; • active gastrointestinal bleeding; • adrenal gland disorders; • presence of superinfection diagnosed with locally established clinical and laboratory criteria without adequate antimicrobial treatment; 10. Cardiac arrest before ICU admission; 11. Participation in another interventional trial in the last 30 days. INTERVENTION AND COMPARATOR: Dexamethasone solution for injection/infusion is the investigational medicinal product as well as the comparator. The trial will assess two doses, 20 mg (investigational) vs 6 mg (comparator). Patients in the intervention group will receive dexamethasone 20 mg intravenously once daily on day 1-5, followed by dexamethasone 10 mg intravenously once daily on day 6-10. Patients in the control group will receive dexamethasone 6 mg day 1-10. All authorized medicinal products containing dexamethasone in the form of solution for i.v. injection/infusion can be used. MAIN OUTCOMES: Primary endpoint: Number of ventilator-free days (VFDs) at 28 days after randomisation, defined as being alive and free from mechanical ventilation. SECONDARY ENDPOINTS: a) Mortality from any cause at 60 days after randomisation; b) Dynamics of inflammatory marker (C-Reactive Protein, CRP) change from Day 1 to Day 14; c) WHO Clinical Progression Scale at Day 14; d) Adverse events related to corticosteroids (new infections, new thrombotic complications) until Day 28 or hospital discharge; e) Independence at 90 days after randomisation assessed by Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days through telephone structured interviews using the Barthel Index. RANDOMISATION: Randomisation will be carried out within the electronic case report form (eCRF) by the stratified permuted block randomisation method. Allocation sequences will be prepared by a statistician independent of the study team. Allocation to the treatment arm of an individual patient will not be available to the investigators before completion of the whole randomisation process. The following stratification factors will be applied: • Age <65 and ≥ 65; • Charlson Comorbidity index (CCI) <3 and ≥3; • CRP <150 mg/L and ≥150 mg/L • Trial centre. Patients will be randomised in a 1 : 1 ratio into one of the two treatment arms. Randomisation through the eCRF will be available 24 hours every day. BLINDING (MASKING): This is an open-label trial in which the participants and the study staff will be aware of the allocated intervention. Blinded pre-planned statistical analysis will be performed. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size is calculated to detect the difference of 3 VFDs at 28 days (primary efficacy endpoint) between the two treatment arms with a two-sided type I error of 0.05 and power of 80%. Based on data from a multi-centre randomised controlled trial in COVID-19 ARDS patients in Brazil and a multi-centre observational study from French and Belgian ICUs regarding moderate to severe ARDS related to COVID-19, investigators assumed a standard deviation of VFD at 28 days as 9. Using these assumptions, a total of 142 patients per treatment arm would be needed. After adjustment for a drop-out rate, 150 per treatment arm (300 patients per study) will be enrolled. TRIAL STATUS: This is protocol version 1.1, 15.01.2021. The trial is due to start on 2 February 2021 and recruitment is expected to be completed by December 2021. TRIAL REGISTRATION: The study protocol was registered on EudraCT No.:2020-005887-70, and on December 11, 2020 on ClinicalTrials.gov (Title: Effect of Two Different Doses of Dexamethasone in Patients With ARDS and COVID-19 (REMED)) Identifier: NCT04663555 with a last update posted on February 1, 2021. FULL PROTOCOL: The full protocol (version 1.1) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the standard formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
COVID-19/therapy , Dexamethasone/administration & dosage , Glucocorticoids/administration & dosage , Respiration, Artificial , Respiratory Distress Syndrome/therapy , COVID-19/complications , Clinical Trials, Phase II as Topic , Disease Progression , Dose-Response Relationship, Drug , Equivalence Trials as Topic , Humans , Length of Stay , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/etiology , SARS-CoV-2
5.
PLoS One ; 17(1): e0261142, 2022.
Article in English | MEDLINE | ID: covidwho-1622334

ABSTRACT

BACKGROUND: The Covid-19 pandemic in the United Kingdom has seen two waves; the first starting in March 2020 and the second in late October 2020. It is not known whether outcomes for those admitted with severe Covid were different in the first and second waves. METHODS: The study population comprised all patients admitted to a 1,500-bed London Hospital Trust between March 2020 and March 2021, who tested positive for Covid-19 by PCR within 3-days of admissions. Primary outcome was death within 28-days of admission. Socio-demographics (age, sex, ethnicity), hypertension, diabetes, obesity, baseline physiological observations, CRP, neutrophil, chest x-ray abnormality, remdesivir and dexamethasone were incorporated as co-variates. Proportional subhazards models compared mortality risk between wave 1 and wave 2. Cox-proportional hazard model with propensity score adjustment were used to compare mortality in patients prescribed remdesivir and dexamethasone. RESULTS: There were 3,949 COVID-19 admissions, 3,195 hospital discharges and 733 deaths. There were notable differences in age, ethnicity, comorbidities, and admission disease severity between wave 1 and wave 2. Twenty-eight-day mortality was higher during wave 1 (26.1% versus 13.1%). Mortality risk adjusted for co-variates was significantly lower in wave 2 compared to wave 1 [adjSHR 0.49 (0.37, 0.65) p<0.001]. Analysis of treatment impact did not show statistically different effects of remdesivir [HR 0.84 (95%CI 0.65, 1.08), p = 0.17] or dexamethasone [HR 0.97 (95%CI 0.70, 1.35) p = 0.87]. CONCLUSION: There has been substantial improvements in COVID-19 mortality in the second wave, even accounting for demographics, comorbidity, and disease severity. Neither dexamethasone nor remdesivir appeared to be key explanatory factors, although there may be unmeasured confounding present.


Subject(s)
COVID-19/mortality , Hospital Mortality/trends , Inpatients/statistics & numerical data , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Aged , Alanine/analogs & derivatives , Alanine/therapeutic use , COVID-19/drug therapy , Cohort Studies , Comorbidity/trends , Dexamethasone/therapeutic use , Female , Hospitalization/statistics & numerical data , Humans , London , Male , Middle Aged , Pandemics/statistics & numerical data , Patient Discharge/statistics & numerical data , Proportional Hazards Models
6.
J Immunotoxicol ; 18(1): 23-29, 2021 12.
Article in English | MEDLINE | ID: covidwho-1593522

ABSTRACT

The coronavirus SARS-CoV-2 of 2019 (COVID-19) causes a pandemic that has been diagnosed in more than 70 million people worldwide. Mild-to-moderate COVID-19 symptoms include coughing, fever, myalgia, shortness of breath, and acute inflammatory lung injury (ALI). In contrast, acute respiratory distress syndrome (ARDS) and respiratory failure occur in patients diagnosed with severe COVID-19. ARDS is mediated, at least in part, by a dysregulated inflammatory response due to excessive levels of circulating cytokines, a condition known as the "cytokine-storm syndrome." Currently, there are FDA-approved therapies that attenuate the dysregulated inflammation that occurs in COVID-19 patients, such as dexamethasone or other corticosteroids and IL-6 inhibitors, including sarilumab, tocilizumab, and siltuximab. However, the efficacy of these treatments have been shown to be inconsistent. Compounds that activate the vagus nerve-mediated cholinergic anti-inflammatory reflex, such as the α7 nicotinic acetylcholine receptor agonist, GTS-21, attenuate ARDS/inflammatory lung injury by decreasing the extracellular levels of high mobility group box-1 (HMGB1) in the airways and the circulation. It is possible that HMGB1 may be an important mediator of the "cytokine-storm syndrome." Notably, high plasma levels of HMGB1 have been reported in patients diagnosed with severe COVID-19, and there is a significant negative correlation between HMGB1 plasma levels and clinical outcomes. Nicotine can activate the cholinergic anti-inflammatory reflex, which attenuates the up-regulation and the excessive release of pro-inflammatory cytokines/chemokines. Therefore, we hypothesize that low molecular weight compounds that activate the cholinergic anti-inflammatory reflex, such as nicotine or GTS-21, may represent a potential therapeutic approach to attenuate the dysregulated inflammatory responses in patients with severe COVID-19.


Subject(s)
Benzylidene Compounds/pharmacology , COVID-19/drug therapy , Cholinergic Agents/pharmacology , Inflammation/drug therapy , Nicotine/metabolism , Pyridines/pharmacology , SARS-CoV-2/physiology , Tobacco Use Disorder/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Cigarette Smoking/adverse effects , Dexamethasone/therapeutic use , HMGB1 Protein/blood , Humans , Pandemics , alpha7 Nicotinic Acetylcholine Receptor/agonists
7.
Chest ; 161(1): e5-e11, 2022 01.
Article in English | MEDLINE | ID: covidwho-1595933

ABSTRACT

CASE PRESENTATION: A 67-year-old obese man (BMI 38.0) with type 2 diabetes mellitus (DM), chronic atrial fibrillation, and chronic lymphocytic leukemia stage II, stable for 8 years after chemotherapy, and a history of smoking presented to the ED with progressive dyspnea and fever due to SARS-CoV-2 infection. He was admitted to a general ward and treated with dexamethasone (6 mg IV once daily) and oxygen. On day 3 of hospital admission, he became progressively hypoxemic and was admitted to the ICU for invasive mechanical ventilation. Dexamethasone treatment was continued, and a single dose of tocilizumab (800 mg) was administered. On day 9 of ICU admission, voriconazole treatment was initiated after tracheal white plaques at bronchoscopy, suggestive of invasive Aspergillus tracheobronchitis, were noticed. However, his medical situation dramatically deteriorated.


Subject(s)
Acute Kidney Injury/virology , Antifungal Agents/therapeutic use , COVID-19/complications , Mucormycosis/diagnosis , Mucormycosis/drug therapy , Pulmonary Aspergillosis/diagnosis , Pulmonary Aspergillosis/drug therapy , Aged , Amphotericin B/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Atrial Fibrillation/complications , Bronchoscopy , Dexamethasone/therapeutic use , Diabetes Mellitus, Type 2/complications , Fatal Outcome , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Male , Nitriles/therapeutic use , Obesity/complications , Oxygen Inhalation Therapy , Pyridines/therapeutic use , Respiration, Artificial , SARS-CoV-2 , Smoking/adverse effects , Tomography, X-Ray Computed , Triazoles/therapeutic use , Voriconazole/therapeutic use
8.
Expert Rev Hematol ; 14(12): 1129-1135, 2021 12.
Article in English | MEDLINE | ID: covidwho-1577548

ABSTRACT

BACKGROUND: Multiple Myeloma (MM) accounts for 1-2% of all malignancies but is the second most common hematological malignancy. It is characterized by a proliferation of malignant plasma cells. The treatment paradigm of MM in Australia is traditionally hospital-based, complex, and costly. While MM comprises 1-2% of cancer diagnoses, it appears in the top 10 cancer diagnoses requiring hospital admission. The cumulative time spent receiving treatment is a significant burden for patients. The ability to receive treatment at home and maximize time away from hospital-based settings is a key preference for patients receiving anticancer therapies over a prolonged period of time. METHODS: The Peter MacCallum Cancer Centre and Royal Melbourne Hospital's combined Clinical Hematology Unit has collaborated with their Hospital in the Home departments to develop several innovative programs to address this. RESULTS: We describe our current active programs and potential developments in home-based MM therapy. CONCLUSION: We have enabled large numbers of patients to receive complex therapies in their own home and the COVID-19 pandemic has increased the pace of the roll out without any compromise in safety. We anticipate that the next raft of immunotherapies will be able to transition into the @Home treatment setting in the coming years.


Subject(s)
COVID-19 , Multiple Myeloma , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bortezomib/therapeutic use , Dexamethasone/therapeutic use , Humans , Multiple Myeloma/drug therapy , Pandemics , SARS-CoV-2
9.
Int J Immunopathol Pharmacol ; 35: 20587384211063976, 2021.
Article in English | MEDLINE | ID: covidwho-1582484

ABSTRACT

The underlying cause of many complications associated with severe COVID-19 is attributed to the inflammatory cytokine storm that leads to acute respiratory distress syndrome (ARDS), which appears to be the leading cause of death in COVID-19. Systemic corticosteroids have anti-inflammatory activity through repression of pro-inflammatory genes and inhibition of inflammatory cytokines, which makes them a potential medical intervention to diminish the upregulated inflammatory response. Early in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, the role of corticosteroids was unclear. Corticosteroid use in other indications such as ARDS and septic shock has proven benefit while its use in other respiratory viral pneumonias is associated with reduced viral clearance and increased secondary infections. This review article evaluates the benefits and harms of systemic corticosteroids in patients with COVID-19 to assist clinicians in improving patient outcomes, including patient safety. Dexamethasone up to 10 days is the preferred regimen to reduce mortality risk in COVID-19 patients requiring oxygen support, mechanical ventilation, or extracorporeal membrane oxygenation. If dexamethasone is unavailable, other corticosteroids can be substituted at equivalent doses. Higher doses of corticosteroids may be beneficial in patients who develop ARDS. Corticosteroids should be avoided early in the disease course when patients do not require oxygen support because of potential harms.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , COVID-19/drug therapy , Adrenal Cortex Hormones/adverse effects , Dexamethasone/adverse effects , Dexamethasone/therapeutic use , Humans , Hydrocortisone/adverse effects , Hydrocortisone/therapeutic use , Influenza, Human/drug therapy , Methylprednisolone/adverse effects , Methylprednisolone/therapeutic use , Prednisolone/adverse effects , Prednisolone/therapeutic use
10.
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
11.
Molecules ; 26(24)2021 Dec 15.
Article in English | MEDLINE | ID: covidwho-1572568

ABSTRACT

The encapsulation mode of dexamethasone (Dex) into the cavity of ß-cyclodextrin (ß-CD), as well as its potential as an inhibitor of the COVID-19 main protease, were investigated using density functional theory with the recent dispersion corrections D4 and molecular docking calculations. Independent gradient model and natural bond orbital approaches allowed for the characterization of the host-guest interactions in the studied systems. Structural and energetic computation results revealed that hydrogen bonds and van der Waals interactions played significant roles in the stabilization of the formed Dex@ß-CD complex. The complexation energy significantly decreased from -179.50 kJ/mol in the gas phase to -74.14 kJ/mol in the aqueous phase. A molecular docking study was performed to investigate the inhibitory activity of dexamethasone against the COVID-19 target protein (PDB ID: 6LU7). The dexamethasone showed potential therapeutic activity as a SARS CoV-2 main protease inhibitor due to its strong binding to the active sites of the protein target, with predicted free energy of binding values of -29.97 and -32.19 kJ/mol as calculated from AutoDock4 and AutoDock Vina, respectively. This study was intended to explore the potential use of the Dex@ß-CD complex in drug delivery to enhance dexamethasone dissolution, thus improving its bioavailability and reducing its side effects.


Subject(s)
COVID-19/drug therapy , Dexamethasone/pharmacology , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , beta-Cyclodextrins/pharmacology , Antiviral Agents/pharmacology , Drug Carriers/pharmacology , Humans , Molecular Docking Simulation
12.
J Korean Med Sci ; 36(43): e306, 2021 Nov 08.
Article in English | MEDLINE | ID: covidwho-1566642

ABSTRACT

Immune thrombocytopenia (ITP) is an autoimmune condition characterized by platelet destruction through antibody-mediated mechanism. ITP is one of the manifestations of a coronavirus disease, as well as an adverse event occurring after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several cases of ITP have been described after vaccination with two mRNA-based vaccines-BTN162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)-against SARS-CoV-2. Herein, we report a case of ITP occurring after vaccination with ChAdOx1 adenovirus vector nCoV-19 (AstraZeneca) vaccine in Korea. A 66-year-old woman presented with multiple ecchymoses on both upper and lower extremities and gingival bleeding, appearing 3 days after receiving the first dose of ChAdOx1 nCoV-19. Her laboratory results showed isolated severe thrombocytopenia without evidence of combined coagulopathy. She was diagnosed with ITP and successfully treated with high-dose dexamethasone and intravenous immunoglobulin. Clinical suspicion to identify vaccine-related ITP is important to promptly initiate appropriate treatment.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Ecchymosis/etiology , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Vaccination/adverse effects , Aged , COVID-19/epidemiology , COVID-19 Vaccines/adverse effects , Dexamethasone/therapeutic use , Female , Humans , Immunoglobulins, Intravenous/therapeutic use , Periodontal Index , Purpura, Thrombocytopenic, Idiopathic/drug therapy , SARS-CoV-2
13.
Sci Rep ; 11(1): 17263, 2021 08 26.
Article in English | MEDLINE | ID: covidwho-1550348

ABSTRACT

Dexamethasone (Dex) is a highly insoluble front-line drug used in cancer therapy. Data from clinical trials indicates that the pharmacokinetics of Dex vary considerably between patients and prolonging drug exposure rather than increasing absolute dose may improve efficacy. Non-toxic, fully biodegradable Dex loaded nanovectors (NV) were formulated, via simple direct hydration within 10 min, as a vehicle to extend exposure and distribution in vivo. Dex-NV were just as effective as the free drug against primary human leukemia cells in vitro and in vivo. Importantly, high levels of DMSO solvent were not required in the NV formulations. Broad distribution of NV was seen rapidly following inoculation into mice. NV accumulated in major organs, including bone marrow and brain, known sanctuary sites for ALL. The study describes a non-toxic, more easily scalable system for improving Dex solubility for use in cancer and can be applied to other medical conditions associated with inflammation.


Subject(s)
Dexamethasone/administration & dosage , Drug Delivery Systems/methods , Nanostructures/chemistry , Polymers/chemistry , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Xenograft Model Antitumor Assays/methods , Animals , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/chemistry , Antineoplastic Agents, Hormonal/pharmacokinetics , Child , Dexamethasone/chemistry , Dexamethasone/pharmacokinetics , Drug Liberation , Humans , Kaplan-Meier Estimate , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Treatment Outcome , Tumor Cells, Cultured , Young Adult
14.
J Med Virol ; 93(12): 6605-6610, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1544306

ABSTRACT

AIMS: We have previously demonstrated that vitamin D deficiency might be associated with worse outcomes in hospitalized Covid-19 patients. The aim of our study was to explore this relationship with dexamethasone therapy. METHODS: We prospectively studied two cohorts of hospitalized Covid-19 patients between March and April and between September and December 2020 (n = 192). Patients were tested for serum 25-hydroxyvitamin D (25-OH-D) levels during admission. The first cohort not treated with dexamethasone (n = 107) was divided into vitamin D deficient (25-OH-D ≤ 30 nmol/L) (n = 47) and replete subgroups (25-OH-D > 30 nmol/L) (n = 60). The second cohort treated with dexamethasone (n = 85) was similarly divided into deficient (25-OH-D ≤ 30 nmol/L) (n = 27) and replete subgroups (25-OH-D > 30 nmol/L) (n = 58). Primary outcome was in-hospital mortality and secondary outcomes were elevation in markers of cytokine storm and ventilatory requirement. RESULTS: No mortality difference was identified between cohorts and subgroups. The "no dexamethasone" cohort 25-OH-D deplete subgroup recorded significantly higher peak D-Dimer levels (1874 vs. 1233 µgFEU/L) (p = 0.0309), CRP (177 vs. 107.5) (p = 0.0055), and ventilatory support requirement (25.5% vs. 6.67%) (p = 0.007) compared to the replete subgroup. Among the 25-OH-D deplete subgroup higher peak neutrophil counts, peak CRP, peak LDH, peak ferritin, and lower trough lymphocyte counts were observed, without statistical significance. In the "dexamethasone" cohort, there was no apparent association between 25-OH-D deficiency and markers of cytokine storm or ventilatory requirement. CONCLUSION: Vitamin D deficiency is associated with elevated markers of cytokine storm and higher ventilatory requirements in hospitalized Covid-19 patients. Dexamethasone treatment appears to mitigate adverse effects of vitamin D deficiency.


Subject(s)
COVID-19/drug therapy , Dexamethasone/therapeutic use , Vitamin D Deficiency/complications , Aged , Aged, 80 and over , COVID-19/complications , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/prevention & control , Cytokines/blood , Female , Hospitalization , Humans , Male , Prospective Studies , Treatment Outcome , Vitamin D/analogs & derivatives , Vitamin D/blood
15.
Biomed Pharmacother ; 144: 112353, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1544808

ABSTRACT

Almost 80% of people confronting COVID-19 recover from COVID-19 disease without any particular treatments. They experience heterogeneous symptoms; a wide range of respiratory symptoms, cough, dyspnea, fever, and viral pneumonia. However, some others need urgent intervention and special treatment to get rid of this widespread disease. So far, there isn't any unique drug for the potential treatment of COVID 19. However, some available therapeutic drugs used for other diseases seem beneficial for the COVID-19 treatment. On the other hand, there is a robust global concern for developing an efficient COVID-19 vaccine to control the COVID-19 pandemic sustainably. According to the WHO report, since 8 October 2021, 320 vaccines have been in progress. 194 vaccines are in the pre-clinical development stage that 126 of them are in clinical progression. Here, in this paper, we have comprehensively reviewed the most recent and updated information about coronavirus and its mutations, all the potential therapeutic approaches for treating COVID-19, developed diagnostic systems for COVID- 19 and the available COVID-19 vaccines and their mechanism of action.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/drug therapy , COVID-19/prevention & control , Biosensing Techniques/methods , COVID-19/diagnosis , COVID-19 Nucleic Acid Testing/methods , Dexamethasone/therapeutic use , Glucocorticoids/therapeutic use , Humans , Molecular Diagnostic Techniques/methods , Mutation , Nucleic Acid Amplification Techniques/methods , Point-of-Care Testing , SARS-CoV-2/genetics , World Health Organization
17.
JAMA ; 326(18): 1807-1817, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1527380

ABSTRACT

Importance: A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. Objective: To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. Interventions: Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. Main Outcomes and Measures: The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days). Results: Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). Conclusions and Relevance: Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference. Trial Registration: ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.


Subject(s)
COVID-19/drug therapy , Dexamethasone/administration & dosage , Glucocorticoids/administration & dosage , Life Support Care , Aged , COVID-19/complications , COVID-19/mortality , Dexamethasone/adverse effects , Dose-Response Relationship, Drug , Female , Glucocorticoids/adverse effects , Humans , Hypoxia/etiology , Hypoxia/therapy , Male , Middle Aged , Mycoses/etiology , Respiration, Artificial , Shock, Septic/etiology , Single-Blind Method
18.
J Clin Invest ; 131(22)2021 11 15.
Article in English | MEDLINE | ID: covidwho-1518200

ABSTRACT

Metabolic pathways regulate immune responses and disrupted metabolism leads to immune dysfunction and disease. Coronavirus disease 2019 (COVID-19) is driven by imbalanced immune responses, yet the role of immunometabolism in COVID-19 pathogenesis remains unclear. By investigating 87 patients with confirmed SARS-CoV-2 infection, 6 critically ill non-COVID-19 patients, and 47 uninfected controls, we found an immunometabolic dysregulation in patients with progressed COVID-19. Specifically, T cells, monocytes, and granulocytes exhibited increased mitochondrial mass, yet only T cells accumulated intracellular reactive oxygen species (ROS), were metabolically quiescent, and showed a disrupted mitochondrial architecture. During recovery, T cell ROS decreased to match the uninfected controls. Transcriptionally, T cells from severe/critical COVID-19 patients showed an induction of ROS-responsive genes as well as genes related to mitochondrial function and the basigin network. Basigin (CD147) ligands cyclophilin A and the SARS-CoV-2 spike protein triggered ROS production in T cells in vitro. In line with this, only PCR-positive patients showed increased ROS levels. Dexamethasone treatment resulted in a downregulation of ROS in vitro and T cells from dexamethasone-treated patients exhibited low ROS and basigin levels. This was reflected by changes in the transcriptional landscape. Our findings provide evidence of an immunometabolic dysregulation in COVID-19 that can be mitigated by dexamethasone treatment.


Subject(s)
Basigin/physiology , COVID-19/immunology , Dexamethasone/pharmacology , SARS-CoV-2 , T-Lymphocytes/metabolism , Adult , COVID-19/metabolism , Cyclophilin A/physiology , Fatty Acids/metabolism , Female , Humans , Male , Middle Aged , Mitochondria/pathology , Reactive Oxygen Species/metabolism
20.
J Korean Med Sci ; 36(43): e306, 2021 Nov 08.
Article in English | MEDLINE | ID: covidwho-1506220

ABSTRACT

Immune thrombocytopenia (ITP) is an autoimmune condition characterized by platelet destruction through antibody-mediated mechanism. ITP is one of the manifestations of a coronavirus disease, as well as an adverse event occurring after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several cases of ITP have been described after vaccination with two mRNA-based vaccines-BTN162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)-against SARS-CoV-2. Herein, we report a case of ITP occurring after vaccination with ChAdOx1 adenovirus vector nCoV-19 (AstraZeneca) vaccine in Korea. A 66-year-old woman presented with multiple ecchymoses on both upper and lower extremities and gingival bleeding, appearing 3 days after receiving the first dose of ChAdOx1 nCoV-19. Her laboratory results showed isolated severe thrombocytopenia without evidence of combined coagulopathy. She was diagnosed with ITP and successfully treated with high-dose dexamethasone and intravenous immunoglobulin. Clinical suspicion to identify vaccine-related ITP is important to promptly initiate appropriate treatment.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Ecchymosis/etiology , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Vaccination/adverse effects , Aged , COVID-19/epidemiology , COVID-19 Vaccines/adverse effects , Dexamethasone/therapeutic use , Female , Humans , Immunoglobulins, Intravenous/therapeutic use , Periodontal Index , Purpura, Thrombocytopenic, Idiopathic/drug therapy , SARS-CoV-2
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