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1.
Intensive Care Med ; 48(5): 580-589, 2022 05.
Article in English | MEDLINE | ID: covidwho-1797659

ABSTRACT

PURPOSE: We assessed long-term outcomes of dexamethasone 12 mg versus 6 mg given daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia. METHODS: We assessed 180-day mortality and health-related quality of life (HRQoL) using EuroQoL (EQ)-5D-5L index values and EQ visual analogue scale (VAS) in the international, stratified, blinded COVID STEROID 2 trial, which randomised 1000 adults with confirmed COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 26 hospitals in Europe and India. In the HRQoL analyses, higher values indicated better outcomes, and deceased patients were given a score of zero. RESULTS: We obtained vital status at 180 days for 963 of 982 patients (98.1%) in the intention-to-treat population, EQ-5D-5L index value data for 922 (93.9%) and EQ VAS data for 924 (94.1%). At 180 days, 164 of 486 patients (33.7%) had died in the 12 mg group versus 184 of 477 (38.6%) in the 6 mg group [adjusted risk difference - 4.3%; 99% confidence interval (CI) - 11.7-3.0; relative risk 0.89; 0.72-1.09; P = 0.13]. The adjusted mean differences between the 12 mg and the 6 mg groups in EQ-5D-5L index values were 0.06 (99% CI - 0.01 to 0.12; P = 0.10) and in EQ VAS scores 4 (- 3 to 10; P = 0.22). CONCLUSION: Among patients with COVID-19 and severe hypoxaemia, dexamethasone 12 mg compared with 6 mg did not result in statistically significant improvements in mortality or HRQoL at 180 days, but the results were most compatible with benefit from the higher dose.


Subject(s)
COVID-19 , Dexamethasone , Hypoxia , Adult , COVID-19/complications , COVID-19/drug therapy , Dexamethasone/administration & dosage , Dose-Response Relationship, Drug , Humans , Hypoxia/complications , Hypoxia/drug therapy , Patient Acuity , Quality of Life , Surveys and Questionnaires , Treatment Outcome
2.
Nature ; 603(7899): 25-27, 2022 03.
Article in English | MEDLINE | ID: covidwho-1730273

Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Clinical Trials as Topic , Drug Repositioning , Host-Pathogen Interactions/drug effects , SARS-CoV-2/drug effects , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Administration, Oral , Alanine/administration & dosage , Alanine/analogs & derivatives , Alanine/therapeutic use , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/economics , Antibodies, Neutralizing/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , COVID-19/economics , COVID-19/immunology , COVID-19/mortality , COVID-19/virology , COVID-19 Vaccines , Cytidine/analogs & derivatives , Cytidine/therapeutic use , Depsipeptides/pharmacology , Depsipeptides/therapeutic use , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Drug Combinations , Drug Synergism , Esters/pharmacology , Esters/therapeutic use , Guanidines/pharmacology , Guanidines/therapeutic use , Hospitalization , Humans , Hydroxylamines/therapeutic use , Internationality , Lactams/therapeutic use , Leucine/therapeutic use , Mice , National Institutes of Health (U.S.)/organization & administration , Nitriles/therapeutic use , Peptide Elongation Factor 1/antagonists & inhibitors , Peptides, Cyclic/pharmacology , Peptides, Cyclic/therapeutic use , Proline/therapeutic use , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , RNA-Dependent RNA Polymerase/antagonists & inhibitors
3.
JAMA Netw Open ; 5(3): e221455, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1729077

ABSTRACT

Importance: Current guidelines recommend use of dexamethasone, 6 mg/d, up to 10 days or until discharge for patients hospitalized with COVID-19. Whether patients who received less than 10 days of corticosteroids during hospitalization for COVID-19 benefit from continuing treatment at discharge has not been determined. Objective: To assess whether continuing dexamethasone treatment at discharge is associated with reduced all-cause readmissions or mortality postdischarge. Design, Setting, and Participants: A retrospective cohort study was conducted at 15 medical centers within Kaiser Permanente Southern California. The population included adults who received less than 10 days of dexamethasone, 6 mg/d, until discharge during hospitalization for COVID-19 and were discharged alive between May 1 and September 30, 2020. Exposures: Continued dexamethasone treatment at discharge. Main Outcomes and Measures: All-cause readmissions or mortality within 14 days from discharge. Results: A total of 1164 patients with a median age of 55 (IQR, 44-66) years were identified. Most patients were of Hispanic ethnicity (822 [70.6%]) and male (674 [57.9%]) and required oxygen support during hospitalization (1048 [90.0%]). Of the 1164 patients, 692 (59.5%) continued dexamethasone, 6 mg/d, at discharge. A balanced cohort was created using propensity score and inverse probability of treatment weighting. The adjusted odds ratio (OR) for readmissions or mortality within 14 days was 0.87 (95% CI, 0.58-1.30) for patients who continued dexamethasone therapy at discharge compared with those who did not. Similar results were produced by a sensitivity analysis that restricted the treatment group to those who received exactly 10 days of dexamethasone (OR, 0.89; 95% CI, 0.55-1.43) and by subgroup analyses stratified by the duration of dexamethasone treatment as an inpatient (1-3 days: OR, 0.71; 95% CI, 0.43-1.16; 4-9 days: OR, 1.01; 95% CI, 0.48-2.12), oxygen requirement at discharge (room air: OR, 0.91; 95% CI, 0.53-1.59; supplemental oxygen use: OR, 0.76; 95% CI, 0.42-1.37), and disease duration at discharge (≤10 days: OR, 0.81; 95% CI, 0.49-1.33; >10 days: OR, 0.94; 95% CI, 0.48-1.86). Conclusions and Relevance: In this cohort study of patients with COVID-19, continuing treatment with dexamethasone, 6 mg/d, at discharge was not associated with a reduction in 14-day all-cause readmission or mortality. This finding suggests that dexamethasone should not be routinely prescribed beyond discharge for individuals with COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Dexamethasone/therapeutic use , Patient Discharge , Patient Readmission , Practice Patterns, Physicians' , SARS-CoV-2 , Adult , Aged , Anti-Inflammatory Agents/administration & dosage , COVID-19/mortality , California , Cohort Studies , Dexamethasone/administration & dosage , Female , Humans , Male , Middle Aged , Retrospective Studies
5.
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
7.
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
8.
Front Endocrinol (Lausanne) ; 12: 747744, 2021.
Article in English | MEDLINE | ID: covidwho-1555359

ABSTRACT

This paper suggests that ATP release induced by the SARS-CoV-2 virus plays a key role in the genesis of the major symptoms and complications of COVID-19. Infection of specific cells which contain the Angiotensin-Converting Enzyme 2 (ACE2) receptor results in a loss of protection of the Mineralocorticoid Receptor (MR). Local activation by cortisol stimulates the release of ATP initially into the basolateral compartment and then by lysosomal exocytosis from the cell surface. This then acts on adjacent cells. In the nose ATP acts as a nociceptive stimulus which results in anosmia. It is suggested that a similar paracrine mechanism is responsible for the loss of taste. In the lung ATP release from type 2 alveolar cells produces the non-productive cough by acting on purinergic receptors on adjacent neuroepithelial cells and activating, via the vagus, the cough reflex. Infection of endothelial cells results in the exocytosis of WeibelPalade bodies. These contain the Von Willebrand Factor responsible for micro-clotting and angiopoietin-2 which increases vascular permeability and plays a key role in the Acute Respiratory Distress Syndrome. To test this hypothesis this paper reports proof of concept studies in which MR blockade using spironolactone and low dose dexamethasone (SpiDex) was given to PCR-confirmed COVID-19 patients. In 80 patients with moderate to severe respiratory failure 40 were given SpiDex and 40 conventional treatment with high dose dexamethasone (HiDex). There was 1 death in the HiDex group and none in the SpiDex. As judged by clinical, biochemical and radiological parameters there were clear statistically significant benefits of SpiDex in comparison to HiDex. A further 20 outpatients with COVID-19 were given SpiDex. There was no control group and the aim was to demonstrate safety. No adverse effects were noted and no patient became hyperkalaemic. 90% were asymptomatic at 10 days. The very positive results suggest that blockade of the MR can produce major benefit in COVID19 patients. Further larger controlled studies of inpatients and outpatients are required not only for SARS-CoV-2 infection per se but also to determine if this treatment affects the incidence of Long COVID.


Subject(s)
Anosmia/complications , COVID-19/diagnosis , COVID-19/therapy , Nociception , SARS-CoV-2 , Symptom Assessment , Adenosine Triphosphate/metabolism , Adult , Aged , Angiopoietin-2/biosynthesis , Angiotensin-Converting Enzyme 2/biosynthesis , Animals , COVID-19/blood , Dexamethasone/administration & dosage , Dexamethasone/blood , Dexamethasone/therapeutic use , Endothelial Cells/metabolism , Female , Humans , Hydrocortisone/metabolism , Kidney/drug effects , Male , Middle Aged , Models, Biological , Polymerase Chain Reaction , Rats , Receptors, Mineralocorticoid/biosynthesis , Spironolactone/blood , von Willebrand Factor/biosynthesis
9.
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
10.
Emerg Microbes Infect ; 11(1): 50-59, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1541487

ABSTRACT

Dexamethasone implementation for COVID-19 management represented a milestone but data regarding its impact and safety have not been consistently reproduced. We aimed to evaluate in-hospital mortality before and after the implementation of corticosteroid treatment (CS-T) for severe and critical COVID-19. We conducted a cohort study that included patients admitted with severe and critical COVID-19. The primary outcome was death during hospitalization. Secondary outcomes included the length of stay (LOS), need for invasive mechanical ventilation (IMV), time to IMV initiation, IMV duration, and development of hospital-acquired infections (HAIs). Bivariate, multivariate, and propensity-score matching analysis were performed. Among 1540 patients, 688 (45%) received CS-T. Death was less frequent in the CS-T group (18 vs 31%, p < .01). Among patients on IMV, death was also less frequent in the CS-T group (25 vs 55%, p < .01). The median time to IMV was longer in the CS-T group (5 vs 3 days, p < .01). HAIs occurred more frequently in the CS-T group (20 vs 10%, p < .01). LOS, IMV, and IMV duration were similar between groups. Multivariate analysis revealed an independent association between CS-T and lower mortality (aOR 0.26, 95% CI 0.19-0.36, p < .001). Propensity-score matching analysis revealed that CS-T was independently associated with lower mortality (aOR 0.33, 95% CI 0.22-0.50, p < .01). Treatment with corticosteroids was associated with reduced in-hospital mortality among patients with severe and critical COVID-19, including those on IMV.


Subject(s)
COVID-19/drug therapy , COVID-19/virology , Dexamethasone/therapeutic use , SARS-CoV-2/drug effects , Aged , COVID-19/diagnosis , COVID-19/epidemiology , Clinical Decision-Making , Comorbidity , Critical Illness , Dexamethasone/administration & dosage , Disease Management , Female , Hospital Mortality , Hospitalization , Humans , Male , Middle Aged , Severity of Illness Index , Treatment Outcome
12.
Pharmacol Rep ; 74(1): 229-240, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1536392

ABSTRACT

BACKGROUND AND OBJECTIVES: Corticosteroids are commonly used in the treatment of hospitalized patients with COVID-19. The goals of the present study were to compare the efficacy and safety of different doses of dexamethasone in the treatment of patients with a diagnosis of moderate to severe COVID-19. METHODS: Hospitalized patients with a diagnosis of moderate to severe COVID-19 were assigned to intravenous low-dose (8 mg once daily), intermediate-dose (8 mg twice daily) or high-dose (8 mg thrice daily) dexamethasone for up to 10 days or until hospital discharge. Clinical response, 60-day survival and adverse effects were the main outcomes of the study. RESULTS: In the competing risk survival analysis, patients in the low-dose group had a higher clinical response than the high-dose group when considering death as a competing risk (HR = 2.03, 95% CI: 1.23-3.33, p = 0.03). Also, the survival was significantly longer in the low-dose group than the high-dose group (HR = 0.36, 95% CI = 0.15-0.83, p = 0.02). Leukocytosis and hyperglycemia were the most common side effects of dexamethasone. Although the incidence was not significantly different between the groups, some adverse effects were numerically higher in the intermediate-dose and high-dose groups than in the low-dose group. CONCLUSIONS: Higher doses of dexamethasone not only failed to improve efficacy but also resulted in an increase in the number of adverse events and worsen survival in hospitalized patients with moderate to severe COVID-19 compared to the low-dose dexamethasone. (IRCT20100228003449N31).


Subject(s)
Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Adult , Aged , Anti-Inflammatory Agents/adverse effects , Dexamethasone/adverse effects , Dose-Response Relationship, Drug , Drug-Related Side Effects and Adverse Reactions/epidemiology , Female , Humans , Hyperglycemia/chemically induced , Incidence , Leukocytosis/chemically induced , Male , Middle Aged , Survival Analysis , Treatment Outcome
13.
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
14.
Inflamm Res ; 71(1): 39-56, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1525531

ABSTRACT

The COVID-19 pandemic created a worldwide debilitating health crisis with the entire humanity suffering from the deleterious effects associated with the high infectivity and mortality rates. While significant evidence is currently available online and targets various aspects of the disease, both inflammatory and noninflammatory kidney manifestations secondary to COVID-19 infection are still largely underrepresented. In this review, we summarized current knowledge about COVID-19-related kidney manifestations, their pathologic mechanisms as well as various pharmacotherapies used to treat patients with COVID-19. We also shed light on the effect of these medications on kidney functions that can further enhance renal damage secondary to the illness.


Subject(s)
COVID-19/drug therapy , COVID-19/physiopathology , Kidney Diseases/physiopathology , Kidney/injuries , Acute Kidney Injury/complications , Aldosterone/metabolism , Angiotensins/chemistry , Antibodies, Monoclonal, Humanized/administration & dosage , Autopsy , Biopsy , COVID-19/complications , COVID-19 Vaccines , Dexamethasone/administration & dosage , Enoxaparin/administration & dosage , Heparin/administration & dosage , Heparin, Low-Molecular-Weight/administration & dosage , Humans , Inflammation , Interleukin 1 Receptor Antagonist Protein/administration & dosage , Kidney Diseases/complications , Kidney Transplantation , Lopinavir/administration & dosage , Pandemics , Renal Replacement Therapy , Renin-Angiotensin System , Ritonavir/administration & dosage , SARS-CoV-2
15.
Medicine (Baltimore) ; 100(29): e26705, 2021 Jul 23.
Article in English | MEDLINE | ID: covidwho-1475905

ABSTRACT

ABSTRACT: Cytokine release syndrome (CRS) or cytokine storm is thought to be the cause of inflammatory lung damage, worsening pneumonia and death in patients with COVID-19. Steroids (Methylprednislone or Dexamethasone) and Tocilizumab (TCZ), an interleukin-6 receptor antagonist, are approved for treatment of CRS in India. The aim of this study was to evaluate the efficacy and safety of combination therapy of TCZ and steroid in COVID-19 associated CRS.This retrospective cohort study was conducted at Noble hospital and Research Centre (NHRC), Pune, India between April 2 and November 2, 2020. All patients administered TCZ and steroids during this period were included. The primary endpoint was incidence of all cause mortality. Secondary outcomes studied were need for mechanical ventilation and incidence of systemic and infectious complications. Baseline and time dependent risk factors significantly associated with death were identified by Relative risk estimation.Out of 2831 admitted patients, 515 (24.3% females) were administered TCZ and steroids. There were 135 deaths (26.2%), while 380 patients (73.8%) had clinical improvement. Mechanical ventilation was required in 242 (47%) patients. Of these, 44.2% (107/242) recovered and were weaned off the ventilator. Thirty seven percent patients were managed in wards and did not need intensive care unit (ICU) admission. Infectious complications like hospital acquired pneumonia, blood stream bacterial and fungal infections were observed in 2.13%, 2.13% and 0.06% patients respectively. Age ≥ 60 years (P = .014), presence of co-morbidities like hypertension (P = .011), IL-6 ≥ 100 pg/ml (P = .002), D-dimer ≥ 1000 ng/ml (P < .0001), CT severity index ≥ 18 (P < .0001) and systemic complications like lung fibrosis (P = .019), cardiac arrhythmia (P < .0001), hypotension (P < .0001) and encephalopathy (P < .0001) were associated with increased risk of death.Combination therapy of TCZ and steroids is likely to be safe and effective in management of COVID-19 associated cytokine release syndrome. Efficacy of this anti-inflammatory combination therapy needs to be validated in randomized controlled trials.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Dexamethasone/therapeutic use , Methylprednisolone/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19/complications , COVID-19/mortality , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/mortality , Dexamethasone/administration & dosage , Drug Therapy, Combination , Female , Humans , India , Intensive Care Units/statistics & numerical data , Length of Stay/statistics & numerical data , Male , Methylprednisolone/administration & dosage , Middle Aged , Retrospective Studies , Treatment Outcome
16.
PLoS One ; 16(9): e0256977, 2021.
Article in English | MEDLINE | ID: covidwho-1394551

ABSTRACT

INTRODUCTION: Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2. Although most patients with COVID-19 develop asymptomatic or mild disease, some patients develop severe disease. The effectiveness of various therapeutic agents, including antiviral drugs, steroids, and anti-inflammatories for COVID-19, have been being confirmed. The effect of administering steroids in early disease is unclear. This study therefore aimed to evaluate the effectiveness and risk of exacerbation of steroids administered preceding antiviral drugs in patients with COVID-19 pneumonia. METHODS: This retrospective, single-center, observational study included consecutive patients with COVID-19 between March 2020 and March 2021. Patients were divided into a steroids-first group and antiviral-drugs-first group. Mortality, duration of hospitalization, incidence rate and duration of intensive care unit (ICU) admission, intubation, and extracorporeal membrane oxygenation (ECMO) induction of the two groups were compared. RESULTS: A total of 258 patients were admitted during the study period. After excluding patients who received symptomatic treatment only, who were taking immunosuppressive drugs, or who were administered antiviral drugs only, 68 patients were included in the analysis, 16 in the steroids-first group and 52 in the antiviral-drugs-first group. The rate of intubation, ICU admission and ECMO induction were significantly higher in the steroids-first group than in the antiviral-drugs-first group (81.3% vs. 33.3, p<0.001, 75.0% vs. 29.4%, p = 0.001, and 31.3% vs. 7.8%, p = 0.017, respectively). Furthermore, patients who received steroids within ten days after starting antiviral drugs had significantly lower rates of ICU admission, intubation, and ECMO induction. (81.3% vs. 42.9% p = 0.011, 75.0% vs. 37.1% p = 0.012, and 31.3% vs. 8.6% p = 0.039, respectively). CONCLUSIONS: Administering steroids prior to antiviral drugs soon after symptom onset can aggravate disease severity. When administration of steroids is considered soon after symptom onset, it may be safer to initiate antiviral drugs first.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Dexamethasone/therapeutic use , Hospitalization/statistics & numerical data , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2/drug effects , Aged , Antiviral Agents/administration & dosage , COVID-19/physiopathology , COVID-19/virology , Dexamethasone/administration & dosage , Drug Administration Schedule , Female , Glucocorticoids/administration & dosage , Glucocorticoids/therapeutic use , Hospital Mortality , Humans , Intensive Care Units/statistics & numerical data , Kaplan-Meier Estimate , Male , Middle Aged , Respiratory Distress Syndrome/physiopathology , Retrospective Studies , SARS-CoV-2/physiology , Severity of Illness Index , Treatment Outcome
17.
Respir Med ; 187: 106571, 2021 10.
Article in English | MEDLINE | ID: covidwho-1347816

ABSTRACT

Since the beginning of COVID-19 pandemic, clinical, radiological and histopathological features consistent with viral-induced organizing pneumonia (OP) have been reported as hallmark characteristics of the disease. Here, we describe the case of ten patients with severe COVID-19 pneumonia treated with methylprednisolone 1mg/kg for showing clinical and radiological features suggestive of OP at least 20 days after symptom onset and despite standard treatment for COVID-19.


Subject(s)
COVID-19/complications , COVID-19/therapy , Dexamethasone/administration & dosage , Glucocorticoids/administration & dosage , Methylprednisolone/administration & dosage , Respiratory Insufficiency/drug therapy , Aged , Drug Administration Schedule , Drug Therapy, Combination , Female , Humans , Male , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/virology
18.
J Korean Med Sci ; 36(29): e203, 2021 Jul 26.
Article in English | MEDLINE | ID: covidwho-1328073

ABSTRACT

Coronavirus disease 2019 (COVID-19) is generally milder in children than in adults, and a substantial proportion of children with the disease have asymptomatic infections. Remdesivir is recommended for severe COVID-19. To date, there are little data on the outcomes of remdesivir treatment in children. We report a case of severe COVID-19 in a previously healthy but obese (body mass index, 27.6; 99.8th percentile of the age) 9-year-old boy treated with remdesivir and dexamethasone. The patient had pneumonia at the time of diagnosis and required supplemental oxygen due to hypoxia one day after diagnosis. The patient developed respiratory distress as his pneumonia progressed rapidly. Therefore, remdesivir with dexamethasone therapy was initiated on hospital day 2. Supplemental oxygen was gradually weaned on hospital day 6 and stopped on hospital day 9. Significant improvement in pneumonic consolidations on chest X-ray was noted on hospital day 8. The patient was discharged on hospital day 21. We did not observe any adverse effects of remdesivir therapy and successfully treated a 9-year-old child with severe COVID-19.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , COVID-19/drug therapy , Dexamethasone/administration & dosage , SARS-CoV-2 , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/adverse effects , Alanine/administration & dosage , Alanine/adverse effects , Child , Drug Therapy, Combination , Humans , Male
19.
Nat Commun ; 12(1): 3554, 2021 06 11.
Article in English | MEDLINE | ID: covidwho-1265949

ABSTRACT

Although the COVID-19 pandemic has left no country untouched there has been limited research to understand clinical and immunological responses in African populations. Here we characterise patients hospitalised with suspected (PCR-negative/IgG-positive) or confirmed (PCR-positive) COVID-19, and healthy community controls (PCR-negative/IgG-negative). PCR-positive COVID-19 participants were more likely to receive dexamethasone and a beta-lactam antibiotic, and survive to hospital discharge than PCR-negative/IgG-positive and PCR-negative/IgG-negative participants. PCR-negative/IgG-positive participants exhibited a nasal and systemic cytokine signature analogous to PCR-positive COVID-19 participants, predominated by chemokines and neutrophils and distinct from PCR-negative/IgG-negative participants. PCR-negative/IgG-positive participants had increased propensity for Staphylococcus aureus and Streptococcus pneumoniae colonisation. PCR-negative/IgG-positive individuals with high COVID-19 clinical suspicion had inflammatory profiles analogous to PCR-confirmed disease and potentially represent a target population for COVID-19 treatment strategies.


Subject(s)
COVID-19/immunology , Adult , Africa South of the Sahara/epidemiology , Anti-Bacterial Agents/administration & dosage , Antibodies/blood , COVID-19/blood , COVID-19/drug therapy , COVID-19/epidemiology , Coinfection/immunology , Cytokines/blood , Dexamethasone/administration & dosage , Female , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Male , Middle Aged , Pandemics , SARS-CoV-2/isolation & purification
20.
Lancet ; 397(10286): 1749, 2021 05 08.
Article in English | MEDLINE | ID: covidwho-1219082
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