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5.
Immunotherapy ; 14(14): 1133-1147, 2022 10.
Article in English | MEDLINE | ID: covidwho-1963293

ABSTRACT

Background: The authors describe the developmental process of intravenous anti-COVID-19 hyperimmune immunoglobulin from anti-SARS-CoV-2 neutralizing antibody-containing plasma. Furthermore, the authors investigated its safety and protective activity in animal models. Materials & methods: The manufacturing process included standard ethanol fractionation, chromatographic purification steps and virus removal or inactivation. Results: The authors produced pure and safe immunoglobulin for intravenous administration, with 98.1 ± 6.5 mg/ml protein content, of which 97.6 ± 0.7% was IgG. The concentration factor of SARS-CoV-2 neutralizing antibodies was 9.4 ± 1.4-times. Safety studies in animals showed no signs of acute/chronic toxicity or allergenic or thrombogenic properties. Intravenous anti-COVID-19 hyperimmune immunoglobulin protected immunosuppressed hamsters against SARS-Cov-2. Conclusion: The obtained results can allow the start of clinical trials to study the safety and efficacy in healthy adults.


An intravenous immunoglobulin with a high concentration of SARS-CoV-2-neutralizing antibodies was prepared from COVID-19 convalescent plasma, which could be utilized as a passive immunization tool in regard to COVID-19 treatment. The manufacturing process employed conforms to commonly held business standards within the intravenous immunoglobulin industry and includes plasma ethanol fractionation following chromatographic purification and special virus removal or inactivation steps. The results of the preclinical in vitro and in vivo experiments demonstrate that the immunoglobulin produced in this study is pure and safe enough to be considered for intravenous applications. The SARS-CoV-2 neutralizing antibody concentration was found to have increased 9.4 ± 1.4-times compared with human plasma. The anti-COVID-19 hyperimmune immunoglobulin showed no signs of toxicity and did not cause any blood clot formations when administered to rabbits. Furthermore, the anti-COVID-19 hyperimmune immunoglobulin was demonstrated to protect immunosuppressed hamsters against SARS-CoV-2.


Subject(s)
COVID-19 , SARS-CoV-2 , Administration, Intravenous , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , COVID-19/therapy , Humans , Immunization, Passive/methods , Immunoglobulins, Intravenous/therapeutic use
6.
N Engl J Med ; 387(2): 148-159, 2022 07 14.
Article in English | MEDLINE | ID: covidwho-1931553

ABSTRACT

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).


Subject(s)
Erythropoietin , Hypothermia, Induced , Hypoxia-Ischemia, Brain , Neuroprotective Agents , Administration, Intravenous , Cerebral Palsy/etiology , Double-Blind Method , Erythropoietin/administration & dosage , Erythropoietin/adverse effects , Erythropoietin/therapeutic use , Humans , Hypothermia, Induced/methods , Hypoxia-Ischemia, Brain/complications , Hypoxia-Ischemia, Brain/drug therapy , Hypoxia-Ischemia, Brain/therapy , Infant , Infant, Newborn , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/adverse effects , Neuroprotective Agents/therapeutic use
7.
Crit Care ; 26(1): 183, 2022 06 18.
Article in English | MEDLINE | ID: covidwho-1894497

ABSTRACT

BACKGROUND: Clarithromycin may act as immune-regulating treatment in sepsis and acute respiratory dysfunction syndrome. However, clinical evidence remains inconclusive. We aimed to evaluate whether clarithromycin improves 28-day mortality among patients with sepsis, respiratory and multiple organ dysfunction syndrome. METHODS: We conducted a multicenter, randomized, clinical trial in patients with sepsis. Participants with ratio of partial oxygen pressure to fraction of inspired oxygen less than 200 and more than 3 SOFA points from systems other than the respiratory function were enrolled between December 2017 and September 2019. Patients were randomized to receive 1 gr of clarithromycin or placebo intravenously once daily for 4 consecutive days. The primary endpoint was 28-day all-cause mortality. Secondary outcomes were 90-day mortality; sepsis response (defined as at least 25% decrease in SOFA score by day 7); sepsis recurrence; and differences in peripheral blood cell populations and leukocyte transcriptomics. RESULTS: Fifty-five patients were allocated to each arm. By day 28, 27 (49.1%) patients in the clarithromycin and 25 (45.5%) in the placebo group died (risk difference 3.6% [95% confidence interval (CI) - 15.7 to 22.7]; P = 0.703, adjusted OR 1.03 [95%CI 0.35-3.06]; P = 0.959). There were no statistical differences in 90-day mortality and sepsis response. Clarithromycin was associated with lower incidence of sepsis recurrence (OR 0.21 [95%CI 0.06-0.68]; P = 0.012); significant increase in monocyte HLA-DR expression; expansion of non-classical monocytes; and upregulation of genes involved in cholesterol homeostasis. Serious and non-serious adverse events were equally distributed. CONCLUSIONS: Clarithromycin did not reduce mortality among patients with sepsis with respiratory and multiple organ dysfunction. Clarithromycin was associated with lower sepsis recurrence, possibly through a mechanism of immune restoration. Clinical trial registration clinicaltrials.gov identifier NCT03345992 registered 17 November 2017; EudraCT 2017-001056-55.


Subject(s)
Clarithromycin , Sepsis , Administration, Intravenous , Clarithromycin/pharmacology , Clarithromycin/therapeutic use , Humans , Multiple Organ Failure/complications , Multiple Organ Failure/drug therapy , Oxygen/therapeutic use , Sepsis/complications
8.
EBioMedicine ; 76: 103856, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1894987

ABSTRACT

BACKGROUND: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is nafamostat mesylate. METHODS: We present the findings of a phase Ib/IIa open label, platform randomised controlled trial of intravenous nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2 mg/kg/h for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. The primary outcomes of our trial were the safety and tolerability of intravenous nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis. FINDINGS: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous nafamostat. 86% of nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The nafamostat group were significantly more likely to experience at least one AE (posterior mean odds ratio 5.17, 95% credible interval (CI) 1.10 - 26.05) and developed significantly higher plasma creatinine levels (posterior mean difference 10.57 micromol/L, 95% CI 2.43-18.92). An average longer hospital stay was observed in nafamostat patients, alongside a lower rate of oxygen free days (rate ratio 0.55-95% CI 0.31-0.99, respectively). There were no other statistically significant differences in endpoints between nafamostat and SoC. PK data demonstrated that intravenous nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. INTERPRETATION: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous nafamostat, and there were additional adverse events. FUNDING: DEFINE was funded by LifeArc (an independent medical research charity) under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzamidines/therapeutic use , COVID-19/drug therapy , Guanidines/therapeutic use , Administration, Intravenous , Adult , Aged , Aged, 80 and over , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Benzamidines/adverse effects , Benzamidines/pharmacokinetics , Biomarkers/blood , Biomarkers/metabolism , COVID-19/mortality , COVID-19/virology , Drug Administration Schedule , Female , Guanidines/adverse effects , Guanidines/pharmacokinetics , Half-Life , Humans , Immunophenotyping , Kaplan-Meier Estimate , Male , Middle Aged , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Treatment Outcome , Viral Load
9.
Am J Health Syst Pharm ; 79(17): 1415-1423, 2022 08 19.
Article in English | MEDLINE | ID: covidwho-1860803

ABSTRACT

PURPOSE: This report calls attention to the potential risks of diminished kidney function when administering immune globulin (IG). The goal is to increase awareness of chronic kidney disease (CKD) and kidney function impairment in patients receiving IG and provide recommendations for screening, monitoring, and management to promote risk prevention and mitigation. SUMMARY: Human IG preparations for intravenous (IVIG) or subcutaneous (SCIG) administration are the mainstay of treatment in patients with primary immunodeficiency diseases. Increasingly, IVIG at high doses (1,000 to 2,400 mg/kg) is also used as a treatment for a variety of autoimmune and inflammatory conditions. Although some autoinflammatory disorders respond to a single course of IVIG therapy, the majority of patients require long-term, regular infusions, thereby increasing the overall risks. Often, both patients and physicians treating adults with IG are unaware of underlying CKD or kidney function impairment. This lack of awareness constitutes a major risk factor for potential worsening, particularly when using high doses of IVIG. Therefore, screening of all patients for CKD and kidney function impairment before the use of IG is essential. Identification of the cause of kidney impairment is strongly encouraged, as IG therapy may need to be modified. CONCLUSION: As detailed here, there are potential risks to patients with impaired kidney function with administration of IG, particularly at high doses. Product selection, volume, route of administration, and rate of infusion may impact those with compromised kidney function. Therefore, screening of all patients for CKD and kidney function impairment before the use of IVIG and SCIG, as well as ongoing monitoring and management, is critical. As with all potential adverse drug reactions, the best approach is to prevent them.


Subject(s)
Immunologic Deficiency Syndromes , Renal Insufficiency, Chronic , Administration, Intravenous , Adult , Humans , Immunoglobulin G/therapeutic use , Immunoglobulins, Intravenous/adverse effects , Immunologic Deficiency Syndromes/drug therapy , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/therapy
11.
Adv Ther ; 39(1): 178-192, 2022 01.
Article in English | MEDLINE | ID: covidwho-1813867

ABSTRACT

Since 1955, the only available H1 antihistamines for intravenous administration have been first-generation formulations and, of those, only intravenously administered (IV) diphenhydramine is still approved in the USA. Orally administered cetirizine hydrochloride, a second-generation H1 antihistamine, has been safely used over-the-counter for many years. In 2019, IV cetirizine was approved for the treatment of acute urticaria. In light of this approval, this narrative review discusses the changing landscape of IV antihistamines for the treatment of histamine-mediated conditions. Specifically, IV antihistamines will be discussed as a treatment option for acute urticaria and angioedema, as premedication to prevent infusion reactions related to anticancer agents and other biologics, and as an adjunct treatment for anaphylaxis and other allergic reactions. Before the development of IV cetirizine, randomized controlled trials of IV antihistamines for these indications were lacking. Three randomized controlled trials have been conducted with IV cetirizine versus IV diphenhydramine in the ambulatory care setting. A phase 3 trial of IV cetirizine 10 mg versus IV diphenhydramine 50 mg was conducted in 262 adults who presented to the urgent care/emergency department with acute urticaria requiring antihistamines. For the primary efficacy endpoint, defined as change from baseline in a 2-h patient-rated pruritus score, non-inferiority of IV cetirizine to IV diphenhydramine was demonstrated (score - 1.6 vs - 1.5, respectively; 95% CI - 0.1, 0.3). Compared with IV diphenhydramine, IV cetirizine demonstrated fewer adverse effects including less sedation, a significantly shorter length of stay in the treatment center, and fewer returns to the treatment center at 24 and 48 h. Similar findings were demonstrated in another phase 2 acute urticaria trial and in a phase 2 trial assessing IV cetirizine for pretreatment for infusion reactions in the oncology/immunology setting. IV cetirizine is associated with similar patient outcomes, fewer adverse effects, and increased treatment center efficiency than IV diphenhydramine.


Subject(s)
Cetirizine , Urticaria , Administration, Intravenous , Adult , Cetirizine/adverse effects , Diphenhydramine/adverse effects , Histamine H1 Antagonists/adverse effects , Humans , Urticaria/chemically induced , Urticaria/drug therapy
12.
Int J Pharm ; 620: 121739, 2022 May 25.
Article in English | MEDLINE | ID: covidwho-1783428

ABSTRACT

As remdesivir, the first FDA-approved drug for SARS-CoV-2 infection, can be used only for hospitalized patients due to intravenous administration, there is an urgent need of effective oral antiviral formulations to be used at early stage of infection in an outpatient setting. The present paper reports on the comparative pharmacokinetics of the electrospun nanofiber remdesivir/sulfobutyl ether beta-cyclodextrin formulation after intravenous and buccal administration. It was postulated that oral transmucosal administration avoids remdesivir from metabolic transformation and intact remdesivir can be detected in plasma, but only the active metabolite GS-441524 could be experimentally detected at a significantly lower plasma level, than that provided by the intravenous route. In buccally treated animals, the metabolite GS-441524 appeared only at 1 h after treatment, while in intravenously treated animals, GS-441524 was possible to quantify even at the first time-point of blood collection. Further optimization of formulation is required to improve pharmacokinetics of remdesivir-sulfobutyl ether beta-cyclodextrin formulation upon buccal administration.


Subject(s)
COVID-19 , SARS-CoV-2 , Adenosine Monophosphate/analogs & derivatives , Administration, Buccal , Administration, Intravenous , Alanine/analogs & derivatives , Animals , Antiviral Agents/pharmacokinetics , Biological Availability , COVID-19/drug therapy , Furans , Humans , Pyrroles , Rabbits , Triazines
13.
N Engl J Med ; 386(14): 1327-1338, 2022 04 07.
Article in English | MEDLINE | ID: covidwho-1778677

ABSTRACT

BACKGROUND: There is a need for oral antibiotic agents that are effective against multidrug-resistant gram-negative uropathogens. Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamase-producing and fluoroquinolone-resistant strains. METHODS: In this phase 3, international, double-blind, double-dummy trial, we evaluated the efficacy and safety of orally administered tebipenem pivoxil hydrobromide as compared with intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis. Patients were randomly assigned, in a 1:1 ratio, to receive oral tebipenem pivoxil hydrobromide (at a dose of 600 mg every 8 hours) or intravenous ertapenem (at a dose of 1 g every 24 hours) for 7 to 10 days (or up to 14 days in patients with bacteremia). The primary efficacy end point was overall response (a composite of clinical cure and favorable microbiologic response) at a test-of-cure visit (on day 19, within a ±2-day window) in the microbiologic intention-to-treat population. The noninferiority margin was 12.5%. RESULTS: A total of 1372 hospitalized adult patients were enrolled; 868 patients (63.3%) were included in the microbiologic intention-to-treat population (50.8% of whom had complicated urinary tract infections and 49.2% of whom had pyelonephritis). An overall response was seen in 264 of 449 patients (58.8%) who received tebipenem pivoxil hydrobromide, as compared with 258 of 419 patients (61.6%) who received ertapenem (weighted difference, -3.3 percentage points; 95% confidence interval [CI], -9.7 to 3.2). Clinical cure at the test-of-cure visit was observed in 93.1% of the patients in the microbiologic intention-to-treat population who received tebipenem pivoxil hydrobromide and 93.6% of patients who received ertapenem (weighted difference, -0.6 percentage point; 95% CI, -4.0 to 2.8); the majority of patients with microbiologic response failures at the test-of-cure visit were asymptomatic patients with recurrent bacteriuria. Secondary and subgroup analyses were supportive of the primary analysis. Adverse events were observed in 25.7% of patients who received tebipenem pivoxil hydrobromide and in 25.6% of patients who received ertapenem; the most common adverse events were mild diarrhea and headache. CONCLUSIONS: Oral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in the treatment of complicated urinary tract infection and acute pyelonephritis and had a similar safety profile. (Funded by Spero Therapeutics and the Department of Health and Human Services; ADAPT-PO ClinicalTrials.gov number, NCT03788967.).


Subject(s)
Anti-Bacterial Agents , Carbapenems , Pyelonephritis , Urinary Tract Infections , Administration, Intravenous , Administration, Oral , Adult , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/therapeutic use , Carbapenems/administration & dosage , Carbapenems/adverse effects , Carbapenems/therapeutic use , Double-Blind Method , Drug Resistance, Multiple, Bacterial , Ertapenem/administration & dosage , Ertapenem/adverse effects , Ertapenem/therapeutic use , Humans , Pyelonephritis/drug therapy , Urinary Tract Infections/drug therapy , Urinary Tract Infections/microbiology
14.
Am J Health Syst Pharm ; 79(13): 1047-1055, 2022 06 23.
Article in English | MEDLINE | ID: covidwho-1722209

ABSTRACT

PURPOSE: Prolonged duration of intravenous (IV) vasopressor dependence in critically ill adult patients with vasodilatory shock results in increased length of stay in both the intensive care unit (ICU) and hospital, translating to higher risk of infection, delirium, immobility, and cost. Acceleration of vasopressor liberation can aid in reducing these risks. Midodrine is an oral α 1-adrenergic receptor agonist that offers a potential means of liberating patients from IV vasopressor therapy. This clinical review summarizes primary literature and proposes a clinical application for midodrine in the recovery phase of vasodilatory shock. SUMMARY: Five studies with a total of over 1,000 patients conducted between 2011 and 2021 were identified. In observational studies, midodrine administration was demonstrated to lead to faster time to liberation from IV vasopressor therapy and shorter ICU length of stay in patients recovering from vasodilatory shock. These findings were not replicated in a prospective, multicenter, randomized controlled trial. In this review, literature evaluating midodrine use for IV vasopressor liberation is summarized and study limitations are discussed. CONCLUSION: On the basis of this review of current literature, recommendations are provided on selecting appropriate candidates for adjunctive midodrine in the recovery phase of vasodilatory shock and considerations are discussed for safely and effectively initiating, titrating, and discontinuing therapy.


Subject(s)
Hypotension , Midodrine , Administration, Intravenous , Adult , Humans , Hypotension/chemically induced , Intensive Care Units , Midodrine/adverse effects , Multicenter Studies as Topic , Prospective Studies , Randomized Controlled Trials as Topic , Vasoconstrictor Agents/adverse effects
15.
Int J Mol Sci ; 22(16)2021 Aug 13.
Article in English | MEDLINE | ID: covidwho-1662675

ABSTRACT

Iron oxide nanoparticles and single domain antibodies from camelids (VHHs) have been increasingly recognized for their potential uses for medical diagnosis and treatment. However, there have been relatively few detailed characterizations of their pharmacokinetics (PK). The aim of this study was to develop imaging methods and pharmacokinetic models to aid the future development of a novel family of brain MRI molecular contrast agents. An efficient near-infrared (NIR) imaging method was established to monitor VHH and VHH conjugated nanoparticle kinetics in mice using a hybrid approach: kinetics in blood were assessed by direct sampling, and kinetics in kidney, liver, and brain were assessed by serial in vivo NIR imaging. These studies were performed under "basal" circumstances in which the VHH constructs and VHH-conjugated nanoparticles do not substantially interact with targets nor cross the blood brain barrier. Using this approach, we constructed a five-compartment PK model that fits the data well for single VHHs, engineered VHH trimers, and iron oxide nanoparticles conjugated to VHH trimers. The establishment of the feasibility of these methods lays a foundation for future PK studies of candidate brain MRI molecular contrast agents.


Subject(s)
Camelids, New World/immunology , Kidney/chemistry , Liver/chemistry , Magnetic Iron Oxide Nanoparticles/chemistry , Single-Domain Antibodies/administration & dosage , Administration, Intravenous , Animals , Brain Chemistry , Female , Fluorometry , Humans , Mice , Models, Theoretical , Particle Size , Single-Domain Antibodies/blood , Single-Domain Antibodies/chemistry
16.
J Laryngol Otol ; 135(5): 442-447, 2021 May.
Article in English | MEDLINE | ID: covidwho-1637623

ABSTRACT

OBJECTIVE: To study the possible association between invasive fungal sinusitis (mucormycosis) and coronavirus disease. METHODS: A prospective observational study was conducted at a tertiary care centre over four months, involving all patients with mucormycosis of the paranasal sinuses suffering from or having a history of coronavirus disease infection. RESULTS: Twenty-three patients presented with mucormycosis, all had an association with coronavirus disease 2019. The ethmoids (100 per cent) were the most common sinuses affected. Intra-orbital extension was seen in 43.47 per cent of cases, while intracranial extension was only seen in 8.69 per cent. Diabetes mellitus was present in 21 of 23 cases, and was uncontrolled in 12 cases. All patients had a history of steroid use during their coronavirus treatment. CONCLUSION: New manifestations of coronavirus disease 2019 are appearing over time. The association between coronavirus and mucormycosis of the paranasal sinuses must be given serious consideration. Uncontrolled diabetes and over-zealous use of steroids are two main factors aggravating the illness, and both of these must be properly checked.


Subject(s)
COVID-19/microbiology , Mucorales/isolation & purification , Mucormycosis/microbiology , Paranasal Sinuses/microbiology , Administration, Intravenous , Antifungal Agents/administration & dosage , Antifungal Agents/therapeutic use , COVID-19/complications , COVID-19/diagnosis , COVID-19/virology , Diabetes Mellitus/epidemiology , Female , Humans , India/epidemiology , Invasive Fungal Infections/diagnosis , Invasive Fungal Infections/epidemiology , Invasive Fungal Infections/microbiology , Magnetic Resonance Imaging/methods , Male , Middle Aged , Mucorales/drug effects , Mucormycosis/diagnosis , Mucormycosis/drug therapy , Mucormycosis/etiology , Pandemics , Paranasal Sinuses/diagnostic imaging , Prospective Studies , SARS-CoV-2 , Sinusitis/diagnosis , Sinusitis/microbiology , Steroids/adverse effects , Steroids/therapeutic use
17.
Respir Res ; 22(1): 317, 2021 Dec 22.
Article in English | MEDLINE | ID: covidwho-1633846

ABSTRACT

BACKGROUND: Data on the safety and efficacy profile of tocilizumab in patients with severe COVID-19 needs to be enriched. METHODS: In this open label, prospective study, we evaluated clinical outcomes in consecutive patients with COVID-19 and PaO2/FiO2 < 200 receiving tocilizumab plus usual care versus usual care alone. Tocilizumab was administered at the time point that PaO2/FiO2 < 200 was observed. The primary outcome was 28-day mortality. Secondary outcomes included time to discharge, change in PaO2/FiO2 at day 5 and change in WHO progression scale at day 10. FINDINGS: Overall, 114 patients were included in the analysis (tocilizumab plus usual care: 56, usual care: 58). Allocation to usual care was associated with significant increase in 28-day mortality compared to tocilizumab plus usual care [Cox proportional-hazards model: HR: 3.34, (95% CI: 1.21-9.30), (p = 0.02)]. There was not a statistically significant difference with regards to hospital discharge over the 28 day period for patients receiving tocilizumab compared to usual care [11.0 days (95% CI: 9.0 to 16.0) vs 14.0 days (95% CI: 10.0-24.0), HR: 1.32 (95% CI: 0.84-2.08), p = 0.21]. ΔPaO2/FiO2 at day 5 was significantly higher in the tocilizumab group compared to the usual care group [42.0 (95% CI: 23.0-84.7) vs 15.8 (95% CI: - 19.4-50.3), p = 0.03]. ΔWHO scale at day 10 was significantly lower in the tocilizumab group compared to the usual care group (-0.5 ± 2.1 vs 0.6 ± 2.6, p = 0.005). CONCLUSION: Administration of tocilizumab, at the time point that PaO2/FiO2 < 200 was observed, improved survival and other clinical outcomes in hospitalized patients with severe COVID-19 irrespective of systemic inflammatory markers levels.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19/drug therapy , COVID-19/mortality , Hospitalization/trends , Patient Acuity , Administration, Intravenous , Aged , COVID-19/diagnosis , Female , Humans , Male , Middle Aged , Prospective Studies , Survival Rate/trends
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