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1.
Lancet ; 397(10285): 1637-1645, 2021 May 01.
Article in English | MEDLINE | ID: covidwho-1655260

ABSTRACT

BACKGROUND: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. METHODS: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg-800 mg (depending on weight) given intravenously. A second dose could be given 12-24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76-0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12-1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77-0·92; p<0·0001). INTERPRETATION: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. FUNDING: UK Research and Innovation (Medical Research Council) and National Institute of Health Research.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19/drug therapy , COVID-19/therapy , Hypoxia/therapy , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/complications , COVID-19/diagnosis , COVID-19/mortality , Female , Hospital Mortality , Hospitalization , Humans , Hypoxia/diagnosis , Hypoxia/virology , Male , Middle Aged , Respiration, Artificial/statistics & numerical data , SARS-CoV-2/isolation & purification , Severity of Illness Index , Treatment Outcome , Young Adult
2.
Lancet Respir Med ; 9(5): 511-521, 2021 05.
Article in English | MEDLINE | ID: covidwho-1537197

ABSTRACT

BACKGROUND: Global randomised controlled trials of the anti-IL-6 receptor antibody tocilizumab in patients admitted to hospital with COVID-19 have shown conflicting results but potential decreases in time to discharge and burden on intensive care. Tocilizumab reduced progression to mechanical ventilation and death in a trial population enriched for racial and ethnic minorities. We aimed to investigate whether tocilizumab treatment could prevent COVID-19 progression in the first multicentre randomised controlled trial of tocilizumab done entirely in a lower-middle-income country. METHODS: COVINTOC is an open-label, multicentre, randomised, controlled, phase 3 trial done at 12 public and private hospitals across India. Adults (aged ≥18 years) admitted to hospital with moderate to severe COVID-19 (Indian Ministry of Health grading) confirmed by positive SARS-CoV-2 PCR result were randomly assigned (1:1 block randomisation) to receive tocilizumab 6 mg/kg plus standard care (the tocilizumab group) or standard care alone (the standard care group). The primary endpoint was progression of COVID-19 (from moderate to severe or from severe to death) up to day 14 in the modified intention-to-treat population of all participants who had at least one post-baseline assessment for the primary endpoint. Safety was assessed in all randomly assigned patients. The trial is completed and registered with the Clinical Trials Registry India (CTRI/2020/05/025369). FINDINGS: 180 patients were recruited between May 30, 2020, and Aug 31, 2020, and randomly assigned to the tocilizumab group (n=90) or the standard care group (n=90). One patient randomly assigned to the standard care group inadvertently received tocilizumab at baseline and was included in the tocilizumab group for all analyses. One patient randomly assigned to the standard care group withdrew consent after the baseline visit and did not receive any study medication and was not included in the modified intention-to-treat population but was still included in safety analyses. 75 (82%) of 91 in the tocilizumab group and 68 (76%) of 89 in the standard care group completed 28 days of follow-up. Progression of COVID-19 up to day 14 occurred in eight (9%) of 91 patients in the tocilizumab group and 11 (13%) of 88 in the standard care group (difference -3·71 [95% CI -18·23 to 11·19]; p=0·42). 33 (36%) of 91 patients in the tocilizumab group and 22 (25%) of 89 patients in the standard care group had adverse events; 18 (20%) and 15 (17%) had serious adverse events. The most common adverse event was acute respiratory distress syndrome, reported in seven (8%) patients in each group. Grade 3 adverse events were reported in two (2%) patients in the tocilizumab group and five (6%) patients in the standard care group. There were no grade 4 adverse events. Serious adverse events were reported in 18 (20%) patients in the tocilizumab group and 15 (17%) in the standard care group; 13 (14%) and 15 (17%) patients died during the study. INTERPRETATION: Routine use of tocilizumab in patients admitted to hospital with moderate to severe COVID-19 is not supported. However, post-hoc evidence from this study suggests tocilizumab might still be effective in patients with severe COVID-19 and so should be investigated further in future studies. FUNDING: Medanta Institute of Education and Research, Roche India, Cipla India, and Action COVID-19 India.


Subject(s)
Antibodies, Monoclonal, Humanized , COVID-19 , Cytokine Release Syndrome , Receptors, Interleukin-6/antagonists & inhibitors , Respiratory Distress Syndrome , SARS-CoV-2/isolation & purification , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/complications , COVID-19/immunology , COVID-19/mortality , COVID-19/therapy , Critical Care/methods , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Drug Monitoring/methods , Female , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , India , Male , Middle Aged , Mortality , Respiration, Artificial/methods , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/etiology , Severity of Illness Index , Treatment Outcome
3.
Infect Control Hosp Epidemiol ; : 1-4, 2021 May 14.
Article in English | MEDLINE | ID: covidwho-1428666

ABSTRACT

We evaluated adverse drug events (ADEs) by chart review in a random national sample of 428 veterans with coronavirus disease 2019 (COVID-19) who received tocilizumab (n = 173 of 428). ADEs (median time, 5 days) occurred in 51 of 173 (29%) and included hepatoxicity (n = 29) and infection (n = 13). Concomitant medication discontinuation occurred in 22% of ADE patients; mortality was 39%.

4.
Rev Esp Geriatr Gerontol ; 55(5): 286-288, 2020.
Article in Spanish | MEDLINE | ID: covidwho-1386531

ABSTRACT

INTRODUCTION: Cytokine storm syndrome (CTS) is a serious complication of patients with SARS-CoV-2 infection. Treatment and evolution in octogenarians are not well defined. Our objective is to describe its clinical characteristics, the treatments and its clinical evolution. PATIENTS AND METHOD: Retrospective observational study of consecutive patients admitted in the period between March 23 and April 12, 2020 with confirmed SARS-CoV-2 infection, with pneumonia by radiological study or chest tomography, whith STC criteria and who received treatment. We classified patients as those who received only glucocorticoid (GC) pulses, or GC and tocilizumab pulses. We determined serum levels of ferritin, CRP and D-dimers. The final variable was survival. RESULTS: 21 patients, (80-88 years). The mean ferritin was 1056 microg/L (317-3,553), CRP 115.8mg/dL (22-306) and D-dimers 2.9m/L (0.45-17.5). All patients received GC pulses and in 2 cases simultaneously tocilizumab. The mean follow-up time was 13.7 days (8-21). The overall mortality was 38.1% (8/21 patients). The 2 patients who received tocilizumab died. The deceased had significantly higher levels of ferritin (1,254 vs. 925microg/L; P=.045) and CRP (197.6 vs. 76mg / dL; P=.007). At the end of the follow-up, a decrease in the biochemical parameters was observed with ferritin of 727microg/L, CRP of 27mg/dl and D-dimers of 1.18mg/L. In 13/21 patients (61.9%), the CTS was controlled without the need to add other treatments. CONCLUSIONS: STC mortality from SARS-CoV-2 is high despite treatment. A greater inflammatory response was associated with a higher mortality. Although it seems that the early use of GC pulses could control it, and the use of other treatments such as tocilizumab shouldo be, with the study design and its limitations, this conclusion cannot be stablished.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Coronavirus Infections/complications , Coronavirus Infections/immunology , Cytokines/immunology , Glucocorticoids/therapeutic use , Immunoproliferative Disorders/drug therapy , Immunoproliferative Disorders/virology , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Aged, 80 and over , COVID-19 , Female , Humans , Male , Pandemics , Retrospective Studies , Syndrome
5.
Rev Esp Quimioter ; 34(4): 337-341, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1317435

ABSTRACT

OBJECTIVE: The study aims to describe characteristics and clinical outcome of patients with SARS-CoV-2 infection that received siltuximab according to a protocol that aimed to early block the activity of IL-6 to avoid the progression of the inflammatory flare. METHODS: Retrospective review of the first 31 patients with SARS-CoV-2 treated with siltuximab, in Hospital Clinic of Barcelona or Hospital Universitario Salamanca, from March to April 2020 with positive polymerase-chain reaction (PCR) from a nasopharyngeal swab. RESULTS: The cohort included 31 cases that received siltuximab with a median (IQR) age of 62 (56-71) and 71% were males. The most frequent comorbidity was hypertension (48%). The median dose of siltuximab was 800 mg ranging between 785 and 900 mg. 7 patients received siltuximab as a salvage therapy after one dose of tocilizumab. At the end of the study, a total of 26 (83.9) patients had been discharged alive and the mortality rate was 16.1% but only 1 out of 24 that received siltuximab as a first line option (4%). CONCLUSIONS: Siltuximab is a well-tolerated alternative to tocilizumab when administered as a first line option in patients with COVID-19 pneumonia within the first 10 days from symptoms onset and high C-reactive protein.


Subject(s)
Antibodies, Monoclonal/therapeutic use , COVID-19/drug therapy , Aged , Antibodies, Monoclonal, Humanized/therapeutic use , C-Reactive Protein/analysis , COVID-19/mortality , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Disease Progression , Female , Humans , Hypertension/complications , Interleukin-6/antagonists & inhibitors , Interleukin-6/blood , Male , Middle Aged , Retrospective Studies , Salvage Therapy , Treatment Outcome
6.
Int J Biol Sci ; 17(8): 2124-2134, 2021.
Article in English | MEDLINE | ID: covidwho-1271048

ABSTRACT

The efficacy of tocilizumab on the prognosis of severe/critical COVID-19 patients is still controversial so far. We aimed to delineate the inflammation characteristics of severe/critical COVID-19 patients and determine the impact of tocilizumab on hospital mortality. Here, we performed a retrospective cohort study which enrolled 727 severe or critical inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Huoshenshan Hospital (Wuhan, China), among which 50 patients received tocilizumab. This study confirmed that most recovered patients manifested relatively normal inflammation levels at admission, whereas most of the deceased cases presented visibly severe inflammation at admission and even progressed into extremely aggravated inflammation before their deaths, proved by some extremely high concentrations of interleukin-6, procalcitonin, C-reactive protein and neutrophil count. Moreover, based on the Cox proportional-hazards models before or after propensity score matching, we demonstrated that tocilizumab treatment could lessen mortality by gradually alleviating excessive inflammation and meanwhile continuously enhancing the levels of lymphocytes within 14 days for severe/critical COVID-19 patients, indicating potential effectiveness for treating COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Inflammation/drug therapy , SARS-CoV-2 , Aged , Aged, 80 and over , C-Reactive Protein/analysis , COVID-19/blood , COVID-19/mortality , COVID-19/physiopathology , Comorbidity , Female , Humans , Inflammation/blood , Interleukin-6/blood , Length of Stay/statistics & numerical data , Leukocyte Count , Male , Middle Aged , Neutrophils , Procalcitonin/blood , Propensity Score , Proportional Hazards Models , Retrospective Studies
7.
Open Access Emerg Med ; 13: 207-211, 2021.
Article in English | MEDLINE | ID: covidwho-1256176

ABSTRACT

BACKGROUND: Anticoagulant therapy for patients with severe coronavirus disease (COVID-19) pneumonia is considered to improve the hypercoagulable and inflammatory state. However, bleeding complications should also be considered. CASE PRESENTATION: A 77-year-old man with a history of falls was diagnosed with COVID-19. Owing to his severe condition, he was intubated and transferred to our hospital for intensive care. Favipiravir, tocilizumab, unfractionated heparin, and ART-123 were administered to treat COVID-19 and manage the antithrombotic prophylaxis for paroxysmal atrial fibrillation (Af). On the 6th day after admission, a hematoma was noted on the left chest wall. Computed tomography (CT) revealed multiple hematomas, including hematomas on his chest wall and obturatorius internus muscle. Emergency angiography transcatheter embolization (TAE) was performed. The patient was transferred to another hospital 23 days after TAE, without complications. CONCLUSION: Our findings show that anticoagulation therapy and a history of falls induced multiple hematomas in a COVID-19 patient and that the condition was managed with TAE. When anticoagulants are considered in the management of Af and COVID-19 associated coagulopathy, it is necessary to closely monitor potential bleeding complications.

8.
Lung ; 199(3): 239-248, 2021 06.
Article in English | MEDLINE | ID: covidwho-1245631

ABSTRACT

BACKGROUND: To date, only dexamethasone has been shown to reduce mortality in coronavirus disease-19 (COVID-19) patients. Tocilizumab has been recently added to the treatment guidelines for hospitalized COVID-19 patients, but data remain conflicting. STUDY DESIGN AND METHODS: Electronic databases such as MEDLINE, EMBASE, and Cochrane central were searched from March 1, 2020, until March 10, 2021, for randomized controlled trials evaluating the efficacy of tocilizumab in hospitalized COVID-19 patients. The outcomes assessed were all-cause mortality, mechanical ventilation, and time to discharge. RESULTS: Nine studies (with 6490 patients) were included in the analysis. In total, 3358 patients received tocilizumab, and 3132 received standard care/placebo. Pooled analysis showed a significantly decreased risk of all-cause mortality (RR 0.89, 95% CI 0.80-0.98, p = 0.02) and progression to mechanical ventilation (RR 0.80, 95% CI 0.71-0.89, p < 0.0001) in the tocilizumab arm compared to standard therapy or placebo. In addition, there was a trend towards improved median time to hospital discharge (RR 1.28, 95% CI 1.12-1.45, p = 0.0002). CONCLUSIONS: Tocilizumab therapy improves outcomes of mortality and need for mechanical ventilation, in hospitalized patients with COVID-19 infection compared with standard therapy or placebo. Our findings suggest the efficacy of tocilizumab therapy in hospitalized COVID-19 patients and strengthen the concept that tocilizumab is a promising therapeutic intervention to improve mortality and morbidity in COVID-19 patients.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , COVID-19 , Receptors, Interleukin-6/antagonists & inhibitors , COVID-19/drug therapy , COVID-19/immunology , COVID-19/mortality , Humans , Immunologic Factors/pharmacology , Outcome Assessment, Health Care , SARS-CoV-2
9.
Future Virol ; 2021 May.
Article in English | MEDLINE | ID: covidwho-1244946

ABSTRACT

Aim: Coronavirus disease 2019 is a life-threatening disease and how to improve survival of the patients is of great importance. Objective: To determine whether tocilizumab (TCZ) shows favorable results in coronavirus disease 2019 patients. Materials & methods: A retrospective study of four patients who received TCZ was conducted from 19 February to 31 March 2020 at Leishenshan Hospital, Wuhan, China. Clinical data of patients were compared before and after the administration of the agent. Results: There was not much difference in the clinical feature improvements and computed tomography images after TCZ administration in two mild patients. The other two severe patients died of disseminated intravascular coagulation and acute respiratory distress syndrome, respectively. Conclusion: Administration of TCZ was not shown a favorable outcome in this preliminary uncontrolled case series.

10.
Biomark Med ; 15(8): 541-549, 2021 06.
Article in English | MEDLINE | ID: covidwho-1229135

ABSTRACT

Aim: COVID-19 pandemic continues and dearth of information remains considering the utility of various inflammatory biomarkers. We carried out the present study to delineate the roles of these biomarkers in various strata of patients with coronavirus infection. Materials & methods: A retrospective study was carried out after obtaining approval from the relevant Ethics Committee. Patients established with COVID-19 infection as shown by positive real-time quantitative PCR test were included. Details on their demographics, diagnosis, whether they received tocilizumab, and the values of the following biomarkers were obtained: IL-6, C-reactive protein (CRP), serum ferritin, D-dimer, procalcitonin, fibrinogen, lactate dehydrogenase and creatinine kinase. Receiver operating characteristic curves were plotted and correlation of biomarkers with IL-6 were estimated. Results: One-hundred and three patients were recruited. We observed that serum ferritin followed by D-dimer had better predictive accuracy in identifying patients with pneumonia compared with asymptomatic; and CRP in addition to the earlier markers had better accuracy for predicting severe illness compared with mild-moderate. Serum IL-6 levels were significantly higher in patients with severe illness admitted in intensive care unit. Significantly, higher levels of IL-6 and serum ferritin were observed in patients receiving tocilizumab. A trend of increased IL-6 levels was observed immediately following the initiation of tocilizumab therapy followed by a drop thereafter. Conclusion: We observed serum ferritin, D-dimer and CRP to accurately predict patients developing severe COVID-19 infections as well as those at risk of developing COVID pneumonia. A trend in IL-6 levels was observed in patients on tocilizumab therapy.


Subject(s)
Biomarkers/blood , C-Reactive Protein/analysis , COVID-19 Testing , COVID-19/diagnosis , Fibrin Fibrinogen Degradation Products/analysis , Procalcitonin/blood , SARS-CoV-2/isolation & purification , Bahrain/epidemiology , COVID-19/blood , COVID-19/epidemiology , COVID-19/virology , Female , Hospitalization , Humans , Inflammation Mediators/blood , Male , Middle Aged , ROC Curve , Retrospective Studies , Severity of Illness Index
11.
J Infect Chemother ; 27(9): 1329-1335, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1225294

ABSTRACT

BACKGROUND: Cytokine release syndrome (CRS), characterized by overproduction of proinflammatory cytokines in the course of severe coronavirus disease 2019 (COVID-19), has been suggested as the major cause of mortality. Tocilizumab, a recombinant humanized monoclonal antibody against human IL-6 receptor, poses a therapeutic option for the treatment of CRS leading to severe acute respiratory syndrome in coronavirus-2 (SARS-CoV-2) infection. METHODS: We performed a single-center retrospective study to reveal the outcome of COVID-19 patients on tocilizumab and proposed "the Cerrahpasa-PREDICT score", a new clinical scoring system using clinical and laboratory parameters that would help predicting the 28-day mortality of COVID-19 patients receiving tocilizumab. RESULTS: Eighty-seven patients (median age: 59 years) were included of whom 75.8% were male. Tocilizumab use significantly improved clinical and laboratory parameters. The 28-day mortality rate on tocilizumab was 16.1%. The Cerrahpasa-PREDICT score, consisting of platelet counts, procalcitonin, D-dimer levels, SO2R and the time from symptom onset to tocilizumab administration had a positive predictive value of 94.5% and negative predictive value of 92.9% for anticipating 28-day mortality. CONCLUSIONS: Severe COVID-19 should closely be monitored for the signs of hyperinflammation. We showed that administration of tocilizumab early in the course of the disease (prior to ICU admission) resulted in a favorable outcome. Close monitoring usually aids identifying patients who would benefit from tocilizumab. In this regard, the Cerrahpasa-PREDICT score might serve as a practical tool for estimating the 28-day mortality in COVID-19 patients who received tocilizumab and would facilitate timely recognition of fatal cases to be evaluated for other therapeutic options.


Subject(s)
COVID-19 , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , Humans , Male , Middle Aged , Retrospective Studies , SARS-CoV-2 , Treatment Outcome
12.
J Med Virol ; 93(4): 2270-2280, 2021 04.
Article in English | MEDLINE | ID: covidwho-1217379

ABSTRACT

Coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 causes substantial morbidity. Tocilizumab, an interleukin-6 receptor antagonist, might improve outcomes by mitigating inflammation. We conducted a retrospective study of patients admitted to the University of Washington Hospital system with COVID-19 and requiring supplemental oxygen. Outcomes included clinical improvement, defined as a two-point reduction in severity on a six-point ordinal scale or discharge, and mortality within 28 days. We used Cox proportional-hazards models with propensity score inverse probability weighting to compare outcomes in patients who did and did not receive tocilizumab. We evaluated 43 patients who received tocilizumab and 45 who did not. Patients receiving tocilizumab were younger with fewer comorbidities but higher baseline oxygen requirements. Tocilizumab treatment was associated with reduced C-reactive protein, fibrinogen, and temperature, but there were no meaningful differences in time to clinical improvement (adjusted hazard ratio [aHR], 0.92; 95% confidence interval [CI], 0.38-2.22) or mortality (aHR, 0.57; 95% CI, 0.21-1.52). A numerically higher proportion of tocilizumab-treated patients had subsequent infections, transaminitis, and cytopenias. Tocilizumab did not improve outcomes in hospitalized patients with COVID-19. However, this study was not powered to detect small differences, and there remains the possibility for a survival benefit.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19/drug therapy , Aged , C-Reactive Protein/metabolism , COVID-19/metabolism , COVID-19/mortality , COVID-19/virology , Female , Fibrinogen/metabolism , Hospitalization , Humans , Immunomodulation , Inflammation/drug therapy , Inflammation Mediators/metabolism , Male , Middle Aged , Receptors, Interleukin-6/metabolism , Retrospective Studies , SARS-CoV-2/drug effects , Treatment Outcome
13.
Medicine (Baltimore) ; 100(18): e25832, 2021 May 07.
Article in English | MEDLINE | ID: covidwho-1216697

ABSTRACT

ABSTRACT: Tocilizumab (TCZ), a monoclonal recombinant antibody against IL-6 receptor, is currently used in managing the cytokine release syndrome (CRS) that occurred in coronavirus disease 2019 (COVID-19) selected cases. The primary objective of our study was to establish the effectiveness of TCZ in patients with severe or critical severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pneumonia.We retrospectively analyzed 25 consecutive patients, admitted in the Academic Emergency Hospital Sibiu, Romania from April 1, 2020 until May 25, 2020, all with confirmed SARS-CoV-2 infection and severe pneumonia. All patients were treated off-label with TCZ, beside their standard care. Adjuvant iron chelator was associated in 11 patients.Six female and 19 male patients admitted in our hospital all with confirmed SARS-CoV-2 infection and severe pneumonia as defined by Chinese Centers for Disease Control and Prevention were enrolled in this study. Seventeen of the 25 enrolled patients (68%) were seriously ill requiring noninvasive ventilation or oxygen mask, and 8 cases (32%) were critically ill requiring invasive mechanical ventilation. All patients received TCZ, and also received hydroxychloroquine, and lopinavir/ritonavir 200/50 mg for 10 days. Adjuvant iron chelator (deferasirox - marketed as Exjade) was associated in 11 patients who had ferritin serum levels above 1000 ng/mL. No side effects were encountered during infusions or after TCZ. We observed a rapid increase in arterial oxygen saturation for 20 of the 25 cases (80%) with a favorable evolution toward healing. Survivors were younger than 60 years old (80%), had less comorbidities (10% no comorbidities, 70% with 1 or 2 comorbidities), lower serum ferritin levels (30% under 1000 ng/mL), and 50% had no serum glucose elevation. Our patients with CRS had no response to corticosteroid therapy. Five out of the 25 patients had an unfavorable evolution to death. The off-label use of TCZ in patients with severe or critically ill form of SARS-CoV-2 infection had good results in our study.Off-label use of TCZ in severe and critical cases of COVID-19 pneumonia is effective in managing the "cytokine storm." Better outcomes were noted in younger patients. Associated adjuvant iron chelators may contribute to a good outcome and needs to be confirmed in larger studies.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Deferasirox/therapeutic use , Iron Chelating Agents/therapeutic use , Pneumonia, Viral/drug therapy , Adult , Aged , Aged, 80 and over , Comorbidity , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Off-Label Use , Pneumonia, Viral/virology , Respiration, Artificial , Retrospective Studies , Romania , SARS-CoV-2
14.
J Med Virol ; 93(2): 831-842, 2021 02.
Article in English | MEDLINE | ID: covidwho-1206798

ABSTRACT

Coronavirus disease 2019 (COVID-19) can lead to a massive cytokine release. The use of the anti-interleukin-6 receptor monoclonal antibody tocilizumab (TCZ) has been proposed in this hyperinflammatory phase, although supporting evidence is limited. We retrospectively analyzed 88 consecutive patients with COVID-19 pneumonia that received at least one dose of intravenous TCZ in our institution between 16 and 27 March 2020. Clinical status from day 0 (first TCZ dose) through day 14 was assessed by a 6-point ordinal scale. The primary outcome was clinical improvement (hospital discharge and/or a decrease of ≥2 points on the 6-point scale) by day 7. Secondary outcomes included clinical improvement by day 14 and dynamics of vital signs and laboratory values. Rates of clinical improvement by days 7 and 14 were 44.3% (39/88) and 73.9% (65/88). Previous or concomitant receipt of subcutaneous interferon-ß (adjusted odds ratio [aOR]: 0.23; 95% confidence interval [CI]: 0.06-0.94; P = .041) and serum lactate dehydrogenase more than 450 U/L at day 0 (aOR: 0.25; 95% CI: 0.06-0.99; P = .048) were negatively associated with clinical improvement by day 7. All-cause mortality was 6.8% (6/88). Body temperature and respiratory and cardiac rates significantly decreased by day 1 compared to day 0. Lymphocyte count and pulse oximetry oxygen saturation/FiO2 ratio increased by days 3 and 5, whereas C-reactive protein levels dropped by day 2. There were no TCZ-attributable adverse events. In this observational single-center study, TCZ appeared to be useful and safe as immunomodulatory therapy for severe COVID-19 pneumonia.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/prevention & control , Immunologic Factors/therapeutic use , SARS-CoV-2/pathogenicity , Administration, Intravenous , Adult , Body Temperature/drug effects , C-Reactive Protein/metabolism , COVID-19/immunology , COVID-19/mortality , COVID-19/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/virology , Female , Heart Rate/drug effects , Humans , Interferon-beta/adverse effects , L-Lactate Dehydrogenase/blood , Male , Middle Aged , Receptors, Interleukin-6/antagonists & inhibitors , Receptors, Interleukin-6/genetics , Receptors, Interleukin-6/immunology , Respiratory Rate/drug effects , Retrospective Studies , SARS-CoV-2/immunology , Severity of Illness Index , Survival Analysis
15.
J Med Virol ; 93(2): 1023-1028, 2021 02.
Article in English | MEDLINE | ID: covidwho-1196468

ABSTRACT

BACKGROUND: We sought to evaluate the effect of tocilizumab (TCB), a recombinant humanized monoclonal antibody against soluble interleukin-6 receptors, in patients hospitalized for coronavirus disease 2019 (COVID-19). METHODS: We included all patients with laboratory-confirmed COVID-19 who had completed hospitalization between March 10, 2020 and April 10, 2020 with follow-up through April 20, 2020. Patients who received TCB in addition to standard of care within 48 h of admission were matched in a 1:2 fashion to a similar cohort who received standard of care alone. Clinical outcomes were compared between matched groups. The primary outcome was de-escalation in oxygen therapy. Secondary outcomes were in-hospital death, septic shock, and acute kidney injury (AKI) requiring hemodialysis. RESULTS: Out of 77 patients who received TCB in addition to standard of care, 34% (n = 26) received TCB within 48 h of admission. One-to-two propensity matching identified 20 versus 40 patients in the TCB and no-TCB treatment arms. In the TCB group, an improvement in oxygenation was observed in 80% (n = 16) of the patients by 7 days post TCB administration. After matching, there was no difference in clinical outcomes between TCB and no-TCB patients. In-hospital death: 10% versus 8%; p = .823, septic shock: 10% versus 11%, p = .912, AKI requiring hemodialysis (10% vs. 13%; p = .734). CONCLUSIONS: Early treatment with TCB in patients admitted for COVID-19 led to an improvement in their oxygen status during hospitalization. This change however did not translate into improved survival when compared to a matched cohort with a similar clinical profile.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/complications , COVID-19/therapy , Hospitalization/statistics & numerical data , Acute Kidney Injury/virology , Adult , Aged , Female , Hospital Mortality , Humans , Male , Middle Aged , Oxygen/metabolism , Receptors, Interleukin-6/antagonists & inhibitors , Renal Dialysis , Retrospective Studies , Shock, Septic/virology , Time Factors , Treatment Outcome , United States
16.
J Med Virol ; 93(3): 1459-1464, 2021 03.
Article in English | MEDLINE | ID: covidwho-1196452

ABSTRACT

BACKGROUND: Tocilizumab (TCZ) has been used in the management of COVID-19-related cytokine release syndrome (CRS). Concerns exist regarding the risk of infections and drug-related toxicities. We sought to evaluate the incidence of these TCZ complications among COVID-19 patients. METHODS: All adult inpatients with COVID-19 between 1 March and 25 April 2020 that received TCZ were included. We compared the rate of late-onset infections (>48 hours following admission) to a control group matched according to intensive care unit admission and mechanical ventilation requirement. Post-TCZ toxicities evaluated included: elevated liver function tests (LFTs), GI perforation, diverticulitis, neutropenia, hypertension, allergic reactions, and infusion-related reactions. RESULTS: Seventy-four patients were included in each group. Seventeen infections in the TCZ group (23%) and 6 (8%) infections in the control group occurred >48 hours after admission (P = .013). Most infections were bacterial with pneumonia being the most common manifestation. Among patients receiving TCZ, LFT elevations were observed in 51%, neutropenia in 1.4%, and hypertension in 8%. The mortality rate among those that received TCZ was greater than the control (39% versus 23%, P = .03). CONCLUSION: Late onset infections were significantly more common among those receiving TCZ. Combining infections and TCZ-related toxicities, 61% of patients had a possible post-TCZ complication. While awaiting clinical trial results to establish the efficacy of TCZ for COVID-19 related CRS, the potential for infections and TCZ related toxicities should be carefully weighed when considering use.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Bacterial Infections/complications , COVID-19/complications , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Mycoses/complications , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Biomarkers, Pharmacological/blood , COVID-19/mortality , Cytokine Release Syndrome/virology , Female , Humans , Inpatients , Male , Middle Aged , Retrospective Studies
17.
J Clin Neurosci ; 88: 108-112, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1174389

ABSTRACT

The novel human coronavirus disease (COVID-19) has been associated with vascular and thrombotic complications, some of which may result from endothelial dysfunction, including the posterior reversible encephalopathy syndrome (PRES). We report a case series of 8 patients with COVID-19 and PRES diagnosed at two academic medical centers between March and July of 2020. The clinical, laboratory and radiographic data, treatment, and short-term outcomes were retrospectively analyzed. The mean age was 57.9 ± 12 years, and 50% were women. Four patients had previous vascular comorbidities. All the patients suffered from severe pneumonia, requiring intensive care unit admission. Five patients were not hypertensive at presentation (all SBP < 127 mmHg). Neurologic symptoms included seizures in 7 patients; impaired consciousness in 5 patients; focal neurological signs in 3 patients; and visual disturbances in 1 patient. All patients underwent brain magnetic resonance imaging which indicated asymmetric T2 prolongation or diffusion changes (50%), extensive fronto-parieto-occipital involvement (25%), vascular irregularities (12.5%) and intracranial hemorrhage (25%). Four patients were treated with tocilizumab. Three patients were discharged without neurologic disability, 2 patients had persistent focal neurologic deficits and 2 expired. One patient's prognosis remains guarded. Together, these data support the relationship between PRES and endothelial dysfunction associated with severe COVID-19. In patients with severe COVID-19, PRES can be triggered by uncontrolled hypertension, or occur independently in the setting of systemic illness and certain medications. Like other infectious processes, critically ill patients with COVID-19 may be at greater risk of PRES because of impaired vasoreactivity or the use of novel agents like Tocilizumab.


Subject(s)
COVID-19/complications , Posterior Leukoencephalopathy Syndrome/etiology , Adult , Aged , Brain/diagnostic imaging , Comorbidity , Consciousness Disorders/etiology , Critical Care/statistics & numerical data , Critical Illness , Cytokine Release Syndrome/epidemiology , Cytokine Release Syndrome/etiology , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Nervous System Diseases/epidemiology , Nervous System Diseases/etiology , Pneumonia/etiology , Pneumonia/therapy , Retrospective Studies , Seizures/etiology , Vision Disorders/etiology
18.
Rev Esp Quimioter ; 34(3): 238-244, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1173137

ABSTRACT

OBJECTIVE: In some patients the immune response triggered by SARS-CoV-2 is unbalanced, presenting an acute respiratory distress syndrome which in many cases requires intensive care unit (ICU) admission. The limitation of ICU beds has been one of the major burdens in the management around the world; therefore, clinical strategies to avoid ICU admission are needed. We aimed to describe the influence of tocilizumab on the need of transfer to ICU or death in non-critically ill patients. METHODS: A retrospective study of 171 patients with SARS-CoV-2 infection that did not qualify as requiring transfer to ICU during the first 24h after admission to a conventional ward, were included. The criteria to receive tocilizumab was radiological impairment, oxygen demand or an increasing of inflammatory parameters, however, the ultimate decision was left to the attending physician judgement. The primary outcome was the need of ICU admission or death whichever came first. RESULTS: A total of 77 patients received tocilizumab and 94 did not. The tocilizumab group had less ICU admissions (10.3% vs. 27.6%, P=0.005) and need of invasive ventilation (0 vs 13.8%, P=0.001). In the multivariable analysis, tocilizumab remained as a protective variable (OR: 0.03, CI 95%: 0.007-0.1, P=0.0001) of ICU admission or death. CONCLUSIONS: Tocilizumab in early stages of the inflammatory flare could reduce an important number of ICU admissions and mechanical ventilation. The mortality rate of 10.3% among patients receiving tocilizumab appears to be lower than other reports. This is a non-randomized study and the results should be interpreted with caution.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/mortality , Hospitalization/statistics & numerical data , Intensive Care Units/statistics & numerical data , Bed Occupancy , COVID-19/immunology , Female , Humans , Male , Middle Aged , Respiration, Artificial/statistics & numerical data , Retrospective Studies , SARS-CoV-2
19.
PLoS One ; 16(4): e0249349, 2021.
Article in English | MEDLINE | ID: covidwho-1172877

ABSTRACT

BACKGROUND: Tocilizumab, an interleukin-6 receptor blocker, has been used in the inflammatory phase of COVID-19, but its impact independent of corticosteroids remains unclear in patients with severe disease. METHODS: In this retrospective analysis of patients with COVID-19 admitted between March 2 and April 14, 2020 to a large academic medical center in New York City, we describe outcomes associated with tocilizumab 400 mg (without methylprednisolone) compared to a propensity-matched control. The primary endpoints were change in a 7-point ordinal scale of oxygenation and ventilator free survival, both at days 14 and 28. Secondary endpoints include incidence of bacterial superinfections and gastrointestinal perforation. Primary outcomes were evaluated using t-test. RESULTS: We identified 33 patients who received tocilizumab and matched 74 controls based on demographics and health measures upon admission. After adjusting for illness severity and baseline ordinal scale, we failed to find evidence of an improvement in hypoxemia based on an ordinal scale at hospital day 14 in the tocilizumab group (OR 2.2; 95% CI, 0.7-6.5; p = 0.157) or day 28 (OR 1.1; 95% CI, 0.4-3.6; p = 0.82). There also was no evidence of an improvement in ventilator-free survival at day 14 (OR 0.8; 95% CI, 0.18-3.5; p = 0.75) or day 28 (OR 1.1; 95% CI, 0.1-1.8; p = 0.23). There was no increase in secondary bacterial infection rates in the tocilizumab group compared to controls (OR 0.37; 95% CI, 0.09-1.53; p = 0.168). CONCLUSIONS: There was no evidence to support an improvement in hypoxemia or ventilator-free survival with use of tocilizumab 400 mg in the absence of corticosteroids. No increase in secondary bacterial infections was observed in the group receiving tocilizumab.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Bacterial Infections , COVID-19 , Disease Outbreaks , Hospitals, Teaching , SARS-CoV-2 , Antibodies, Monoclonal, Humanized/adverse effects , Bacterial Infections/etiology , Bacterial Infections/mortality , COVID-19/drug therapy , COVID-19/mortality , Disease-Free Survival , Female , Humans , Male , Middle Aged , New York City/epidemiology , Respiration, Artificial , Retrospective Studies , Survival Rate
20.
Crit Care Explor ; 3(4): e0395, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1168636

ABSTRACT

To identify the most efficacious timing for tocilizumab administration in critically ill patients infected with severe acute respiratory syndrome coronavirus-2. DESIGN: Observational multicenter cohort study. SETTING: A total of 23 acute care hospitals in four states. PATIENTS: One-hundred eighteen patients admitted between March 13, 2020, and April 16, 2020. Eighty-one patients received tocilizumab, and 37 were untreated and served as a control group. MEASUREMENTS AND MAIN RESULTS: The main outcome was mortality and was analyzed by timing of tocilizumab dosing. Early dosing was defined as a tocilizumab dose administered prior to or within 1 day of intubation. Late dosing was defined as a dose administered greater than 1 day after intubation. A control group that was treated only with standard of care, and without tocilizumab, was used for comparison. Early tocilizumab therapy was associated with a statistically significant decrease in mortality as compared to patients who were untreated (p = 0.003). Dosing tocilizumab late was associated with an increased mortality compared with the untreated group (p = 0.006). CONCLUSIONS: Early tocilizumab administration was associated with decreased mortality in critically ill severe acute respiratory syndrome coronavirus-2 patients, but a potential detriment was suggested by dosing later in a patient's course.

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