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Alkhunaizi L, Almutairi JA, Almanea SH, Alzahuf SM, Fehaid M, Alharthi A, Alhebs T, Alshuqayfi SM, Alotaibi R, Alharbi M, Abdalwahab ZE, Aloqaybi A, Talebi SH, Kharaba AM. Impact of Corticosteroid Therapy on ICU Patient Outcomes in Severe COVID-19 Cases: A Retrospective Cohort Study in Saudi Arabia. Cureus 2024; 16:e53412. [PMID: 38435152 PMCID: PMC10908548 DOI: 10.7759/cureus.53412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2024] [Indexed: 03/05/2024] Open
Abstract
BACKGROUND The COVID-19 pandemic has presented significant challenges in clinical management, and intensive care units (ICUs) worldwide have become epicenters of high-stakes treatment decisions. Among these, corticosteroid therapy has risen as a pivotal, yet controversial, treatment modality. In Saudi Arabia, where unique demographic and health system characteristics intersect, understanding the specific effects of corticosteroids on ICU patient outcomes is not just critical but a pressing necessity in tailoring effective COVID-19 management strategies. OBJECTIVE This study aims to elucidate the effects of corticosteroid therapy on the outcomes of severe COVID-19 patients in Saudi Arabian ICUs, providing critical insights into treatment efficacy and guiding future clinical practices. MATERIALS AND METHODS In this cohort study, we meticulously reviewed the medical records of 1085 severe COVID-19 patients admitted to Saudi Arabian ICUs. Our analysis focused on demographic details, ICU outcomes, and the extent and implications of corticosteroid therapy. The study employed comprehensive methods for data collection, evaluation criteria, and statistical analysis, ensuring a thorough understanding of the impact of corticosteroids in this context. RESULTS The study encompassed 1085 patients, predominantly male (74.5%, N=806), with an average age of 56 and a mean BMI of 30.07. A significant portion (72.3%, N=784) received corticosteroid therapy. These patients generally experienced longer ICU (mean 23 days) and hospital stays (mean 16 days), along with higher rates of microbiological cure (72.3%, N=648) and increased ICU discharge likelihood. Conversely, corticosteroid recipients showed higher mortality rates at ICU discharge. The statistical analysis confirmed the significance of these findings, reinforcing their importance in managing COVID-19 in ICUs. CONCLUSION The research highlights the intricate dynamics of corticosteroid use in treating severe COVID-19 cases in ICUs. While associated with prolonged ICU stays and increased mortality, corticosteroids also correlate with higher microbiological cure rates and discharge likelihood. These insights call for careful deliberation in applying corticosteroid therapy, with implications for enhancing clinical protocols and guiding future research in severe COVID-19 treatment.
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Affiliation(s)
- Lama Alkhunaizi
- College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, SAU
| | | | - Sarah H Almanea
- Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, SAU
| | | | - Mohammed Fehaid
- Neurology, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
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Vera-Lastra O, Ordinola Navarro A, Medina G, Cruz-Domínguez MP, Jara LJ. The effect of COVID-19 on patients with preexisting autoimmune diseases. AUTOIMMUNITY, COVID-19, POST-COVID19 SYNDROME AND COVID-19 VACCINATION 2023:495-528. [DOI: 10.1016/b978-0-443-18566-3.00001-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Sarri G, Bennett D, Debray T, Deruaz‐Luyet A, Soriano Gabarró M, Largent JA, Li X, Liu W, Lund JL, Moga DC, Gokhale M, Rentsch CT, Wen X, Yanover C, Ye Y, Yun H, Zullo AR, Lin KJ. ISPE-Endorsed Guidance in Using Electronic Health Records for Comparative Effectiveness Research in COVID-19: Opportunities and Trade-Offs. Clin Pharmacol Ther 2022; 112:990-999. [PMID: 35170021 PMCID: PMC9087010 DOI: 10.1002/cpt.2560] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 02/02/2022] [Indexed: 11/08/2022]
Abstract
As the scientific research community along with healthcare professionals and decision makers around the world fight tirelessly against the coronavirus disease 2019 (COVID-19) pandemic, the need for comparative effectiveness research (CER) on preventive and therapeutic interventions for COVID-19 is immense. Randomized controlled trials markedly under-represent the frail and complex patients seen in routine care, and they do not typically have data on long-term treatment effects. The increasing availability of electronic health records (EHRs) for clinical research offers the opportunity to generate timely real-world evidence reflective of routine care for optimal management of COVID-19. However, there are many potential threats to the validity of CER based on EHR data that are not originally generated for research purposes. To ensure unbiased and robust results, we need high-quality healthcare databases, rigorous study designs, and proper implementation of appropriate statistical methods. We aimed to describe opportunities and challenges in EHR-based CER for COVID-19-related questions and to introduce best practices in pharmacoepidemiology to minimize potential biases. We structured our discussion into the following topics: (1) study population identification based on exposure status; (2) ascertainment of outcomes; (3) common biases and potential solutions; and (iv) data operational challenges specific to COVID-19 CER using EHRs. We provide structured guidance for the proper conduct and appraisal of drug and vaccine effectiveness and safety research using EHR data for the pandemic. This paper is endorsed by the International Society for Pharmacoepidemiology (ISPE).
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Affiliation(s)
| | - Dimitri Bennett
- Takeda Global Evidence and OutcomesTakeda Pharmaceuticals USA, IncCambridgeMassachusettsUSA
- Center for Clinical Epidemiology and BiostatisticsPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Thomas Debray
- Julius Center for Health Sciences and Primary CareUniversity Medical Centre UtrechtUtrechtThe Netherlands
- Smart Data Analysis and StatisticsUtrechtThe Netherlands
| | - Anouk Deruaz‐Luyet
- Global Epidemiology and Real‐World Evidence CoECorporate Medical AffairsBoehringer Ingelheim International GmbHIngelheim‐am‐RheinGermany
| | - Montse Soriano Gabarró
- Bayer Partnerships and Integrated Evidence Generation OfficeIntegrated Evidence Generation & Business InnovationMedical Affairs & PharmacovigilanceBayer AGBerlinGermany
| | | | - Xiaojuan Li
- Department of Population MedicineHarvard Medical School and Harvard Pilgrim Health Care InstituteBostonMassachusettsUSA
| | - Wei Liu
- Division of EpidemiologyOffice of Surveillance and EpidemiologyCenter for Drug Evaluation and Research, Food and Drug AdministrationSilver SpringMarylandUSA
| | - Jennifer L. Lund
- Department of EpidemiologyGillings School of Global Public HealthUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Daniela C. Moga
- Department of Pharmacy Practice and ScienceCollege of PharmacyUniversity of KentuckyLexingtonKentuckyUSA
| | - Mugdha Gokhale
- Department of EpidemiologyGillings School of Global Public HealthUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of EpidemiologyMerckWest PointPennsylvaniaUSA
| | - Christopher T. Rentsch
- Faculty of Epidemiology and Population HealthDepartment of Non‐communicable Disease EpidemiologyLondon School of Hygiene & Tropical MedicineLondonUK
- Department of Internal MedicineYale School of MedicineNew HavenConnecticutUSA
| | - Xuerong Wen
- Health OutcomesPharmacy PracticeCollege of PharmacyUniversity of Rhode IslandKinstonRhode IslandUSA
| | | | - Yizhou Ye
- Global Epidemiology, Pharmacovigilance and Patient SafetyAbbVie IncNorth ChicagoIllinoisUSA
| | - Huifeng Yun
- Department of EpidemiologyUniversity of Alabama at BirminghamBirminghamAlabamaUSA
| | - Andrew R. Zullo
- Department of Health Services, Policy, and PracticeBrown University School of Public HealthProvidenceRhode IslandUSA
- Department of EpidemiologyBrown University School of Public HealthProvidenceRhode IslandUSA
- Center of Innovation in Long‐Term Services and SupportsProvidence Veterans Affairs Medical CenterProvidenceRhode IslandUSA
- Department of PharmacyLifespan‐Rhode Island HospitalProvidenceRhode IslandUSA
| | - Kueiyu Joshua Lin
- Brigham and Women’s Hospital and Harvard Medical SchoolBostonMassachusettsUSA
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Arias M, Oliveros H, Lechtig S, Bustos RH. Biologics in COVID-19 So Far: Systematic Review. Pharmaceuticals (Basel) 2022; 15:ph15070783. [PMID: 35890081 PMCID: PMC9321859 DOI: 10.3390/ph15070783] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/07/2022] [Accepted: 06/10/2022] [Indexed: 12/17/2022] Open
Abstract
This systematic review aimed to reevaluate the available evidence of the use of biologics as treatment candidates for the treatment of severe and advanced COVID-19 disease; what are the rationale for their use, which are the most studied, and what kind of efficacy measures are described? A search through Cochrane, Embase, Pubmed, Medline, medrxiv.org, and Google scholar was performed on the use of biologic interventions in COVID-19/SARS-CoV-2 infection, viral pneumonia, and sepsis, until 11 January 2022. Throughout the research, we identified 4821 records, of which 90 were selected for qualitative analysis. Amongst the results, we identified five popular targets of use: IL6 and IL1 inhibitors, interferons, mesenchymal stem cells treatment, and anti-spike antibodies. None of them offered conclusive evidence of their efficacy with consistency and statistical significance except for some studies with anti-spike antibodies; however, Il6 and IL1 inhibitors as well as interferons show encouraging data in terms of increased survival and favorable clinical course that require further studies with better methodology standardization.
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Affiliation(s)
- Milton Arias
- Department of Clinical Pharmacology, Evidence-Based Therapeutics Group, Faculty of Medicine, Universidad de La Sabana and Clínica Universidad de La Sabana, Autopista Norte de Bogotá, Chía 140013, Colombia; (M.A.); (S.L.)
| | - Henry Oliveros
- Department of Epidemiology, Health Research Group, Faculty of Medicine, Universidad de La Sabana, Campus del Puente del Común, Km. 7, Autopista Norte de Bogotá, Chía 140013, Colombia;
| | - Sharon Lechtig
- Department of Clinical Pharmacology, Evidence-Based Therapeutics Group, Faculty of Medicine, Universidad de La Sabana and Clínica Universidad de La Sabana, Autopista Norte de Bogotá, Chía 140013, Colombia; (M.A.); (S.L.)
| | - Rosa-Helena Bustos
- Department of Clinical Pharmacology, Evidence-Based Therapeutics Group, Faculty of Medicine, Universidad de La Sabana and Clínica Universidad de La Sabana, Autopista Norte de Bogotá, Chía 140013, Colombia; (M.A.); (S.L.)
- Correspondence: ; Tel.: +57-1608615555
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Chauvineau-Grenier A, Bastard P, Casanova JL, Rossi B. Autoantibodies Neutralizing Type I INFs May Be Associated with Efficacy of Tocilizumab in COVID-19 Pneumonia. J Clin Immunol 2022; 42:1107-1110. [PMID: 35676568 PMCID: PMC9177133 DOI: 10.1007/s10875-022-01295-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 05/24/2022] [Indexed: 11/24/2022]
Affiliation(s)
| | - Paul Bastard
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.,University of Paris, Imagine Institute, Paris, France.,St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.,University of Paris, Imagine Institute, Paris, France.,St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.,Howard Hughes Medical Institute, New York, NY, USA
| | - Benjamin Rossi
- Department of Internal Medicine, Robert Ballanger Hospital, Aulnay-Sous-Bois, France
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Piscoya A, Parra del Riego A, Cerna-Viacava R, Rocco J, Roman YM, Escobedo AA, Pasupuleti V, White CM, Hernandez AV. Efficacy and harms of tocilizumab for the treatment of COVID-19 patients: A systematic review and meta-analysis. PLoS One 2022; 17:e0269368. [PMID: 35657993 PMCID: PMC9165853 DOI: 10.1371/journal.pone.0269368] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 05/19/2022] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION We systematically assessed benefits and harms of tocilizumab (TCZ), which is an antibody blocking IL-6 receptors, in hospitalized COVID-19 patients. METHODS Five electronic databases and two preprint webpages were searched until March 4, 2021. Randomized controlled trials (RCTs) and inverse probability treatment weighting (IPTW) cohorts assessing TCZ effects in hospitalized, COVID-19 adult patients were included. Primary outcomes were all-cause mortality, clinical worsening, clinical improvement, need for mechanical ventilation, and adverse events (AE). Inverse variance random-effects meta-analyses were performed with quality of evidence (QoE) evaluated using GRADE methodology. RESULTS Nine RCTs (n = 7,021) and nine IPTW cohorts (n = 7,796) were included. TCZ significantly reduced all-cause mortality in RCTs (RR 0.89, 95%CI 0.81-0.98, p = 0.03; moderate QoE) and non-significantly in cohorts (RR 0.67, 95%CI 0.44-1.02, p = 0.08; very low QoE) vs. control (standard of care [SOC] or placebo). TCZ significantly reduced the need for mechanical ventilation (RR 0.80, 95%CI 0.71-0.90, p = 0.001; moderate QoE) and length of stay (MD -1.92 days, 95%CI -3.46 to -0.38, p = 0.01; low QoE) vs. control in RCTs. There was no significant difference in clinical improvement or worsening between treatments. AEs, severe AEs, bleeding and thrombotic events were similar between arms in RCTs, but there was higher neutropenia risk with TCZ (very low QoE). Subgroup analyses by disease severity or risk of bias (RoB) were consistent with main analyses. Quality of evidence was moderate to very low in both RCTs and cohorts. CONCLUSIONS In comparison to SOC or placebo, TCZ reduced all-cause mortality in all studies and reduced mechanical ventilation and length of stay in RCTs in hospitalized COVID-19 patients. Other clinical outcomes were not significantly impacted. TCZ did not have effect on AEs, except a significant increased neutropenia risk in RCTs. TCZ has a potential role in the treatment of hospitalized COVID-19 patients.
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Affiliation(s)
- Alejandro Piscoya
- Unidad de Revisiones Sistemáticas y Meta-análisis (URSIGET), Universidad San Ignacio de Loyola (USIL), Lima, Peru
- Hospital Guillermo Kaelin de La Fuente, Lima, Peru
| | | | - Renato Cerna-Viacava
- Escuela de Medicina, Universidad Peruana de Ciencias Aplicadas (UPC), Lima, Peru
- Department of Medicine, Henry Ford Hospital, Detroit, Michigan, United States of America
| | - Jonathon Rocco
- Health Outcomes, Policy, and Evidence Synthesis (HOPES) Group, University of Connecticut School of Pharmacy, Storrs, Connecticut, United States of America
| | - Yuani M. Roman
- Health Outcomes, Policy, and Evidence Synthesis (HOPES) Group, University of Connecticut School of Pharmacy, Storrs, Connecticut, United States of America
| | - Angel A. Escobedo
- Epidemiology Unit, National Institute of Gastroenterology, La Habana, Cuba
| | | | - C. Michael White
- Health Outcomes, Policy, and Evidence Synthesis (HOPES) Group, University of Connecticut School of Pharmacy, Storrs, Connecticut, United States of America
| | - Adrian V. Hernandez
- Unidad de Revisiones Sistemáticas y Meta-análisis (URSIGET), Universidad San Ignacio de Loyola (USIL), Lima, Peru
- Health Outcomes, Policy, and Evidence Synthesis (HOPES) Group, University of Connecticut School of Pharmacy, Storrs, Connecticut, United States of America
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Chauvineau-Grenier A, Bastard P, Servajean A, Gervais A, Rosain J, Jouanguy E, Cobat A, Casanova JL, Rossi B. Autoantibodies Neutralizing Type I Interferons in 20% of COVID-19 Deaths in a French Hospital. J Clin Immunol 2022; 42:459-470. [PMID: 35083626 PMCID: PMC8791677 DOI: 10.1007/s10875-021-01203-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 12/19/2021] [Indexed: 01/08/2023]
Abstract
Recent studies reported the presence of pre-existing autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) in at least 15% of patients with critical COVID-19 pneumonia. In one study, these auto-Abs were found in almost 20% of deceased patients across all ages. We aimed to assess the prevalence and clinical impact of the auto-Abs to type I IFNs in the Seine-Saint-Denis district, which was one of the most affected areas by COVID-19 in France during the first wave. We tested for the presence of auto-Abs neutralizing type I IFNs in a cohort of patients admitted for critical COVID-19 pneumonia during the first wave in the spring of 2020 in the medicine departments at Robert Ballanger Hospital, Aulnay sous Bois. We found circulating auto-Abs that neutralized 100 pg/mL IFN-α2 and/or IFN-ω in the plasma (diluted 1/10) of 7.9% (11 of 139) of the patients hospitalized for critical COVID-19. The presence of neutralizing auto-Abs was associated with an increased risk of mortality, as these auto-Abs were detected in 21% of patients who died from COVID-19 pneumonia. Deceased patients with and without auto-Abs did not present overt clinical differences. These results confirm both the importance of type I IFN immunity in host defense against SARS-CoV-2 infection and the usefulness of detection of auto-Abs neutralizing type I IFNs in the management of patients.
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Affiliation(s)
| | - Paul Bastard
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Antoine Servajean
- University of Paris, UFR de Médecine, site Xavier Bichat, Paris, France
| | - Adrian Gervais
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Jérémie Rosain
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, Imagine Institute, Paris, France
| | - Emmanuelle Jouanguy
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- University of Paris, UFR de Médecine, site Xavier Bichat, Paris, France
| | - Aurélie Cobat
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
- Howard Hughes Medical Institute, New York, NY, USA
| | - Benjamin Rossi
- Department of Internal Medicine, Robert Ballanger Hospital, Aulnay-Sous-Bois, France
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Rubio‐Rivas M, Forero CG, Mora‐Luján JM, Montero A, Formiga F, Homs NA, Albà‐Albalate J, Sánchez L, Rello J, Corbella X. Beneficial and harmful outcomes of tocilizumab in severe COVID-19: A systematic review and meta-analysis. Pharmacotherapy 2021; 41:884-906. [PMID: 34558742 PMCID: PMC8661749 DOI: 10.1002/phar.2627] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 09/05/2021] [Accepted: 09/07/2021] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The results of studies of tocilizumab (TCZ) in COVID-19 are contradictory. Our study aims to update medical evidence from controlled observational studies and randomized clinical trials (RCTs) on the use of TCZ in hospitalized patients with COVID-19. METHODS We searched the following databases from January 1, 2020 to April 13, 2021 (date of the last search): MEDLINE database through the PubMed search engine and Scopus, using the terms ("COVID-19" [Supplementary Concept]) AND "tocilizumab" [Supplementary Concept]). RESULTS Sixty four studies were included in the present study: 54 were controlled observational studies (50 retrospective and 4 prospective) and 10 were RCTs. The overall results provided data from 20,616 hospitalized patients with COVID-19: 7668 patients received TCZ in addition to standard of care (SOC) (including 1915 patients admitted to intensive care units (ICU) with reported mortality) and 12,948 patients only receiving SOC (including 4410 patients admitted to the ICU with reported mortality). After applying the random-effects model, the hospital-wide (including ICU) pooled mortality odds ratio (OR) of patients with COVID-19 treated with TCZ was 0.73 (95% confidence interval (CI) = 0.56-0.93). The pooled hospital-wide mortality OR was 1.25 (95% CI = 0.74-2.18) in patients admitted at conventional wards versus 0.66 (95% CI = 0.59-0.76) in patients admitted to the ICU. The pooled OR of hospital-wide mortality (including ICU) of COVID-19 patients treated with TCZ plus corticosteroids (CS) was 0.67 (95% CI = 0.54-0.84). The pooled in-hospital mortality OR was 0.71 (95% CI = 0.35-1.42) when TCZ was early administered (≤10 days from symptom onset) versus 0.83 (95% CI 0.48-1.45) for late administration (>10 days from symptom onset). The meta-analysis did not find significantly higher risk for secondary infections in COVID-19 patients treated with TCZ. CONCLUSIONS TCZ prevented mortality in patients hospitalized for COVID-19. This benefit was seen to a greater extent in patients receiving concomitant CS and when TCZ administration occurred within the first 10 days after symptom onset.
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Affiliation(s)
- Manuel Rubio‐Rivas
- Department of Internal MedicineBellvitge University HospitalBellvitge Biomedical Research Institute‐IDIBELLUniversity of BarcelonaBarcelonaSpain
| | - Carlos G. Forero
- School of MedicineUniversitat Internacional de CatalunyaBarcelonaSpain
| | - José María Mora‐Luján
- Department of Internal MedicineBellvitge University HospitalBellvitge Biomedical Research Institute‐IDIBELLUniversity of BarcelonaBarcelonaSpain
| | - Abelardo Montero
- Department of Internal MedicineBellvitge University HospitalBellvitge Biomedical Research Institute‐IDIBELLUniversity of BarcelonaBarcelonaSpain
| | - Francesc Formiga
- Department of Internal MedicineBellvitge University HospitalBellvitge Biomedical Research Institute‐IDIBELLUniversity of BarcelonaBarcelonaSpain
| | - Narcís A. Homs
- Department of Internal MedicineBellvitge University HospitalBellvitge Biomedical Research Institute‐IDIBELLUniversity of BarcelonaBarcelonaSpain
| | - Joan Albà‐Albalate
- Department of Internal MedicineBellvitge University HospitalBellvitge Biomedical Research Institute‐IDIBELLUniversity of BarcelonaBarcelonaSpain
| | - Laura Sánchez
- Department of Internal MedicineBellvitge University HospitalBellvitge Biomedical Research Institute‐IDIBELLUniversity of BarcelonaBarcelonaSpain
| | - Jordi Rello
- School of MedicineUniversitat Internacional de CatalunyaBarcelonaSpain
- Centro de Investigación Biomédica en Red (CIBERES)Instituto de Salud Carlos IIIMadridSpain
- CRIPSVall d’Hebrón Institute of ResearchBarcelonaSpain
| | - Xavier Corbella
- Department of Internal MedicineBellvitge University HospitalBellvitge Biomedical Research Institute‐IDIBELLUniversity of BarcelonaBarcelonaSpain
- School of MedicineUniversitat Internacional de CatalunyaBarcelonaSpain
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Kyriakopoulos C, Ntritsos G, Gogali A, Milionis H, Evangelou E, Kostikas K. Tocilizumab administration for the treatment of hospitalized patients with COVID-19: A systematic review and meta-analysis. Respirology 2021; 26:1027-1040. [PMID: 34605114 PMCID: PMC8661720 DOI: 10.1111/resp.14152] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 08/26/2021] [Accepted: 09/07/2021] [Indexed: 12/15/2022]
Abstract
Tocilizumab has been repurposed against the ‘cytokine storm’ in the setting of coronavirus disease 2019 (COVID‐19). Our aim was to evaluate the efficacy of tocilizumab in the management of hospitalized COVID‐19 patients. We searched MEDLINE, CENTRAL and medRxiv for studies of tocilizumab in hospitalized COVID‐19 patients. Primary objective was the effectiveness of tocilizumab on mortality. Secondary objectives included the need for invasive mechanical ventilation (IMV), composite endpoints of mortality or IMV and intensive care unit (ICU) admission or IMV, length of hospitalization and differences in mortality in subgroups (ICU and non‐ICU patients and patients receiving or not receiving concomitant corticosteroids). We included 52 studies (nine randomized controlled trials [RCTs] and 43 observational) with a total of 27,004 patients. In both RCTs and observational studies, the use of tocilizumab was associated with a reduction in mortality; 11% in RCTs (risk ratio [RR] 0.89, 95% CI 0.82 to 0.96) and 31% in observational studies (RR 0.69, 95% CI 0.58 to 0.83). The need for IMV was reduced by 19% in RCTs (RR 0.81, 95% CI 0.71 to 0.93), while no significant reduction was observed in observational studies. Both RCTs and observational studies showed a benefit from tocilizumab on the composite endpoint of mortality or IMV. Tocilizumab improved mortality both in ICU and non‐ICU patients. Reduction in mortality was evident in observational studies regardless of the use of systemic corticosteroids, while that was not the case in the RCTs. Tocilizumab was associated with lower mortality and other clinically relevant outcomes in hospitalized patients with moderate‐to‐critical COVID‐19.
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Affiliation(s)
- Christos Kyriakopoulos
- Respiratory Medicine Department, University of Ioannina Faculty of Medicine, Ioannina, Greece
| | - Georgios Ntritsos
- Department of Hygiene and Epidemiology, University of Ioannina Faculty of Medicine, Ioannina, Greece
| | - Athena Gogali
- Respiratory Medicine Department, University of Ioannina Faculty of Medicine, Ioannina, Greece
| | - Haralampos Milionis
- Internal Medicine Department, University of Ioannina Faculty of Medicine, Ioannina, Greece
| | - Evangelos Evangelou
- Department of Hygiene and Epidemiology, University of Ioannina Faculty of Medicine, Ioannina, Greece
| | - Konstantinos Kostikas
- Respiratory Medicine Department, University of Ioannina Faculty of Medicine, Ioannina, Greece
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Chauvineau-Grenier A, Bastard P, Servajean A, Gervais A, Rosain J, Jouanguy E, Cobat A, Casanova JL, Rossi B. Autoantibodies neutralizing type I interferons in 20% of COVID-19 deaths in a French hospital. RESEARCH SQUARE 2021. [PMID: 34611657 PMCID: PMC8491850 DOI: 10.21203/rs.3.rs-915062/v1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Recent studies reported the presence of pre-existing autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) in at least 15% of patients with critical or severe COVID-19 pneumonia. In one study, these auto-Abs were found in almost 20% of deceased patients across all ages. We aimed to assess the prevalence and clinical impact of the auto-Abs to type I IFNs in Seine-Saint-Denis district, which was one of the most affected areas by COVID-19 in France during the first wave. We tested for the presence of auto-Abs neutralizing type I IFNs in a cohort of patients admitted for critical COVID-19 pneumonia during the first wave in the spring of 2020 in medicine departments at Robert Ballanger Hospital, Aulnay sous Bois. We found circulating auto-Abs that neutralized 100 pg/mL IFN-α2 and/or IFN-ω in plasma 1/10 in 7.9% (11 of 139) of patients hospitalized for critical COVID-19. The presence of neutralizing auto-Abs was associated with an increased risk of mortality as these auto-Abs were detected in 21% of patients who died from COVID-19 pneumonia. Deceased patients with and without auto-Abs did not present overt clinical differences. These results confirm both the importance of IFN-I immunity in host defense against SARS-CoV-2 infection and the usefulness of detection of auto-Abs neutralizing type I IFNs in the management of patients.
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Russo G, Solimini A, Zuccalà P, Zingaropoli MA, Carraro A, Pasculli P, Perri V, Marocco R, Kertusha B, Del Borgo C, Del Giudice E, Fondaco L, Tieghi T, D’Agostino C, Oliva A, Vullo V, Ciardi MR, Mastroianni CM, Lichtner M. Real-life use of tocilizumab with or without corticosteroid in hospitalized patients with moderate-to-severe COVID-19 pneumonia: A retrospective cohort study. PLoS One 2021; 16:e0257376. [PMID: 34506608 PMCID: PMC8432821 DOI: 10.1371/journal.pone.0257376] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 08/31/2021] [Indexed: 12/15/2022] Open
Abstract
Objective To evaluate the effectiveness of Tocilizumab (with or without corticosteroids) in a real-life context among moderate-to-severe COVID-19 patients hospitalized at the Infectious Diseases ward of two hospitals in Lazio region, Italy, during the first wave of SARS-CoV-2 pandemic. Method We conducted a retrospective cohort study among moderate-to-severe COVID-19 pneumonia to assess the influence of tocilizumab (with or without corticosteroids) on: 1) primary composite outcome: risk for death/invasive mechanical ventilation/ICU-transfer at 14 days from hospital admission; 2) secondary outcome: COVID-related death only. Both outcomes were also assessed at 28 days and restricted to baseline more severe cases. We also evaluated the safety of tocilizumab. Results Overall, 412 patients were recruited, being affected by mild (6.8%), moderate (66.3%) or severe (26.9%) COVID-19 at baseline. The median participant’ age was 63 years, 56.5% were men, the sum of comorbidities was 1.34 (±1.44), and the median time from symptom onset to hospital admission was 7 [3–10] days. Patients were subdivided in 4 treatment groups: standard of care (SoC) only (n = 172), SoC plus corticosteroid (n = 65), SoC plus tocilizumab (n = 50), SoC plus tocilizumab and corticosteroid (n = 125). Twenty-six (6.3%) patients underwent intubation, and 37 (9%) COVID-related deaths were recorded. After adjusting for several factors, multivariate analysis showed that tocilizumab (with or without corticosteroids) was associated to improved primary and secondary outcomes at 14 days, and at 28-days only when tocilizumab administered without corticosteroid. Among more severe cases the protective effect of tocilizumab (± corticosteroids) was observed at both time-points. No safety concerns were recorded. Conclusion Although contrasting results from randomized clinical trials to date, in our experience tocilizumab was a safe and efficacious therapeutic option for patients with moderate-to-severe COVID-19 pneumonia. Its efficacy was improved by the concomitant administration of corticosteroids in patients affected by severe-COVID-19 pneumonia at baseline.
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Affiliation(s)
- Gianluca Russo
- Department of Public Health and Infectious Diseases, Policlinico Umberto 1 Hospital, Sapienza University of Rome, Rome, Italy
- * E-mail:
| | - Angelo Solimini
- Department of Public Health and Infectious Diseases, Policlinico Umberto 1 Hospital, Sapienza University of Rome, Rome, Italy
| | - Paola Zuccalà
- Infectious Diseases Unit, S. Maria Goretti Hospital/Sapienza University of Rome, Latina, Italy
| | - Maria Antonella Zingaropoli
- Department of Public Health and Infectious Diseases, Policlinico Umberto 1 Hospital, Sapienza University of Rome, Rome, Italy
| | - Anna Carraro
- Infectious Diseases Unit, S. Maria Goretti Hospital/Sapienza University of Rome, Latina, Italy
| | - Patrizia Pasculli
- Department of Public Health and Infectious Diseases, Policlinico Umberto 1 Hospital, Sapienza University of Rome, Rome, Italy
| | - Valentina Perri
- Department of Public Health and Infectious Diseases, Policlinico Umberto 1 Hospital, Sapienza University of Rome, Rome, Italy
| | - Raffaella Marocco
- Infectious Diseases Unit, S. Maria Goretti Hospital/Sapienza University of Rome, Latina, Italy
| | - Blerta Kertusha
- Infectious Diseases Unit, S. Maria Goretti Hospital/Sapienza University of Rome, Latina, Italy
| | - Cosmo Del Borgo
- Infectious Diseases Unit, S. Maria Goretti Hospital/Sapienza University of Rome, Latina, Italy
| | - Emanuela Del Giudice
- Infectious Diseases Unit, S. Maria Goretti Hospital/Sapienza University of Rome, Latina, Italy
| | - Laura Fondaco
- Infectious Diseases Unit, S. Maria Goretti Hospital/Sapienza University of Rome, Latina, Italy
| | - Tiziana Tieghi
- Infectious Diseases Unit, S. Maria Goretti Hospital/Sapienza University of Rome, Latina, Italy
| | - Claudia D’Agostino
- Department of Public Health and Infectious Diseases, Policlinico Umberto 1 Hospital, Sapienza University of Rome, Rome, Italy
| | - Alessandra Oliva
- Department of Public Health and Infectious Diseases, Policlinico Umberto 1 Hospital, Sapienza University of Rome, Rome, Italy
| | - Vincenzo Vullo
- Department of Public Health and Infectious Diseases, Policlinico Umberto 1 Hospital, Sapienza University of Rome, Rome, Italy
| | - Maria Rosa Ciardi
- Department of Public Health and Infectious Diseases, Policlinico Umberto 1 Hospital, Sapienza University of Rome, Rome, Italy
| | - Claudio Maria Mastroianni
- Department of Public Health and Infectious Diseases, Policlinico Umberto 1 Hospital, Sapienza University of Rome, Rome, Italy
| | - Miriam Lichtner
- Department of Public Health and Infectious Diseases, Policlinico Umberto 1 Hospital, Sapienza University of Rome, Rome, Italy
- Infectious Diseases Unit, S. Maria Goretti Hospital/Sapienza University of Rome, Latina, Italy
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12
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Khan FA, Stewart I, Fabbri L, Moss S, Robinson K, Smyth AR, Jenkins G. Systematic review and meta-analysis of anakinra, sarilumab, siltuximab and tocilizumab for COVID-19. Thorax 2021; 76:907-919. [PMID: 33579777 PMCID: PMC7886668 DOI: 10.1136/thoraxjnl-2020-215266] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 01/10/2021] [Accepted: 01/21/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND There is accumulating evidence for an overly activated immune response in severe COVID-19, with several studies exploring the therapeutic role of immunomodulation. Through systematic review and meta-analysis, we assess the effectiveness of specific interleukin inhibitors for the treatment of COVID-19. METHODS Electronic databases were searched on 7 January 2021 to identify studies of immunomodulatory agents (anakinra, sarilumab, siltuximab and tocilizumab) for the treatment of COVID-19. The primary outcomes were severity on an Ordinal Scale measured at day 15 from intervention and days to hospital discharge. Key secondary endpoints included overall mortality. RESULTS 71 studies totalling 22 058 patients were included, 6 were randomised trials. Most studies explored outcomes in patients who received tocilizumab (60/71). In prospective studies, tocilizumab was associated with improved unadjusted survival (risk ratio 0.83, 95% CI 0.72 to 0.96, I2=0.0%), but conclusive benefit was not demonstrated for other outcomes. In retrospective studies, tocilizumab was associated with less severe outcomes on an Ordinal Scale (generalised OR 1.34, 95% CI 1.10 to 1.64, I2=98%) and adjusted mortality risk (HR 0.52, 95% CI 0.41 to 0.66, I2=76.6%). The mean difference in duration of hospitalisation was 0.36 days (95% CI -0.07 to 0.80, I2=93.8%). There was substantial heterogeneity in retrospective studies, and estimates should be interpreted cautiously. Other immunomodulatory agents showed similar effects to tocilizumab, but insufficient data precluded meta-analysis by agent. CONCLUSION Tocilizumab was associated with a lower relative risk of mortality in prospective studies, but effects were inconclusive for other outcomes. Current evidence for the efficacy of anakinra, siltuximab or sarilumab in COVID-19 is insufficient, with further studies urgently needed for conclusive findings. PROSPERO REGISTRATION NUMBER CRD42020176375.
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Affiliation(s)
- Fasihul A Khan
- Respiratory Medicine, University of Nottingham, Nottingham, UK
| | - Iain Stewart
- Respiratory Medicine, University of Nottingham, Nottingham, UK
| | - Laura Fabbri
- Respiratory Medicine, University of Nottingham, Nottingham, UK
| | - Samuel Moss
- Respiratory Medicine, University of Nottingham, Nottingham, UK
| | | | - Alan Robert Smyth
- Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, UK
| | - Gisli Jenkins
- Respiratory Medicine, University of Nottingham, Nottingham, UK
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13
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Jiang W, Li W, Wu Q, Han Y, Zhang J, Luo T, Guo Y, Yang Y, Zhu P, Xia X. Efficacy and Safety of Tocilizumab Treatment COVID-19 Patients: A Case-Control Study and Meta-Analysis. Infect Dis Ther 2021; 10:1677-1698. [PMID: 34244956 PMCID: PMC8269405 DOI: 10.1007/s40121-021-00483-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 06/15/2021] [Indexed: 11/20/2022] Open
Abstract
INTRODUCTION As the pandemic progresses, the pathophysiology of COVID-19 is becoming more apparent, and the potential for tocilizumab is increasing. However, the clinical efficacy and safety of tocilizumab in the treatment of COVID-19 patients remain unclear. METHODS To assess the efficacy and safety of tocilizumab treatment in COVID-19 patients, we performed a retrospective case-control study. The study was conducted, including 95 patients treated with tocilizumab plus standard treatment and matched controls with 95 patients treated with standard treatment therapy by propensity score from February to April 2020. We searched some databases using the search terms for studies published from January 1, 2020, to June 1, 2021. RESULTS Our case-control study found a lower mortality rate in the tocilizumab treatment group than in the standard treatment group (9.47% versus 16.84%, P = 0.134), but the results were not statistically significant. We also found that the mortality rate in tocilizumab treatment groups was significantly lower than in the standard treatment group in the stratified ICU analysis (OR 0.52, 95% CI 0.44-0.61, P = 0.048 and OR 0.31, 95% CI 0.10-0.99, P = 0.044). We selected 49 studies (including 6568 cases and 11,660 controls) that met the inclusion criteria in the meta-analysis. In the overall analysis, we performed a meta-analysis that showed significantly decreased mortality after patients received tocilizumab (OR 0.81, 95% CI 0.69-0.95, P = 0.008). We also revealed significant associations within some subgroups. The sequential trial analysis showed a true-positive result. No significant associations were observed between tocilizumab and elevated secondary infection risk, discharge, adverse events, and mechanical ventilation in the overall analysis. CONCLUSION Tocilizumab significantly decreased mortality in COVID-19 patients with no increased discharge, secondary infection risk, adverse events, and mechanical ventilation in a meta-analysis. Our data suggest that clinicians should pay attention to tocilizumab therapy as an effective and safe treatment for COVID-19 patients.
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Affiliation(s)
- Weijun Jiang
- COVID-19 Research Center, Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, Jiangsu, China
| | - Weiwei Li
- COVID-19 Research Center, Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, Jiangsu, China
| | - Qiuyue Wu
- COVID-19 Research Center, Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, Jiangsu, China
| | - Ying Han
- COVID-19 Research Center, Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, Jiangsu, China
| | - Jing Zhang
- COVID-19 Research Center, Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, Jiangsu, China
| | - Tao Luo
- COVID-19 Research Center, Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, Jiangsu, China
| | - Yanju Guo
- COVID-19 Research Center, Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, Jiangsu, China
| | - Yang Yang
- COVID-19 Research Center, Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, Jiangsu, China
| | - Peiran Zhu
- COVID-19 Research Center, Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, Jiangsu, China
| | - Xinyi Xia
- COVID-19 Research Center, Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210002, Jiangsu, China.
- Joint Expert Group for COVID-19, Department of Laboratory Medicine and Blood Transfusion, Wuhan Huoshenshan Hospital, Wuhan, 430100, Hubei, China.
- Department of Laboratory Medicine and Blood Transfusion, Wuhan Huoshenshan Hospital, Wuhan, 430100, Hubei, China.
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Mahroum N, Watad A, Bridgewood C, Mansour M, Nasr A, Hussein A, Khamisy-Farah R, Farah R, Gendelman O, Lidar M, Shoenfeld Y, Amital H, Kong JD, Wu J, Bragazzi NL, McGonagle D. Systematic Review and Meta-Analysis of Tocilizumab Therapy versus Standard of Care in over 15,000 COVID-19 Pneumonia Patients during the First Eight Months of the Pandemic. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:9149. [PMID: 34501738 PMCID: PMC8431489 DOI: 10.3390/ijerph18179149] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/14/2021] [Accepted: 08/23/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND Tocilizumab is an anti-IL-6 therapy widely adopted in the management of the so-called "cytokine storm" related to SARS-CoV-2 virus infection, but its effectiveness, use in relation to concomitant corticosteroid therapy and safety were unproven despite widespread use in numerous studies, mostly open label at the start of the pandemic. METHODS We performed a systematic review and meta-analysis of case-control studies utilising tocilizumab in COVID-19 on different databases (PubMed/MEDLINE/Scopus) and preprint servers (medRxiv and SSRN) from inception until 20 July 2020 (PROSPERO CRD42020195690). Subgroup analyses and meta-regressions were performed. The impact of tocilizumab and concomitant corticosteroid therapy or tocilizumab alone versus standard of care (SOC) on the death rate, need for mechanical ventilation, ICU admission and bacterial infections were assessed. RESULTS Thirty-nine studies with 15,531 patients (3657 cases versus 11,874 controls) were identified. Unadjusted estimates (n = 28) failed to demonstrate a protective effect of tocilizumab on survival (OR 0.74 ([95%CI 0.55-1.01], p = 0.057), mechanical ventilation prevention (OR 2.21 [95%CI 0.53-9.23], p = 0.277) or prevention of ICU admission (OR 3.79 [95%CI 0.38-37.34], p = 0.254). Considering studies with adjusted, estimated, tocilizumab use was associated with mortality rate reduction (HR 0.50 ([95%CI 0.38-0.64], p < 0.001) and prevention of ICU admission (OR 0.16 ([95%CI 0.06-0.43], p < 0.001). Tocilizumab with concomitant steroid use versus SOC was protective with an OR of 0.49 ([95%CI 0.36-0.65], p < 0.05) as was tocilizumab alone versus SOC with an OR of 0.59 ([95%CI 0.34-1.00], p < 0.001). Risk of infection increased (2.36 [95%CI 1.001-5.54], p = 0.050; based on unadjusted estimates). CONCLUSION Despite the heterogeneity of included studies and large number of preprint articles, our findings from the first eight of the pandemic in over 15,000 COVID-19 cases suggested an incremental efficacy of tocilizumab in severe COVID-19 that were confirmed by subsequent meta-analyses of large randomized trials of tocilizumab. This suggests that analysis of case-control studies and pre-print server data in the early stages of a pandemic appeared robust for supporting incremental benefits and lack of major therapeutic toxicity of tocilizumab for severe COVID-19.
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Affiliation(s)
- Naim Mahroum
- Zabludowicz Center for Autoimmune Diseases, Department of Medicine B., Sheba Medical Center, Ramat Gan 5265601, Israel; (N.M.); (A.W.); (O.G.); (Y.S.); (H.A.)
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;
- International School of Medicine, Istanbul Medipol University, Istanbul 34810, Beykoz, Turkey
| | - Abdulla Watad
- Zabludowicz Center for Autoimmune Diseases, Department of Medicine B., Sheba Medical Center, Ramat Gan 5265601, Israel; (N.M.); (A.W.); (O.G.); (Y.S.); (H.A.)
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK; (C.B.); (D.M.)
- Rheumatology Unit, Sheba Medical Center, Ramat Gan 5265601, Israel
| | - Charlie Bridgewood
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK; (C.B.); (D.M.)
| | - Muhammad Mansour
- Department of Surgery A, Galilee Medical Center, Nahariya 2210001, Israel;
- Faculty of Medicine of the Galilee, Bar-Ilan University, Safed 13100, Israel
- Division of General Surgery, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada
| | - Ahmad Nasr
- Department of Pathology, Papa Giovanni XXIII Hospital, 24127 Bergamo, Italy;
- Department of Pathology, University of Milano-Bicocca, 20126 Milan, Italy
| | - Amr Hussein
- Medical Faculty, University of Parma, 43125 Parma, Italy;
| | - Rola Khamisy-Farah
- Clalit Health Service, Akko, Azrieli Faculty of Medicine, Bar-Ilan University, Safed 13100, Israel;
| | - Raymond Farah
- Department of Internal Medicine, Ziv Medical Center, Safed 13100, Israel;
| | - Omer Gendelman
- Zabludowicz Center for Autoimmune Diseases, Department of Medicine B., Sheba Medical Center, Ramat Gan 5265601, Israel; (N.M.); (A.W.); (O.G.); (Y.S.); (H.A.)
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;
| | - Merav Lidar
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;
- Rheumatology Unit, Sheba Medical Center, Ramat Gan 5265601, Israel
| | - Yehuda Shoenfeld
- Zabludowicz Center for Autoimmune Diseases, Department of Medicine B., Sheba Medical Center, Ramat Gan 5265601, Israel; (N.M.); (A.W.); (O.G.); (Y.S.); (H.A.)
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;
- Medical Department, Saint Petersburg State University, 199034 Saint Petersburg, Russia
- Ariel University, Kiryat HaMada 3, Ariel 40700, Israel
| | - Howard Amital
- Zabludowicz Center for Autoimmune Diseases, Department of Medicine B., Sheba Medical Center, Ramat Gan 5265601, Israel; (N.M.); (A.W.); (O.G.); (Y.S.); (H.A.)
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;
| | - Jude Dzevela Kong
- Laboratory for Industrial and Applied Mathematics (LIAM), Department of Mathematics and Statistics, York University, Toronto, ON M3J 1P3, Canada; (J.D.K.); (J.W.)
| | - Jianhong Wu
- Laboratory for Industrial and Applied Mathematics (LIAM), Department of Mathematics and Statistics, York University, Toronto, ON M3J 1P3, Canada; (J.D.K.); (J.W.)
| | - Nicola Luigi Bragazzi
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK; (C.B.); (D.M.)
- Laboratory for Industrial and Applied Mathematics (LIAM), Department of Mathematics and Statistics, York University, Toronto, ON M3J 1P3, Canada; (J.D.K.); (J.W.)
- Postgraduate School of Public Health, Department of Health Sciences (DISSAL), University of Genoa, 16132 Genoa, Italy
| | - Dennis McGonagle
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds LS7 4SA, UK; (C.B.); (D.M.)
- Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK
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Zhu Y, Zhong J, Dong L. Epidemiology and Clinical Management of Rheumatic Autoimmune Diseases in the COVID-19 Pandemic: A Review. Front Med (Lausanne) 2021; 8:725226. [PMID: 34490312 PMCID: PMC8416911 DOI: 10.3389/fmed.2021.725226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 07/27/2021] [Indexed: 12/15/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) has been in pandemic for more than 1 year, with serious negative effects produced worldwide. During this period, there have been a lot of studies on rheumatic autoimmune diseases (RADs) combined with COVID-19. The purpose of this study is to review and summarize these experiences. Pubmed, Web of science, Embase and the Cochrane library were searched from January 15, 2020 to July 15, 2021 using RADs and COVID-19 related keywords. Based on a comprehensive review of studies covering 16 countries, the prevalence of COVID-19 does not necessarily increase in RADs patients compared to the general population. In RADs population infected with COVID-19, a high proportion of female patients (54.44~95.2%), elderly patients (≥50y, 48~75.88%), and patients with pre-existing comorbidities (respiratory, 4.8~60.4%; endocrine, 8.52~44.72%; cardiovascular, 15.7~64.73%) were observed, although, this does not appear to have a decisive effect on disease severity. Many anti-rheumatic treatments have been extensively evaluated for their efficacy of treating COVID-19 in RADs patients, with TNF-α inhibitors and IL-6 receptor antagonist receiving more positive reviews. However, there is no conclusive information for most of the therapeutic regimens due to the lack of high-level evidence. Inflammatory markers or neutrophil-lymphocyte-ratio may be applied as indicators for clinical prognosis or therapeutic regimens adjustment. Thus, more research is still needed to address the prevalence, treatment, and clinical monitoring of RADs patients in COVID-19 pandemic.
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Affiliation(s)
| | - Jixin Zhong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lingli Dong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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16
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Saib A, Amara W, Wang P, Cattan S, Dellal A, Regaieg K, Nahon S, Nallet O, Nguyen LS. Lack of efficacy of hydroxychloroquine and azithromycin in patients hospitalized for COVID-19 pneumonia: A retrospective study. PLoS One 2021; 16:e0252388. [PMID: 34106964 PMCID: PMC8189518 DOI: 10.1371/journal.pone.0252388] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 05/17/2021] [Indexed: 01/08/2023] Open
Abstract
Background Hydroxychloroquine combined with azithromycin (HCQ/AZI) has initially been used against coronavirus disease-2019 (COVID-19). In this retrospective study, we assessed the clinical effects of HCQ/AZI, with a 28-days follow-up. Methods In a registry-study which included patients hospitalized for COVID-19 between March 15 and April 2, 2020, we compared patients who received HCQ/AZI to those who did not, regarding a composite outcome of mortality and mechanical ventilation with a 28-days follow-up. QT was monitored for patients treated with HCQ/AZI. Were excluded patients in intensive care units, palliative care and ventilated within 24 hours of admission. Three analyses were performed to adjust for selection bias: propensity score matching, multivariable survival, and inverse probability score weighting (IPSW) analyses. Results Overall, 203 patients were included: 60 patients treated by HCQ/AZI and 143 control patients. During the 28-days follow-up, 32 (16.3%) patients presented the primary outcome and 23 (12.3%) patients died. Propensity-score matching identified 52 unique pairs of patients with similar characteristics. In the matched cohort (n = 104), HCQ/AZI was not associated with the primary composite outcome (log-rank p-value = 0.16). In the overall cohort (n = 203), survival and IPSW analyses also found no benefit from HCQ/AZI. In the HCQ/AZI group, 11 (18.3%) patients prolonged QT interval duration, requiring treatment cessation. Conclusions HCQ/AZI combination therapy was not associated with lower in-hospital mortality and mechanical ventilation rate, with a 28-days follow-up. In the HCQ/AZI group, 18.3% of patients presented a prolonged QT interval requiring treatment cessation, however, control group was not monitored for this adverse event, making comparison impossible.
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Affiliation(s)
- Anis Saib
- Cardiology Department, Groupe Hospitalier Intercommunal Le Raincy-Montfermeil, Montfermeil, France
| | - Walid Amara
- Cardiology Department, Groupe Hospitalier Intercommunal Le Raincy-Montfermeil, Montfermeil, France
| | - Pascal Wang
- Pneumology Department, Groupe Hospitalier Intercommunal Le Raincy-Montfermeil, Montfermeil, France
| | - Simon Cattan
- Cardiology Department, Groupe Hospitalier Intercommunal Le Raincy-Montfermeil, Montfermeil, France
| | - Azeddine Dellal
- Rheumatology Department, Groupe Hospitalier Intercommunal Le Raincy-Montfermeil, Montfermeil, France
| | - Kais Regaieg
- Intensive Care Medicine Department, Groupe Hospitalier Intercommunal Le Raincy-Montfermeil, Montfermeil, France
| | - Stephane Nahon
- Gastroenterology Department, Groupe Hospitalier Intercommunal Le Raincy-Montfermeil, Montfermeil, France
| | - Olivier Nallet
- Cardiology Department, Groupe Hospitalier Intercommunal Le Raincy-Montfermeil, Montfermeil, France
| | - Lee S. Nguyen
- Research & Innovation Department (RICAP), CMC Ambroise Paré, Neuilly-sur-Seine, France
- * E-mail:
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17
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Chen CX, Hu F, Wei J, Yuan LT, Wen TM, Gale RP, Liang Y. Systematic review and meta-analysis of tocilizumab in persons with coronavirus disease-2019 (COVID-19). Leukemia 2021; 35:1661-1670. [PMID: 34002026 PMCID: PMC8127467 DOI: 10.1038/s41375-021-01264-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 04/08/2021] [Accepted: 04/26/2021] [Indexed: 02/04/2023]
Abstract
We performed a meta-analysis to determine safety and efficacy of tocilizumab in persons with coronavirus disease-2019 (COVID-19). We searched PubMed, Web of Science and Medline using Boolean operators for studies with the terms coronavirus OR COVID-19 OR 2019-nCoV OR SARS-CoV-2 AND tocilizumab. Review Manager 5.4 was used to analyze data and the modified Newcastle-Ottawa and Jadad scales for quality assessment. We identified 32 studies in 11,487 subjects including three randomized trials and 29 cohort studies with a comparator cohort, including historical controls (N = 5), a matched cohort (N = 12), or concurrent controls (N = 12). Overall, tocilizumab decreased risk of death (Relative Risk [RR] = 0.74; 95% confidence interval [CI], 0.59, 0.93; P = 0.008; I2 = 80%) but not of surrogate endpoints including ICU admission (RR = 1.40 [0.64,3.06]; P = 0.4; I2 = 88%), invasive mechanical ventilation (RR = 0.83 [0.57,1.22]; P = 0.34; I2 = 65%) or secondary infections (RR = 1.30 [0.97,1.74]; P = 0.08; I2 = 65%) and increased interval of hospitalization of subjects discharged alive(mean difference [MD] = 2 days [<1, 4 days]; P = 0.006; I2 = 0). RRs of death in studies with historical controls (RR = 0.28 [0.16,0.49; P < 0.001]; I2 = 62%) or a matched cohort (RR = 0.68 [0.53, 0.87]; P = 0.002; I2 = 42%) were decreased. In contrast, RRs of death in studies with a concurrent control (RR = 1.10 [0.77, 1.56]; P = 0.60; I2 = 85%) or randomized (RR = 1.18 [0.57,2.44]; P = 0.66; I2 = 0) were not decreased. A reduced risk of death was not confirmed in our analyses which questions safety and efficacy of tocilizumab in persons with COVID-19.
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Affiliation(s)
- Chong-Xiang Chen
- Department of Hematologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China
- Department of ICU, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Fang Hu
- Department of Hematologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jin Wei
- Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Le-Tao Yuan
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Tian-Meng Wen
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Robert Peter Gale
- Department of Immunology and Inflammation, Haematology Research Centre, Imperial College London, London, UK
| | - Yang Liang
- Department of Hematologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
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18
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Impact of tocilizumab on clinical outcomes in severe covid-19 patients and risk of secondary infection: A case-control study. MARMARA MEDICAL JOURNAL 2021. [DOI: 10.5472/marumj.942700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Petrelli F, Cherri S, Ghidini M, Perego G, Ghidini A, Zaniboni A. Tocilizumab as treatment for COVID-19: A systematic review and meta-analysis. World J Methodol 2021; 11:95-109. [PMID: 34026583 PMCID: PMC8127418 DOI: 10.5662/wjm.v11.i3.95] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 12/02/2020] [Accepted: 03/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The majority of patients with coronavirus disease 2019 (COVID-19) have good prognoses, but some develop a critical illness that can lead to death. Evidence shows severe acute respiratory syndrome is closely related to the induced cytokine storm. Interleukin-6 is a key player; its role in systemic inflammation is well known. AIM To evaluate the effect of tocilizumab (TCZ), an interleukin-6 receptor antagonist, on the outcomes for patients with COVID-19 pneumonia. METHODS PubMed, EMBASE, SCOPUS, Web of Science, MedRxiv, Science Direct, and the Cochrane Library were searched from inception to 9th June 2020 for observational or prospective studies reporting results of hospitalized adult patients with COVID-19 infection treated with TCZ. Effect sizes were reported as odds ratios (ORs) with 95% confidence intervals (CIs), and an OR less than 1 was associated with a better outcome in those treated with TCZ. RESULTS Overall 13476 patients (33 studies; n = 3264 received TCZ) with COVID-19 pneumonia and various degree of severity were included. Outcome was improved with TCZ. In the primary analysis (n = 19 studies reporting data), mortality was reduced in patients treated with TCZ (OR = 0.64, 95%CI: 0.47-0.87; P < 0.01). In 9 studies where risk of death with TCZ use was controlled for other variables mortality was reduced by 57% (OR = 0.43, 95%CI: 0.27-0.7; P < 0.01). Intensive care need (mechanical ventilation) was also reduced (OR = 0.36, 95%CI: 0.14-0.89; P = 0.02). CONCLUSION In COVID-19-infected patients treated with TCZ, outcome may be improved compared to those not treated with TCZ.
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Affiliation(s)
| | - Sara Cherri
- Department of Clinical Oncology, Fondazione Poliambulanza, Brescia 25124, Italy
| | - Michele Ghidini
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | | | - Antonio Ghidini
- Department of Medicine, Casa di Cura Igea, Milano 20100, Italy
| | - Alberto Zaniboni
- Department of Oncology, Fondazione Poliambulanza, Brescia 25124, Italy
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20
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Rezaei S, Fatemi B, Karimi Majd Z, Minaei H, Peikanpour M, Anjidani N, Taheri A, Dastan F, Mosaed R. Efficacy and safety of Tocilizumab in severe and critical COVID-19: A Systematic Review and Meta-Analysis. Expert Rev Clin Immunol 2021; 17:499-511. [PMID: 33823733 PMCID: PMC8040491 DOI: 10.1080/1744666x.2021.1908128] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 03/22/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Currently published papers and clinical guidelines regarding the effects of tocilizumab in severe and critical COVID-19 are contradictory. The aim of this meta-analysis was to combine the results of clinical studies of different designs to investigate the efficacy and safety of tocilizumab in severely-to-critically ill COVID-19 patients. METHODS A systematic search was performed in PubMed, Embase, CENTRAL, ClinicalTrials.gov, Scopus, and preprint servers up to 26 December 2020. Since a substantial heterogeneity was expected, a random-effects model was applied to calculate the pooled effect size (ES) and 95% confidence interval (CI) for each study outcome. RESULTS Forty-five comparative studies involving 13,189 patients and 28 single-arm studies involving 1,770 patients were analyzed. The risk of mortality (RR of 0.76 [95%CI 0.65 to 0.89], P < 0.01) and intubation (RR of 0.48 [95%CI 0.24 to 0.97], P = 0.04) were lower in tocilizumab patients compared with controls. We did not find any significant difference in secondary infections, length of hospital stay, hospital discharge before day 14, and ICU admission between groups. CONCLUSION Tocilizumab can improve clinical outcomes and reduce mortality rates in severe to critical COVID-19 patients. Large-scale randomized controlled trials are still required to improve the statistical power of meta-analysis.
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Affiliation(s)
- Soheila Rezaei
- Department of Pharmacoeconomics and Pharma Management, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Fatemi
- Department of Pharmacoeconomics and Pharma Management, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Karimi Majd
- Department of Pharmacoeconomics and Pharma Management, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Minaei
- Department of Pharmacoeconomics and Pharma Management, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Peikanpour
- Department of Pharmacoeconomics and Pharma Management, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Ali Taheri
- Medical Department, Orchid Pharmed Company, Tehran, Iran
| | - Farzaneh Dastan
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Mosaed
- Department of Clinical Pharmacy, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran
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21
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Hariyanto TI, Hardyson W, Kurniawan A. Efficacy and Safety of Tocilizumab for Coronavirus Disease 2019 (Covid-19) Patients: A Systematic Review and Meta-analysis. Drug Res (Stuttg) 2021; 71:265-274. [PMID: 33401328 DOI: 10.1055/a-1336-2371] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Currently, the data regarding the effectiveness and safety of tocilizumab as treatment for COVID-19 infection is still conflicting. This study aims to give clear evidence regarding the potential benefit and safety of tocilizumab in improving the outcome of COVID-19 patients. METHODS We systematically searched the PubMed and Europe PMC database using specific keywords related to our aims until November 1st, 2020. All articles published on COVID-19 and tocilizumab were retrieved. Statistical analysis was done using Review Manager 5.4 software. RESULTS A total of 38 studies with a total of 13 412 COVID-19 patients were included in our analysis. Our meta-analysis showed that tocilizumab treatment is associated with reduction of mortality rate from COVID-19 [OR 0.54 (95% CI 0.42-0.71), p<0.00001, I 2=79%, random-effect modelling], but did not alter the severity of COVID-19 [OR 1.05 (95% CI 0.92-1.20), p=0.47, I 2=84%, random-effect modelling] and length of hospital stay [Mean Difference 1.77 days (95% CI -0.61-4.14 days), p=0.15, I 2=97%, random-effect modelling]. Tocilizumab also does not associated with serious adverse events compared with standard of care treatment [OR 0.91 (95% CI 0.71-1.15), p=0.42, I 2=46%, random-effect modelling]. CONCLUSION Our study does not support the routine use of tocilizumab for COVID-19 patients. Future studies should focus more on other potential therapies for COVID-19 patients.
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Affiliation(s)
| | - Willie Hardyson
- Faculty of Medicine, Pelita Harapan University, Karawaci, Tangerang, Indonesia
| | - Andree Kurniawan
- Department of Internal Medicine, Faculty of Medicine, Pelita Harapan University, Karawaci, Tangerang, Indonesia
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Ngo BT, Marik P, Kory P, Shapiro L, Thomadsen R, Iglesias J, Ditmore S, Rendell M, Varon J, Dubé M, Nanda N, In G, Arkfeld D, Chaudhary P, Campese VM, Hanna DL, Sawcer DE, Ehresmann G, Peng D, Smogorewski M, Armstrong A, Dasgupta R, Sattler F, Brennan-Rieder D, Mussini C, Mitja O, Soriano V, Peschanski N, Hayem G, Confalonieri M, Piccirillo MC, Lobo-Ferreira A, Bello Rivero I, Turkia M, Vingevoll EH, Griffin D, Hung IF. The time to offer treatments for COVID-19. Expert Opin Investig Drugs 2021; 30:505-518. [PMID: 33721548 PMCID: PMC8074648 DOI: 10.1080/13543784.2021.1901883] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 03/08/2021] [Indexed: 12/23/2022]
Abstract
Background: COVID-19 has several overlapping phases. Treatments to date have focused on the late stage of disease in hospital. Yet, the pandemic is by propagated by the viral phase in out-patients. The current public health strategy relies solely on vaccines to prevent disease.Methods: We searched the major national registries, pubmed.org, and the preprint servers for all ongoing, completed and published trial results.Results: As of 2/15/2021, we found 111 publications reporting findings on 14 classes of agents, and 9 vaccines. There were 62 randomized controlled studies, the rest retrospective observational analyses. Only 21 publications dealt with outpatient care. Remdesivir and high titer convalescent plasma have emergency use authorization for hospitalized patients in the U.S.A. There is also support for glucocorticoid treatment of the COVID-19 respiratory distress syndrome. Monoclonal antibodies are authorized for outpatients, but supply is inadequate to treat all at time of diagnosis. Favipiravir, ivermectin, and interferons are approved in certain countries.Expert Opinion: Vaccines and antibodies are highly antigen specific, and new SARS-Cov-2 variants are appearing. We call on public health authorities to authorize treatments with known low-risk and possible benefit for outpatients in parallel with universal vaccination.
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Affiliation(s)
- Binh T. Ngo
- Department of Internal Medicine, Eastern Virginia Medical School, Pulmonary and Critical Care Medicine, Norfolk, USA
- The Rose Salter Medical Research Foundation, Newport Coast, USA
| | - Paul Marik
- Department of Internal Medicine, Eastern Virginia Medical School, Pulmonary and Critical Care Medicine, Norfolk, USA
| | - Pierre Kory
- Pulmonary and Critical Care Medicine, Aurora St. Luke’s Medical Center, Milwaukee, USA
| | - Leland Shapiro
- Department of Internal Medicine, Rocky Mountain Regional Veterans Affairs Medical Center in Aurora, CO and University of Colorado Anschutz Medical Campus in Aurora, CO Supported by the Emily Foundation, Boston, USA
| | | | - Jose Iglesias
- Department of Internal Medicine, Jersey Shore University Medical Center, Hackensack Meridian School of Medicine at Seton Hall, Neptune, USA
| | | | - Marc Rendell
- The Rose Salter Medical Research Foundation, Newport Coast, USA
| | - Joseph Varon
- United Memorial Medical Center, University of Texas School of Medicine, Houston, USA
| | - Michael Dubé
- Department of Internal Medicine, Eastern Virginia Medical School, Pulmonary and Critical Care Medicine, Norfolk, USA
| | - Neha Nanda
- Department of Internal Medicine, Eastern Virginia Medical School, Pulmonary and Critical Care Medicine, Norfolk, USA
| | - Gino In
- Department of Internal Medicine, Eastern Virginia Medical School, Pulmonary and Critical Care Medicine, Norfolk, USA
| | - Daniel Arkfeld
- Department of Internal Medicine, Eastern Virginia Medical School, Pulmonary and Critical Care Medicine, Norfolk, USA
| | - Preet Chaudhary
- Department of Internal Medicine, Eastern Virginia Medical School, Pulmonary and Critical Care Medicine, Norfolk, USA
| | - Vito M. Campese
- Department of Internal Medicine, Eastern Virginia Medical School, Pulmonary and Critical Care Medicine, Norfolk, USA
| | - Diana L. Hanna
- Department of Internal Medicine, Eastern Virginia Medical School, Pulmonary and Critical Care Medicine, Norfolk, USA
| | - David E. Sawcer
- Department of Internal Medicine, Eastern Virginia Medical School, Pulmonary and Critical Care Medicine, Norfolk, USA
| | - Glenn Ehresmann
- Department of Internal Medicine, Eastern Virginia Medical School, Pulmonary and Critical Care Medicine, Norfolk, USA
| | - David Peng
- Department of Internal Medicine, Eastern Virginia Medical School, Pulmonary and Critical Care Medicine, Norfolk, USA
| | - Miroslaw Smogorewski
- Department of Internal Medicine, Eastern Virginia Medical School, Pulmonary and Critical Care Medicine, Norfolk, USA
| | - April Armstrong
- Department of Internal Medicine, Eastern Virginia Medical School, Pulmonary and Critical Care Medicine, Norfolk, USA
| | - Rajkumar Dasgupta
- Department of Internal Medicine, Eastern Virginia Medical School, Pulmonary and Critical Care Medicine, Norfolk, USA
| | - Fred Sattler
- Department of Internal Medicine, Eastern Virginia Medical School, Pulmonary and Critical Care Medicine, Norfolk, USA
| | | | - Cristina Mussini
- Department of Infectious Disease, University of Modena and Reggio Emilia, Modena, Italy
| | - Oriol Mitja
- Department of Internal Medicine, Hospital Universitari Germans Trias I Pujol, Badalona, Spain
| | - Vicente Soriano
- Director, Centro Medico, UNIR Health Sciences School & Medical Center, Madrid, Spain
| | - Nicolas Peschanski
- Department of Emergency Medicine, UniversityHospital of Rennes, Rennes, France
| | - Gilles Hayem
- Department of Rheumatology, Hôpital Paris Saint-Joseph, Paris, France
| | - Marco Confalonieri
- Department of Respiratory Diseases, Azienda Ospedaliero-Universitaria Di Trieste, Trieste, Italia
| | | | - Antonio Lobo-Ferreira
- Unidade De Investigação Cardiovascular (Unic), Faculdade De Medicina, Da Universidade Do Porto, Centro Hospitalar Universitário De São João, Porto, and Hospital Rainha Santa Isabel, Marco De Canaveses, Portugal
| | - Iraldo Bello Rivero
- Department of Clinical Investigations, Center for Genetic Engineering and Biotechnology, Havana, Cuba
| | | | | | - Daniel Griffin
- Department of Internal Medicine, Rocky Mountain Regional Veterans Affairs Medical Center in Aurora, CO and University of Colorado Anschutz Medical Campus in Aurora, CO Supported by the Emily Foundation, Boston, USA
- Department of Internal Medicine and Department of Biochemistry and Molecular Biophysics, ProHEALTH, an OPTUM Company, Columbia University, College of Physicians and Surgeons, USA
| | - Ivan Fn Hung
- Department of Internal Medicine, Rocky Mountain Regional Veterans Affairs Medical Center in Aurora, CO and University of Colorado Anschutz Medical Campus in Aurora, CO Supported by the Emily Foundation, Boston, USA
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Perazzolo S, Zhu L, Lin W, Nguyen A, Ho RJY. Systems and Clinical Pharmacology of COVID-19 Therapeutic Candidates: A Clinical and Translational Medicine Perspective. J Pharm Sci 2021; 110:1002-1017. [PMID: 33248057 PMCID: PMC7689305 DOI: 10.1016/j.xphs.2020.11.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/17/2020] [Accepted: 11/17/2020] [Indexed: 12/15/2022]
Abstract
Over 50 million people have been infected with the SARS-CoV-2 virus, while around 1 million have died due to COVID-19 disease progression. COVID-19 presents flu-like symptoms that can escalate, in about 7-10 days from onset, into a cytokine storm causing respiratory failure and death. Although social distancing reduces transmissibility, COVID-19 vaccines and therapeutics are essential to regain socioeconomic normalcy. Even if effective and safe vaccines are found, pharmacological interventions are still needed to limit disease severity and mortality. Integrating current knowledge and drug candidates (approved drugs for repositioning among >35 candidates) undergoing clinical studies (>3000 registered in ClinicalTrials.gov), we employed Systems Pharmacology approaches to project how antivirals and immunoregulatory agents could be optimally evaluated for use. Antivirals are likely to be effective only at the early stage of infection, soon after exposure and before hospitalization, while immunomodulatory agents should be effective in the later-stage cytokine storm. As current antiviral candidates are administered in hospitals over 5-7 days, a long-acting combination that targets multiple SARS-CoV-2 lifecycle steps may provide a long-lasting, single-dose treatment in outpatient settings. Long-acting therapeutics may still be needed even when vaccines become available as vaccines are likely to be approved based on a 50% efficacy target.
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Affiliation(s)
- Simone Perazzolo
- Department of Pharmaceutics, School of Pharmacy, Seattle, WA 98195, USA; Targeted and Long-Acting Drug Combination Anti-Retroviral Therapeutic (TLC-ART) Program, University of Washington, Seattle, WA 98195, USA; NanoMath, Seattle, WA 98115, USA.
| | - Linxi Zhu
- Department of Pharmaceutics, School of Pharmacy, Seattle, WA 98195, USA; Targeted and Long-Acting Drug Combination Anti-Retroviral Therapeutic (TLC-ART) Program, University of Washington, Seattle, WA 98195, USA
| | - Weixian Lin
- Department of Pharmaceutics, School of Pharmacy, Seattle, WA 98195, USA; First School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Alexander Nguyen
- Molecular Engineering & Sciences Institute, University of Washington, Seattle, WA 98195, USA
| | - Rodney J Y Ho
- Department of Pharmaceutics, School of Pharmacy, Seattle, WA 98195, USA; Targeted and Long-Acting Drug Combination Anti-Retroviral Therapeutic (TLC-ART) Program, University of Washington, Seattle, WA 98195, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
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24
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Zuo Z, Wu T, Pan L, Zuo C, Hu Y, Luo X, Jiang L, Xia Z, Xiao X, Liu J, Ye M, Deng M. Modalities and Mechanisms of Treatment for Coronavirus Disease 2019. Front Pharmacol 2021; 11:583914. [PMID: 33643033 PMCID: PMC7908061 DOI: 10.3389/fphar.2020.583914] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 12/03/2020] [Indexed: 12/15/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly throughout the world. Although COVID-19 has a relatively low case severity rate compared to SARS and Middle East Respiratory syndrome it is a major public concern because of its rapid spread and devastating impact on the global economy. Scientists and clinicians are urgently trying to identify drugs to combat the virus with hundreds of clinical trials underway. Current treatments could be divided into two major part: anti-viral agents and host system modulatory agents. On one hand, anti-viral agents focus on virus infection process. Umifenovir blocks virus recognizing host and entry. Remdesivir inhibits virus replication. Chloroquine and hydroxychloroquine involve preventing the whole infection process, including virus transcription and release. On the other hand, host system modulatory agents are associated with regulating the imbalanced inflammatory reaction and biased immune system. Corticosteroid is believed to be commonly used for repressing hyper-inflammation, which is one of the major pathologic mechanisms of COVID-19. Convalescent plasma and neutralizing antibodies provide essential elements for host immune system and create passive immunization. Thrombotic events are at high incidence in COVID-19 patients, thus anti-platelet and anti-coagulation are crucial, as well. Here, we summarized these current or reproposed agents to better understand the mechanisms of agents and give an update of present research situation.
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Affiliation(s)
- Zhihong Zuo
- Department of Biochemistry and Molecular Biology and Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Ting Wu
- Department of Biochemistry and Molecular Biology and Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
- Department of Cardiovascular Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Liangyu Pan
- Department of Biochemistry and Molecular Biology and Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
| | - Chenzhe Zuo
- Department of Biochemistry and Molecular Biology and Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yingchuo Hu
- Department of Biochemistry and Molecular Biology and Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
| | - Xuan Luo
- Hunan Yuanpin Cell Biotechnology Co., Ltd., Changsha, China
| | - Liping Jiang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Zanxian Xia
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, China
- Hunan Key Laboratory of Animal Models for Human Diseases, Hunan Key Laboratory of Medical Genetics and Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
| | - Xiaojuan Xiao
- Department of Biochemistry and Molecular Biology and Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
| | - Jing Liu
- Department of Biochemistry and Molecular Biology and Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
| | - Mao Ye
- Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Molecular Engineering for Theranostics, Hunan University, Changsha, China
| | - Meichun Deng
- Department of Biochemistry and Molecular Biology and Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
- Hunan Key Laboratory of Animal Models for Human Diseases, Hunan Key Laboratory of Medical Genetics and Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China
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Zahr N, Urien S, Llopis B, Pourcher V, Paccoud O, Bleibtreu A, Mayaux J, Gandjbakhch E, Hekimian G, Combes A, Benveniste O, Saadoun D, Allenbach Y, Pinna B, Cacoub P, Funck-Brentano C, Salem JE. Pharmacokinetics and pharmacodynamics of hydroxychloroquine in hospitalized patients with COVID-19. Therapie 2021; 76:285-295. [PMID: 33558079 PMCID: PMC7842207 DOI: 10.1016/j.therap.2021.01.056] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 01/03/2021] [Accepted: 01/22/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Hydroxychloroquine (HCQ) dosage required to reach circulating levels that inhibit SARS-Cov-2 are extrapolated from pharmacokinetic data in non-COVID-19 patients. METHODS We performed a population-pharmacokinetic analysis from 104 consecutive COVID-19 hospitalized patients (31 in intensive care units, 73 in medical wards, n=149 samples). Plasma HCQ concentration were measured using high performance liquid chromatography with fluorometric detection. Modelling used Monolix-2019R2. RESULTS HCQ doses ranged from 200 to 800mg/day administered for 1 to 11days and median HCQ plasma concentration was 151ng/mL. Among the tested covariates, only bodyweight influenced elimination oral clearance (CL) and apparent volume of distribution (Vd). CL/F (F for unknown bioavailability) and Vd/F (relative standard-error, %) estimates were 45.9L/h (21.2) and 6690L (16.1). The derived elimination half-life (t1/2) was 102h. These parameters in COVID-19 differed from those reported in patients with lupus, where CL/F, Vd/F and t1/2 are reported to be 68L/h, 2440 L and 19.5h, respectively. Within 72h of HCQ initiation, only 16/104 (15.4%) COVID-19 patients had HCQ plasma levels above the in vitro half maximal effective concentration of HCQ against SARS-CoV-2 (240ng/mL). HCQ did not influence inflammation status (assessed by C-reactive protein) or SARS-CoV-2 viral clearance (assessed by real-time reverse transcription-PCR nasopharyngeal swabs). CONCLUSION The interindividual variability of HCQ pharmacokinetic parameters in severe COVID-19 patients was important and differed from that previously reported in non-COVID-19 patients. Loading doses of 1600mg HCQ followed by 600mg daily doses are needed to reach concentrations relevant to SARS-CoV-2 inhibition within 72hours in≥60% (95% confidence interval: 49.5-69.0%) of COVID-19 patients.
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Affiliation(s)
- Noël Zahr
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology and Clinical Investigation Center, INSERM, CIC-1901, Sorbonne Université, Faculty of Medicine, 75013 Paris, France.
| | - Saik Urien
- AP-HP, Université de Paris, INSERM, Cochin Hospital, Department of Pediatric and Perinatal Pharmacology, 75014 Paris, France
| | - Benoit Llopis
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology and Clinical Investigation Center, INSERM, CIC-1901, Sorbonne Université, Faculty of Medicine, 75013 Paris, France
| | - Valérie Pourcher
- AP-HP, Sorbonne Université, INSERM 1136, Institut Pierre-Louis d'Épidémiologie et de Santé Publique, Pitié-Salpêtrière Hospital, Service de Maladies Infectieuses et Tropicales, 75013 Paris, France
| | - Olivier Paccoud
- AP-HP, Sorbonne Université, INSERM 1136, Institut Pierre-Louis d'Épidémiologie et de Santé Publique, Pitié-Salpêtrière Hospital, Service de Maladies Infectieuses et Tropicales, 75013 Paris, France
| | - Alexandre Bleibtreu
- AP-HP, Sorbonne Université, INSERM 1136, Institut Pierre-Louis d'Épidémiologie et de Santé Publique, Pitié-Salpêtrière Hospital, Service de Maladies Infectieuses et Tropicales, 75013 Paris, France
| | - Julien Mayaux
- AP-HP, Sorbonne Université, Service de Pneumologie, Médecine intensive - Réanimation (Département "R3S"), Groupe Hospitalier Universitaire Pitié-Salpêtrière-Charles-Foix, 75013 Paris, France
| | - Estelle Gandjbakhch
- AP-HP, Sorbonne Université, Service de Cardiologie, Groupe Hospitalier Universitaire Pitié-Salpêtrière-Charles-Foix, 75013 Paris, France
| | - Guillaume Hekimian
- AP-HP, Sorbonne Université, Médecine intensive-Réanimation Médicale Groupe Hospitalier Universitaire Pitié-Salpêtrière-Charles-Foix, 75013 Paris, France
| | - Alain Combes
- AP-HP, Sorbonne Université, Médecine intensive-Réanimation Médicale Groupe Hospitalier Universitaire Pitié-Salpêtrière-Charles-Foix, 75013 Paris, France
| | - Olivier Benveniste
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Internal Medicine and Clinical Immunology, Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, 75013 Paris, France
| | - David Saadoun
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Internal Medicine and Clinical Immunology, Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, 75013 Paris, France
| | - Yves Allenbach
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Internal Medicine and Clinical Immunology, Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, 75013 Paris, France
| | - Bruno Pinna
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology and Clinical Investigation Center, INSERM, CIC-1901, Sorbonne Université, Faculty of Medicine, 75013 Paris, France
| | - Patrice Cacoub
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Internal Medicine and Clinical Immunology, Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, 75013 Paris, France
| | - Christian Funck-Brentano
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology and Clinical Investigation Center, INSERM, CIC-1901, Sorbonne Université, Faculty of Medicine, 75013 Paris, France
| | - Joe-Elie Salem
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology and Clinical Investigation Center, INSERM, CIC-1901, Sorbonne Université, Faculty of Medicine, 75013 Paris, France
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26
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AlBahrani S, Al-Tawfiq JA, Alshaer AR, Shilash A, Alswefy K, Al-Zayer RS, Abouelela AM. A Case Series of Severe Hospitalized COVID-19 Patients Treated with Tocilizumab and Glucocorticoids: A Report from Saudi Arabian Hospital. J Epidemiol Glob Health 2021; 11:233-237. [PMID: 33605118 PMCID: PMC8242122 DOI: 10.2991/jegh.k.210112.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 01/09/2021] [Indexed: 12/15/2022] Open
Abstract
Background: The clinical spectrum of COVID-19 is variable and ranges from asymptomatic, mildly symptomatic, moderately severe and severe disease. A small proportion might develop severe disease and may have cytokine storm. One of the therapeutic options to treat such cases is Tocilizumab (TCZ). In this study, we present cases of severe COVID-19 treated with TCZ and glucocorticoids and discuss the treatment responses. Methods: This is a retrospective observational study of severe COVID-19 cases treated with TCZ and glucocorticoids. The case series examined the characteristics and outcome of those patients. Results: This study included 40 Severe Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) confirmed patients who received TCZ and glucocorticoids. The mean age of the included patients was 57.55 (±Standard deviation 12.86) years. There were 34 (85%) males, 19 (47.5%) were obese (BMI >30), 13 (32.5%) over weight, and five (12.5%) normal weight. The mean days from positive SARS-CoV-2 polymerase chain reaction (PCR) test to admission was 1.641 (±3.2) days. Of the patients, 18 (45%) had diabetes mellitus, 14 (35%) had hypertension. The mean days from hospital admission to ICU was 1.8 (±2.6), 20 (50%) required mechanical ventilation, 39 (97.5%) had received prone position, seven (17.5%) had renal replacement therapy, 13 (32.5%) required inotropes, four (10%) had plasmapheresis, one (2.5%) had intravenous immunoglobulin, all patients received steroid therapy, and the majority 31 (77.5%) did not receive any anti-viral therapy. Of all the patients, six (15%) died, 28 (70%) were discharged and six (15%) were still in hospital. Conclusion: The overall mortality rate was lower than those cited in meta-analysis. As our understanding of the COVID-19 continues, the approach and therapeutics are also evolving.
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Affiliation(s)
| | - Jaffar A Al-Tawfiq
- Infectious Disease Unit, Specialty Internal Medicine, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia.,Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.,Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Amal Shilash
- King Fahad Military Medical Complex, Dhahran, Saudi Arabia
| | - Khalid Alswefy
- King Fahad Military Medical Complex, Dhahran, Saudi Arabia
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27
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Cortegiani A, Ippolito M, Greco M, Granone V, Protti A, Gregoretti C, Giarratano A, Einav S, Cecconi M. Rationale and evidence on the use of tocilizumab in COVID-19: a systematic review. Pulmonology 2021; 27:52-66. [PMID: 32713784 PMCID: PMC7369580 DOI: 10.1016/j.pulmoe.2020.07.003] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 07/07/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Tocilizumab is an IL-6 receptor-blocking agent proposed for the treatment of severe COVID-19. The aim of this systematic review was to describe the rationale for the use of tocilizumab for the treatment of COVID-19 and to summarize the available evidence regarding its efficacy and safety. METHODS MEDLINE, PubMed, EMBASE, pre-print repositories (bioRxiv and medRxiv) and two trial Registries were searched for studies on the use of tocilizumab in COVID-19 or SARS-CoV-2 infection, viral pneumonia, and/or sepsis until 20th June 2020. RESULTS We identified 3 indirect pre-clinical studies and 28 clinical studies including 5776 patients with COVID-19 (13 with a comparison group, 15 single-arm). To date, no randomized trials have been published. We retrieved no studies at low risk of bias. Forty-five ongoing studies were retrieved from trial registries. CONCLUSIONS There is insufficient evidence regarding the clinical efficacy and safety of tocilizumab in patients with COVID-19. Its use should be considered experimental, requiring ethical approval and clinical trial oversight.
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Affiliation(s)
- A Cortegiani
- Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.), University of Palermo. Department of Anesthesia Intensive Care and Emergency, Policlinico Paolo Giaccone, Palermo, Italy.
| | - M Ippolito
- Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.), University of Palermo. Department of Anesthesia Intensive Care and Emergency, Policlinico Paolo Giaccone, Palermo, Italy.
| | - M Greco
- Department of Anesthesiology and Intensive Care, Humanitas Clinical and Research Center - IRCCS, Milan, Italy; Department of Biomedical Science, Humanitas University, Milan, Italy.
| | - V Granone
- Department of Anesthesiology and Intensive Care, Humanitas Clinical and Research Center - IRCCS, Milan, Italy; Department of Biomedical Science, Humanitas University, Milan, Italy.
| | - A Protti
- Department of Anesthesiology and Intensive Care, Humanitas Clinical and Research Center - IRCCS, Milan, Italy; Department of Biomedical Science, Humanitas University, Milan, Italy.
| | - C Gregoretti
- Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.), University of Palermo. Department of Anesthesia Intensive Care and Emergency, Policlinico Paolo Giaccone, Palermo, Italy; Fondazione "Giglio", Cefalù, Italy.
| | - A Giarratano
- Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.), University of Palermo. Department of Anesthesia Intensive Care and Emergency, Policlinico Paolo Giaccone, Palermo, Italy.
| | - S Einav
- IntensiveCare Unit of the Shaare Zedek Medical Medical Centre and Hebrew University Faculty of Medicine, Jerusalem, Israel.
| | - M Cecconi
- Department of Anesthesiology and Intensive Care, Humanitas Clinical and Research Center - IRCCS, Milan, Italy; Department of Biomedical Science, Humanitas University, Milan, Italy.
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28
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Han Q, Guo M, Zheng Y, Zhang Y, De Y, Xu C, Zhang L, Sun R, Lv Y, Liang Y, Xu F, Pang J, Chen Y. Current Evidence of Interleukin-6 Signaling Inhibitors in Patients With COVID-19: A Systematic Review and Meta-Analysis. Front Pharmacol 2020; 11:615972. [PMID: 33384605 PMCID: PMC7769953 DOI: 10.3389/fphar.2020.615972] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 11/17/2020] [Indexed: 12/16/2022] Open
Abstract
Background: Interleukin-6 (IL-6) is known to be detrimental in coronavirus disease 2019 (COVID-19) because of its involvement in driving cytokine storm. This systematic review and meta-analysis aimed to assess the safety and efficacy of anti-IL-6 signaling (anti-IL6/IL-6R/JAK) agents on COVID-19 based on the current evidence. Methods: Studies were identified through systematic searches of PubMed, EMBASE, ISI Web of Science, Cochrane library, ongoing clinical trial registries (clinicaltrials.gov), and preprint servers (medRxiv, ChinaXiv) on August 10, 2020, as well as eligibility checks according to predefined selection criteria. Statistical analysis was performed using Review Manager (version 5.3) and STATA 12.0. Results: Thirty-one studies were included in the pooled analysis of mortality, and 12 studies were identified for the analysis of risk of secondary infections. For mortality analysis, 5630 COVID-19 cases including 2,132 treated patients and 3,498 controls were analyzed. Anti-IL-6 signaling agents plus standard of care (SOC) significantly decreased the mortality rate compared to SOC alone (pooled OR = 0.61, 95% CI 0.45-0.84, p = 0.002). For the analysis of secondary infection risk, 1,624 patients with COVID-19 including 639 treated patients and 985 controls were included, showing that anti-IL-6 signaling agents did not increase the rate of secondary infections (pooled OR = 1.21, 95% CI 0.70-2.08, p = 0.50). By contrast, for patients with critical COVID-19 disease, anti-IL-6 signaling agents failed to reduce mortality compared to SOC alone (pooled OR = 0.75, 95% CI 0.42-1.33, p = 0.33), but they tended to increase the risk of secondary infections (pooled OR = 1.85, 95% CI 0.95-3.61, p = 0.07). A blockade of IL-6 signaling failed to reduce the mechanical ventilation rate, ICU admission rate, or elevate the clinical improvement rate. Conclusion: IL-6 signaling inhibitors reduced the mortality rate without increasing secondary infections in patients with COVID-19 based on current studies. For patients with critical disease, IL-6 signaling inhibitors did not exhibit any benefit.
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Affiliation(s)
- Qi Han
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Mingyue Guo
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Yue Zheng
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Ying Zhang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Yanshan De
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Changchang Xu
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Lin Zhang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Ruru Sun
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Ying Lv
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Yan Liang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Feng Xu
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Jiaojiao Pang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Yuguo Chen
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
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29
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Gutiérrez-Abejón E, Tamayo E, Martín-García D, Álvarez FJ, Herrera-Gómez F. Clinical Profile, Treatment and Predictors during the First COVID-19 Wave: A Population-Based Registry Analysis from Castile and Leon Hospitals. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:E9360. [PMID: 33327546 PMCID: PMC7765016 DOI: 10.3390/ijerph17249360] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/04/2020] [Accepted: 12/07/2020] [Indexed: 01/08/2023]
Abstract
The first wave of the COVID-19 pandemic collapsed the hospitals in Castile and Leon (Spain). An analysis of the clinical characteristics, drug therapies and principal outcome predictors in the COVID-19 hospitalized patients from 1 March to 31 May 2020 is presented through a population-based registry study. Hospital stay variables, ventilation mode data and clinical outcomes were observed. In Castile and Leon hospitals, 7307 COVID-19 patients were admitted, with 57.05% being male and a median of 76 years. The mortality rate was 24.43%, with a high incidence of severe acute respiratory syndrome (SARS) (14.03%) and acute kidney injury (AKI) (10.87%). The most used medicines were antibiotics (90.83%), antimalarials (42.63%), steroids (44.37%) and antivirals, such as lopinavir/ritonavir (42.63%). The use of tocilizumab (9.37%) and anti-SIRS (systemic inflammatory response syndrome) medicines (7.34%) were remarkable. Fundamentally, death occurred more likely over 65 years of age (OR: 9.05). In addition, the need for ventilation was associated with a higher probability of death (OR: 3.59), SARS (OR: 5.14) and AKI (OR: 2.31). The drug-use pattern had been modified throughout the COVID-19 first wave. Multiple factors, such as age, gender and the need for mechanical ventilation, were related to the worst evolution prognosis of the disease.
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Affiliation(s)
- Eduardo Gutiérrez-Abejón
- Pharmacological Big Data Laboratory, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain; (F.J.Á.); (F.H.-G.)
- Technical Direction of Pharmaceutical Assistance, Gerencia Regional de Salud de Castilla y León, 47007 Valladolid, Spain
| | - Eduardo Tamayo
- BioCritic. Group for Biomedical Research in Critical Care Medicine, 47005 Valladolid, Spain;
- Department of Anaesthesiology, Hospital Clínico Universitario de Valladolid, 47003 Valladolid, Spain
- Department of Surgery, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain
| | - Débora Martín-García
- Department of Nephrology, Hospital Clínico Universitario de Valladolid, 47003 Valladolid, Spain;
| | - F. Javier Álvarez
- Pharmacological Big Data Laboratory, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain; (F.J.Á.); (F.H.-G.)
- BioCritic. Group for Biomedical Research in Critical Care Medicine, 47005 Valladolid, Spain;
- CEIm, Hospital Clínico Universitario de Valladolid, 47003 Valladolid, Spain
| | - Francisco Herrera-Gómez
- Pharmacological Big Data Laboratory, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain; (F.J.Á.); (F.H.-G.)
- BioCritic. Group for Biomedical Research in Critical Care Medicine, 47005 Valladolid, Spain;
- Department of Nephrology, Hospital Virgen de la Concha, 49022 Zamora, Spain
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30
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Rubio-Rivas M, Ronda M, Padulles A, Mitjavila F, Riera-Mestre A, García-Forero C, Iriarte A, Mora JM, Padulles N, Gonzalez M, Solanich X, Gasa M, Suarez-Cuartin G, Sabater J, Perez-Fernandez XL, Santacana E, Leiva E, Ariza-Sole A, Dallaglio PD, Quero M, Soriano A, Pasqualetto A, Koo M, Esteve V, Antoli A, Moreno-Gonzalez R, Yun S, Cerda P, Llaberia M, Formiga F, Fanlo M, Montero A, Chivite D, Capdevila O, Bolao F, Pinto X, Llop J, Sabate A, Guardiola J, Cruzado JM, Comin-Colet J, Santos S, Jodar R, Corbella X. Beneficial effect of corticosteroids in preventing mortality in patients receiving tocilizumab to treat severe COVID-19 illness. Int J Infect Dis 2020; 101:290-297. [PMID: 33035673 PMCID: PMC7537652 DOI: 10.1016/j.ijid.2020.09.1486] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 09/26/2020] [Accepted: 09/30/2020] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES To assess the characteristics and risk factors for mortality in patients with severe coronavirus disease-2019 (COVID-19) treated with tocilizumab (TCZ), alone or in combination with corticosteroids (CS). METHODS From March 17 to April 7, 2020, a real-world observational retrospective analysis of consecutive hospitalized adult patients receiving TCZ to treat severe COVID-19 was conducted at our 750-bed university hospital. The main outcome was all-cause in-hospital mortality. RESULTS A total of 1,092 patients with COVID-19 were admitted during the study period. Of them, 186 (17%) were treated with TCZ, of which 129 (87.8%) in combination with CS. Of the total 186 patients, 155 (83.3 %) patients were receiving noninvasive ventilation when TCZ was initiated. Mean time from symptoms onset and hospital admission to TCZ use was 12 (±4.3) and 4.3 days (±3.4), respectively. Overall, 147 (79%) survived and 39 (21%) died. By multivariate analysis, mortality was associated with older age (HR = 1.09, p < 0.001), chronic heart failure (HR = 4.4, p = 0.003), and chronic liver disease (HR = 4.69, p = 0.004). The use of CS, in combination with TCZ, was identified as a protective factor against mortality (HR = 0.26, p < 0.001) in such severe COVID-19 patients receiving TCZ. No serious superinfections were observed after a 30-day follow-up. CONCLUSIONS In patients with severe COVID-19 receiving TCZ due to systemic host-immune inflammatory response syndrome, the use of CS in addition to TCZ therapy, showed a beneficial effect in preventing in-hospital mortality.
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Affiliation(s)
- Manuel Rubio-Rivas
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
| | - Mar Ronda
- Department of Pharmacy, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Ariadna Padulles
- Department of Pharmacy, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Francesca Mitjavila
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Antoni Riera-Mestre
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Carlos García-Forero
- School of Medicine, Universitat Internacional de Catalunya, Sant Cugat del Vallès, Barcelona, Spain
| | - Adriana Iriarte
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Jose M Mora
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Nuria Padulles
- Department of Pharmacy, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Monica Gonzalez
- Department of Pharmacy, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Xavier Solanich
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Merce Gasa
- Department of Pulmonary Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain; Research Network in Respiratory Diseases (CIBERES), Madrid, Spain
| | - Guillermo Suarez-Cuartin
- Department of Pulmonary Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain; Research Network in Respiratory Diseases (CIBERES), Madrid, Spain
| | - Joan Sabater
- Department of Intensive Care, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain; Innate Immunity and Pathology of Critical Patient-IDIBELL, Barcelona, Spain
| | - Xose L Perez-Fernandez
- Department of Intensive Care, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain; Innate Immunity and Pathology of Critical Patient-IDIBELL, Barcelona, Spain
| | - Eugenia Santacana
- Department of Pharmacy, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Elisabet Leiva
- Department of Pharmacy, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Albert Ariza-Sole
- Department of Cardiology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Paolo D Dallaglio
- Department of Cardiology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Maria Quero
- Department of Nephrology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Antonio Soriano
- Department of Gastroenterology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Alberto Pasqualetto
- Department of Anesthesiology and Reanimation, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Maylin Koo
- Department of Anesthesiology and Reanimation, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Virginia Esteve
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Arnau Antoli
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Rafael Moreno-Gonzalez
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Sergi Yun
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Pau Cerda
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Mariona Llaberia
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Francesc Formiga
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Marta Fanlo
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Abelardo Montero
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - David Chivite
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Olga Capdevila
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Ferran Bolao
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Xavier Pinto
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Josep Llop
- Department of Pharmacy, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Antoni Sabate
- Department of Anesthesiology and Reanimation, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Jordi Guardiola
- Department of Gastroenterology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Josep M Cruzado
- Department of Nephrology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Josep Comin-Colet
- Department of Cardiology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Salud Santos
- Department of Pulmonary Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain; Research Network in Respiratory Diseases (CIBERES), Madrid, Spain
| | - Ramon Jodar
- Department of Pharmacy, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Xavier Corbella
- Department of Internal Medicine, Bellvitge University Hospital, Bellvitge Biomedical Research Institute-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain; School of Medicine, Universitat Internacional de Catalunya, Sant Cugat del Vallès, Barcelona, Spain.
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