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Yendewa GA, Olasehinde T, Mulindwa F, Salata RA, Mohareb AM, Jacobson JM. Chronic Hepatitis B and COVID-19 Clinical Outcomes in the United States: A Multisite Retrospective Cohort Study. Open Forum Infect Dis 2025; 12:ofaf013. [PMID: 39896985 PMCID: PMC11786054 DOI: 10.1093/ofid/ofaf013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 01/08/2025] [Indexed: 02/04/2025] Open
Abstract
Background There is conflicting evidence regarding the impact of chronic hepatitis B virus (HBV) on SARS-CoV-2 outcomes. Additionally, the impact of SARS-CoV-2 vaccination and variant periods on outcomes in HBV/SARS-CoV-2 coinfection remain unexplored. Methods We utilized the TriNetX database to compare adults with HBV/SARS-CoV-2 (vs SARS-CoV-2 alone) across 97 US healthcare systems from 2020 to 2023. We assessed the odds of all inpatient hospitalizations, intensive care unit admissions, mechanical ventilation, 30-day, 90-day, and overall mortality. In sensitivity analyses, we excluded HIV, hepatitis C virus, and transplant cases and stratified the HBV/SARS-CoV-2 cohort by cirrhosis status. We applied propensity score matching to address confounding and reported odds ratios (OR) with 95% confidence intervals (CI). Results Of 4 206 774 individuals with SARS-CoV-2, about 0.2% (8293) were HBV/SARS-CoV-2. Individuals with HBV/SARS-CoV-2 (vs SARS-CoV-2 alone) had higher odds of intensive care unit admissions (OR, 1.18; 95% CI, 1.02-1.36), 90-day (OR, 1.22; 95% CI, 1.01-1.41) and overall mortality (OR, 1.18; 95% CI, 1.06-1.33). In sensitivity analyses, those with HBV/SARS-CoV-2 and cirrhosis had a 2.0- to 2.50-fold higher odds of adverse outcomes. Notably, even individuals with HBV/SARS-CoV-2 without cirrhosis had higher odds of mortality. Vaccinated (vs unvaccinated) individuals with HBV/SARS-CoV-2 had 57%, 54%, and 29% reduction in 30-day, 90-day, and overall mortality, respectively. The pre-Delta variant period was associated with higher odds of hospitalization compared to the Omicron but not the Delta period. Conclusions Chronic HBV was associated with worse SARS-CoV-2 outcomes, whereas SARS-CoV-2 vaccination reduced the likelihood of adverse outcomes.
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Affiliation(s)
- George A Yendewa
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Division of Infectious Diseases and HIV Medicine, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Temitope Olasehinde
- Division of Infectious Diseases and HIV Medicine, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Frank Mulindwa
- Department of Medicine, United Health Services Wilson Medical Center, Johnson City, New York, USA
| | - Robert A Salata
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Division of Infectious Diseases and HIV Medicine, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Amir M Mohareb
- Center for Global Health, Massachusetts General Hospital, Boston, Massachusetts, USA
- Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Jeffrey M Jacobson
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Division of Infectious Diseases and HIV Medicine, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
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Mori N, Nanki T, Hirakawa A, Yamato M, Kaneko Y, Shiokawa R, Ozaki R, Kawabata N, Ohmagari N. Tocilizumab in combination with standard of care in patients with severe COVID-19 pneumonia: Efficacy and safety from a phase 3 clinical trial in Japan. J Infect Chemother 2025; 31:102524. [PMID: 39326494 DOI: 10.1016/j.jiac.2024.09.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 08/21/2024] [Accepted: 09/13/2024] [Indexed: 09/28/2024]
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) is characterized by high interleukin-6 levels. Clinical data supporting tocilizumab, a monoclonal antibody that targets interleukin-6 receptor-alpha, for treating Japanese patients with severe COVID-19 pneumonia are needed. METHODS This single-arm phase 3 study investigated tocilizumab (8 mg/kg) plus standard of care (SOC) in Japanese patients hospitalized with severe COVID-19 pneumonia. Clinical status was assessed using a 7-category ordinal scale on day 28 (primary endpoint) and day 14 (secondary endpoint). Other secondary endpoints were time to improvement (≥2 category improvement) and time to hospital discharge. Safety was assessed as the incidence of adverse events (AEs). RESULTS Among 48 patients enrolled, 44 (91.7 %) scored ≥3 on the 7-category ordinal scale at baseline. At day 28, 35 patients (72.9 %) scored 1 and 5 (10.4 %) scored 7 on the 7-category ordinal scale; 36 (75.0 %, 95 % confidence interval [CI]: 60.40 %-86.36 %) and 39 (81.3 %, 95 % CI: 67.37 %-91.05 %) patients achieved ≥2- and ≥1-category improvement, respectively; 6 patients (12.5 %, 95 % CI: 4.73 %-25.25 %) demonstrated ≥1-category worsening. At day 14, 25 (52.1 %, 95 % CI: 37.19 %-66.71 %) and 33 patients (68.8 %, 95 % CI: 53.75 %-81.34 %) achieved ≥2- and ≥1-category improvement, respectively; 5 patients (10.4 %, 95 % CI: 3.47 %-22.66 %) demonstrated ≥1-category worsening. Median times (95 % CI) to improvement and hospital discharge were 11 (9-15) and 15 (11-18) days, respectively. Forty patients (83.3 %) experienced AEs; the incidence of ≥grade 3 AEs was 25 %. CONCLUSION Tocilizumab plus SOC may provide improved clinical status in Japanese patients with severe COVID-19 pneumonia; no new safety signals were identified.
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Affiliation(s)
- Nobuyoshi Mori
- Division of Infectious Diseases, Department of Medicine, St. Luke's International Hospital, Tokyo, Japan.
| | - Toshihiro Nanki
- Division of Rheumatology, Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan
| | - Akihiro Hirakawa
- Department of Clinical Biostatistics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masaya Yamato
- Division of General Internal Medicine and Infectious Diseases, Rinku General Medical Center, Osaka, Japan
| | - Yuko Kaneko
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | | | - Ryoto Ozaki
- Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
| | | | - Norio Ohmagari
- Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan
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Malioukis A, Snead RS, Marczika J, Ambalavanan R. Pathophysiological, Neuropsychological, and Psychosocial Influences on Neurological and Neuropsychiatric Symptoms of Post-Acute COVID-19 Syndrome: Impacts on Recovery and Symptom Persistence. Biomedicines 2024; 12:2831. [PMID: 39767737 PMCID: PMC11673694 DOI: 10.3390/biomedicines12122831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/09/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025] Open
Abstract
Although the impact of post-acute COVID-19 syndrome (PACS) on patients and public health is undeniably significant, its etiology remains largely unclear. Much research has been conducted on the pathophysiology, shedding light on various aspects; however, due to the multitude of symptoms and clinical conditions that directly or indirectly define PACS, it is challenging to establish definitive causations. In this exploration, through systematically reviewing the latest pathophysiological findings related to the neurological symptoms of the syndrome, we aim to examine how psychosocial and neuropsychological symptoms may overlap with neurological ones, and how they may not only serve as risk factors but also contribute to the persistence of some primary symptoms of the disorder. Findings from our synthesis suggest that psychological and psychosocial factors, such as anxiety, depression, and loneliness, may interact with neurological symptoms in a self-reinforcing feedback loop. This cycle seems to be affecting both physical and psychological distress, potentially increasing the persistence and severity of PACS symptoms. By pointing out this interaction, in this review study, we attempt to offer a new perspective on the interconnected nature of psychological, psychosocial, and neurological factors, emphasizing the importance of integrated treatment approaches to disrupt this cycle and improve outcomes when possible.
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Lima V, Morais STB, Ferreira VG, Almeida MB, Silva MPB, de A. Lopes T, de Oliveira JM, Raimundo JRS, Furtado DZS, Fonseca FLA, Oliveira RV, Cardoso DR, Carrilho E, Assunção NA. Multiplatform Metabolomics: Enhancing the Severity Risk Prognosis of SARS-CoV-2 Infection. ACS OMEGA 2024; 9:45746-45758. [PMID: 39583673 PMCID: PMC11579725 DOI: 10.1021/acsomega.4c02557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 10/21/2024] [Accepted: 10/28/2024] [Indexed: 11/26/2024]
Abstract
Concerns about the SARS-CoV-2 outbreak (COVID-19) continue to persist even years later, with the emergence of new variants and the risk of disease severity. Common clinical symptoms, like cough, fever, and respiratory symptoms, characterize the noncritical patients, classifying them from mild to moderate. In a more severe and complex scenario, the virus infection can affect vital organs, resulting, for instance, in pneumonia and impaired kidney and heart function. However, it is well-known that subclinical symptoms at a metabolic level can be observed previously but require a proper diagnosis because viral replication on the host leaves a track with a different profile depending on the severity of the illness. Metabolomic profiles of mild, moderate, and severe COVID-19 patients were obtained by multiple platforms (LC-HRMS and MALDI-MS), increasing the chance to elucidate a prognosis for severity risk. A strong link was discovered between phenylalanine metabolism and increased COVID-19 severity symptoms, a pathway linked to cardiac and neurological consequences. Glycerophospholipids and sphingolipid metabolisms were also dysregulated linearly with the increasing symptom severity, which can be related to virus proliferation, immune system avoidance, and apoptosis escaping. Our data, endorsed by other literature, strengthens the notion that these pathways might play a vital role in a patient's prognosis.
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Affiliation(s)
- Vinicius
S. Lima
- Programa
de Pós-Graduação em Medicina Translacional, Departamento
de Medicina, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil
| | - Sinara T. B. Morais
- Instituto
de Química de São Carlos, Universidade de São Paulo, São Carlos 13566-590, Brazil
| | - Vinicius G. Ferreira
- Instituto
de Química de São Carlos, Universidade de São Paulo, São Carlos 13566-590, Brazil
- Instituto
Nacional de Ciência e Tecnologia de Bioanalítica, INCTBio, Campinas 13083-861, Brazil
| | - Mariana B. Almeida
- Instituto
de Química de São Carlos, Universidade de São Paulo, São Carlos 13566-590, Brazil
- Instituto
Nacional de Ciência e Tecnologia de Bioanalítica, INCTBio, Campinas 13083-861, Brazil
| | - Manuel Pedro Barros Silva
- Programa
de Pós-Graduação em Medicina Translacional, Departamento
de Medicina, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil
| | - Thais de A. Lopes
- Departamento
de Química, Universidade Federal
de São Carlos, São Carlos, São Paulo 13565-905, Brazil
| | - Juliana M. de Oliveira
- Departamento
de Química, Universidade Federal
de São Carlos, São Carlos, São Paulo 13565-905, Brazil
| | | | - Danielle Z. S. Furtado
- Programa
de Pós-Graduação em Medicina Translacional, Departamento
de Medicina, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil
| | - Fernando L. A. Fonseca
- Faculdade
de Medicina do ABC, Santo André, São Paulo 09060-870, Brazil
- Departamento
de Química, Universidade Federal
de São Paulo, São
Paulo 05508-070, Brazil
| | - Regina V. Oliveira
- Departamento
de Química, Universidade Federal
de São Carlos, São Carlos, São Paulo 13565-905, Brazil
| | - Daniel R. Cardoso
- Instituto
de Química de São Carlos, Universidade de São Paulo, São Carlos 13566-590, Brazil
| | - Emanuel Carrilho
- Instituto
de Química de São Carlos, Universidade de São Paulo, São Carlos 13566-590, Brazil
- Instituto
Nacional de Ciência e Tecnologia de Bioanalítica, INCTBio, Campinas 13083-861, Brazil
| | - Nilson A. Assunção
- Programa
de Pós-Graduação em Medicina Translacional, Departamento
de Medicina, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil
- Departamento
de Química, Universidade Federal
de São Paulo, São
Paulo 05508-070, Brazil
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Saricaoglu EM, Coskun B, Ayhan M, Akinci E, Kayaaslan B, Aypak A, Tekce AYT, Hasanoglu I, Kaya A, Eser F, Bilir YA, Ozdemir B, Buzgan T, Guner R. A New Laboratory Tool for COVID-19 Severity Prediction, CENIL Score. Diagnostics (Basel) 2024; 14:2557. [PMID: 39594223 PMCID: PMC11592550 DOI: 10.3390/diagnostics14222557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 10/29/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND/OBJECTIVES Several studies investigated the risk factors for severe COVID-19-related outcomes. Early identification and proper treatment of COVID-19 patients who may develop severe pneumonia are crucial. The aim of this study was to detect the importance of the laboratory parameters for risk prediction of severe pneumonia in COVID-19 patients. METHODS This retrospective cohort study included COVID-19 patients' laboratory parameters at admission. Biochemical, hematological, coagulation, and inflammatory parameters values were compared between the non-severe and severe groups. RESULTS A total of 534 COVID-19 patients were screened, and 472 of them were included in this study. The mean age of patients was 64 (±3.1) years; 242 (51.3%) were men. A total of 204 (43.2%) patients were diagnosed as severe cases. The independent predictors of severe illness were C-reactive peptide, Eosinophil, neutrophil-lymphocyte ratio, interleukin-6, and lactate dehydrogenase. These parameters were named as CENIL scores from 0 to 5 points. The findings of this study indicate that these biomarkers identified tend to increase progressively with disease severity in severe COVID-19 patients. Additionally, the CENIL risk score identified a specific cut-off value of 3, highlighting it as a critical threshold for identifying patients at high risk of severe COVID-19 progression. CONCLUSIONS In this study, we identified biomarkers-including CRP, eosinophil count, NLR, IL-6, and LDH-named as CENIL risk score that can help predict the likelihood of severe disease at diagnosis. Clinicians may be more vigilant regarding the development of severe disease in patients with high CENIL risk scores, guided by clinical and radiological findings.
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Affiliation(s)
- Elif Mukime Saricaoglu
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Ankara University, Ankara 06100, Turkey
| | - Belgin Coskun
- Department of Infectious Diseases and Clinical Microbiology, Ankara City Hospital, Ankara 06800, Turkey; (B.C.); (M.A.); (Y.A.B.); (B.O.)
| | - Muge Ayhan
- Department of Infectious Diseases and Clinical Microbiology, Ankara City Hospital, Ankara 06800, Turkey; (B.C.); (M.A.); (Y.A.B.); (B.O.)
| | - Esragul Akinci
- Department of Infectious Diseases and Clinical Microbiology, Ankara City Hospital, University of Health Sciences, Ankara 06290, Turkey; (E.A.); (A.A.); (A.Y.T.T.)
| | - Bircan Kayaaslan
- Department of Infectious Diseases and Clinical Microbiology, Ankara City Hospital, Ankara Yıldırım Beyazıt University, Ankara 06690, Turkey; (B.K.); (I.H.); (A.K.); (F.E.); (T.B.); (R.G.)
| | - Adalet Aypak
- Department of Infectious Diseases and Clinical Microbiology, Ankara City Hospital, University of Health Sciences, Ankara 06290, Turkey; (E.A.); (A.A.); (A.Y.T.T.)
| | - Ayse Yasemin Tezer Tekce
- Department of Infectious Diseases and Clinical Microbiology, Ankara City Hospital, University of Health Sciences, Ankara 06290, Turkey; (E.A.); (A.A.); (A.Y.T.T.)
| | - Imran Hasanoglu
- Department of Infectious Diseases and Clinical Microbiology, Ankara City Hospital, Ankara Yıldırım Beyazıt University, Ankara 06690, Turkey; (B.K.); (I.H.); (A.K.); (F.E.); (T.B.); (R.G.)
| | - Ayse Kaya
- Department of Infectious Diseases and Clinical Microbiology, Ankara City Hospital, Ankara Yıldırım Beyazıt University, Ankara 06690, Turkey; (B.K.); (I.H.); (A.K.); (F.E.); (T.B.); (R.G.)
| | - Fatma Eser
- Department of Infectious Diseases and Clinical Microbiology, Ankara City Hospital, Ankara Yıldırım Beyazıt University, Ankara 06690, Turkey; (B.K.); (I.H.); (A.K.); (F.E.); (T.B.); (R.G.)
| | - Yesim Aybar Bilir
- Department of Infectious Diseases and Clinical Microbiology, Ankara City Hospital, Ankara 06800, Turkey; (B.C.); (M.A.); (Y.A.B.); (B.O.)
| | - Burcu Ozdemir
- Department of Infectious Diseases and Clinical Microbiology, Ankara City Hospital, Ankara 06800, Turkey; (B.C.); (M.A.); (Y.A.B.); (B.O.)
| | - Turan Buzgan
- Department of Infectious Diseases and Clinical Microbiology, Ankara City Hospital, Ankara Yıldırım Beyazıt University, Ankara 06690, Turkey; (B.K.); (I.H.); (A.K.); (F.E.); (T.B.); (R.G.)
| | - Rahmet Guner
- Department of Infectious Diseases and Clinical Microbiology, Ankara City Hospital, Ankara Yıldırım Beyazıt University, Ankara 06690, Turkey; (B.K.); (I.H.); (A.K.); (F.E.); (T.B.); (R.G.)
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Saied YM, Abou Warda AE, Allam RM, Syed W, Basil A. Al-Rawi M, Iqbal A, Elgendy MO, M. El-Sabaa R, Hassan A. The Impact of Infliximab on Hyperinflammation State in Hospitalized COVID-19 Patients: A Retrospective Study. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1670. [PMID: 39459457 PMCID: PMC11509666 DOI: 10.3390/medicina60101670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 09/21/2024] [Accepted: 10/02/2024] [Indexed: 10/28/2024]
Abstract
Background and Objectives: Elevated levels of pro-inflammatory cytokines have been linked to increased mortality in COVID-19 patients. Infliximab, a tumor necrosis factor inhibitor, has been reported to improve outcomes in COVID-19 patients by targeting the hyperinflammatory response. Our objective was to evaluate the effectiveness of incorporating Infliximab into standard care guidelines for the management of COVID-19. Materials and Methods: A retrospective analysis was conducted on 111 participants who were moderate to severe COVID-19 patients admitted to the hospital. Among them, 74 individuals received solely standard treatment, while 37 received standard therapy plus Infliximab. The primary outcomes of the study centered around the changes in laboratory test parameters. The secondary clinical findings included clinical recovery defined as improvement in patient oxygenation, time till recovery, and assessing necessity for ICU admission, and mortality rates. Results: There was no statistical difference observed in the inflammatory markers including, LDH, Ferritin, CRP, neutrophil to lymphocyte ratio (NLR), and P/F ratio between both groups and in the clinical outcomes including clinical recovery (p = 1.0), time to improvement (p = 0.436), and mortality rate (p = 0.601). However, there was a significant increase in secondary infection (45.9%, 20.3%; p = 0.005), and in liver enzymes, ALT (79.5, 50.0 IU/L; p = 0.02) and AST (57.5, 38.0 IU/L; p = 0.019) in the Infliximab group and the standard care group, respectively. Conclusions: Infliximab therapy did not demonstrate significant benefits compared to standard of care in moderate to severe hospitalized COVID-19 patients.
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Affiliation(s)
- Yasmine M. Saied
- Microbiology and Immunology Postgraduate Program, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Ahmed Essam Abou Warda
- Clinical Pharmacy Department, Faculty of Pharmacy, October 6 University, Giza 12585, Egypt;
| | - Rasha Mahmoud Allam
- Cancer Epidemiology and Biostatistics, National Cancer Institute, Cairo University, Cairo 11796, Egypt;
| | - Wajid Syed
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Mahmood Basil A. Al-Rawi
- Department of Optometry, College of Applied Medical Sciences, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Ayesha Iqbal
- Department of Pharmacy Practice and Policy, University Park Campus, University of Nottingham, Nottingham NG7 2QL, UK;
- Office of Lifelong Learning and the Physician Learning Program, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G1C9, Canada
| | - Marwa O. Elgendy
- Department of Clinical Pharmacy, Beni-Suef University Hospitals, Beni-Suef University, Beni-Suef 62521, Egypt;
- Department of Clinical Pharmacy, Faculty of Pharmacy, Nahda University (NUB), Beni-Suef 62764, Egypt
| | - Ramy M. El-Sabaa
- Clinical Pharmacy Department, Faculty of Pharmacy, Menoufia University, Menoufia 32511, Egypt;
| | - Ahmed Hassan
- Clinical Pharmacy Department, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt;
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Amante EJB, David-Wang AS, Tee ML, Punzalan FER, Añonuevo JC, Fernandez LC, Albay AB, Malabad JCM, Climacosa FMM, Pajes ANNI, Cuaño PMGM, Alejandría MM. Intravenous Tocilizumab versus Standard of Care in the Treatment of Severe and Critical COVID-19-related Pneumonia: A Single-center, Double-blind, Placebo-controlled, Phase 3 Trial. ACTA MEDICA PHILIPPINA 2024; 58:7-13. [PMID: 38846161 PMCID: PMC11151130 DOI: 10.47895/amp.vi0.6175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/09/2024]
Abstract
Background Severe and critical COVID-19 disease is characterized by hyperinflammation involving pro-inflammatory cytokines, particularly IL-6. Tocilizumab is a monoclonal antibody that blocks IL-6 receptors. Objectives This study evaluated the efficacy of tocilizumab in Filipino patients with severe to critical COVID-19 disease. Methods This phase 3 randomized double-blind trial, included patients hospitalized for severe or critical COVID-19 in a 1:1 ratio to receive either tocilizumab plus local standard of care or placebo plus standard of care. Patients were eligible for a repeat IV infusion within 24-48 hours if they deteriorated or did not improve. Treatment success or clinical improvement was defined as at least two categories of improvement from baseline in the WHO 7-point Ordinal Scale of patient status, in an intention-to-treat manner. Results Forty-nine (49) patients were randomized in the tocilizumab arm and 49 in the placebo arm. There was no significant difference in age, comorbidities, COVID-19 severity, need for mechanical ventilation, presence of acute respiratory distress syndrome, or biomarker levels between groups. Use of adjunctive therapy was similar between groups, with corticosteroid used in 91.8% in tocilizumab group and 81.6% in the placebo group, while remdesivir was used in 98% of participants in both groups.There was no significant difference between groups in terms of treatment success in both the intention-to-treat analysis (relative risk=1.05, 95% CI: 0.85-1.30) and per-protocol analysis (relative risk=0.98, 95% CI: 0.80 to 1.21). There was no significant difference in time to improvement of at least two categories relative to baseline on the 7-point Ordinal Scale of clinical status. Conclusion The use of tocilizumab on top of standard of care in the management of patients with severe to critical COVID-19 did not result in significant improvement as defined by the WHO 7-point Ordinal Scale of patient status, nor in significant improvement in incidence of mechanical ventilation, incidence of ICU admission, length of ICU stay, and mortality rate.
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Affiliation(s)
- Eric Jason B. Amante
- Department of Medicine, Philippine General Hospital, University of the Philippines Manila
- College of Medicine, University of the Philippines Manila
| | - Aileen S. David-Wang
- Department of Medicine, Philippine General Hospital, University of the Philippines Manila
- College of Medicine, University of the Philippines Manila
| | - Michael L. Tee
- Department of Medicine, Philippine General Hospital, University of the Philippines Manila
- College of Medicine, University of the Philippines Manila
| | - Felix Eduardo R. Punzalan
- Department of Medicine, Philippine General Hospital, University of the Philippines Manila
- College of Medicine, University of the Philippines Manila
| | - John C. Añonuevo
- Department of Medicine, Philippine General Hospital, University of the Philippines Manila
- College of Medicine, University of the Philippines Manila
| | - Lenora C. Fernandez
- Department of Medicine, Philippine General Hospital, University of the Philippines Manila
- College of Medicine, University of the Philippines Manila
| | - Albert B. Albay
- Department of Medicine, Philippine General Hospital, University of the Philippines Manila
- College of Medicine, University of the Philippines Manila
| | | | | | - A. Nico Nahar I. Pajes
- Department of Medicine, Philippine General Hospital, University of the Philippines Manila
- College of Medicine, University of the Philippines Manila
| | - Patricia Maria Gregoria M. Cuaño
- Department of Medicine, Philippine General Hospital, University of the Philippines Manila
- College of Medicine, University of the Philippines Manila
| | - Marissa M. Alejandría
- Department of Medicine, Philippine General Hospital, University of the Philippines Manila
- College of Medicine, University of the Philippines Manila
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Kutlutürk I, Tokuç EÖ, Karabaş L, Rückert R, Kaya M, Karagöz A, Munk MR. How the immune response to the structural proteins of SARS-CoV-2 affects the retinal vascular endothelial cells: an immune thrombotic and/or endotheliopathy process with in silico modeling. Immunol Res 2024; 72:50-71. [PMID: 37642808 DOI: 10.1007/s12026-023-09412-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 07/28/2023] [Indexed: 08/31/2023]
Abstract
Thrombotic events associated with SARS-CoV-2 at the vascular endothelium still remains unclear. The aim of the current study is to determine the relationship between cellular proteins on the (ocular) vascular endothelial surface and the immune thrombotic and/or endotheliopathy process elicited by SARS-CoV-2 using an in-silico modeling. The structural S (spike glycoprotein), N (nucleocapsid protein), M (membrane protein), and E (envelope protein) proteins, an accessory protein (ORF1ab) of SARS-CoV-2 and 158 cellular proteins associated with retinal vascular endothelial cell surface or structure were included in this study for comparison of three-dimensional (3D) structure and sequence. Sixty-nine of the retinal proteins were obtained from the Uniprot database. Remaining proteins not included in the database were included in the study after they were converted into 3D structures using the RaptorX web tool. Sequence and three-dimensional structure of SARS-COV-2 S, N, M, E, ORF1ab proteins and retinal vascular endothelial proteins were compared with mTM-align server. Proteins with significant similarity (score above 0.5) were validated with the TM-align web server. Immune and thrombosis-related protein-receptor interactions of similar proteins was checked with CABS-dock. We detected a high level of structural similarity between E protein and ACE, ACE2, LAT1, and TM9SF4 endothelial proteins. In addition, PECAM-1 was found to be structurally similar to ORF1ab and S protein. When we evaluated the likelihood/potential to stimulate an immune responses/a cytokine release, TLR-2 and TLR-3, which are highly susceptible to SARS-CoV2, showed a potential receptor-protein interaction with retinal vascular endothelial proteins. Our study demonstrates that SARS-CoV-2 proteins may have structural similarities with vascular endothelial proteins, and therefore, as immunological target sites, the counterpart proteins on the endothelial surface of many organs may also be secondarily affected by any immune response against SARS-CoV-2 structural proteins.
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Affiliation(s)
- Işıl Kutlutürk
- Division of Ophthalmology, Ümraniye Trn. And Rch. Hospital, Istanbul, Turkey.
| | - Ecem Önder Tokuç
- Ophthalmology Department, University of Health Science, Derince Training and Research Hospital, Izmit-Kocaeli, Turkey
| | - Levent Karabaş
- Ophthalmology Department, Kocaeli University School of Medicine, Izmit-Kocaeli, Turkey
| | | | | | - Ali Karagöz
- Koşuyolu High Specialization Education and Research Hospital, Istanbul, Turkey
| | - Marion R Munk
- Inselspital, University Hospital Bern, Bern, Switzerland
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- Augenarzt-Praxisgemeinschaft Gutblick AG, Bern, Switzerland
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9
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Uemura Y, Ozaki R, Shinozaki T, Ohtsu H, Shimizu Y, Izumi K, Saito S, Matsunaga N, Ohmagari N. Comparative effectiveness of tocilizumab vs standard care in patients with severe COVID-19-related pneumonia: a retrospective cohort study utilizing registry data as a synthetic control. BMC Infect Dis 2023; 23:849. [PMID: 38049729 PMCID: PMC10694888 DOI: 10.1186/s12879-023-08840-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 11/23/2023] [Indexed: 12/06/2023] Open
Abstract
BACKGROUND The severity of coronavirus disease 2019 (COVID-19) infections has led to the development of several therapeutic agents, with tocilizumab becoming increasingly used to treat patients with COVID-19-related pneumonia. This study compared the use of tocilizumab treatment with the standard of care (SOC) to determine its efficacy against severe COVID-19-related pneumonia in Japan. METHODS This retrospective cohort study was designed to evaluate the efficacy of tocilizumab in two different databases: the JA42434 single-arm study and COVID-19 Registry Japan (COVIREGI-JP), with a synthetic control group from the COVIREGI-JP cohort as a benchmark for the tocilizumab group. The study's primary objective was to evaluate the efficacy of tocilizumab in treating severe COVID-19-related pneumonia compared to the SOC among patients included in the above two databases. The SOC group was extracted as the synthetic control group using exact matching and a propensity score matching in sequence per subject. As a secondary objective, the efficacy of tocilizumab compared to the SOC was evaluated exclusively among patients included in the COVIREGI-JP database. In each objective, the primary endpoint was defined as the time to discharge or the status of awaiting discharge. RESULTS For the primary endpoint, the hazard ratio (HR) of the tocilizumab group against the SOC group was 1.070 (95% confidence interval [CI]: 0.565-2.028). The median time from Study Day 1 to discharge or the state of awaiting discharge was 15 days in the tocilizumab group and 16 days in the SOC group. The HRs for the secondary endpoints, namely, time to improvement in the clinical state, time to clinical failure, and time to recovery, were 1.112 (95% CI: 0.596-2.075), 0.628 (95% CI: 0.202-1.953), and 1.019 (95% CI: 0.555-1.871), respectively. Similarly, the HR of the primary endpoint for the secondary objective was 0.846 (95% CI: 0.582-1.230). CONCLUSIONS Tocilizumab did not demonstrate a positive effect on time to discharge or the state of awaiting discharge. Furthermore, no statistically significant differences in other clinical outcomes, such as time to improvement in the clinical state, time to clinical failure, and time to recovery, were observed among the groups.
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Affiliation(s)
- Yukari Uemura
- Biostatistics Section, Department of Data Science, Center for Clinical Sciences, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjyuku-ku, Tokyo, 162-8655, Japan.
| | - Ryoto Ozaki
- Biometrics Department, Clinical Development Division, Chugai Pharmaceutical CO., LTD, Tokyo, Japan
| | - Tomohiro Shinozaki
- Department of Information and Computer Technology, Faculty of Engineering, Tokyo University of Science, Tokyo, Japan
| | - Hiroshi Ohtsu
- Clinical Pharmacology and Regulatory Sciences, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yousuke Shimizu
- Biostatistics Section, Department of Data Science, Center for Clinical Sciences, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjyuku-ku, Tokyo, 162-8655, Japan
| | - Kazuo Izumi
- Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
| | - Sho Saito
- Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Nobuaki Matsunaga
- Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Norio Ohmagari
- Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan
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10
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Maimunah U, Maharani ARK, Soegiarto G, Rahniayu A, Gunawan VA, Wiratama PA, Djuanda SN, Supriadi S, Marhana IA, Semedi BP, Lefi A, Kusumastuti EH, Suyanto E, Lilihata JG, Anggoro A, Rinjani LGP, Rosyid AN, Wahyu D, Fauziah D, Rahaju AS, Kurniasari N, Ariani G, Nugroho GMS, Yandi IKR, Nugraha RA. Correlation between interleukin-6 expression in post-mortem core liver biopsy and degree of liver injury in patients with fatal COVID-19. NARRA J 2023; 3:e463. [PMID: 38455630 PMCID: PMC10919438 DOI: 10.52225/narra.v3i3.463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 12/04/2023] [Indexed: 03/09/2024]
Abstract
Excessive release of interleukin-6 (IL-6) during the progression of coronavirus disease 2019 (COVID-19) induces cytokine storms, resulting in multi-organ damages including liver injury, similar in nature with mechanism of viral hepatitis. Systemic IL-6 has been associated with the incidence of liver injury among COVID-19 patients; however, studies on IL-6 expression in the liver tissue are completely lacking. The aim of this study was to measure the IL-6 expression in the liver tissues and to determine its correlation with the degree of liver injury in fatal COVID-19 patients. Through this first cross-sectional study, IL-6 expression was measured through immunohistochemical staining and the degree of liver injury was identified based on level of serum alanine aminotransferase (ALT). The Spearman correlation test was used to identify the correlation between IL-6 expression and the degree of liver injury. A total of 47 deceased COVID-19 patients were included and IL-6 expression was observed in all post-mortem liver specimens, ranging from mild to strong expression. Liver injury at various degrees (mild to severe) was found in more than half (59.5%) of the cases. The Spearman correlation analysis suggested a statistically insignificant correlation between liver IL-6 expression and the degree of liver injury (r=0.152; p=0.309). In conclusion, even IL-6 expression was observed in all post-mortem liver specimens, there was an insignificant correlation between IL-6 expression in the liver tissue with the degree of liver injury among fatal COVID-19 patients, suggesting that IL-6 was not the only main factor contributing to liver damage in COVID-19 patients.
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Affiliation(s)
- Ummi Maimunah
- Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Andi RK. Maharani
- Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Gatot Soegiarto
- Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Alphania Rahniayu
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pathology Anatomy, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Vania A. Gunawan
- Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Priangga A. Wiratama
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pathology Anatomy, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Stephanie N. Djuanda
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pathology Anatomy, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Supriadi Supriadi
- Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Isnin A. Marhana
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pulmonology and Respiratory Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Bambang P. Semedi
- Department of Anesthesiology and Reanimation, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Anesthesiology and Reanimation, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia;
| | - Achmad Lefi
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Cardiology and Vascular Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Etty H. Kusumastuti
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pathology Anatomy, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Edi Suyanto
- Department of Forensics and Medicolegal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Forensics and Medicolegal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Jilientasia G. Lilihata
- Department of Anesthesiology and Reanimation, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Anesthesiology and Reanimation, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia;
| | - Adhitri Anggoro
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pulmonology and Respiratory Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Lalu GP. Rinjani
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Cardiology and Vascular Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Alfian N. Rosyid
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pulmonology and Respiratory Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Dwi Wahyu
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pulmonology and Respiratory Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Dyah Fauziah
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pathology Anatomy, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Anny S. Rahaju
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pathology Anatomy, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Nila Kurniasari
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pathology Anatomy, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Grace Ariani
- Department of Pathology Anatomy, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pathology Anatomy, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Gilang MS. Nugroho
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pulmonology and Respiratory Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - I KR. Yandi
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Pulmonology and Respiratory Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Ricardo A. Nugraha
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Cardiology and Vascular Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
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11
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Mustafa SS, Stern RA, Patel PC, Chu DK. COVID-19 Treatments: Then and Now. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:3321-3333. [PMID: 37558163 DOI: 10.1016/j.jaip.2023.07.045] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 07/21/2023] [Accepted: 07/27/2023] [Indexed: 08/11/2023]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has evolved over the past 3+ years, and strategies to prevent illness and treat infection have changed over time. As COVID-19 transitions from a pandemic to an endemic infection, widespread nonpharmaceutical interventions such as mask mandates and governmental policies requiring social distancing have given way to more selective strategies for risk mitigation. Monoclonal antibody therapies used for disease prevention and treatment lost utility owing to the emergence of resistant viral variants. Oral antiviral medications have become the mainstay of treatment in nonhospitalized individuals, whereas systemic corticosteroids remain the cornerstone of therapy in those requiring supplemental oxygen. Emerging literature also supports the use of additional immune-modulating therapies in select admitted patients. Importantly, the COVID-19 pandemic highlighted both unprecedented research and development of medical interventions while also drawing attention to significant pitfalls in the global response. This review provides a comprehensive update in prevention and management of COVID-19.
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Affiliation(s)
- S Shahzad Mustafa
- Department of Medicine, Rochester Regional Health, Rochester, NY; Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.
| | - Rebecca A Stern
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Pratish C Patel
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Derek K Chu
- Department of Medicine, Evidence in Allergy Group, Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ont, Canada
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12
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Rose-John S, Jenkins BJ, Garbers C, Moll JM, Scheller J. Targeting IL-6 trans-signalling: past, present and future prospects. Nat Rev Immunol 2023; 23:666-681. [PMID: 37069261 PMCID: PMC10108826 DOI: 10.1038/s41577-023-00856-y] [Citation(s) in RCA: 168] [Impact Index Per Article: 84.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/01/2023] [Indexed: 04/19/2023]
Abstract
Interleukin-6 (IL-6) is a key immunomodulatory cytokine that affects the pathogenesis of diverse diseases, including autoimmune diseases, chronic inflammatory conditions and cancer. Classical IL-6 signalling involves the binding of IL-6 to the membrane-bound IL-6 receptor α-subunit (hereafter termed 'mIL-6R') and glycoprotein 130 (gp130) signal-transducing subunit. By contrast, in IL-6 trans-signalling, complexes of IL-6 and the soluble form of IL-6 receptor (sIL-6R) signal via membrane-bound gp130. A third mode of IL-6 signalling - known as cluster signalling - involves preformed complexes of membrane-bound IL-6-mIL-6R on one cell activating gp130 subunits on target cells. Antibodies and small molecules have been developed that block all three forms of IL-6 signalling, but in the past decade, IL-6 trans-signalling has emerged as the predominant pathway by which IL-6 promotes disease pathogenesis. The first selective inhibitor of IL-6 trans-signalling, sgp130, has shown therapeutic potential in various preclinical models of disease and olamkicept, a sgp130Fc variant, had promising results in phase II clinical studies for inflammatory bowel disease. Technological developments have already led to next-generation sgp130 variants with increased affinity and selectivity towards IL-6 trans-signalling, along with indirect strategies to block IL-6 trans-signalling. Here, we summarize our current understanding of the biological outcomes of IL-6-mediated signalling and the potential for targeting this pathway in the clinic.
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Affiliation(s)
- Stefan Rose-John
- Biochemical Institute, Medical Faculty, Christian-Albrechts-University, Kiel, Germany
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
- Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Christoph Garbers
- Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation (GC:I3), Otto-von-Guericke-University, Magdeburg, Germany
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke-University, Magdeburg, Germany
| | - Jens M Moll
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Jürgen Scheller
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
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13
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Shivram H, Hackney JA, Rosenberger CM, Teterina A, Qamra A, Onabajo O, McBride J, Cai F, Bao M, Tsai L, Regev A, Rosas IO, Bauer RN. Transcriptomic and proteomic assessment of tocilizumab response in a randomized controlled trial of patients hospitalized with COVID-19. iScience 2023; 26:107597. [PMID: 37664617 PMCID: PMC10470387 DOI: 10.1016/j.isci.2023.107597] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/16/2023] [Accepted: 08/08/2023] [Indexed: 09/05/2023] Open
Abstract
High interleukin (IL)-6 levels are associated with greater COVID-19 severity. IL-6 receptor blockade by tocilizumab (anti-IL6R; Actemra) is used globally for the treatment of severe COVID-19, yet a molecular understanding of the therapeutic benefit remains unclear. We characterized the immune profile and identified cellular and molecular pathways modified by tocilizumab in peripheral blood samples from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial of the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19. We identified markers of inflammation, lymphopenia, myeloid dysregulation, and organ injury that predict disease severity and clinical outcomes. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab and identified novel pharmacodynamic biomarkers. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysregulation associated with severe COVID-19, indicating greater anti-inflammatory activity relative to placebo and potentially leading to faster recovery in patients hospitalized with COVID-19.
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Affiliation(s)
| | | | | | | | - Aditi Qamra
- Hoffmann-La Roche Ltd, Mississauga, ON L5N 5M8, Canada
| | | | | | - Fang Cai
- Genentech, South San Francisco, CA 94080, USA
| | - Min Bao
- Genentech, South San Francisco, CA 94080, USA
| | - Larry Tsai
- Genentech, South San Francisco, CA 94080, USA
| | - Aviv Regev
- Genentech, South San Francisco, CA 94080, USA
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14
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Vannucchi V, Pelagatti L, Barone F, Bertini L, Celli T, Boccia N, Veneziani F, Cimolato B, Landini G. Delirium and IL-6 added to clinical scores improves their performance: a prospective analysis of CALL, PREDI-CO, MRS score applied to a population of patients admitted to internal medicine ward. Intern Emerg Med 2023; 18:1689-1700. [PMID: 37329431 PMCID: PMC10504150 DOI: 10.1007/s11739-023-03336-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 06/01/2023] [Indexed: 06/19/2023]
Abstract
This study aimed to evaluate the effectiveness of various scoring systems in predicting in-hospital mortality for COVID-19 patients admitted to the internal medicine ward. We conducted a prospective collection of clinical data from patients admitted to the Internal Medicine Unit at Santa Maria Nuova Hospital in Florence, Italy, with confirmed pneumonia caused by SARS-CoV-2. We calculated three scoring systems: the CALL score, the PREDI-CO score, and the COVID-19 in-hospital Mortality Risk Score (COVID-19 MRS). The primary endpoint was in-hospital mortality. : A total of 681 patients were enrolled in the study, with a mean age of 68.8 ± 16.1 years, and 54.8% of them were male. Non-survivors had significantly higher scores in all prognostic systems compared to survivors (MRS: 13 [12- 15] vs. 10 [8-12]; CALL: 12 [10-12] vs. 9 [7-11]; PREDI-CO: 4 [3-6] vs. 2 [1-4]; all p<0.001). The receiver operating characteristic (ROC) analysis yielded the following area under the curve (AUC) values: MRS 0.85, CALL 0.78, PREDI-CO 0.77. The addition of Delirium and IL6 to the scoring systems improved their discriminative ability, resulting in AUC values of 0.92 for MRS, 0.87 for CALL, and 0.84 for PREDI-CO. The mortality rate increased significantly across increasing quartiles (p<0.001). In conclusion the COVID-19 in-hospital Mortality Risk Score (MRS) demonstrated reasonable prognostic stratification for patients admitted to the internal medicine ward with SARS-CoV-2-induced pneumonia. The inclusion of Delirium and IL6 as additional prognostic indicators in the scoring systems enhanced their predictive performance, specifically in determining in-hospital mortality among COVID-19 patients.
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Affiliation(s)
- Vieri Vannucchi
- Internal Medicine, Santa, Maria Nuova Hospital, Piazza di Santa Maria Nuova 1, 50121 Florence, Italy
| | - Lorenzo Pelagatti
- Internal Medicine, Santa, Maria Nuova Hospital, Piazza di Santa Maria Nuova 1, 50121 Florence, Italy
- High-Dependency Unit, AOU Careggi, Florence, Italy
| | - Fabio Barone
- School of Medicine, University of Florence, Florence, Italy
| | - Laura Bertini
- Internal Medicine, Santa, Maria Nuova Hospital, Piazza di Santa Maria Nuova 1, 50121 Florence, Italy
| | - Tommaso Celli
- Internal Medicine, Santa, Maria Nuova Hospital, Piazza di Santa Maria Nuova 1, 50121 Florence, Italy
| | - Nunzia Boccia
- Internal Medicine, Santa, Maria Nuova Hospital, Piazza di Santa Maria Nuova 1, 50121 Florence, Italy
| | - Francesca Veneziani
- Laboratory of Clinical Pathology, Santa Maria Nuova Hospital, Florence, Italy
- Laboratory of Clinical Pathology, San Giovanni di Dio Hospital, Florence, Italy
| | - Barbara Cimolato
- Internal Medicine, Santa, Maria Nuova Hospital, Piazza di Santa Maria Nuova 1, 50121 Florence, Italy
| | - Giancarlo Landini
- Internal Medicine, Santa, Maria Nuova Hospital, Piazza di Santa Maria Nuova 1, 50121 Florence, Italy
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15
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Zhu K, Tsai O, Chahal D, Hussaini T, Yoshida EM. COVID-19 and Liver Disease: An Evolving Landscape. Semin Liver Dis 2023; 43:351-366. [PMID: 37604206 DOI: 10.1055/a-2157-3318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/23/2023]
Abstract
The COVID-19 pandemic has resulted in significant worldwide morbidity and mortality. In this review, we examine the intricate relationships between COVID-19 and liver diseases. While respiratory manifestations of COVID-19 are well known, its impact and consequences in patients with liver diseases remain an area of ongoing investigation. COVID-19 can induce liver injury through various mechanisms and is associated with higher mortality in individuals with preexisting chronic liver disease. Mortality increases with the severity of chronic liver disease and the level of care required. The outcomes in patients with autoimmune hepatitis remain unclear, whereas liver transplant recipients are more likely to experience symptomatic COVID-19 but have comparable outcomes to the general population. Despite suboptimal immunological response, COVID-19 vaccinations are safe and effective in liver disease, although cases of autoimmune hepatitis-like syndrome have been reported. In conclusion, COVID-19 has significant implications in liver diseases; early recognition and treatments are important for improving patient outcomes.
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Affiliation(s)
- Kai Zhu
- Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Olivia Tsai
- Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Daljeet Chahal
- Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada
- BC Liver Transplant Program, Vancouver, British Columbia, Canada
| | - Trana Hussaini
- BC Liver Transplant Program, Vancouver, British Columbia, Canada
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Eric M Yoshida
- Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada
- BC Liver Transplant Program, Vancouver, British Columbia, Canada
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16
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Nikkhoo B, Mohammadi M, Hasani S, Sigari N, Borhani A, Ramezani C, Charajoo A, Badri S, Rostami F, Etemadi M, Rahmani K. Elevated interleukin (IL)-6 as a predictor of disease severity among Covid-19 patients: a prospective cohort study. BMC Infect Dis 2023; 23:311. [PMID: 37161412 PMCID: PMC10169099 DOI: 10.1186/s12879-023-08294-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 04/29/2023] [Indexed: 05/11/2023] Open
Abstract
BACKGROUND accompanied to the spreading of coronavirus disease 2019 (Covid-19) in the world, identifying factors related to the severity of the disease is one of the interests of physician and medical researchers. We hypothesized that interleukin 6 serum level is associated with severe outcome. METHODS In this longitudinal prospective cohort study we enrolled 208 confirmed COVID-19 patients who were admitted to the Tohid Hospital (Sanandaj, Iran). Patients were classified into two groups based on IL-6 value in the first day of admission, elevated (n = 107) or not elevated/normal (n = 101), and followed until the occurrence of final outcome (death or discharge from the hospital). Data were analyzed using univariate methods, Chi-squared and independent two sample T test. The relationship between the independent variables and our interesting outcomes were investigated by multiple linear and penalized logistic regression modeling. RESULTS A total of 208 patients, 51% female and mean age 53.6 ± 16.3 years, including 107 elevated and 101 non-elevated IL-6 patients, were followed. No significant difference was observed between the two groups in demographic and clinical characteristics. Although not significant, logistic regression results showed that the chance of death occurrence among patients with elevated IL-6 are 3.91 times higher. According to the multiple linear regression modeling, elevated IL-6 significantly increased the duration of hospital stay (P = 0.02). Frequency of ICU admission (P = 0.04) and mean of ICU stay (P = 0.8) are also higher in elevated IL-6 group. CONCLUSION This study revealed that elevated IL-6 is significantly related to prolongation of hospital stay in Covid-19 patients. Although not significant, the occurrence of death among patients who had increased IL-6 in the time of admission was higher than patients with normal or lower serum levels of IL-6.
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Affiliation(s)
- Bahram Nikkhoo
- Liver and Digestive Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | | | - Sabah Hasani
- Lung Diseases and Allergy Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Naseh Sigari
- Lung Diseases and Allergy Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Aryan Borhani
- Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Chia Ramezani
- Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Arian Charajoo
- Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Shaho Badri
- Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Farzin Rostami
- Kurdistan University of Medical Sciences, Sanandaj, Iran
| | | | - Khaled Rahmani
- Liver and Digestive Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.
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17
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Sarhan NM, Warda AEA, Ibrahim HSG, Schaalan MF, Fathy SM. Evaluation of infliximab/tocilizumab versus tocilizumab among COVID-19 patients with cytokine storm syndrome. Sci Rep 2023; 13:6456. [PMID: 37081046 PMCID: PMC10116445 DOI: 10.1038/s41598-023-33484-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 04/13/2023] [Indexed: 04/22/2023] Open
Abstract
Coronavirus Disease 2019 (COVID-19) continues to spread rapidly. Monoclonal antibodies as well as anti-tumor necrosis factor are considered promising treatments for COVID-19. A prospective cohort study in which patients are divided into three groups. Group 1: moderate and severe COVID-19 patients received standard treatment; Group 2: moderate and severe COVID-19 patients received tocilizumab; Group 3: moderate and severe COVID-19 patients received treatment with infliximab and tocilizumab. 153 patients were recruited in the study. 40 received standard treatment alone, 70 received tocilizumab with standard treatment, and 43 received tocilizumab/infliximab with standard treatment. There was a significant difference in length of hospital stay (10.3, 8.9, and 7.6 days respectively P = 0.03), need for a non-invasive mechanical ventilator (4, 5, and one patient; P = 1.2E-8), intensive care admission (32, 45, and 16 patients; P = 2.5E-5), the occurrence of sepsis (18, 12, and 10 patients; P = 0.005) and in death (42.5%, 14.2%, and 7%; P = 0.0008) which were significantly lower in tocilizumab/infliximab group compared to tocilizumab and standard of care groups. Our study showed that tocilizumab/ infliximab in addition to standard of care was considered a promising treatment for moderate and severe COVID-19 patients.Trial registration number: ClinicalTrials.gov NCT04734678; date of registration: 02/02/2021.
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Affiliation(s)
- Neven Mohamed Sarhan
- Clinical Pharmacy Department, Faculty of Pharmacy, Misr International University, Cairo, Egypt.
| | - Ahmed Essam Abou Warda
- Clinical Pharmacy Department, Faculty of Pharmacy, October 6 University, Giza, 12585, Egypt
| | | | - Mona Farag Schaalan
- Clinical Pharmacy Department, Faculty of Pharmacy, Misr International University, Cairo, Egypt
| | - Shaimaa Mohamed Fathy
- Clinical Pharmacy Department, Faculty of Pharmacy, October 6 University, Giza, 12585, Egypt
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18
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Cavaillon JM, Artigas A, Barratt-Due A, Giamarellos-Bourboulis EJ, Gómez H, Hayem G, Vlaar APJ, Wiersinga WJ. SEVERE CORONAVIRUS DISEASE 2019: FROM PATHOGENESIS TO THERAPY. Shock 2023; 59:10-15. [PMID: 36469709 DOI: 10.1097/shk.0000000000001956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
ABSTRACT The COVID-19 pandemic has been a challenge to propose efficient therapies. Because severe SARS-CoV2 infection is a viral sepsis eventually followed by an immunological autoinflammatory phenomenon, many approaches have been inspired by the previous attempts made in bacterial sepsis, while specific antiviral strategies (use of interferon or specific drugs) have been additionally investigated. We summarize our current thinking on the use of SARS-CoV-2 antivirals, corticosteroids, anti-IL-1, anti-IL-6, anti-C5a, as well as stem cell therapy in severe COVID-19. Patient stratification and appropriate time window will be important to be defined to guide successful treatment.
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Affiliation(s)
| | - Antonio Artigas
- Intensive Care Department, Corporacion Sanitaria Universitaria Parc Tauli CIBER Enfermedades Respiratorias, Autonomous University of Barcelona, Sabadell, Spain
| | | | | | - Hernando Gómez
- Program for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh Medical Center, Pennsylvania, PA
| | - Gilles Hayem
- Rheumatology Department, Paris Saint-Joseph Hospital, Paris, France
| | - Alexander P J Vlaar
- Department of Intensive Care, Amsterdam University Medical Center, University of Amsterdam, the Netherlands
| | - W Joost Wiersinga
- Division of Infectious Diseases, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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19
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Bankole AA, Nwaonu J, Saeed J. Impact of SARS-CoV-2/COVID-19 on Provision of Medical Care to Patients With Systemic Autoimmune Rheumatic Disease and the Practice of Rheumatology. Cureus 2023; 15:e35402. [PMID: 36987476 PMCID: PMC10040147 DOI: 10.7759/cureus.35402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/24/2023] [Indexed: 03/30/2023] Open
Abstract
The SARS-CoV-2 pandemic has had a significant impact on the healthcare field that resulted in changes to the way safe and effective medical care is delivered. The effects range from service disruption including ambulatory clinic closure due to both patient and provider concerns, to lack of capacity in hospital services. In rheumatology, there were other effects including viral infection-related autoantibody production, concerns about the use of systemic immunosuppression in the presence of an infectious pandemic and even concerns for viral infection-induced flares of rheumatic disease. Coronavirus disease 2019 (COVID-19) led to the rapid adoption of innovative technologies that permitted the introduction and increased use of telemedicine via a number of platforms. Rapid discoveries and innovations led to the development of diagnostic and therapeutic agents in the management of COVID-19. Scientific advancement and discoveries around COVID-19 infection, symptoms, autoantibody production, chronic sequela and the repurposing of rheumatic immunosuppressive agents led to improved survival and an expanded role for the rheumatologist. Rheumatologists may sometimes be involved in the diagnosis and management of the hospitalized COVID-19 patient. In the ambulatory clinic, a rheumatologist also helps to differentiate between symptoms of long COVID and those of systemic autoimmune rheumatic disease (SARD). Rheumatologists must also grapple with the concerns related to immunosuppressive therapy and the risk of COVID-19 infections. In addition, there are concerns around vaccine effectiveness in people with SARD and those on immunosuppressive medications. Although the SARS-CoV-2 pandemic and the effects on healthcare resulted in difficulties, both patients and providers have risen to the challenge. The long-term outcome of COVID-19 for the medical system and rheumatologists in particular is not yet fully understood and will need further study. This review concentrates on the changing role of the rheumatologists, improved understanding of rheumatic disease and immunosuppressive therapies in the wake of the pandemic and how this has led to an improvement in the care of patients with COVID-19.
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Affiliation(s)
| | - Jane Nwaonu
- Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, USA
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20
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Lasierra Monclús AB, González Á, Bernabéu Andreu FA, Caballé Martín I, Buño Soto A, Ibarz M, González Rodríguez C, Puzo Foncillas J. Effects of the COVID-19 pandemic on the activity of clinical laboratories in Spain, evolution in the 2019-2021 period. ADVANCES IN LABORATORY MEDICINE 2022; 3:361-382. [PMID: 37363429 PMCID: PMC10197302 DOI: 10.1515/almed-2022-0107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 08/12/2022] [Indexed: 06/28/2023]
Abstract
Objectives To assess the impact of the COVID-19 pandemic on the activity of clinical laboratories in Spain. Methods A descriptive, observational, retrospective, multicenter study. Results Between March and December 2020, there was a statistically significant decrease in the number of test requests (-17.7%, p=<0.001) and total tests performed (-18.3%, p<0.001) with respect to the same period in 2019. A decrease was observed in the number of requests from primary care (-37.4%) (p<0.001) and in the number of foecal occult blood (-45.8%); qualitative urine (-30.1%); PSA (-28.5%); TSH (-27.8%); total cholesterol (-27.2%) and HbA1c (-24.7%) tests performed, p<0.001. A significant increase was found in the number of requests from ICUs (76.6%, p<0.001) and number of IL-6 (+22,350.9), D-dimer (+617.2%), troponin (+46.8%) and arterial blood gas (+3.9%) tests carried out, p<0.001. During the first months of 2021, there were significant changes in the number of requests for qualitative urine (-8.7%, p<0.001), PSA (-6.3%, p=0.009), IL-6 (+66,269.2, p<0.001), D-dimer (+603.6%, p<0.001), troponin (+28.7%, p<0.001), arterial blood gas (+26,2%, p=0.014) and ferritin (+16.0%, p=0.002) tests performed. Conclusions There were changes in the origin and number of test requested to clinical laboratories in Spain. The number of requests for the evaluation and monitoring of COVID-19 patients increased, whereas requests for the control of non-COVID patients and for population screening decreased. Long-term analysis reveals that the volume of tests performed for the control of chronic diseases returned to normal over time, whereas the increase observed in the volume of tests performed for the management of COVID-19 patients is maintained.
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Affiliation(s)
| | - Álvaro González
- Service of Biochemistry, Clínica Universidad de Navarra, Pamplona, Spain
| | | | | | - Antonio Buño Soto
- Service of Clinical Analysis, Hospital Universitario La Paz, Madrid, Spain
| | - Mercè Ibarz
- Service of Clinical Analysis, Hospital Universitario Arnau de Vilanova, Lleida, Spain
| | | | - José Puzo Foncillas
- Service of Clinical Analysis and Biochemistry, Hospital Universitario San Jorge, Huesca, Spain
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21
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Kawamata T, Tanino Y, Nikaido T, Minemura H, Sato Y, Togawa R, Watanabe N, Yamada R, Sato R, Onuma T, Tomita H, Saito M, Rikimaru M, Suzuki Y, Tsukada Y, Nakamura K, Kanemitsu K, Iseki K, Shibata Y. Clinical effect of early administration of tocilizumab following the initiation of corticosteroid therapy for patients with COVID-19. J Infect Chemother 2022; 28:1639-1644. [PMID: 36057415 PMCID: PMC9428329 DOI: 10.1016/j.jiac.2022.08.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 08/20/2022] [Accepted: 08/24/2022] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in Wuhan in December 2019, and has since caused a global pandemic. The efficacy of several drugs has been evaluated, and it is now evident that tocilizumab has a beneficial effect, especially combined with corticosteroids, in patients with Coronavirus Disease 2019 (COVID-19). However, the optimal timing of tocilizumab administration has not yet been established. The goal of the present study was to determine the optimal timing of tocilizumab administration after starting corticosteroid therapy in patients with COVID-19. METHODS We retrospectively analyzed the clinical characteristics of patients who were hospitalized for COVID-19 and treated with tocilizumab and corticosteroids in our hospital. The patients were divided into concurrent and sequential groups. The concurrent group received tocilizumab ≤24 h after corticosteroids, and the sequential group received tocilizumab >24 h after corticosteroid administration. RESULTS The baseline clinical characteristics of tocilizumab administration were similar between the two groups. White blood cell counts were significantly lower and C-reactive protein levels were significantly higher in the concurrent group than the sequential group. In the concurrent group, tocilizumab administration led to a significant decrease in maximum body temperature. In addition, there were significantly more oxygen-free days in the concurrent group than in the sequential group. However, survival rate was not significantly different between the concurrent and the sequential groups. CONCLUSIONS In the combination therapy with tocilizumab and corticosteroids, early administration of tocilizumab after starting corticosteroid treatment is effective when treating COVID-19.
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Affiliation(s)
| | | | | | | | - Yuki Sato
- Department of Pulmonary Medicine, Japan.
| | | | | | | | - Riko Sato
- Department of Pulmonary Medicine, Japan.
| | | | | | | | | | | | | | - Kiwamu Nakamura
- Department of Infection Control, Fukushima Medical University, Hikarigaoka 1, Fukushima, 960-1295, Japan.
| | - Keiji Kanemitsu
- Department of Infection Control, Fukushima Medical University, Hikarigaoka 1, Fukushima, 960-1295, Japan.
| | - Ken Iseki
- Department of Emergency and Critical Care Medicine, Japan.
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22
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Yu SY, Koh DH, Choi M, Ryoo S, Huh K, Yeom JS, Yoon YK. Clinical efficacy and safety of interleukin-6 receptor antagonists (tocilizumab and sarilumab) in patients with COVID-19: a systematic review and meta-analysis. Emerg Microbes Infect 2022; 11:1154-1165. [PMID: 35343397 PMCID: PMC9037226 DOI: 10.1080/22221751.2022.2059405] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
This study investigated the efficacy and safety of interleukin-6 (IL-6) receptor antagonists with standard care treatment in patients with coronavirus disease 2019 (COVID-19). The randomized controlled trials were identified through systematic searches of electronic databases through February 10, 2022. In total, 17 trials comprising 8,614 patients were included. Compared with exclusive standard care or placebo, IL-6 receptor antagonists with standard of care treatment were associated with a significantly reduced all-cause mortality at 28 days (pooled risk ratios [RR], 0.88; 95% confidence interval (CI), 0.82-0.95; 17 studies) and progression to invasive mechanical ventilation (RR, 0.79; 95% CI, 0.71-0.88; nine studies). Particularly, the subgroup of patients with moderate-to-severe COVID-19 showed a significant mortality benefit (RR, 0.89; 95% CI, 0.81-0.96; four studies) and a reduced risk for mechanical ventilation (RR, 0.80; 95% CI, 0.70-0.91; three studies) with tocilizumab treatment. The frequency of serious adverse events was lower in the tocilizumab treatment group than in the standard of care treatment group (RR, 0.83; 95% CI, 0.71-0.97; 11 studies), with no significant difference in the sarilumab treatment group (RR, 1.12; 95% CI, 0.89-1.40; four studies). Our meta-analysis demonstrated that tocilizumab treatment showed promising results in reducing 28-day mortality and progression to mechanical ventilation in patients with moderate-to-severe COVID-19, without the burden of serious adverse events.Trial registration: Clinical Trials Registry India identifier: CTRI/2020/05/025369.The proper registration is PROSPERO: registration number CRD42021294120.
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Affiliation(s)
- Su-Yeon Yu
- Division for Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Republic of Korea
| | - Dae-Hyup Koh
- Division for Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Republic of Korea
| | - Miyoung Choi
- Division for Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Republic of Korea
| | - Seungeun Ryoo
- Division for Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Republic of Korea
| | - Kyungmin Huh
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Joon Sup Yeom
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young Kyung Yoon
- Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
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23
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Ozkan F, Sari S. Comparison of Anakinra and Tocilizumab in Anticytokine Therapy in the Treatment of Coronavirus Disease-2019. Indian J Crit Care Med 2022; 26:1091-1098. [PMID: 36876207 PMCID: PMC9983662 DOI: 10.5005/jp-journals-10071-24320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 08/10/2022] [Indexed: 11/23/2022] Open
Abstract
Background It is known that coronavirus disease-2019 (COVID-19) pneumonia causes cytokine storm, and treatment modalities are being developed on inhibition of proinflammatory cytokines. We aimed to investigate the effects of anticytokine therapy on clinical improvement and the differences between anticytokine treatments. Materials and methods A total of 90 patients with positive COVID-19 polymerase chain reaction (PCR) test were divided into three groups, group I (n = 30) was given anakinra, group II (n = 30) was given tocilizumab, and group III (n = 30) was given standard treatment. Group I was treated with anakinra for 10 days; tocilizumab, intravenously, was given in group II. Group III patients were selected from those who did not receive any anticytokine treatment other than the standard treatment. Laboratory values, Glasgow coma scale (GCS), and PaO2/FiO2 values were analyzed on days 1, 7, and 14. Results The seventh-day mortality rates were 6.7% in group II, 23.3% in group I, and 16.7% in group III. In group II, the ferritin levels on the 7th and 14th days were significantly lower (p = 0.004), and the lymphocyte levels on the seventh day were significantly higher (p = 0.018). Examining the changes between the first intubation days, in the early period (seventh day), group I was found to be 21.7%, group II was 26.9%, and group III was 47.6%. Conclusion We observed the positive effects of the use of tocilizumab on clinical improvement in the early period; mechanical ventilation requirement was delayed and at a lower rate. Anakinra treatment did not change mortality and PaO2/FiO2 rates. Mechanical ventilation requirements occurred earlier in the patients who were not receiving any anticytokine therapy. Studies with larger patient populations are needed to demonstrate the potential efficacy of anticytokine therapy. How to cite this article Ozkan F, Sari S. Comparison of Anakinra and Tocilizumab in Anticytokine Therapy in the Treatment of Coronavirus Disease-2019. Indian J Crit Care Med 2022;26(10):1091-1098.
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Affiliation(s)
- Feyza Ozkan
- Department of Anesthesiology and Reanimation, Yozgat City Hospital, Yozgat, Turkey
| | - Süleyman Sari
- Department of Anesthesiology and Reanimation, Yozgat City Hospital, Yozgat, Turkey
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24
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Bizjak DA, Stangl M, Börner N, Bösch F, Durner J, Drunin G, Buhl JL, Abendroth D. Kynurenine serves as useful biomarker in acute, Long- and Post-COVID-19 diagnostics. Front Immunol 2022; 13:1004545. [PMID: 36211365 PMCID: PMC9537769 DOI: 10.3389/fimmu.2022.1004545] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/06/2022] [Indexed: 12/02/2022] Open
Abstract
Introduction In patients with SARS-CoV-2, innate immunity is playing a central role, depicted by hyperinflammation and longer lasting inflammatory response. Reliable inflammatory markers that cover both acute and long-lasting COVID-19 monitoring are still lacking. Thus, we investigated one specific inflammatory marker involved as one key player of the immune system, kynurenine (Kyn), and its use for diagnosis/detection of the Long-/Post-COVID syndrome in comparison to currently used markers in both serum and saliva samples. Material and methods The study compromised in total 151 inpatients with a SARS-CoV-2 infection hospitalized between 03/2020 and 09/2021. The group NC (normal controls) included blood bank donors (n=302, 144f/158m, mean age 47.1 ± 18.3 years (range 18-75)). Two further groups were generated based on Group A (n=85, 27f/58m, mean age 63.1 ± 18.3 years (range 19-90), acute admission to the hospital) and Group B (n=66, 22f/44m, mean age 66.6 ± 17.6 years (range 17-90), admitted either for weaning or for rehabilitation period due to Long-COVID symptoms/syndrome). Plasma concentrations of Kyn, C-Reactive Protein (CRP) and interleukin-6 (IL-6) were measured on admission. In Group B we determined Kyn 4 weeks after the negative PCR-test. In a subset of patients (n=11) concentrations of Kyn and CRP were measured in sera and saliva two, three and four months after dismission. We identified 12 patients with Post-COVID symptoms >20 weeks with still significant elevated Kyn-levels. Results Mean values for NC used as reference were 2.79 ± 0.61 µM, range 1.2-4.1 µM. On admission, patients showed significantly higher concentrations of Kyn compared to NC (p-values < 0.001). Kyn significantly correlated with IL-6 peak-values (r=0.411; p-values <0.001) and CRP (r=0.488, p-values<0.001). Kyn values in Group B (Long-/Post-COVID) showed still significant higher values (8.77 ± 1.72 µM, range 5.5-16.6 µM), whereas CRP values in Group B were in the normal range. Conclusion Serum and saliva Kyn are reflecting the acute and long-term pathophysiology of the SARS-CoV-2 disease concerning the innate immune response and thus may serve a useful biomarker for diagnosis and monitoring both Long- and Post-COVID syndrome and its therapy.
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Affiliation(s)
| | - Manfred Stangl
- Division of General, Visceral and Transplant Surgery, Hospital Großhadern, Ludwig-Maximilians-University, Munich, Germany
| | - Nikolaus Börner
- Division of General, Visceral and Transplant Surgery, Hospital Großhadern, Ludwig-Maximilians-University, Munich, Germany
| | - Florian Bösch
- Division of General, Visceral and Transplant Surgery, Hospital Großhadern, Ludwig-Maximilians-University, Munich, Germany
| | - Joachim Durner
- Neurology Department, Special Medical Clinic Ichenhausen, Ichenhausen, Germany
| | - Gergana Drunin
- Neurology Department, Special Medical Clinic Ichenhausen, Ichenhausen, Germany
| | - Jasmine-Leonike Buhl
- Division of Sports and Rehabilitation Medicine, Ulm University Hospital, Ulm, Germany
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25
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Alnamshan MM. Potential histopathological and immunological effects of SARS-CoV-2 on the liver. BRAZ J BIOL 2022; 82:e262008. [PMID: 36074418 DOI: 10.1590/1519-6984.262008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 07/05/2022] [Indexed: 12/15/2022] Open
Abstract
The coronavirus disease outbreak of 2019 (COVID-19) poses a serious threat to public health worldwide. Lung injury is the most common complication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. However, other organs, including the liver, can also be affected. Currently, there is limited evidence that liver impairment is associated with severe SARS-CoV-2 infection. Clinicians will need to determine whether liver injury is caused by an underlying liver condition, COVID-19 therapy, the virus directly, or immune-mediated inflammation or represents a complicated disease course in the context of COVID-19. To address the scarcity of data on histopathological changes and immunological effects on the liver with COVID-19 positivity, we analyze and summarize recent findings. We searched PubMed, Medline, Google Scholar, Science Direct, Scopus, and Web of Science databases up to December 1, 2021, identifying published studies with the search terms "Histopathology in COVID-19," "COVID-19," "Pathological changes in liver in COVID-19," "Liver pathology in COVID-19," "immunological effects in liver in COVID-19," and "SARS-CoV-2." This concise review will aid clinicians and researchers in better understanding the tissue histopathology and immunological consequences of SARS-CoV-2 on the liver, enabling improved care planning and avoiding future dangers.
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Affiliation(s)
- M M Alnamshan
- Imam Abdulrahman Bin Faisal University, College of Science, Department of Biology, Dammam, Saudi Arabia
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26
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Haibel H, Poddubnyy D, Angermair S, Allers K, Vahldiek JL, Schumann M, Schneider T. Successful treatment of severe COVID-19 pneumonia, a case series with simultaneous interleukin-1 and interleukin-6 blockade with 1-month follow-up. Ther Adv Musculoskelet Dis 2022; 14:1759720X221116405. [PMID: 36071720 PMCID: PMC9444821 DOI: 10.1177/1759720x221116405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 07/12/2022] [Indexed: 11/17/2022] Open
Abstract
Interleukin (IL)-6 and IL-1 blockade showed beneficial results in patients with severe COVID-19 pneumonia and evidence of cytokine release at the early disease stage. Here, we report outcomes of open-label therapy with a combination of blocking IL-6 with tocilizumab 8 mg/kg up to 800 mg and IL-1 receptor antagonist anakinra 100–300 mg over 3–5 days. Thirty-one adult patients with severe COVID-19 pneumonia and signs of cytokine release, mean age 54 (30–79) years, 5 female, 26 male, and mean symptom duration 6 (3–10) days were treated. Patients with more than 10 days of symptoms, evidence of bacterial infection/elevated procalcitonin and other severe lung diseases were excluded. Computed tomography (CT) scans of the lung were performed initially and after 1 month; inflammatory activity was assessed on a scale 0–25. Twenty-five patients survived without intubation and mechanical lung ventilation, two patients died. C-reactive protein decreased in 19/31 patients to normal ranges. The mean activity CT score decreased from 14 (8–20) to 6 (0–16, n = 16). In conclusion, most of our patients recovered fast and sustained, indicating that early interruption of cytokine release might be very effective in preventing patients from mechanical ventilation, death, and long-term damage.
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Affiliation(s)
- Hildrun Haibel
- Department of Gastroenterology, Infectiology and Rheumatology, Charité-University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Denis Poddubnyy
- Department of Gastroenterology, Infectiology and Rheumatology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Stefan Angermair
- Department of Anestesiology and Surgical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Kristina Allers
- Department of Gastroenterology, Infectiology and Rheumatology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Janis L Vahldiek
- Department of Radiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Schumann
- Department of Gastroenterology, Infectiology and Rheumatology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Thomas Schneider
- Department of Gastroenterology, Infectiology and Rheumatology, Charité-Universitätsmedizin Berlin, Berlin, Germany
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27
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Ramirez Zegarra R, Dall’Asta A, Revelli A, Ghi T. COVID-19 and Gestational Diabetes: The Role of Nutrition and Pharmacological Intervention in Preventing Adverse Outcomes. Nutrients 2022; 14:nu14173562. [PMID: 36079820 PMCID: PMC9460671 DOI: 10.3390/nu14173562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/14/2022] [Accepted: 08/23/2022] [Indexed: 12/15/2022] Open
Abstract
Pregnant women with GDM affected by COVID-19 seem to be at higher risk of adverse maternal and neonatal outcomes, especially those with overweight or obesity. Good glycemic control seems to be the most effective measure in reducing the risk of GDM and severe COVID-19. For such purposes, the Mediterranean diet, micronutrient supplementation, and physical activity are considered the first line of treatment. Failure to achieve glycemic control leads to the use of insulin, and this clinical scenario has been shown to be associated with an increased risk of adverse maternal and neonatal outcomes. In this review, we explore the current evidence pertaining to the pathogenesis of SARS-CoV-2 leading to the main complications caused by COVID-19 in patients with GDM. We also discuss the incidence of complications caused by COVID-19 in pregnant women with GDM according to their treatment.
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Affiliation(s)
- Ruben Ramirez Zegarra
- Obstetrics and Gynaecology Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
- Department of Obstetrics and Gynaecology, University Hospital Rechts der Isar, Technical University of Munich, 81675 Munich, Germany
| | - Andrea Dall’Asta
- Obstetrics and Gynaecology Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Alberto Revelli
- Sant’Anna Hospital, Department of Surgical Sciences, University of Turin, 10126 Turin, Italy
| | - Tullio Ghi
- Obstetrics and Gynaecology Unit, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
- Correspondence:
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28
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Abd HA, Kasim AA, Shareef LG. Serum levels of α1-antitrypsin, interleukin-1β and interleukin-6 in Iraqi COVID-19 patients: A cross-sectional study. F1000Res 2022; 11:921. [DOI: 10.12688/f1000research.124473.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/02/2023] Open
Abstract
Background: More than half of the individuals diagnosed with coronavirus disease 2019 (COVID-19) have been found to have high levels of interleukin (IL)-6. A recent report showed that more elevated serum IL-6 level predicts COVID-19 disease severity and patients’ clinical outcomes. Therefore, this study aimed to compare the serum levels of α1-antitrypsin (AAT), IL-1β, and IL-6 between COVID-19 patients and healthy individuals. Methods: During the data collection phase, 90 individuals were enrolled, 45 healthy controls, and 45 patients confirmed with COVID-19 using reverse transcription-quantitative PCR (RT-qPCR) at a specialized isolation hospital in Baghdad between November 2021 and March 2022. In this cross-sectional research, venous blood samples were taken, and serum was isolated and stored for quantitative ELISA measurements of AAT, IL-1β, and IL-6 (ELISA). IBM SPSS version 24 was used to analyze the data. Results: This study revealed a significant increase in the serum levels of AAT, IL-1β, and IL-6 in the COVID-19 patients' group compared to the healthy control group with p-values < 0.001 for each of these markers. Conclusions: AAT concentrations were higher during COVID-19; this elevation is essential during infection. IL-1β and IL-6 levels were also elevated during the infection period; however, dysregulated high levels may lead to cytokine release syndrome. Therefore, these three biomarkers can be regarded as diagnostically crucial parameters.
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Incidence and risk factors of COVID-19 associated pneumothorax. PLoS One 2022; 17:e0271964. [PMID: 35930528 PMCID: PMC9355189 DOI: 10.1371/journal.pone.0271964] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 07/11/2022] [Indexed: 01/08/2023] Open
Abstract
Background Pneumothorax has been increasingly observed among patients with coronavirus disease-2019 (COVID-19) pneumonia, specifically in those patients who develop acute respiratory distress syndrome (ARDS). In this study, we sought to determine the incidence and potential risk factors of pneumothorax in critically ill adults with COVID-19. Method This retrospective cohort study included adult patients with laboratory-confirmed SARS-CoV-2 infection admitted to one of the adult intensive care units of a tertiary, academic teaching hospital from May 2020 through May 2021. Results Among 334 COVID-19 cases requiring ICU admission, the incidence of pneumothorax was 10% (33 patients). Patients who experienced pneumothorax more frequently required vasopressor support (28/33 [84%] vs. 191/301 [63%] P = 0.04), were more likely to be proned (25/33 [75%] vs. 111/301 [36%], P<0.001), and the presence of pneumothorax was associated with prolonged duration of mechanical ventilation; 21 (1–97) versus 7 (1–79) days, p<0.001 as well as prolonged hospital length of stay (29 [9–133] vs. 15 [1–90] days, P<0.001), but mortality was not significantly different between groups. Importantly, when we performed a Cox proportional hazard ratio (HR) model of multivariate parameters, we found that administration of tocilizumab significantly increased the risk of developing pneumothorax (HR = 10.7; CI [3.6–32], P<0.001). Conclusion Among 334 critically ill patients with COVID-19, the incidence of pneumothorax was 10%. Presence of pneumothorax was associated with prolonged duration of mechanical ventilation and length of hospital stay. Strikingly, receipt of tocilizumab was associated with an increased risk of developing pneumothorax.
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Ma L, Willey J. The interplay between inflammation and thrombosis in COVID-19: Mechanisms, therapeutic strategies, and challenges. THROMBOSIS UPDATE 2022; 8:100117. [PMID: 38620713 PMCID: PMC9270234 DOI: 10.1016/j.tru.2022.100117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 06/08/2022] [Accepted: 07/06/2022] [Indexed: 12/15/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19), caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can cause life-threatening pathology characterized by a dysregulated immune response and coagulopathy. While respiratory failure induced by inflammation is the most common cause of death, micro-and macrovascular thrombosis leading to multiple organ failure are also causes of mortality. Dysregulation of systemic inflammation observed in severe COVID-19 patients is manifested by cytokine release syndrome (CRS) - the aberrant release of high levels of proinflammatory cytokines, such as IL-6, IL-1, TNFα, MP-1, as well as complement. CRS is often accompanied by activation of endothelial cells and platelets, coupled with perturbation of the balance between the pro-and antithrombotic mechanisms, resulting in thrombosis. Inflammation and thrombosis form a vicious circle, contributing to morbidity and mortality. Treatment of hyperinflammation has been shown to decrease thrombosis, while anti-thrombotic treatment also downregulates cytokine release. This review highlights the relationship between COVID-19-mediated systemic inflammation and thrombosis, the molecular pathways involved, the therapies targeting these processes, and the challenges currently encountered.
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Affiliation(s)
- Li Ma
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
| | - Joanne Willey
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
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Chertok Shacham E, Ishay A. New insights on Effects of Glucocorticoids in SARS-CoV-2 infection. Endocr Pract 2022; 28:1100-1106. [PMID: 35870803 PMCID: PMC9300587 DOI: 10.1016/j.eprac.2022.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/20/2022] [Accepted: 07/14/2022] [Indexed: 01/08/2023]
Abstract
Objective Since January 2020, the highly contagious novel coronavirus SARS-CoV-2 has caused a global pandemic. Severe COVID-19 leads to a massive release of proinflammatory mediators, leading to diffuse damage to the lung parenchyma, and the development of acute respiratory distress syndrome. Treatment with the highly potent glucocorticoid (GC) dexamethasone was found to be effective in reducing mortality in severely affected patients. Methods To review the effects of glucocorticoids in the context of COVID-19 we performed a literature search in the PubMed database using the terms COVID-19 and glucocorticoid treatment. We identified 1429 article publications related to COVID-19 and glucocorticoid published from 1.1.2020 to the present including 238 review articles and 36 Randomized Controlled Trials. From these studies, we retrieved 13 Randomized Controlled Trials and 86 review articles that were relevant to our review topics. We focused on the recent literature dealing with glucocorticoid metabolism in critically ill patients and investigating the effects of glucocorticoid therapy on the immune system in COVID-19 patients with severe lung injury. Results In our review, we have discussed the regulation of the hypothalamic-pituitary-adrenal axis in patients with critical illness, selection of a specific GC for critical illness-related GC insufficiency, and recent studies that investigated hypothalamic-pituitary-adrenal dysfunction in patients with COVID-19. We have also addressed the specific activation of the immune system with chronic endogenous glucocorticoid excess, as seen in patients with Cushing syndrome, and, finally, we have discussed immune activation due to coronavirus infection and the possible mechanisms leading to improved outcomes in patients with COVID-19 treated with GCs. Conclusion For clinical endocrinologists prescribing GCs for their patients, a precise understanding of both the molecular- and cellular-level mechanisms of endogenous and exogenous GCs is imperative, including timing of administration, dosage, duration of treatment, and specific formulations of GCs.
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Affiliation(s)
| | - Avraham Ishay
- Endocrinology Unit, HaEmek Medical Center, Afula, Israel; Faculty of medicine, Technion - Israel Institute of Technology, Haifa, Israel
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Kirillova A, Lado A, Blatt N. Application of Monoclonal Antibody Drugs in Treatment of COVID-19: a Review. BIONANOSCIENCE 2022; 12:1436-1454. [PMID: 35729973 PMCID: PMC9198616 DOI: 10.1007/s12668-022-00997-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2022] [Indexed: 01/08/2023]
Abstract
Coronavirus infection can have various degrees of severity and outcomes. In some cases, it causes excessive production of pro-inflammatory cytokines, a so-called cytokine storm, leading to acute respiratory distress syndrome. Unfortunately, the exact pathophysiology and treatment, especially for severe cases of COVID-19, are still uncertain. Results of preliminary studies showed that immunosuppressive therapy, such as interleukin (IL)-6, IL-1, and TNF-α antagonists commonly used in rheumatology, can be considered as treatment options for COVID-19, especially in severe cases. The review focused on the most common and currently studied monoclonal antibody drugs, as well as up-to-date data on the pathogenesis of COVID-19, host immune response against SARS-CoV-2 and its association with cytokine storm. It also covered effects of interleukin (IL)-6, IL-1, and TNF-α blockers on the course of coronavirus infection and outcome in patients treated for the main autoimmune disease and subsequently infected with COVID-19.
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Affiliation(s)
- Aleksandra Kirillova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation
| | - Anna Lado
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation
| | - Nataliya Blatt
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russian Federation
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33
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Declercq J, De Leeuw E, Lambrecht BN. Inflammasomes and IL-1 family cytokines in SARS-CoV-2 infection: From prognostic marker to therapeutic agent. Cytokine 2022; 157:155934. [PMID: 35709568 PMCID: PMC9170572 DOI: 10.1016/j.cyto.2022.155934] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 06/01/2022] [Accepted: 06/02/2022] [Indexed: 01/08/2023]
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Tugce Yaman Y, Akbal Vural O, Bolat G, Abaci S. Peptide nanotubes/self-assembled polydopamine molecularly imprinted biochip for the impedimetric detection of human Interleukin-6. Bioelectrochemistry 2022; 145:108053. [DOI: 10.1016/j.bioelechem.2022.108053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 12/12/2022]
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Altunal LN, Aydın M, Özel AS, Çam G. Appropriate Use of Tocilizumab in COVID-19: Early Use is Beneficial. INFECTIOUS DISEASES & CLINICAL MICROBIOLOGY 2022; 4:116-121. [PMID: 38633336 PMCID: PMC10985809 DOI: 10.36519/idcm.2022.116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 04/04/2022] [Indexed: 04/19/2024]
Abstract
Objective Interleukin-6 inhibitor Tocilizumab (TCZ) is effective to prevent the mortality of severe COVID-19 by suppressing the cytokine storm, however, its appropriate use needs to be detailed. We aimed to describe the appropriate use of TCZ in severe to critical cases with COVID-19 pneumonia in the early phase of the pandemic. Materials and Methods This single-center, retrospective, observational study was conducted in a polymerase chain reaction (PCR) positive COVID-19 patients who received TCZ between April 01, 2020 and June 30, 2020, in Ümraniye Research and Training Hospital İstanbul, Turkey. The factors affecting mortality were compared. Results A total of 67 patients met the inclusion criteria during the study period. Overall, 76% of those patients were male, with a median age of 61 years. The 28-day mortality rate was 51% among all patients who were hospitalised for COVID-19 pneumonia. A logistic regression model identified the predictors of 28-day fatality; the number of comorbidities, high levels of C-reactive protein (CRP) before initiation of TCZ, initiation of TCZ in the intensive care unit (ICU) and not receiving an additional dose of TCZ. Conclusion The number of comorbidities, high levels of CRP, initiation of TCZ in the ICU and not receiving the additional dose of TCZ were significant risk factors for fatality among patients with COVID-19 who received TCZ. Early initiation of TCZ when cytokine storm is suspected is appropriate for the prevention of fatality.
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Affiliation(s)
- Lütfiye Nilsun Altunal
- Department of Infectious Diseases, Health Sciences University
Ümraniye Training and Research Hospital, İstanbul, Turkey
| | - Mehtap Aydın
- Department of Infectious Diseases, Health Sciences University
Ümraniye Training and Research Hospital, İstanbul, Turkey
| | - Ayşe Serra Özel
- Department of Infectious Diseases, Health Sciences University
Ümraniye Training and Research Hospital, İstanbul, Turkey
| | - Gülsüm Çam
- Department of Infectious Diseases, Health Sciences University
Ümraniye Training and Research Hospital, İstanbul, Turkey
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Lee AJ, Feng E, Chew MV, Balint E, Poznanski SM, Giles E, Zhang A, Marzok A, Revill SD, Vahedi F, Dubey A, Ayaub E, Jimenez-Saiz R, McGrath JJC, Ritchie TM, Jordana M, Jonigk DD, Ackermann M, Ask K, Miller M, Richards CD, Ashkar AA. Type I interferon regulates proteolysis by macrophages to prevent immunopathology following viral infection. PLoS Pathog 2022; 18:e1010471. [PMID: 35512020 PMCID: PMC9113601 DOI: 10.1371/journal.ppat.1010471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 05/17/2022] [Accepted: 03/24/2022] [Indexed: 11/18/2022] Open
Abstract
The ability to treat severe viral infections is limited by our understanding of the mechanisms behind virus-induced immunopathology. While the role of type I interferons (IFNs) in early control of viral replication is clear, less is known about how IFNs can regulate the development of immunopathology and affect disease outcomes. Here, we report that absence of type I IFN receptor (IFNAR) is associated with extensive immunopathology following mucosal viral infection. This pathology occurred independent of viral load or type II immunity but required the presence of macrophages and IL-6. The depletion of macrophages and inhibition of IL-6 signaling significantly abrogated immunopathology. Tissue destruction was mediated by macrophage-derived matrix metalloproteinases (MMPs), as MMP inhibition by doxycycline and Ro 28–2653 reduced the severity of tissue pathology. Analysis of post-mortem COVID-19 patient lungs also displayed significant upregulation of the expression of MMPs and accumulation of macrophages. Overall, we demonstrate that IFNs inhibit macrophage-mediated MMP production to prevent virus-induced immunopathology and uncover MMPs as a therapeutic target towards viral infections.
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Affiliation(s)
- Amanda J. Lee
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Emily Feng
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Marianne V. Chew
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Elizabeth Balint
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Sophie M. Poznanski
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Elizabeth Giles
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Ali Zhang
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada
| | - Art Marzok
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada
| | - Spencer D. Revill
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
- Department of Medicine, Firestone Institute of Respiratory Health, McMaster University, Hamilton, Ontario, Canada
| | - Fatemeh Vahedi
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Anisha Dubey
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
- Department of Medicine, Firestone Institute of Respiratory Health, McMaster University, Hamilton, Ontario, Canada
| | - Ehab Ayaub
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
- Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada
- Department of Medicine, Firestone Institute of Respiratory Health, McMaster University, Hamilton, Ontario, Canada
| | - Rodrigo Jimenez-Saiz
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Joshua J. C. McGrath
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Tyrah M. Ritchie
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Manel Jordana
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Danny D. Jonigk
- Institute of Pathology, Hannover Medical School, Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany
| | - Maximilian Ackermann
- Institute of Pathology and Molecular Pathology, Helios University Clinic Wuppertal, University of Witten/Herdecke, Wuppertal, Germany
- Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Kjetil Ask
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
- Department of Medicine, Firestone Institute of Respiratory Health, McMaster University, Hamilton, Ontario, Canada
| | - Matthew Miller
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada
| | - Carl D. Richards
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Ali A. Ashkar
- Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
- * E-mail:
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Abstract
Cardiometabolic disease describes a combination of metabolic abnormalities that increases the risk of type 2 diabetes and cardiovascular diseases, including pathological changes such as insulin resistance, hyperglycemia, dyslipidemia, abdominal obesity, and hypertension, and environmental risk factors such as smoking, sedentary lifestyle, poor diet, and poverty. As the number of coronavirus disease 2019 (COVID-19) patients continues to rise, type 2 diabetes, cardiovascular disease, hypertension, and obesity, all components of, or sequelae of cardiometabolic disease, were identified among others as key risk factors associated with increased mortality in these patients. Numerous studies have been done to further elucidate this relationship between COVID-19 and cardiometabolic disease. Cardiometabolic disease is associated with both increased susceptibility to COVID-19 and worse outcomes of COVID-19, including intensive care, mechanical ventilation, and death. The proinflammatory state of cardiometabolic disease specifically obesity, has been associated with a worse prognosis in COVID-19 patients. There has been no evidence to suggest that antihypertensives and antidiabetic medications should be discontinued in COVID-19 patients but these patients should be closely monitored to ensure that their blood pressure and blood glucose levels are stable. Assessment of vaccination efficacy in cardiometabolic disease patients is also discussed.
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Affiliation(s)
- Chan W. Kim
- From the Cardiology Division, Department of Medicine, Westchester Medical Center and New York Medical College, Valhalla, NY
| | - Wilbert S. Aronow
- From the Cardiology Division, Department of Medicine, Westchester Medical Center and New York Medical College, Valhalla, NY
| | - William H. Frishman
- From the Cardiology Division, Department of Medicine, Westchester Medical Center and New York Medical College, Valhalla, NY
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Zhang W, Qin C, Fei Y, Shen M, Zhou Y, Zhang Y, Zeng X, Zhang S. Anti-inflammatory and immune therapy in severe coronavirus disease 2019 (COVID-19) patients: An update. Clin Immunol 2022; 239:109022. [PMID: 35477027 PMCID: PMC9040414 DOI: 10.1016/j.clim.2022.109022] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 04/12/2022] [Accepted: 04/20/2022] [Indexed: 12/15/2022]
Abstract
In March 2020, when coronavirus disease 2019 (COVID-19) was just beginning to spread around the world, we presented the potential benefits and controversies of anti-inflammatory therapy in COVID-19 patients based on the limited experience and proposed some types of anti-inflammatory drugs with potential therapeutic value, while without evidence-based data. In the past one more year, many clinical trials or real-world studies have been performed, either confirm or deny the efficacy of certain anti-inflammatory drugs in the treatment of COVID-19. In this review we summarize the progress of anti-inflammatory and immune therapy in COVID-19, including glucocorticoids, IL-6 antagonist, IL-1 inhibitor, kinase inhibitors, non-steroidal anti-inflammatory drugs and chloroquine/hydroxychloroquine.
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Affiliation(s)
- Wen Zhang
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing 100730, China
| | - Chenman Qin
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing 100730, China; Department of Rheumatology of Immunology, People's Hospital of Jiaozuo City, Jiaozuo 454002, China
| | - Yunyun Fei
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing 100730, China
| | - Min Shen
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing 100730, China
| | - Yangzhong Zhou
- Department of internal medicine, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College Hospital, Beijing 100730, China
| | - Yan Zhang
- Department of Hematology, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College Hospital, Beijing 100730, China
| | - Xiaofeng Zeng
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing 100730, China.
| | - Shuyang Zhang
- Department of Cardiology, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, Beijing 100730, China.
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Ribeiro Baptista B, d'Humières T, Schlemmer F, Bendib I, Justeau G, Al-Assaad L, Hachem M, Codiat R, Bardel B, Abou Chakra L, Belmondo T, Audureau E, Hue S, Mekontso-Dessap A, Derumeaux G, Boyer L. Identification of factors impairing exercise capacity after severe COVID-19 pulmonary infection: a 3-month follow-up of prospective COVulnerability cohort. Respir Res 2022; 23:68. [PMID: 35317815 PMCID: PMC8938727 DOI: 10.1186/s12931-022-01977-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 03/06/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Patient hospitalized for coronavirus disease 2019 (COVID-19) pulmonary infection can have sequelae such as impaired exercise capacity. We aimed to determine the frequency of long-term exercise capacity limitation in survivors of severe COVID-19 pulmonary infection and the factors associated with this limitation. METHODS Patients with severe COVID-19 pulmonary infection were enrolled 3 months after hospital discharge in COVulnerability, a prospective cohort. They underwent cardiopulmonary exercise testing, pulmonary function test, echocardiography, and skeletal muscle mass evaluation. RESULTS Among 105 patients included, 35% had a reduced exercise capacity (VO2peak < 80% of predicted). Compared to patients with a normal exercise capacity, patients with reduced exercise capacity were more often men (89.2% vs. 67.6%, p = 0.015), with diabetes (45.9% vs. 17.6%, p = 0.002) and renal dysfunction (21.6% vs. 17.6%, p = 0.006), but did not differ in terms of initial acute disease severity. An altered exercise capacity was associated with an impaired respiratory function as assessed by a decrease in forced vital capacity (p < 0.0001), FEV1 (p < 0.0001), total lung capacity (p < 0.0001) and DLCO (p = 0.015). Moreover, we uncovered a decrease of muscular mass index and grip test in the reduced exercise capacity group (p = 0.001 and p = 0.047 respectively), whilst 38.9% of patients with low exercise capacity had a sarcopenia, compared to 10.9% in those with normal exercise capacity (p = 0.001). Myocardial function was normal with similar systolic and diastolic parameters between groups whilst reduced exercise capacity was associated with a slightly shorter pulmonary acceleration time, despite no pulmonary hypertension. CONCLUSION Three months after a severe COVID-19 pulmonary infection, more than one third of patients had an impairment of exercise capacity which was associated with a reduced pulmonary function, a reduced skeletal muscle mass and function but without any significant impairment in cardiac function.
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Affiliation(s)
| | - Thomas d'Humières
- Université Paris Est Créteil (UPEC), FHU SENEC, IMRB, INSERM, Créteil, France.,Département de Physiologie-Explorations Fonctionnelles, Hôpitaux Universitaires Henri Mondor, AP-HP, Avenue Maréchal de Lattre de Tassigny, Créteil, France
| | - Frédéric Schlemmer
- Université Paris Est Créteil (UPEC), FHU SENEC, IMRB, INSERM, Créteil, France.,Unité de Pneumologie, Service de Médecine Intensive Réanimation, Hôpitaux Universitaires Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France
| | - Inès Bendib
- Université Paris Est Créteil (UPEC), FHU SENEC, IMRB, INSERM, Créteil, France.,Département de Physiologie-Explorations Fonctionnelles, Hôpitaux Universitaires Henri Mondor, AP-HP, Avenue Maréchal de Lattre de Tassigny, Créteil, France.,Médecine Intensive Réanimation, Hôpitaux Universitaires Henri Mondor, AP-HP, Créteil, France
| | - Grégoire Justeau
- Université Paris Est Créteil (UPEC), FHU SENEC, IMRB, INSERM, Créteil, France
| | - Lara Al-Assaad
- Département de Physiologie-Explorations Fonctionnelles, Hôpitaux Universitaires Henri Mondor, AP-HP, Avenue Maréchal de Lattre de Tassigny, Créteil, France
| | - Mouna Hachem
- Université Paris Est Créteil (UPEC), FHU SENEC, IMRB, INSERM, Créteil, France.,Unité de Pneumologie, Service de Médecine Intensive Réanimation, Hôpitaux Universitaires Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France
| | - Rebecca Codiat
- Département de Physiologie-Explorations Fonctionnelles, Hôpitaux Universitaires Henri Mondor, AP-HP, Avenue Maréchal de Lattre de Tassigny, Créteil, France
| | - Benjamin Bardel
- Département de Physiologie-Explorations Fonctionnelles, Hôpitaux Universitaires Henri Mondor, AP-HP, Avenue Maréchal de Lattre de Tassigny, Créteil, France
| | - Laure Abou Chakra
- Département de Physiologie-Explorations Fonctionnelles, Hôpitaux Universitaires Henri Mondor, AP-HP, Avenue Maréchal de Lattre de Tassigny, Créteil, France
| | - Thibaut Belmondo
- Département d'Hématologie et d'Immunologie Biologiques, AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France
| | - Etienne Audureau
- Biostatistics Department, Henri Mondor Hospital, Assistance Publique Hôpitaux de Paris, Créteil, France.,CEpiA IMRB U955, FHU SENEC, Université Paris Est (UPEC), Créteil, France
| | - Sophie Hue
- Université Paris Est Créteil (UPEC), FHU SENEC, IMRB, INSERM, Créteil, France.,Département d'Hématologie et d'Immunologie Biologiques, AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France
| | - Armand Mekontso-Dessap
- Université Paris Est Créteil (UPEC), FHU SENEC, IMRB, INSERM, Créteil, France.,Médecine Intensive Réanimation, Hôpitaux Universitaires Henri Mondor, AP-HP, Créteil, France
| | - Geneviève Derumeaux
- Université Paris Est Créteil (UPEC), FHU SENEC, IMRB, INSERM, Créteil, France.,Département de Physiologie-Explorations Fonctionnelles, Hôpitaux Universitaires Henri Mondor, AP-HP, Avenue Maréchal de Lattre de Tassigny, Créteil, France
| | - Laurent Boyer
- Université Paris Est Créteil (UPEC), FHU SENEC, IMRB, INSERM, Créteil, France. .,Département de Physiologie-Explorations Fonctionnelles, Hôpitaux Universitaires Henri Mondor, AP-HP, Avenue Maréchal de Lattre de Tassigny, Créteil, France.
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Zhang J, Chen C, Yang Y, Yang J. Effectiveness of tocilizumab in the treatment of hospitalized adults COVID-19: A systematic review and meta-analysis. Medicine (Baltimore) 2022; 101:e28967. [PMID: 35244063 PMCID: PMC8896441 DOI: 10.1097/md.0000000000028967] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 02/06/2022] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Since December 2019, the coronavirus disease (COVID-19) has spread worldwide, leading to a global health threat. This study aimed to investigate the effectiveness of tocilizumab in COVID-19 patients. METHODS We systematically searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and World Health Organization International Clinical Trials Registry Platform to March 10, 2021 for randomized controlled trials in which patients were randomly assigned to receive tocilizumab plus usual care or usual care alone in hospitalized adults with COVID-19. A random-effects meta-analysis model was used to pool studies. All data analyses were performed using Review Manager version 5.4. RESULTS Eleven studies with 6579 patients were included in our meta-analysis, of which 3406 and 3173 were assigned to tocilizumab and control groups, respectively. Tocilizumab significantly reduced the 28 to 30-day mortality (relative risk [RR] = 0.89, 95% confidence interval [CI] 0.80-0.99, P = .04), incidence of mechanical ventilation (MV) (RR = 0.79, 95% CI 0.71-0.89, P < .001), composite outcome of MV or death (RR = 0.81, 95% CI 0.72-0.90, P < .001), time-to-hospital discharge (hazard ratio = 1.30, 95% CI 1.16-1.45, P < .001), intensive care unit admission (RR = 0.64, 95% CI 0.47-0.88, P = .006), serious infection (RR = 0.61, 95% CI 0.40-0.94, P = .02), and number of serious adverse events (RR = 0.64, 95% CI 0.47-0.86, P = .004). CONCLUSION Tocilizumab reduced short-term mortality, incidence of MV, composite outcome of death or MV, intensive care unit admission, serious infection, serious adverse events, and time-to-hospital discharge in hospitalized COVID-19 patients. Further studies are required to determine the optimal dose.
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Affiliation(s)
- Jing Zhang
- Department of Intensive Care Unit, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China
| | - Chun Chen
- Department of Nephrology, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China
| | - Yi Yang
- Department of Intensive Care Unit, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China
| | - Jin Yang
- Department of Intensive Care Unit, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China
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41
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Tom J, Bao M, Tsai L, Qamra A, Summers D, Carrasco-Triguero M, McBride J, Rosenberger CM, Lin CJF, Stubbings W, Blyth KG, Carratalà J, François B, Benfield T, Haslem D, Bonfanti P, van der Leest CH, Rohatgi N, Wiese L, Luyt CE, Kheradmand F, Rosas IO, Cai F. Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial. Crit Care Med 2022; 50:398-409. [PMID: 34612846 PMCID: PMC8855771 DOI: 10.1097/ccm.0000000000005229] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVES To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia. DESIGN Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. SETTING Hospitals in North America and Europe. PATIENTS Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care. INTERVENTION Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo. MEASUREMENTS AND MAIN RESULTS Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo. CONCLUSIONS Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28.
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Affiliation(s)
| | - Min Bao
- Genentech, South San Francisco, CA
| | | | - Aditi Qamra
- Hoffmann-La Roche Ltd, Mississauga, ON, Canada
| | - David Summers
- Roche Products Ltd, Welwyn Garden City, United Kingdom
| | | | | | | | | | | | - Kevin G Blyth
- Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
- Department of Respiratory Medicine, Queen Elizabeth University Hospital, Glasgow, United Kingdom
| | - Jordi Carratalà
- Department of Infectious Diseases, Bellvitge University Hospital, Bellvitge Biomedical Research Institute, University of Barcelona and Spanish Network for Research in Infectious Diseases, Barcelona, Spain
| | - Bruno François
- Intensive Care Unit and Inserm CIC1435 and UMR1092, CHU Limoges, Limoges, France
| | - Thomas Benfield
- Center of Research and Disruption of Infectious Diseases, Department of Infectious Diseases, Copenhagen University Hospital, Amager Hvidovre, Hvidovre, Denmark
| | - Derrick Haslem
- Medical Oncology, Intermountain Medical Group, St George, UT
| | - Paolo Bonfanti
- School of Medicine and Surgery, University of Milano-Bicocca and Infectious Diseases Unit Azienda Ospedaliera San Gerardo di Monza, Monza, Italy
| | | | - Nidhi Rohatgi
- Division of Hospital Medicine, Stanford University School of Medicine, Stanford, CA
| | - Lothar Wiese
- Department of Infectious Diseases, Zealand University Hospital, Roskilde, Denmark
| | - Charles Edouard Luyt
- Service de Réanimation, Institut de Cardiologie, Hopital de la Pitié Salpêtrière, Paris, France
| | | | - Ivan O Rosas
- Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Fang Cai
- Genentech, South San Francisco, CA
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Hermine O, Mariette X, Porcher R, Resche-Rigon M, Tharaux PL, Ravaud P. Effect of Interleukin-6 Receptor Antagonists in Critically Ill Adult Patients with COVID-19 Pneumonia: two Randomised Controlled Trials of the CORIMUNO-19 Collaborative Group. Eur Respir J 2022; 60:13993003.02523-2021. [PMID: 35115337 PMCID: PMC8819469 DOI: 10.1183/13993003.02523-2021] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 12/23/2021] [Indexed: 01/08/2023]
Abstract
Background Our objective was to determine whether anti-interleukin (IL)-6 receptors improve outcomes of critically ill patients with coronavirus disease 2019 (COVID-19) pneumonia. We report on two cohort-embedded, investigator-initiated, multicentre, open-label, Bayesian randomised controlled clinical trials. Methods Patients were randomly assigned to receive either usual care (UC) or UC+tocilizumab (TCZ) 8 mg·kg−1 (TOCI-2 trial) or UC or UC+sarilumab (SARI) 200 mg (SARI-2 trial), both intravenously on day 1 and, if clinically indicated, on day 3. Results Between 31 March and 20 April 2020, 97 patients were randomised in the TOCI-2 trial, to receive UC (n=46) or UC+TCZ (n=51). At day 14, numbers of patients who did not need noninvasive ventilation (NIV) or mechanical ventilation (MV) and were alive with TCZ or UC were similar (47% versus 42%; median posterior hazard ratio (HR) 1.19, 90% credible interval (CrI) 0.71–2.04), with a posterior probability of HR >1 of 71.4%. Between 27 March and 4 April 2020, 91 patients were randomised in the SARI-2 trial, to receive UC (n=41) or UC+SARI (n=50). At day 14, numbers of patients who did not need NIV or MV and were alive with SARI or UC were similar (38% versus 33%; median posterior HR 1.05, 90% CrI 0.55–2.07), with a posterior probability of HR >1 of 54.9%. Overall, the risk of death up to day 90 was: UC+TCZ 24% versus UC 30% (HR 0.67, 95% CI 0.30–1.49) and UC+SARI 29% versus UC 39% (HR 0.74, 95% CI 0.35–1.58). Both TCZ and SARI increased serious infectious events. Conclusion In critically ill patients with COVID-19, anti-IL-6 receptors did not significantly increase the number of patients alive without any NIV or MV by day 14. In two prospective randomised studies of COVID-19 patients in the ICU, anti-IL-6 receptor did not significantly increase early survival without mechanical ventilation. However, due to the small number of patients, no definitive conclusion could be drawn.https://bit.ly/3GoFAJV
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Affiliation(s)
- Olivier Hermine
- Département d'hématologie, Hôpital Necker, Assistance Publique Hôpitaux de Paris, Université de Paris, Paris, France .,Laboratory of physiopathology and treatment of Hematological malignancies, Institut imagine, INSERM U1153, Université de Paris, Paris, France
| | - Xavier Mariette
- Département de rhumatologie, Bicêtre Hôpital, Assistance Publique Hôpitaux de Paris, Université de Paris Sud, Paris France
| | - Raphael Porcher
- Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS-UMR1153), Inserm / Université Paris, Centre d'épidémiologie clinique, Hôpital Hôtel-Dieu
| | - Matthieu Resche-Rigon
- Service de biostatistique et information médicale, INSERM U153, Hôpital Saint Louis, Assistance Publique Hôpitaux de Paris, Université de Paris, Paris France.,These authors contributed equally
| | - Pierre-Louis Tharaux
- INSERM U970 Paris Cardiovascular Centre (PARCC), Université de Paris, Paris, France
| | - Philippe Ravaud
- Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS-UMR1153), Inserm / Université Paris, Centre d'épidémiologie clinique, Hôpital Hôtel-Dieu
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Janus Kinase Signaling Pathway and Its Role in COVID-19 Inflammatory, Vascular, and Thrombotic Manifestations. Cells 2022; 11:cells11020306. [PMID: 35053424 PMCID: PMC8773838 DOI: 10.3390/cells11020306] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 01/05/2022] [Accepted: 01/07/2022] [Indexed: 12/12/2022] Open
Abstract
Acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection continues to be a worldwide public health crisis. Among the several severe manifestations of this disease, thrombotic processes drive the catastrophic organ failure and mortality in these patients. In addition to a well-established cytokine storm associated with the disease, perturbations in platelets, endothelial cells, and the coagulation system are key in triggering systemic coagulopathy, involving both the macro- and microvasculatures of different organs. Of the several mechanisms that might contribute to dysregulation of these cells following SARS-CoV-2 infection, the current review focuses on the role of activated Janus kinase (JAK) signaling in augmenting thrombotic processes and organ dysfunction. The review concludes with presenting the current understanding and emerging controversies concerning the potential therapeutic applications of JAK inhibitors for ameliorating the inflammation-thrombosis phenotype in COVID-19 patients.
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Psychological Symptoms in COVID-19 Patients: Insights into Pathophysiology and Risk Factors of Long COVID-19. BIOLOGY 2022; 11:biology11010061. [PMID: 35053059 PMCID: PMC8773222 DOI: 10.3390/biology11010061] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/26/2021] [Accepted: 12/27/2021] [Indexed: 12/17/2022]
Abstract
There is growing evidence of studies associating COVID-19 survivors with increased mental health consequences. Mental health implications related to a COVID-19 infection include both acute and long-term consequences. Here we discuss COVID-19-associated psychiatric sequelae, particularly anxiety, depression, and post-traumatic stress disorder (PTSD), drawing parallels to past coronavirus outbreaks. A literature search was completed across three databases, using keywords to search for relevant articles. The cause may directly correlate to the infection through both direct and indirect mechanisms, but the underlying etiology appears more complex and multifactorial, involving environmental, psychological, and biological factors. Although most risk factors and prevalence rates vary across various studies, being of the female gender and having a history of psychiatric disorders seem consistent. Several studies will be presented, demonstrating COVID-19 survivors presenting higher rates of mental health consequences than the general population. The possible mechanisms by which the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the brain, affecting the central nervous system (CNS) and causing these psychiatric sequelae, will be discussed, particularly concerning the SARS-CoV-2 entry via the angiotensin-converting enzyme 2 (ACE-2) receptors and the implications of the immune inflammatory signaling on neuropsychiatric disorders. Some possible therapeutic options will also be considered.
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Almeida PRL, Person OC, Puga MEDS, Giusti MF, Pinto ACPN, Rocha AP, Atallah ÁN. Effectiveness and safety of tocilizumab for COVID-19: a systematic review and meta-analysis of randomized clinical trials. SAO PAULO MED J 2022; 141:168-176. [PMID: 36102463 PMCID: PMC10005468 DOI: 10.1590/1516-3180.2022.0170.r1.01072022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 07/01/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Tocilizumab is an anti-human interleukin 6 receptor monoclonal antibody that has been used to treat coronavirus disease 2019 (COVID-19). However, there is no consensus on its efficacy for the treatment of COVID-19. OBJECTIVE To evaluate the effectiveness and safety of tocilizumab for treating COVID-19. DESIGN AND SETTING Systematic Review of randomized controlled trials (RCTs), Universidade Federal de São Paulo (UNIFESP), São Paulo (SP), Brazil. METHODS We searched MEDLINE via PubMed, EMBASE, CENTRAL, and IBECS for RCTs published up to March 2021. Two authors selected studies and assessed the risk of bias and the certainty of the evidence following Cochrane Recommendations. RESULTS Eight RCTs with 6,139 participants were included. We were not able to find differences between using tocilizumab compared to standard care on mortality in hospitalized patients with COVID-19 (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.84 to 1.13; 8 trials; 5,950 participants; low-certainty evidence). However, hospitalized patients under tocilizumab plus standard care treatment seemed to present a significantly lower risk of needing mechanical ventilation (risk ratio = 0.78; 95% CI 0.64-0.94 moderate-certainty of evidence). CONCLUSIONS To date, the best evidence available shows no difference between using tocilizumab plus standard care compared to standard care alone for reducing mortality in patients with COVID-19. However, as a finding with a practical implication, the use of tocilizumab in association to standard care probably reduces the risk of progressing to mechanical ventilation in those patients. REGISTRATION osf.io/qe4fs.
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Affiliation(s)
- Paula Ribeiro Lopes Almeida
- MD. Otorhinolaryngologist and Postgraduate Student in Evidence-Based Health, Universidade Federal de São Paulo (UNIFESP), São Paulo (SP), Brasil
| | - Osmar Clayton Person
- MD, PhD. Full Professor, Department of Otorhinolaryngology, Universidade Santo Amaro (UNISA), São Paulo (SP), Brazil
| | | | | | - Ana Carolina Pereira Nunes Pinto
- PhD. Physiotherapist and Professor, Evidence-Based Health Program, Universidade Federal de São Paulo (UNIFESP), São Paulo (SP), Brazil
| | - Aline Pereira Rocha
- MSc. Pharmacist and Doctoral Student, Evidence-Based Health Program, Universidade Federal de São Paulo (UNIFESP), São Paulo (SP), Brazil
| | - Álvaro Nagib Atallah
- MD, PhD. Full Professor and Head of the Discipline of Emergency Medicine and Evidence-Based Medicine, Universidade Federal de São Paulo (UNIFESP), São Paulo (SP)
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Serial measurement of cytokines strongly predict COVID-19 outcome. PLoS One 2021; 16:e0260623. [PMID: 34855834 PMCID: PMC8639000 DOI: 10.1371/journal.pone.0260623] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 11/12/2021] [Indexed: 12/22/2022] Open
Abstract
Purpose Cytokines are major mediators of COVID-19 pathogenesis and several of them are already being regarded as predictive markers for the clinical course and outcome of COVID-19 cases. A major pitfall of many COVID-19 cytokine studies is the lack of a benchmark sampling timing. Since cytokines and their relative change during an infectious disease course is quite dynamic, we evaluated the predictive value of serially measured cytokines for COVID-19 cases. Methods In this single-center, prospective study, a broad spectrum of cytokines were determined by multiplex ELISA assay in samples collected at admission and at the third day of hospitalization. Appropriateness of cytokine levels in predicting mortality were assessed by receiver-operating characteristic (ROC) analyses for both sampling times in paralel to conventional biomarkers. Results At both sampling points, higher levels of IL-6, IL-7, IL-10, IL-15, IL-27 IP-10, MCP-1, and GCSF were found to be more predictive for mortality (p<0.05). Some of these cytokines, such as IL-6, IL-10, IL-7 and GCSF, had higher sensitivity and specificity in predicting mortality. AUC values of IL-6, IL-10, IL-7 and GCSF were 0.85 (0.65 to 0.92), 0.88 (0.73 to 0.96), 0.80 (0.63 to 0.91) and 0.86 (0.70 to 0.95), respectively at hospital admission. Compared to hospital admission, on the 3rd day of hospitalization serum levels of IL-6 and, IL-10 decreased significantly in the survivor group, unlike the non-survivor group (IL-6, p = 0.015, and IL-10, p = 0.016). Conclusion Our study results suggest that single-sample-based cytokine analyzes can be misleading and that cytokine levels measured serially at different sampling times provide a more precise and accurate estimate for the outcome of COVID-19 patients.
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Kruglova TS, Fomina DS, Poteshkina NG, Frolova NF, Beloglazova IP, Mutovina ZY, Samsonova IV, Kovalevskaja EA, Zagrebneva AI, Serdotetckova SA, Chernov AA, Lysenko MA. Criteria for the optimal use of interleukin-6 receptor blockers in patients with COVID-19. TERAPEVT ARKH 2021; 93:1316-1324. [DOI: 10.26442/00403660.2021.11.201248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 01/26/2022] [Indexed: 11/22/2022]
Abstract
Aim. To determine the criteria for the optimal use of IL-6 receptor blockers in patients with COVID-19 community-acquired pneumonia based on predictors of adverse outcomes.
Materials and methods. The single-center, non-randomized prospective study included 190 patients with community-acquired pneumonia caused by coronavirus 2 between the beginning of March and the end of May 2020. Of these, 89 patients received tocilizumab and 101 patients received sarilumab. The study inclusion criterion for the patient was indications for initiating therapy with one of the inhibitors of IL-6 receptors (anti-IL-6R) according to the Interim guidelines (versions 4 and 5). The exclusion criterion was the need to re-prescribe genetically engineered biological therapy (GEBT). The severity of the patient's condition was assessed according to the early warning score (NEWS2), the volume of lung tissue lesions was assessed according to computed tomography (CT). Laboratory monitoring included counting the absolute (abs) number of lymphocytes, serum levels of C-reactive protein (CRP), interleukin 6 (IL-6), D-dimer, lactate dehydrogenase, fibrinogen. Statistical data processing was conducted by nonparametric methods using the IBM SPSS Statistics V-22 software.
Results. The phenotype of a patient with a negative outcome prognosis was described: a male patient over 50 years of age with aggravated premorbid background (with cardiovascular diseases, obesity and/or chronic renal disease), lung lesion CT 34, saturation less than 93% upon inhalation of atmospheric air, persisting for 2448 hours after GEBT. According to the blood test, lymphopenia was below 1000 U/L and CRP levels were above 50 mg/L. The laboratory parameters and clinical picture of the patient progressively worsened after 911 days of illness, regardless of the use of Anti-IL-6R. The features of patients monitoring when administering IL-6 receptor blockers have been determined.
Conclusion. IL-6 receptor blockers should be administered to patients hospitalized with severe COVID-19 before the development of hyperinflammatory reactions. The optimal "therapeutic window" is 78 days of illness.
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Avni T, Leibovici L, Cohen I, Atamna A, Guz D, Paul M, Gafter-Gvili A, Yahav D. Tocilizumab in the treatment of COVID-19-a meta-analysis. QJM 2021; 114:577-586. [PMID: 34010403 PMCID: PMC8243364 DOI: 10.1093/qjmed/hcab142] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 05/05/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Interleukin-6 inhibitors showed promising results in observational trials of patients with coronavirus disease 2019 (COVID-19). AIM To evaluate whether interleukin-6 inhibitor tocilizumab (TCZ) reduces mortality among hospitalized COVID-19 patients. DESIGN A systematic review and meta-analysis. METHODS Systematic review and meta-analysis of randomized controlled trials (RCTs) comparing TCZ vs. placebo/control, for treatment of adults with COVID-19. Primary outcome was 28-30 days all-cause mortality. Search was conducted up to 1 April 2021. Two independent reviewers screened citations, extracted data and assessed risk of bias. Relative risk (RR) with 95% confidence intervals (CI) were pooled. We performed subgroup analysis for patients with critical illness and sensitivity analyses. RESULTS Eight RCTs were included, assessing 6481 patients with mostly severe non-critical COVID-19 infection. TCZ was associated with a reduction in all-cause 28-30-day mortality compared to placebo/control (RR = 0.89, 95% CI 0.82-0.96). Among the subgroup of critically ill patients no reduced mortality was demonstrated (RR = 0.94, 95% CI 0.74-1.19). No mortality benefit with TCZ was demonstrated in trials that used steroids for >80% of patients. TCZ was associated with significantly reduced risk for mechanical ventilation (MV); for combined endpoint of death or MV and for intensive care unit (ICU) admission. No significant difference in adverse events was demonstrated. Risk of serious superinfection was significantly lower with TCZ (RR = 0.57, 95% CI 0.35-0.93). CONCLUSION The treatment with TCZ reduces 28-30 days all-cause mortality, ICU admission, superinfections, MV and the combined endpoint of death or MV. Among critically ill patients, and when steroids were used for most patients, no mortality benefit was demonstrated. Additional research should further define sub-groups that would benefit most and preferred timing of administration of TCZ in severe COVID-19.
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Affiliation(s)
- Tomer Avni
- Medicine A
- Unit of Infectious Diseases
- Sackler Faculty of Medicine, Tel-Aviv
University, Israel
- Corresponding
author: Tomer Avni, MD. Medicine A, Rabin
Medical Center, Beilinson Hospital, 39 Jabotinsky Road, Petah-Tikva 49100,
Israel. Tel. +972-3-9377116;
| | - Leonard Leibovici
- Research Authority, Rabin Medical Center, Beilinson
Hospital
- Sackler Faculty of Medicine, Tel-Aviv
University, Israel
| | - Ido Cohen
- Sackler Faculty of Medicine, Tel-Aviv
University, Israel
| | - Alaa Atamna
- Unit of Infectious Diseases
- Sackler Faculty of Medicine, Tel-Aviv
University, Israel
| | | | - Mical Paul
- Infectious diseases Unit, Rambam Health Care Campus and Rappaport
Faculty of Medicine, Technion—Israel Institute of
Technology, Haifa, Israel
| | | | - Dafna Yahav
- Unit of Infectious Diseases
- Sackler Faculty of Medicine, Tel-Aviv
University, Israel
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Declercq J, Van Damme KFA, De Leeuw E, Maes B, Bosteels C, Tavernier SJ, De Buyser S, Colman R, Hites M, Verschelden G, Fivez T, Moerman F, Demedts IK, Dauby N, De Schryver N, Govaerts E, Vandecasteele SJ, Van Laethem J, Anguille S, van der Hilst J, Misset B, Slabbynck H, Wittebole X, Liénart F, Legrand C, Buyse M, Stevens D, Bauters F, Seys LJM, Aegerter H, Smole U, Bosteels V, Hoste L, Naesens L, Haerynck F, Vandekerckhove L, Depuydt P, van Braeckel E, Rottey S, Peene I, Van Der Straeten C, Hulstaert F, Lambrecht BN. Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial. THE LANCET RESPIRATORY MEDICINE 2021; 9:1427-1438. [PMID: 34756178 PMCID: PMC8555973 DOI: 10.1016/s2213-2600(21)00377-5] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/29/2021] [Accepted: 08/16/2021] [Indexed: 12/29/2022]
Abstract
Background Infections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome. Methods We did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO2:FiO2) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 μg/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 μg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 μg/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 × 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (1:2). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (1:1:1). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete. Findings Between April 4, and Dec 6, 2020, 342 patients were randomly assigned to IL-1 blockade (n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54–73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2–4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10–16) in the IL-1 blockade group versus 12 days (10–15) in the no IL-1 blockade group (hazard ratio [HR] 0·94 [95% CI 0·73–1·21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10–16) versus 12 days (11–16) in the no IL-6 blockade group (HR 1·00 [0·78–1·29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups. Interpretation Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk. Funding Belgian Health Care Knowledge Center and VIB Grand Challenges program.
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Affiliation(s)
- Jozefien Declercq
- Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium
| | - Karel F A Van Damme
- Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium
| | - Elisabeth De Leeuw
- Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium
| | - Bastiaan Maes
- Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium
| | - Cedric Bosteels
- Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium
| | - Simon J Tavernier
- Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Primary Immunodeficiency Research Laboratory, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Stefanie De Buyser
- Biostatistics Unit, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Roos Colman
- Biostatistics Unit, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Maya Hites
- Clinic of Infectious Diseases, Cliniques Universitaires de Bruxelles, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Gil Verschelden
- Clinic of Infectious Diseases, Cliniques Universitaires de Bruxelles, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Tom Fivez
- Intensive Care Unit, ZOL Genk General Hospital, Genk, Belgium
| | - Filip Moerman
- Department of Infectious Diseases, CHR de La Citadelle General Hospital, Liège, Belgium
| | - Ingel K Demedts
- Department of Pulmonary Medicine, AZ Delta General Hospital, Roeselare, Belgium
| | - Nicolas Dauby
- Institute for Medical Immunology, Université Libre de Bruxelles and CHU Saint-Pierre University Hospital, Brussels, Belgium
| | | | - Elke Govaerts
- Department of Pulmonary Medicine, AZ Sint-Lucas General Hospital, Ghent, Belgium
| | | | - Johan Van Laethem
- Department of Internal Medicine, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | | | - Jeroen van der Hilst
- Department of Infectious Diseases and Immune Pathology, Jessa General Hospital and Limburg Clinical Research Center, Hasselt University, Hasselt, Belgium
| | - Benoit Misset
- Department of Intensive Care Medicine, University Hospital, Liège, Belgium
| | - Hans Slabbynck
- Department of Pulmonary Medicine, ZNA General Hospital, Antwerp, Belgium
| | - Xavier Wittebole
- Intensive Care Unit, Saint Luc University Hospital, UC Louvain, Brussels, Belgium
| | - Fabienne Liénart
- Department of Internal Medicine, CHU Tivoli University Hospital, La Louvière, Belgium
| | - Catherine Legrand
- Institute of Statistics, Biostatistics and Actuarial Sciences (ISBA), Louvain Institute for Data Analysis and Modeling, Louvain-la-Neuve, Belgium
| | - Marc Buyse
- (22)IDDI, Louvain-la-Neuve, and Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt, Belgium
| | - Dieter Stevens
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium
| | - Fre Bauters
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium
| | - Leen J M Seys
- Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Helena Aegerter
- Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Ursula Smole
- Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Victor Bosteels
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Laboratory of ER Stress and Inflammation, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium
| | - Levi Hoste
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Primary Immunodeficiency Research Laboratory, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Leslie Naesens
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Primary Immunodeficiency Research Laboratory, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Filomeen Haerynck
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Primary Immunodeficiency Research Laboratory, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Linos Vandekerckhove
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Infectious Diseases, University Hospital Ghent, Ghent, Belgium
| | - Pieter Depuydt
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Intensive Care Unit, University Hospital Ghent, Ghent, Belgium
| | - Eva van Braeckel
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium
| | - Sylvie Rottey
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Drug Research Unit, Ghent University, Ghent, Belgium
| | - Isabelle Peene
- Department of Rheumatology, AZ Sint-Jan Brugge-Oostende, Brugge, Belgium
| | | | | | - Bart N Lambrecht
- Laboratory of Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent University, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Pulmonary Medicine, University Hospital Ghent, Ghent, Belgium.
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Iturricastillo G, Ávalos Pérez-Urría E, Couñago F, Landete P. Scientific evidence in the COVID-19 treatment: A comprehensive review. World J Virol 2021; 10:217-228. [PMID: 34631473 PMCID: PMC8474978 DOI: 10.5501/wjv.v10.i5.217] [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: 03/17/2021] [Revised: 05/12/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023] Open
Abstract
In December 2019, cases of unknown origin pneumonia appeared in Wuhan, China; the causal agent of this pneumonia was a new virus of the coronaviridae family called severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). According to the clinical severity, symptoms and response to the different treatments, the evolution of the disease is divided in three phases. We analysed the most used treatments for coronavirus disease 2019 and the phase in which they are supposed to be effective. In the viral phase, remdesivir has demonstrated reduction in recovery time but no mortality reduction. Other drugs proposed for viral phase such as convalescent plasma and lopinavir/ritonavir did not demonstrate to be effective. In the inflammatory phase, corticosteroids demonstrated reduction of 28-d mortality in patients who needed oxygen, establishing that a corticosteroid regimen should be part of the standard treatment of critically ill patients. There are other immunosuppressive and immunomodulatory treatments such as anakinra, sarilumab, tocilizumab, colchicine or baricitinib that are being studied. Other treatments that were proposed at the beginning, like hydroxichloroquine or azithromycin, demonstrated no efficacy and increased mortality when combined.
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Affiliation(s)
- Gorane Iturricastillo
- Department of Pulmonology, Hospital Universitario de La Princesa, Madrid 28006, Spain
| | | | - Felipe Couñago
- Department of Radiation Oncology, Hospital Universitario Quirónsalud Madrid, Pozuelo de Alarcón 28223, Spain
- Department of Radiation Oncology, Hospital La Luz, Madrid 28003, Spain
- Department of Radiation Oncology Universidad Europea de Madrid, Madrid 28670, Spain
| | - Pedro Landete
- Department of Pulmonology, Hospital Universitario de La Princesa, Madrid 28006, Spain
- Department of Pulmonology, Universidad Autónoma de Madrid, Madrid 28049, Spain
- Department of Pulmonology, Instituto Investigación Princesa, Madrid 28006, Spain
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