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Tomos I, Grigoropoulos I, Kosti C, Chrysikos S, Digalaki A, Thomas K, Hillas G, Kazakou P, Antoniadou A, Kavatha D, Dimakou K. Comparison of effectiveness and safety between baricitinib and tocilizumab in severe COVID-19: a retrospective study. Expert Rev Respir Med 2025; 19:389-397. [PMID: 40017107 DOI: 10.1080/17476348.2025.2473486] [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: 12/02/2024] [Revised: 02/16/2025] [Accepted: 02/25/2025] [Indexed: 03/01/2025]
Abstract
BACKGROUND Immunomodulators tocilizumab and baricitinib have been used for the treatment of severe COVID-19, however, there are only few published studies comparing their efficacy. RESEARCH DESIGN AND METHODS All consecutive non-ICU hospitalized severe COVID-19 patients who received baricitinib or tocilizumab, were included retrospectively. Primary outcomes were mortality or intubation on day 14, time to oxygen therapy weaning and duration of hospitalization. Safety was measured as treatment-related adverse events. RESULTS 321 hospitalized patients with severe COVID-19 were included (mean age 62.4 years ± 14.7); 241 (75.1%) received baricitinib (mean age 64.2 years ± 15.2) and 80 (24.9%) tocilizumab (mean age 57.3 ± 11.7). Patients who received baricitinib presented significantly lower risk of mortality or intubation on day 14, compared to the tocilizumab group after adjusting for age, sex, vaccination, Charlson comorbidity index, body mass index, remdesivir administration and WHO ordinal scale at enrollment (OR: 0.42, 95% CI: 0.20-0.86). In the augmented inverse-probability weighting regression, the protective role of baricitinib remained statistically significant (OR: 0.76, 95% CI: 0.66-0.88). No difference in secondary bacterial infections was detected, but tocilizumab was associated with significant higher rate of liver injury (Odds Ratio, 95%CI, p < 0.001). CONCLUSIONS Our study suggests survival and safety are significantly better for baricitinib compared to tocilizumab in severe COVID-19. Clinical randomized trials are needed for confirmation.
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Affiliation(s)
- Ioannis Tomos
- 5th Department of Respiratory Medicine, 'SOTIRIA' Chest Diseases Hospital of Athens, Athens, Greece
| | - Ioannis Grigoropoulos
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens School of Medicine, Haidari, Greece
| | - Chrysavgi Kosti
- 5th Department of Respiratory Medicine, 'SOTIRIA' Chest Diseases Hospital of Athens, Athens, Greece
| | - Serafeim Chrysikos
- 5th Department of Respiratory Medicine, 'SOTIRIA' Chest Diseases Hospital of Athens, Athens, Greece
| | - Antonia Digalaki
- 5th Department of Respiratory Medicine, 'SOTIRIA' Chest Diseases Hospital of Athens, Athens, Greece
| | - Konstantinos Thomas
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens School of Medicine, Haidari, Greece
| | - Georgios Hillas
- 5th Department of Respiratory Medicine, 'SOTIRIA' Chest Diseases Hospital of Athens, Athens, Greece
| | - Pinelopi Kazakou
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens School of Medicine, Haidari, Greece
| | - Anastasia Antoniadou
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens School of Medicine, Haidari, Greece
| | - Dimitra Kavatha
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens School of Medicine, Haidari, Greece
| | - Katerina Dimakou
- 5th Department of Respiratory Medicine, 'SOTIRIA' Chest Diseases Hospital of Athens, Athens, Greece
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Zheng L, Zhang Q, Luo P, Shi F, Zhang Y, He X, An Y, Cheng G, Pan X, Li Z, Zhou B, Wang J. Chemical Proteomics Approaches for Screening Small Molecule Inhibitors Covalently Binding to SARS-Cov-2. Adv Biol (Weinh) 2024; 8:e2300612. [PMID: 39410782 DOI: 10.1002/adbi.202300612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 02/01/2024] [Indexed: 11/13/2024]
Abstract
Although various strategies have been used to prevent and treat SARS-CoV-2, the spread and evolution of SARS-CoV-2 is still progressing rapidly. The emerging variants Omicron and its sublineage have a greater ability to spread and escape nearly all current monoclonal antibodies treatments, highlighting an urgent need to develop therapeutics targeting current and emerging Omicron variants or recombinants with breadth and potency. Here, some small molecule drugs are rapidly identified that could covalently binding to receptor binding domain (RBD) protein of Omicron through the combined application of artificial intelligence (AI) and activity-based protein profiling (ABPP) technology. The surface plasmon resonance (SPR) and pseudo-virus neutralization experiments further reveal that an FDA-approved drug gallic acid has robust neutralization potency against Omicron pseudo-virus with the IC50 values of 23.56 × 10-6 m. Taken together, a platform combining AI intelligence, biochemical, SPR, molecular docking, and pseudo-virus-based screening for rapid identification and evaluation of potential anti-SARS-CoV-2 small molecule drugs is established and the effectiveness of the platform is validated.
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Affiliation(s)
- Liuhai Zheng
- Department of Pulmonary and Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen, 518020, China
- Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Qian Zhang
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Piao Luo
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Fei Shi
- Department of Pulmonary and Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen, 518020, China
| | - Ying Zhang
- State Key Laboratory for Quality Esurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Xiaoxue He
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430207, China
| | - Yehai An
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Guangqing Cheng
- Department of Pulmonary and Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen, 518020, China
| | - Xiaoyan Pan
- Department of Pulmonary and Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen, 518020, China
| | - Zhijie Li
- Department of Pulmonary and Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen, 518020, China
| | - Boping Zhou
- Department of Pulmonary and Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen, 518020, China
| | - Jigang Wang
- Department of Pulmonary and Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Institute of Respiratory Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen, 518020, China
- School of Traditional Chinese Medicine and School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
- State Key Laboratory for Quality Esurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
- State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng, 475004, China
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Patanwala AE, Jager NGL, Radosevich JJ, Brüggemann R. An update on drug-drug interactions for care of the acutely ill in the era of COVID-19. Am J Health Syst Pharm 2023; 80:1301-1308. [PMID: 37368815 PMCID: PMC10516707 DOI: 10.1093/ajhp/zxad152] [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: 06/25/2023] [Indexed: 06/29/2023] Open
Abstract
PURPOSE To provide key pharmacological concepts underlying drug-drug interactions (DDIs), a decision-making framework, and a list of DDIs that should be considered in the context of contemporary acutely ill patients with COVID-19. SUMMARY DDIs are frequently encountered in the acutely ill. The implications of DDIs include either increased risk of drug toxicity or decreased effectiveness, which may have severe consequences in the acutely ill due to lower physiological and neurocognitive reserves in these patients. In addition, an array of additional therapies and drug classes have been used for COVID-19 that were not typically used in the acute care setting. In this update on DDIs in the acutely ill, we provide key pharmacological concepts underlying DDIs, including a discussion of the gastric environment, the cytochrome P-450 (CYP) isozyme system, transporters, and pharmacodynamics in relation to DDIs. We also provide a decision-making framework that elucidates the identification of DDIs, risk assessment, selection of alternative therapies, and monitoring. Finally, important DDIs pertaining to contemporary acute care clinical practice related to COVID-19 are discussed. CONCLUSION Interpreting and managing DDIs should follow a pharmacologically based approach and a systematic decision-making process to optimize patient outcomes.
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Affiliation(s)
- Asad E Patanwala
- Faculty of Medicine and Health, School of Pharmacy, The University of Sydney, Camperdown, New South Wales, and Department of Pharmacy, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
| | - Nynke G L Jager
- Department of Pharmacy, Radboud University Medical Center, Nijmegen, and Radboudumc Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - John J Radosevich
- Department of Pharmacy Services, Dignity Health–St. Joseph’s Hospital & Medical Center, Phoenix, AZ, USA
| | - Roger Brüggemann
- Department of Pharmacy, Radboud University Medical Center, Nijmegen, and Radboudumc Institute for Health Sciences Center of Expertise in Mycology Radboudumc/CWZ, Radboud University Medical Center, Nijmegen, the Netherlands
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Sunny S, Tran A, Lee J, Abdallah M, Chaudhry N, Quale J. Comparison of Tocilizumab vs Baricitinib in Clinical Outcomes Among Hospitalized Patients With COVID-19: Experience From a Public Hospital System in New York City. Open Forum Infect Dis 2023; 10:ofad426. [PMID: 37608917 PMCID: PMC10442059 DOI: 10.1093/ofid/ofad426] [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: 04/25/2023] [Accepted: 08/08/2023] [Indexed: 08/24/2023] Open
Abstract
Background Tocilizumab and baricitinib are immunomodulators that have been repurposed for the treatment of coronavirus disease 2019 (COVID-19). Whether one medication should be preferred over the other has not been established. Methods This multicenter retrospective cohort study comprised hospitalized patients with COVID-19 who received either tocilizumab or baricitinib. The primary outcome was improvement in respiratory status (at least 1-point reduction on the respiratory ordinal scale) at day 7 and up to day 28. Secondary outcomes included mortality, disposition, deep vein thrombosis, pulmonary embolism, or positive blood culture. Outcomes were stratified by baseline respiratory status and variant-predominating periods. Results were reported for the overall and propensity-matched cohorts. Results A total of 921 patients received tocilizumab and 638 received baricitinib. The propensity-matched cohort included 597 patients in each group. At day 7 in the overall and propensity-matched cohorts, significantly more patients had improvement in respiratory status in the baricitinib group. These improvements were seen in patients requiring supplemental oxygen and noninvasive ventilation/high-flow oxygen but not in patients requiring mechanical ventilation. Favorable outcomes with baricitinib were observed during the Alpha and Omicron periods. By day 28, there were no differences in the changes of respiratory status for the treatment groups in either cohort. Also, no differences were seen in mortality, disposition, development of deep vein thrombosis/pulmonary embolism, or bloodstream infections. Conclusions Baricitinib treatment was associated with more favorable respiratory improvement at day 7 when compared with tocilizumab, but no differences were observed up to day 28.
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Affiliation(s)
- Subin Sunny
- Division of Infectious Diseases, Department of Medicine, NYC Health + Hospitals/Kings County, Brooklyn, New York, USA
| | - Ami Tran
- Division of Infectious Diseases, Department of Medicine, NYC Health + Hospitals/Kings County, Brooklyn, New York, USA
| | - Jennifer Lee
- Division of Infectious Diseases, Department of Medicine, NYC Health + Hospitals/Kings County, Brooklyn, New York, USA
| | - Marie Abdallah
- Division of Infectious Diseases, Department of Medicine, NYC Health + Hospitals/Kings County, Brooklyn, New York, USA
| | - Nimra Chaudhry
- Department of Pharmacy, NYC Health + Hospitals/Queens, Queens, New York, USA
| | - John Quale
- Division of Infectious Diseases, Department of Medicine, NYC Health + Hospitals/Kings County, Brooklyn, New York, USA
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Reid NK, Joyner KR, Lewis-Wolfson TD. Baricitinib Versus Tocilizumab for the Treatment of Moderate to Severe COVID-19. Ann Pharmacother 2023; 57:769-775. [PMID: 36314277 PMCID: PMC9618915 DOI: 10.1177/10600280221133376] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND To date, minimal data directly compare tocilizumab with baricitinib for treatment in moderate to severe COVID-19. OBJECTIVE To compare the rates of in-hospital mortality with progression to mechanical ventilation in patients with COVID-19 who received either tocilizumab or baricitinib. METHODS The authors conducted a single-centered, institutional review board-approved, retrospective cohort study. Patients who were 18 years or older who were hospitalized with COVID-19 and who received tocilizumab or baricitinib were included. The primary end point is a composite outcome of progression to mechanical ventilation or in-hospital mortality. Secondary end points include components of the composite outcome and progression to higher level of care, duration of mechanical ventilation, and hospital and intensive care length of stay. Safety end points include the incidence of infections and thrombosis. RESULTS A total of 176 patients were included, of whom 61 (34.7%) received tocilizumab and 115 (65.3%) received baricitinib. In the primary outcome, there was no difference between the groups (52.5% tocilizumab vs 44.3% baricitinib, P = 0.305). For safety outcomes, there was a higher instance of thrombosis (11.5% tocilizumab vs 3.5% baricitinib, P = 0.042) and rates of antibiotic use after initiation of therapy (55.7% tocilizumab vs 38.3% baricitinib, P = 0.026) in the tocilizumab group. CONCLUSION AND RELEVANCE There was no significant difference in the composite outcome in patients who received tocilizumab or baricitinib for the treatment of COVID-19. However, there was an increase in rates of thrombosis in those receiving tocilizumab compared with baricitinib. These results need to be confirmed in larger prospective, randomized trials.
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Affiliation(s)
| | - Kayla Rena Joyner
- Department of Pharmacy Practice, Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, VA, USA
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Patel NM, Collotta D, Aimaretti E, Ferreira Alves G, Kröller S, Coldewey SM, Collino M, Thiemermann C. Inhibition of the JAK/STAT Pathway With Baricitinib Reduces the Multiple Organ Dysfunction Caused by Hemorrhagic Shock in Rats. Ann Surg 2023; 278:e137-e146. [PMID: 35837955 PMCID: PMC10249600 DOI: 10.1097/sla.0000000000005571] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE The aim of this study was to investigate (a) the effects of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway inhibitor (baricitinib) on the multiple organ dysfunction syndrome (MODS) in a rat model of hemorrhagic shock (HS) and (b) whether treatment with baricitinib attenuates the activation of JAK/STAT, NF-κB, and NLRP3 caused by HS. BACKGROUND Posttraumatic MODS, which is in part due to excessive systemic inflammation, is associated with high morbidity and mortality. The JAK/STAT pathway is a regulator of numerous growth factor and cytokine receptors and, hence, is considered a potential master regulator of many inflammatory signaling processes. However, its role in trauma-hemorrhage is unknown. METHODS An acute HS rat model was performed to determine the effect of baricitinib on MODS. The activation of JAK/STAT, NF-κB, and NLRP3 pathways were analyzed by western blotting in the kidney and liver. RESULTS We demonstrate here for the first time that treatment with baricitinib (during resuscitation following severe hemorrhage) attenuates the organ injury and dysfunction and the activation of JAK/STAT, NF-κB, and NLRP3 pathways caused by HS in the rat. CONCLUSIONS Our results point to a role of the JAK/STAT pathway in the pathophysiology of the organ injury and dysfunction caused by trauma/hemorrhage and indicate that JAK inhibitors, such as baricitinib, may be repurposed for the treatment of the MODS after trauma and/or hemorrhage.
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Affiliation(s)
- Nikita M. Patel
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Debora Collotta
- Department of Neurosciences “Rita Levi Montalcini,” University of Turin, Turin, Italy
| | - Eleonora Aimaretti
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | | | - Sarah Kröller
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
- Septomics Research Center, Jena University Hospital, Jena, Germany
| | - Sina M. Coldewey
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
- Septomics Research Center, Jena University Hospital, Jena, Germany
| | - Massimo Collino
- Department of Neurosciences “Rita Levi Montalcini,” University of Turin, Turin, Italy
| | - Christoph Thiemermann
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Xue Y, Mei H, Chen Y, Griffin JD, Liu Q, Weisberg E, Yang J. Repurposing clinically available drugs and therapies for pathogenic targets to combat SARS-CoV-2. MedComm (Beijing) 2023; 4:e254. [PMID: 37193304 PMCID: PMC10183156 DOI: 10.1002/mco2.254] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 02/11/2023] [Accepted: 03/07/2023] [Indexed: 05/18/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has affected a large portion of the global population, both physically and mentally. Current evidence suggests that the rapidly evolving coronavirus subvariants risk rendering vaccines and antibodies ineffective due to their potential to evade existing immunity, with enhanced transmission activity and higher reinfection rates that could lead to new outbreaks across the globe. The goal of viral management is to disrupt the viral life cycle as well as to relieve severe symptoms such as lung damage, cytokine storm, and organ failure. In the fight against viruses, the combination of viral genome sequencing, elucidation of the structure of viral proteins, and identifying proteins that are highly conserved across multiple coronaviruses has revealed many potential molecular targets. In addition, the time- and cost-effective repurposing of preexisting antiviral drugs or approved/clinical drugs for these targets offers considerable clinical advantages for COVID-19 patients. This review provides a comprehensive overview of various identified pathogenic targets and pathways as well as corresponding repurposed approved/clinical drugs and their potential against COVID-19. These findings provide new insight into the discovery of novel therapeutic strategies that could be applied to the control of disease symptoms emanating from evolving SARS-CoV-2 variants.
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Affiliation(s)
- Yiying Xue
- Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Husheng Mei
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical ScienceChinese Academy of SciencesHefeiChina
- University of Science and Technology of ChinaHefeiAnhuiChina
| | - Yisa Chen
- Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - James D. Griffin
- Department of Medical Oncology, Dana‐Farber Cancer InstituteBostonMassachusettsUSA
- Department of Medicine, Harvard Medical SchoolBostonMassachusettsUSA
| | - Qingsong Liu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical ScienceChinese Academy of SciencesHefeiChina
- University of Science and Technology of ChinaHefeiAnhuiChina
- Hefei Cancer HospitalChinese Academy of SciencesHefeiChina
| | - Ellen Weisberg
- Department of Medical Oncology, Dana‐Farber Cancer InstituteBostonMassachusettsUSA
- Department of Medicine, Harvard Medical SchoolBostonMassachusettsUSA
| | - Jing Yang
- Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and TechnologyTongji UniversityShanghaiChina
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical ScienceChinese Academy of SciencesHefeiChina
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Koh JY, Ko JH, Lim SY, Bae S, Huh K, Cho SY, Kang CI, Chung DR, Chung CR, Kim SH, Peck KR, Lee JS. Triple immune modulator therapy for aberrant hyperinflammatory responses in severe COVID-19. Clin Immunol 2023; 251:109628. [PMID: 37119951 PMCID: PMC10139747 DOI: 10.1016/j.clim.2023.109628] [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: 01/20/2023] [Revised: 04/11/2023] [Accepted: 04/26/2023] [Indexed: 05/01/2023]
Abstract
A dysregulated hyperinflammatory response is a key pathogenesis of severe COVID-19, but optimal immune modulator treatment has not been established. To evaluate the clinical effectiveness of double (glucocorticoids and tocilizumab) and triple (plus baricitinib) immune modulator therapy for severe COVID-19, a retrospective cohort study was conducted. For the immunologic investigation, a single-cell RNA sequencing analysis was performed in serially collected PBMCs and neutrophil specimens. Triple immune modulator therapy was a significant factor in a multivariable analysis for 30-day recovery. In the scRNA-seq analysis, type I and II IFN response-related pathways were suppressed by GC, and the IL-6-associated signature was additionally downregulated by TOC. Adding BAR to GC and TOC distinctly downregulated the ISGF3 cluster. Adding BAR also regulated the pathologically activated monocyte and neutrophil subpopulation induced by aberrant IFN signals. Triple immune modulator therapy in severe COVID-19 improved 30-day recovery through additional regulation of the aberrant hyperinflammatory immune response.
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Affiliation(s)
| | - Jae-Hoon Ko
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - So Yun Lim
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seongman Bae
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 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
| | - Sun Young Cho
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Cheol-In Kang
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Doo Ryeon Chung
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Chi Ryang Chung
- Department of Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sung-Han Kim
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Kyong Ran Peck
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
| | - Jeong Seok Lee
- Genome Insight, Inc., San Diego, La Jolla, CA, USA; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
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Thakur M, Babu A, Khatik GL, Datusalia AK, Khatri R, Kumar A. Role of baricitinib in COVID-19 patients: A systematic review and meta-analysis. World J Meta-Anal 2023; 11:125-133. [DOI: 10.13105/wjma.v11.i4.125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 01/27/2023] [Accepted: 03/29/2023] [Indexed: 04/14/2023] Open
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Karampitsakos T, Papaioannou O, Tsiri P, Katsaras M, Katsimpris A, Kalogeropoulos AP, Malakounidou E, Zarkadi E, Tsirikos G, Georgiopoulou V, Sotiropoulou V, Koulousousa E, Chourpiliadi C, Matsioulas A, Lagadinou M, Sampsonas F, Akinosoglou K, Marangos M, Tzouvelekis A. Tocilizumab versus baricitinib in hospitalized patients with severe COVID-19: an open label, randomized controlled trial. Clin Microbiol Infect 2023; 29:372-378. [PMID: 36273769 PMCID: PMC9636985 DOI: 10.1016/j.cmi.2022.10.015] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/08/2022] [Accepted: 10/09/2022] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Randomized controlled trials comparing tocilizumab and baricitinib in patients with coronavirus disease 2019 (COVID-19) are needed. This was an open-label, randomized controlled trial aiming to address this unmet need. METHODS To determine whether baricitinib was non-inferior to tocilizumab, we assessed whether the upper boundary of the two-sided 95% CI of the hazard ratio (HR) did not exceed 1.50. The primary outcome was mechanical ventilation or death by day 28. Secondary outcomes included time to hospital discharge by day 28 and change in WHO progression scale at day 10. RESULTS We assigned 251 patients with COVID-19 and a PaO2/FiO2 ratio of <200 to receive either tocilizumab (n = 126) or baricitinib (n = 125) plus standard of care. Baricitinib was non-inferior to tocilizumab for the primary composite outcome of mechanical ventilation or death by day 28 (mechanical ventilation or death for patients who received baricitinib, 39.2% [n = 49/125]; mechanical ventilation or death for patients who received tocilizumab, 44.4% [n = 56/126]; HR, 0.83; 95% CI, 0.56-1.21; p 0.001 for non-inferiority). Baricitinib was non-inferior to tocilizumab for the time to hospital discharge within 28 days (patients who received baricitinib- discharged alive: 58.4% [n = 73/125] vs. patients who received tocilizumab- discharged alive: 52.4% [n = 66/126]; HR, 0.85; 95% CI, 0.61-1.18; p < 0.001 for non-inferiority). There was no significant difference between the baricitinib and tocilizumab arms in the change in WHO scale at day 10 (0.0 [95% CI, 0.0-0.0] vs. 0.0 [95% CI, 0.0-1.0]; p 0.83). DISCUSSION In the setting of this trial, baricitinib was non-inferior to tocilizumab with regards to the composite outcome of mechanical ventilation or death by day 28 and the time to discharge by day 28 in patients with severe COVID-19.
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Affiliation(s)
| | - Ourania Papaioannou
- Department of Respiratory Medicine, University Hospital of Patras, Rio, Greece
| | - Panagiota Tsiri
- Department of Respiratory Medicine, University Hospital of Patras, Rio, Greece
| | - Matthaios Katsaras
- Department of Respiratory Medicine, University Hospital of Patras, Rio, Greece
| | - Andreas Katsimpris
- 'G.Gennimatas' Hospital, National and Kapodistrian University of Athens, Athens, Greece; Institute for Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
| | | | - Elli Malakounidou
- Department of Respiratory Medicine, University Hospital of Patras, Rio, Greece
| | - Eirini Zarkadi
- Department of Respiratory Medicine, University Hospital of Patras, Rio, Greece
| | - Georgios Tsirikos
- Department of Respiratory Medicine, University Hospital of Patras, Rio, Greece
| | | | | | - Electra Koulousousa
- Department of Respiratory Medicine, University Hospital of Patras, Rio, Greece
| | | | | | - Maria Lagadinou
- Department of Internal Medicine, University Hospital of Patras, Rio, Greece
| | - Fotios Sampsonas
- Department of Respiratory Medicine, University Hospital of Patras, Rio, Greece
| | | | - Markos Marangos
- Department of Internal Medicine, University Hospital of Patras, Rio, Greece
| | - Argyris Tzouvelekis
- Department of Respiratory Medicine, University Hospital of Patras, Rio, Greece.
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11
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Lakatos B, Szabó BG, Bobek I, Kiss-Dala N, Gáspár Z, Riczu A, Petrik B, Farkas BF, Sebestyén G, Gopcsa L, Bekő G, Sinkó J, Reményi P, Szlávik J, Mathiász D, Vályi-Nagy I. Baricitinib vs tocilizumab treatment for hospitalized adult patients with severe COVID-19 and associated cytokine storm: a prospective, investigational, real-world study. Int J Infect Dis 2022; 125:233-240. [PMID: 36328291 PMCID: PMC9621622 DOI: 10.1016/j.ijid.2022.10.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/21/2022] [Accepted: 10/25/2022] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVES Our aim was to compare outcomes of hospitalized adults with severe COVID-19 and cytokine storm treated with tocilizumab or baricitinib. METHODS A prospective, investigational, real-world study was performed from April 2020 to April 2021 at our center. COVID-19 severity was classified by World Health Organization criteria, and cytokine storm was documented along predefined criteria. Eligible patients were enrolled at diagnosis if they fulfilled a priori inclusion criteria and received standard-of-care plus tocilizumab or baricitinib for >48 hours. Patients were followed per protocol for 28 days post-diagnosis. The primary outcome was all-cause mortality; secondary outcomes were invasive mechanical ventilation and major infectious complications. RESULTS Of 463 patients, 102/463 (22.1%) received tocilizumab, and 361/463 (77.9%) baricitinib. Baseline characteristics were balanced. At 28 days, there was no difference in all-cause mortality (22/102, 21.6% vs 64/361, 17.7%; P-value = 0.38). Requirement for invasive mechanical ventilation was more frequent after tocilizumab (52/102, 50.9% vs 96/361, 26.6%; P <0.01), rate of major infectious complications was similar (32/102, 31.4% vs 96/361, 26.6%; P-value = 0.34). In logistic regression, the immunomodulatory drug was not retained as a predictor of all-cause mortality. Kaplan-Meier analysis revealed statistically similar survival distributions. CONCLUSION All-cause mortality was similar between adults treated with baricitinib or tocilizumab for severe COVID-19 with cytokine storm.
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Affiliation(s)
- Botond Lakatos
- South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary; Semmelweis University, Department of Internal Medicine and Hematology, Division of Infectology, Budapest, Hungary.
| | - Bálint Gergely Szabó
- South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary; Semmelweis University, Department of Internal Medicine and Hematology, Division of Infectology, Budapest, Hungary
| | - Ilona Bobek
- South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - Noémi Kiss-Dala
- South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary; Semmelweis University, Doctoral School of Clinical Medicine, Budapest, Hungary
| | - Zsófia Gáspár
- South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary; Semmelweis University, Doctoral School of Clinical Medicine, Budapest, Hungary
| | - Alexandra Riczu
- South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - Borisz Petrik
- South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | | | - Gabriella Sebestyén
- South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - László Gopcsa
- South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - Gabriella Bekő
- South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - János Sinkó
- South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - Péter Reményi
- South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - János Szlávik
- South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - Dóra Mathiász
- South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - István Vályi-Nagy
- South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
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12
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Niu J, Lin Z, He Z, Yang X, Qin L, Feng S, Guan L, Zhou L, Chen R. Janus kinases inhibitors for coronavirus disease-2019: A pairwise and Bayesian network meta-analysis. Front Med (Lausanne) 2022; 9:973688. [PMID: 36507538 PMCID: PMC9727257 DOI: 10.3389/fmed.2022.973688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 11/03/2022] [Indexed: 11/24/2022] Open
Abstract
Background JAK (Janus kinases) inhibitors have been proposed as a promising treatment option for the coronavirus disease-2019 (COVID-19). However, the benefits of JAK inhibitors and the optimum thereof for COVID-19 have not been adequately defined. Methods Databases were searched from their inception dates to 17 June 2022. Eligible studies included randomized controlled trials and observational studies. Extracted data were analyzed by pairwise and network meta-analysis. The primary outcome was the coefficient of mortality. Results Twenty-eight studies of 8,206 patients were included and assessed qualitatively (modified Jadad and Newcastle-Ottawa Scale scores). A pairwise meta-analysis revealed that JAK inhibitors effectively reduced the mortality (OR = 0.54; 95% CI: 0.46-0.63; P < 0.00001; I 2 = 32%) without increasing the risk of adverse events (OR = 1.02; 95% CI: 0.88-1.18; P = 0.79; I 2 = 12%). In a network meta-analysis, clinical efficacy benefits were seen among different types of JAK inhibitors (baricitinib, ruxolitinib, and tofacitinib) without the observation of a declined incidence of adverse events. The assessment of rank probabilities indicated that ruxolitinib presented the greatest likelihood of benefits regarding mortality and adverse events. Conclusion JAK inhibitors appear to be a promising treatment for COVID-19 concerning reducing mortality, and they do not increase the risk of adverse events vs. standard of care. A network meta-analysis suggests that mortality benefits are associated with specific JAK inhibitors, and among these, ruxolitinib presents the greatest likelihood of having benefits for mortality and adverse events. Systematic review registration [www.crd.york.ac.uk/prospero], identifier [CRD42022343338].
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Affiliation(s)
- Jianyi Niu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Respiratory Mechanics Laboratory, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhiwei Lin
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Respiratory Mechanics Laboratory, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhenfeng He
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Respiratory Mechanics Laboratory, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaojing Yang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Respiratory Mechanics Laboratory, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Lijie Qin
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Respiratory Mechanics Laboratory, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shengchuan Feng
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Respiratory Mechanics Laboratory, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Lili Guan
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Respiratory Mechanics Laboratory, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Luqian Zhou
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Respiratory Mechanics Laboratory, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Rongchang Chen
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Respiratory Mechanics Laboratory, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Shenzhen Respiratory Diseases, Institute of Shenzhen Respiratory Diseases, Shenzhen People’s Hospital (The First Affiliated Hospital of Southern University of Science and Technology, The Second Clinical Medical College of Jinan University), Shenzhen, Guangdong, China
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13
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Manoharan S, Ying LY. Does baricitinib reduce mortality and disease progression in SARS-CoV-2 virus infected patients? A systematic review and meta analysis. Respir Med 2022; 202:106986. [PMID: 36150282 PMCID: PMC9477792 DOI: 10.1016/j.rmed.2022.106986] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 06/07/2022] [Accepted: 09/06/2022] [Indexed: 11/29/2022]
Abstract
Background There are conflicting reports on the results of several of the latest clinical trials related to the use of baricitinib in the management of COVID-19 patients. The aim of the current systematic review and meta-analysis was to evaluate the efficacy of baricitinib in COVID-19 patients. Methods Databases like ScienceDirect, PubMed/Medline, Publons, Google Scholar and other sources like ClinicalTrials.gov, Cochrane, medRxiv, Research Square and reference lists were thoroughly searched. Results Fifteen (15) articles which met the inclusion criteria were qualitatively and quantitatively analysed. Based on Cochrane and Newcastle-Ottawa Scale (NOS) risk of bias (RoB) analyses, 14/15 articles are grouped as high-quality. Meta-analyses revealed that randomised control trials (RCTs) and non-randomised control trials (nRCTs) statistically significantly reduced the mortality rate in COVID-19 patients, with a risk ratio (RR) in the fixed-effect model was RR = 0.64 [95% CI: 0.51 to 0.79; p < 0.0001] and RR = 0.58 [95% CI: 0.45 to 0.73; p < 0.00001], respectively, with insignificant heterogeneity and no publication bias found. For block/reduce disease progression (BDP), baricitinib did not statistically significantly reduce disease progression for RCTs. The RR in the random effect model was RR = 0.80 [95% CI: 0.58 to 1.10: p = 0.17], with significant heterogeneity, where I2 was 60%. On the other hand, baricitinib statistically significantly reduced disease progression in nRCTs, as the RR of the fixed effect model was RR = 0.54 [95% CI: 0.37 to 0.78; p = 0.001] with insignificant heterogeneity. Conclusion The current meta-analyses revealed that baricitinib statistically significantly reduced mortality rate and disease progression in COVID-19 patients. Prospero registration number CRD42021281556
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Affiliation(s)
- Sivananthan Manoharan
- Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, Setia Alam, 40170, Shah Alam, Selangor, Malaysia.
| | - Lee Ying Ying
- Asia Metropolitan University, Bandar Baru Seri Alam, 81750, Johor Bahru, Johor, Malaysia
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14
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Malekinejad Z, Baghbanzadeh A, Nakhlband A, Baradaran B, Jafari S, Bagheri Y, Raei F, Montazersaheb S, Farahzadi R. Recent clinical findings on the role of kinase inhibitors in COVID-19 management. Life Sci 2022; 306:120809. [PMID: 35841979 PMCID: PMC9278000 DOI: 10.1016/j.lfs.2022.120809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/07/2022] [Accepted: 07/11/2022] [Indexed: 11/25/2022]
Abstract
The highly pathogenic, novel coronavirus disease (COVID-19) outbreak has emerged as a once-in-a-century pandemic with poor consequences, urgently calling for new therapeutics, cures, and supportive interventions. It has already affected over 250 million people worldwide; thereby, there is a need for novel therapies to alleviate the related complications. There is a paradigm shift in developing drugs and clinical practices to combat COVID-19. Several clinical trials have been performed or are testing diverse pharmacological interventions to alleviate viral load and complications such as cytokine release storm (CRS). Kinase-inhibitors have appeared as potential antiviral agents for COVID-19 patients due to their efficacy against CRS. Combination of kinase inhibitors with other therapies can achieve more efficacy against COVID-19. Based on the pre-clinical trials, kinase inhibitors such as Janus kinase-signal transducer and activator of transcription (JAK/STAT) inhibitors, Brutton's tyrosin kinase (BTK) inhibitors, p38 mitogen-activated protein kinases (p38 MAPK) inhibitors, Glycogen synthase kinase 3 (GSK-3) inhibitors can be a promising strategy against COVID-19. Kinase inhibitors possess crucial pharmacological properties for a successful re-purposing in terms of dual anti-inflammatory and anti-viral effects. This review will address the current clinical evidence and the newest discovery regarding the application of kinase inhibitors in COVID-19. An outlook on ongoing clinical trials (clinicaltrials.gov) and unpublished data is also presented here. Besides, Kinase inhibitors' function on COVID-19-mediated CRS is discussed.
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Affiliation(s)
- Zahra Malekinejad
- Faculty of Veterinary Medicine, Tabriz Branch, Islamic Azad University, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ailar Nakhlband
- Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sevda Jafari
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yasin Bagheri
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faezeh Raei
- Departement of Chemical and Petroleum Engineering, Sharif University of Technology, Tehran, Iran
| | - Soheila Montazersaheb
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Raheleh Farahzadi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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15
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Ramasamy C, Narayan G, Mishra AK, John KJ, Lal A. Nosocomial Infections in COVID-19 Patients Treated with Immunomodulators: A Narrative Review. Front Biosci (Schol Ed) 2022; 14:26. [PMID: 36575837 DOI: 10.31083/j.fbs1404026] [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: 06/29/2022] [Revised: 09/05/2022] [Accepted: 09/07/2022] [Indexed: 01/05/2023]
Abstract
Nosocomial infections pose an imminent challenge to hospitalized Coronavirus disease-19 (COVID-19) patients due to complex interplay of dysregulated immune response combined with immunomodulator therapy. In the pre-pandemic era, immunomodulatory therapy has shown benefit in certain autoimmune conditions with untamed inflammatory response. Efforts to recapitulate these immunomodulatory effects in COVID-19 patients has gained impetus and were followed by NIH COVID-19 expert panel recommendations. The current NIH guideline recommends interleukin-6 inhibitors (tocilizumab and sarilumab) and Janus kinase inhibitors (baricitinib and tofacitinib). Several landmark research trials like COVAVTA, EMPACTA, REMDACTA, STOP-COVID and COV BARRIER have detailed the various effects associated with administration of immunomodulators. The historical evidence of increased infection among patients receiving immunomodulators for autoimmune conditions, raised concerns regarding administration of immunomodulators in COVID-19 patients. The aim of this review article is to provide a comprehensive update on the currently available literature surrounding this issue. We reviewed 40 studies out of which 37 investigated IL-6 inhibitors and 3 investigated JAK inhibitors. Among the studies reviewed, the reported rates of nosocomial infections among the COVID-19 patients treated with immunomodulators were similar to patients receiving standard of care for COVID-19. However, these studies were not powered to assess the side effect profile of these medications. Immunomodulators, by dampening the pyrogenic response and inflammatory markers may delay detection of infections among the patients. This underscores the importance of long-term surveillance which are necessary to discover the potential risks associated with these agents.
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Affiliation(s)
- Chidambaram Ramasamy
- Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA 01608, USA
| | - Gayatri Narayan
- Department of Internal Medicine, Saint Vincent Hospital, Worcester, MA 01608, USA
| | - Ajay Kumar Mishra
- Department of Cardiology, Saint Vincent Hospital, Worcester, MA 01608, USA
| | - Kevin John John
- Department of Critical Care, Bangalore Baptist Hospital, 560032 Bangalore, Karnataka, India
| | - Amos Lal
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN 55905, USA
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16
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Dupuis D, Fritz K, Ike E, Arogundade O, Adewara EO, Monday EO, Ayinde BO. Current Use of Baricitinib in COVID-19 Treatment and Its Future: An Updated Literature Review. Cureus 2022; 14:e28680. [PMID: 36199657 PMCID: PMC9526681 DOI: 10.7759/cureus.28680] [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] [Accepted: 09/01/2022] [Indexed: 11/05/2022] Open
Abstract
The levels of infectivity and mortality that ensued due to the coronavirus disease 2019 (COVID-19) pandemic caused an apparent global outcry. The health system, burdened by increasing deaths and hospitalizations, sought more effective treatment. This necessitated scientists and researchers to utilize existing drugs such as baricitinib, which has proved itself as anti-inflammatory and immunomodulatory. A qualitative systematic review was conducted using databases such as Google Scholar, Science Direct, PubMed, and BioMed Central to locate relevant articles published from 2019 onward on the effectiveness of baricitinib. After evaluation of the full-text articles, 16 were selected for review. Overall, baricitinib was seen as beneficial in decreasing respiratory failure and the use of mechanical ventilation, also preventing deterioration of COVID-19 symptoms. When used as a single agent or combined with other drugs, baricitinib improves the peripheral capillary oxygen saturation (SpO2)/fraction of inspired oxygen (FiO2) ratio. The drug does not introduce any major side effects, but a mild increase in liver enzymes has been observed. Baricitinib proves to be a safe and effective treatment for COVID-19. Administered as monotherapy or in conjunction with other drugs, baricitinib provides tremendous clinical benefit to infected patients and shows good potential in terms of efficacy for future COVID-19 regimens.
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Affiliation(s)
- Derma Dupuis
- Department of Research, All Saints University, School of Medicine, Roseau, DMA
| | - Kasinda Fritz
- Department of Research, All Saints University, School of Medicine, Roseau, DMA
| | - Emeka Ike
- Department of Research, All Saints University, School of Medicine, Roseau, DMA
| | | | - Enoch O Adewara
- Faculty of Medicine, All Saints University, School of Medicine, Roseau, DMA
| | - Esther O Monday
- Faculty of Medicine, All Saints University, School of Medicine, Roseau, DMA
| | - Bolaji O Ayinde
- Faculty of Medicine, All Saints University, School of Medicine, Roseau, DMA
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17
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Khaledi M, Sameni F, Yahyazade S, Radandish M, Owlia P, Bagheri N, Afkhami H, Mahjoor M, Esmaelpour Z, Kohansal M, Aghaei F. COVID-19 and the potential of Janus family kinase (JAK) pathway inhibition: A novel treatment strategy. Front Med (Lausanne) 2022; 9:961027. [PMID: 36111104 PMCID: PMC9469902 DOI: 10.3389/fmed.2022.961027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
Recent evidence proposed that the severity of the coronavirus disease 2019 (COVID-19) in patients is a consequence of cytokine storm, characterized by increased IL-1β, IL-6, IL-18, TNF-α, and IFN-γ. Hence, managing the cytokine storm by drugs has been suggested for the treatment of patients with severe COVID-19. Several of the proinflammatory cytokines involved in the pathogenesis of COVID-19 infection recruit a distinct intracellular signaling pathway mediated by JAKs. Consequently, JAK inhibitors, including baricitinib, pacritinib, ruxolitinib, and tofacitinib, may represent an effective therapeutic strategy for controlling the JAK to treat COVID-19. This study indicates the mechanism of cytokine storm and JAK/STAT pathway in COVID-19 as well as the medications used for JAK/STAT inhibitors.
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Affiliation(s)
- Mansoor Khaledi
- Department of Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Fatemeh Sameni
- Department of Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Sheida Yahyazade
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maedeh Radandish
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parviz Owlia
- Molecular Microbiology Research Center, Faculty of Medicine, Shahed University, Tehran, Iran
- *Correspondence: Parviz Owlia ;
| | - Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
- Nader Bagheri
| | | | - Mohamad Mahjoor
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Esmaelpour
- Reference Laboratory for Bovine Tuberculosis, Razi Vaccine and Serum Research Institute, Karaj, Iran
| | - Maryam Kohansal
- Department of Medical Biotechnology, Fasa University of Medical Sciences, Fasa, Iran
| | - Farzad Aghaei
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Tahsini Tekantapeh S, Ghojazadeh M, Ghamari AA, Mohammadi A, Soleimanpour H. Therapeutic and anti-inflammatory effects of baricitinib on mortality, ICU transfer, clinical improvement, and CRS-related laboratory parameters of hospitalized patients with moderate to severe COVID-19 pneumonia: a systematic review and meta-analysis. Expert Rev Respir Med 2022; 16:1109-1132. [PMID: 35981253 DOI: 10.1080/17476348.2022.2114899] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND Due to the high incidence and mortality of the worldwide COVID-19 pandemic, beneficial effects of effective antiviral and anti-inflammatory drugs used in other diseases, especially rheumatic diseases, were observed in the treatment of COVID-19. METHODS Clinical and laboratory parameters of eight included cohort studies and five Randomized Control Trials between the baricitinib group and the control group were analyzed on the first day of admission and days 7, 14, and 28 during hospitalization. RESULTS According to the meta-analysis result of eight included cohort studies with 2088 patients, the Pooled Risk Ratios were 0.46 (P<0.001) for mortality, 6.14 (P< 0.001) for hospital discharge, and the mean differences of 76.78 (P< 0.001) for PaO2/FiO2 ratio was -47.32 (P= 0.02) for CRP, in the baricitinib group vs. control group on the seventh or fourteenth day of the treatment compared to the first day. Based on the meta-analysis of five RCT studies with 11825 patients, the pooled RR was 0.84 (P= 0.001) for mortality and 1.07 (P= 0.014) for patients' recovery. The mean differences were -0.80 (P<0.001) for hospitalization days, -0.51(P= 0.33) for time to recovery in the baricitinib group vs. control group. CONCLUSIONS Baricitinib prescription is strongly recommended in moderate to severe COVID-19. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration number: CRD42021254541.
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Affiliation(s)
| | - Morteza Ghojazadeh
- Research Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Akbar Ghamari
- Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aida Mohammadi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Soleimanpour
- Road Traffic Injury research center, Tabriz university of medical sciences, Tabriz, Iran
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19
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Nasonov EL, Korotaeva TV. Janus kinase inhibitors in immunoinflammatory diseases: 10 years of clinical practice in rheumatology. RHEUMATOLOGY SCIENCE AND PRACTICE 2022; 60:131-148. [DOI: 10.47360/1995-4484-2022-131-148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Despite great advances in the diagnosis and treatment of Immune-mediated inflammatory diseases (IMIDs), which have led to a significant improvement in the prognosis in many patients, the central medical problems of this pathology – restoring the quality of life and reducing mortality to the population level – are far from being resolved. This served as a powerful stimulus for the study of new approaches to the pharmacotherapy of IMIDs, one of which is associated with the discovery of targets for small-molecule therapeutics that inhibit intracellular “signaling” molecules JAKs (Janus kinases). The current achievements, trends and recommendations regarding the use of JAK inhibitors in the treatment of IMIDs and also in the hyper-response phase of COVID-19 are reviewed.
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Affiliation(s)
- E. L. Nasonov
- V.A. Nasonova Research Institute of Rheumatology; I.M. Sechenov First Moscow State Medical University of the Ministry of Health Care of Russian Federation (Sechenov University)
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Roddy J, Wells D, Schenck K, Santosh S, Santosh S. Tocilizumab Versus Baricitinib in Patients Hospitalized With COVID-19 Pneumonia and Hypoxemia: A Multicenter Retrospective Cohort Study. Crit Care Explor 2022; 4:e0702. [PMID: 35783551 PMCID: PMC9243240 DOI: 10.1097/cce.0000000000000702] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
In patients hospitalized with COVID-19 pneumonia, both tocilizumab and baricitinib have been shown to have clinical benefit compared with placebo. To date, there are few data comparing the two treatments, and their relative benefits and harms are unknown. This study aims to evaluate the effectiveness of tocilizumab versus baricitinib in patients hospitalized with COVID-19 pneumonia and hypoxemia. DESIGN Retrospective cohort study. SETTING Seven inpatient acute-care hospitals in Wisconsin. PARTICIPANTS Patients hospitalized with COVID-19, hypoxemia, and Pao2-to-Fio2 ratio less than or equal to 300 mm Hg, who received either tocilizumab or baricitinib. INTERVENTIONS Electronic chart review. MEASUREMENTS AND MAIN RESULTS Patients were divided into tocilizumab and baricitinib cohorts based on actual medication received. The primary outcome was hospital discharge alive and free from mechanical ventilation within 60 days, assessed by logistic regression. Three hundred eighty-two patients were included: 194 in the tocilizumab cohort and 188 in the baricitinib cohort. Most baseline characteristics in the two cohorts were similar. All patients received dexamethasone. Two patients were lost to follow-up. In the remaining 380 patients, probability of successful discharge in the two cohorts was quantitatively similar in unadjusted, multivariate-adjusted, and propensity score-matched analyses. Hospital length of stay, rates of thromboembolic events, and rates of hospital-acquired infections were all similar in the two cohorts. CONCLUSIONS In patients hospitalized with COVID-19 pneumonia and hypoxemia who receive dexamethasone, treatment with tocilizumab or baricitinib appears to result in similar outcomes.
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Affiliation(s)
- John Roddy
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
| | | | | | - Shrihari Santosh
- University of Colorado at Boulder, Leeds School of Business, Boulder, CO
| | - Sadashiv Santosh
- Division of Pulmonary, Critical Care, and Sleep Medicine, Saint Louis University School of Medicine, Saint Louis, MO
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21
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Al-Hajeri H, Baroun F, Abutiban F, Al-Mutairi M, Ali Y, Alawadhi A, Albasri A, Aldei A, AlEnizi A, Alhadhood N, Al-Herz A, Alkadi A, Alkanderi W, Almathkoori A, Almutairi N, Alsayegh S, Alturki A, Bahbahani H, Dehrab A, Ghanem A, Haji Hasan E, Hayat S, Saleh K, Tarakmeh H. Therapeutic role of immunomodulators during the COVID-19 pandemic- a narrative review. Postgrad Med 2022; 134:160-179. [PMID: 35086413 PMCID: PMC8862162 DOI: 10.1080/00325481.2022.2033563] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 01/18/2022] [Indexed: 02/07/2023]
Abstract
The emergency state caused by COVID-19 saw the use of immunomodulators despite the absence of robust research. To date, the results of relatively few randomized controlled trials have been published, and methodological approaches are riddled with bias and heterogeneity. Anti-SARS-CoV-2 antibodies, convalescent plasma and the JAK inhibitor baricitinib have gained Emergency Use Authorizations and tentative recommendations for their use in clinical practice alone or in combination with other therapies. Anti-SARS-CoV-2 antibodies are predominating the management of non-hospitalized patients, while the inpatient setting is seeing the use of convalescent plasma, baricitinib, tofacitinib, tocilizumab, sarilumab, and corticosteroids, as applicable. Available clinical data also suggest the potential clinical benefit of the early administration of blood-derived products (e.g. convalescent plasma, non-SARS-CoV-2-specific immunoglobins) and the blockade of factors implicated in the hyperinflammatory state of severe COVID-19 (Interleukin 1 and 6; Janus Kinase). Immune therapies seem to have a protective effect and using immunomodulators alone or in combination with viral replication inhibitors and other treatment modalities might prevent progression into severe COVID-19 disease, cytokine storm and death. Future trials should address existing gaps and reshape the landscape of COVID-19 management.
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Affiliation(s)
- Hebah Al-Hajeri
- Department of Rheumatology and Internal Medicine, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait
| | - Fatemah Baroun
- Department of Rheumatology and Internal Medicine, AlJahra Hospital, Al-Jahra, Kuwait
| | - Fatemah Abutiban
- Department of Rheumatology and Internal Medicine, Jaber Al-Ahmad Hospital, South Surra, Kuwait
| | | | - Yasser Ali
- Rheumatology Unit, Department of Internal Medicine, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait
| | - Adel Alawadhi
- Rheumatology Unit, Department of Internal Medicine, Al-Amiri Hospital, Kuwait City, Kuwait
| | - Anwar Albasri
- Rheumatology Unit, Department of Internal Medicine, Jaber Al-Ahmad Hospital, South Surra, Kuwait
| | - Ali Aldei
- Rheumatology Unit, Department of Internal Medicine, Al-Amiri Hospital, Kuwait City, Kuwait
| | - Ahmad AlEnizi
- Rheumatology Unit, Department of Internal Medicine, AlJahra Hospital, AlJahra, Kuwait
| | - Naser Alhadhood
- Rheumatology Unit, Department of Internal Medicine, Farwaneyah Hospital, AlFarwaniya, Kuwait
| | - Adeeba Al-Herz
- Rheumatology Unit, Department of Internal Medicine, Al-Amiri Hospital, Kuwait City, Kuwait
| | - Amjad Alkadi
- Rheumatology Unit, Department of Internal Medicine, Al-Sabah Hospital, Alsabah, Kuwait
| | - Waleed Alkanderi
- Rheumatology Unit, Department of Internal Medicine, Farwaneyah Hospital, AlFarwaniya, Kuwait
| | - Ammar Almathkoori
- Rheumatology Unit, Department of Internal Medicine, Al-Adan Hospital, Hadiya, Kuwait
| | - Nora Almutairi
- Rheumatology Unit, Department of Internal Medicine, Al-Sabah Hospital, Alsabah, Kuwait
| | - Saud Alsayegh
- Rheumatology Unit, Department of Internal Medicine, Jaber Al-Ahmad Armed Forces, Kuwait City, Kuwait
| | - Ali Alturki
- Rheumatology Unit, Department of Internal Medicine, Al-Adan Hospital, Hadiya, Kuwait
| | - Husain Bahbahani
- Rheumatology Unit, Department of Internal Medicine, Farwaneyah Hospital, AlFarwaniya, Kuwait
| | - Ahmad Dehrab
- Rheumatology Unit, Department of Internal Medicine, Al-Amiri Hospital, Kuwait City, Kuwait
| | - Aqeel Ghanem
- Rheumatology Unit, Department of Internal Medicine, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait
| | - Eman Haji Hasan
- Rheumatology Unit, Department of Internal Medicine, Al-Amiri Hospital, Kuwait City, Kuwait
| | - Sawsan Hayat
- Rheumatology Unit, Department of Internal Medicine, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait
| | - Khuloud Saleh
- Rheumatology Unit, Department of Internal Medicine, Farwaneyah Hospital, AlFarwaniya, Kuwait
| | - Hoda Tarakmeh
- Rheumatology Unit, Department of Internal Medicine, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait
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22
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Kai Y, Matsuda M, Suzuki K, Kasamatsu T, Kajita A, Uno K, Muro S. Tocilizumab and Baricitinib for Recovery From Acute Exacerbation of Combined Pulmonary Fibrosis and Emphysema Secondary to COVID-19 Infection: A Case Report. Cureus 2022; 14:e23411. [PMID: 35481309 PMCID: PMC9033509 DOI: 10.7759/cureus.23411] [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] [Accepted: 03/22/2022] [Indexed: 11/23/2022] Open
Abstract
Pneumonia secondary to coronavirus disease 2019 (COVID-19) is exacerbated by a disproportionate increase in the systemic inflammatory response and cytokine storm due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Herein, we report the successful treatment of severe COVID-19 pneumonia using a combination of tocilizumab and baricitinib in a patient with combined pulmonary fibrosis and emphysema (CPFE). A 67-year-old male with type 2 diabetes mellitus and CPFE presented with fever and dyspnea and was diagnosed with COVID-19. Upon admission, his respiratory failure was managed using high-flow nasal cannula (HFNC) therapy; however, despite treatment with remdesivir and systemic steroids, his respiratory failure continued to worsen. Therefore, baricitinib was administered from the ninth day of hospitalization for 14 days. Furthermore, his blood interleukin-6 (IL-6) levels showed an increase until day 13. Thus, tocilizumab was administered on the 13th day, which led to symptomatic improvement by day 18. The patient was discharged from our hospital on day 42. This case indicates that combination therapy with tocilizumab and baricitinib improves the efficacy of COVID-19 treatment in patients with comorbidities.
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Affiliation(s)
- Yoshiro Kai
- Department of Respiratory Medicine, Minami-Nara General Medical Center, Nara, JPN
| | - Masayuki Matsuda
- Department of Respiratory Medicine, Minami-Nara General Medical Center, Nara, JPN
| | - Kentaro Suzuki
- Department of Respiratory Medicine, Minami-Nara General Medical Center, Nara, JPN
| | - Takehito Kasamatsu
- Department of Infectious Diseases, Minami-Nara General Medical Center, Nara, JPN
| | - Akihiro Kajita
- Department of Infectious Diseases, Minami-Nara General Medical Center, Nara, JPN
| | - Kenji Uno
- Department of Infectious Diseases, Minami-Nara General Medical Center, Nara, JPN
| | - Shigeo Muro
- Department of Respiratory Medicine, Nara Medical University, Nara, JPN
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23
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Limen RY, Sedono R, Sugiarto A, Hariyanto TI. Janus kinase (JAK)-inhibitors and coronavirus disease 2019 (Covid-19) outcomes: a systematic review and meta-analysis. Expert Rev Anti Infect Ther 2022; 20:425-434. [PMID: 34538216 PMCID: PMC8500309 DOI: 10.1080/14787210.2021.1982695] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 09/07/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Currently, JAK-inhibitors are repurposed for therapy of Covid-19 because of their ability in restraining immune response, yet the corroboration regarding their advantage is still unclear. This study sought to analyze the efficacy of JAK-inhibitors to ameliorate the outcomes of Covid-19 sufferer.Research design and methods: Using specific keywords, we comprehensively go through the potential articles on ClinicalTrials.gov, Europe PMC, and PubMed sources until June 2nd, 2021. All published studies on JAK-inhibitors and Covid-19 were collected. RESULTS There were 14 studies with 4,363 Covid-19 patients contained in the meta-analysis. Based on our data, we suggested that JAK-inhibitors corresponded with increased recovery rate (RR 1.17; 95%CI: 1.01-1.36, p= 0.040, I2 = 91%, random-effect modeling); shortened time to recovery (mean difference -0.96; 95%CI: -1.15, -0.77, p< 0.00001, I2 = 28%, random-effect modeling); reduction of clinical deterioration risk (RR 0.66; 95%CI: 0.48-0.89, p= 0.008, I2 = 57%, random-effect modeling); and reduction of Covid-19 mortality (RR 0.52; 95%CI: 0.36-0.76, p= 0.0006, I2 = 33%, random-effect modeling). CONCLUSIONS This study propose that JAK-inhibitors perhaps provide advantageous effects on Covid-19 outcomes. JAK-inhibitors may be given during 1-2 weeks of disease to optimize its beneficial effects in halting the exaggerated immune response.
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Affiliation(s)
- Ronal Yosua Limen
- Department of Anesthesiology and Intensive Care, Universitas Indonesia – Rumah Sakit Cipto Mangunkusumo, Jakarta, Indonesia
| | - Rudyanto Sedono
- Department of Anesthesiology and Intensive Care, Universitas Indonesia – Rumah Sakit Cipto Mangunkusumo, Jakarta, Indonesia
| | - Adhrie Sugiarto
- Department of Anesthesiology and Intensive Care, Universitas Indonesia – Rumah Sakit Cipto Mangunkusumo, Jakarta, Indonesia
| | - Timotius Ivan Hariyanto
- Department of Anesthesiology and Intensive Care, Universitas Indonesia – Rumah Sakit Cipto Mangunkusumo, Jakarta, Indonesia
- Faculty of Medicine, Pelita Harapan University, Tangerang, Indonesia
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24
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Zhang X, Shang L, Fan G, Gu X, Xu J, Wang Y, Huang L, Cao B. The Efficacy and Safety of Janus Kinase Inhibitors for Patients With COVID-19: A Living Systematic Review and Meta-Analysis. Front Med (Lausanne) 2022; 8:800492. [PMID: 35155477 PMCID: PMC8828941 DOI: 10.3389/fmed.2021.800492] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 12/16/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Cytokine storm observed in patients with severe Coronavirus Disease 2019 (COVID-19) contributes to poor clinical outcomes and increased mortality. Janus kinases (JAKs) are important mediators in the cytokine storm. Therefore, we conduct a living systematic review and meta-analysis of the literature investigating efficacy and safety of JAK inhibitors for patients with COVID-19. METHODS Databases were searched up to December 1, 2021 for interventional and observational studies comparing JAK inhibitor treatment with concurrent control in patients with COVID-19. Efficacy and safety outcomes were evaluated by pooled risk ratio (RR). RESULTS Of 3,170 records retrieved, 15 studies were eligible and 13 were evaluated in the meta-analysis (n = 3,977). Based on data from three randomized controlled trials (RCTs), baricitinib treatment significantly decreased mortality by day 28 in hospitalized patients with COVID-19 (RR = 0.64, 95% CI 0.51-0.80) without increasing the incidence of adverse outcomes. In subgroup analysis, patients who required supplemental oxygen (RR = 0.62, 95% CI 0.41-0.95) or high-flow oxygen/non-invasive ventilation (RR = 0.59, 95% CI 0.42-0.85) at baseline benefited most. Pooled analysis of all eligible studies for JAK inhibitors (baricitinib, ruxolitinib, tofacitinib, and nezulcitinib) demonstrated a significant decrease in mortality (RR = 0.62, 95% CI 0.49-0.78) with no increase in the risk of adverse events. CONCLUSION Baricitinib probably decreases mortality in hospitalized adult patients with COVID-19, especially for patients who required supplemental oxygen or high-flow oxygen/non-invasive ventilation at baseline. The efficacy and safety of other JAK inhibitors, such as ruxolitinib, tofacitinib, and nezulcitinib, await more evidence. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021261414, identifier: CRD42021261414.
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Affiliation(s)
- Xueyang Zhang
- School of Medicine, Tsinghua University, Beijing, China
| | - Lianhan Shang
- Beijing University of Chinese Medicine, Beijing, China,Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Guohui Fan
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China,Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Xiaoying Gu
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China,Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
| | - Jiuyang Xu
- School of Medicine, Tsinghua University, Beijing, China,Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Yeming Wang
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Lixue Huang
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China,Department of Pulmonary and Critical Care Medicine, Capital Medical University, Beijing, China
| | - Bin Cao
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China,Department of Pulmonary and Critical Care Medicine, Capital Medical University, Beijing, China,Tsinghua University-Peking University Joint Center for Life Sciences, Beijing, China,*Correspondence: Bin Cao
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25
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Senderovich H, Vinoraj D, Stever M, Waicus S. Efficacy of COVID-19 treatments among geriatric patients: a systematic review. Ther Adv Infect Dis 2022; 9:20499361221095666. [PMID: 35677110 PMCID: PMC9168946 DOI: 10.1177/20499361221095666] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 03/29/2022] [Indexed: 11/29/2022] Open
Abstract
Introduction A majority of the fatalities due to COVID-19 have been observed in those over the age of 60. There is no approved and universally accepted treatment for geriatric patients. The aim of this review is to assess the current literature on efficacy of COVID-19 treatments in geriatric populations. Methods A systematic review search was conducted in PubMed, MedRxiv, and JAMA databases with the keywords COVID-19, geriatric, hydroxychloroquine, dexamethasone, budesonide, remdesivir, favipiravir, ritonavir, molnupiravir, tocilizumab, bamlanivimab, baricitinib, sotrovimab, fluvoxamine, convalescent plasma, prone position, or anticoagulation. Articles published from January 2019 to January 2022 with a population greater than or equal to 60 years of age were included. Interventions examined included hydroxychloroquine, remdesivir, favipiravir, dexamethasone, budesonide, tocilizumab, bamlanivimab, baricitinib, sotrovimab, convalescent plasma, prone position, and anticoagulation therapy. Outcome measures included viral load, viral markers, ventilator-free days, or clinical improvement. Results The search revealed 302 articles, 52 met inclusion criteria. Hydroxychloroquine, dexamethasone, and remdesivir revealed greater side effects or inefficiency in geriatric patients with COVID-19. Favipiravir, bamlanivimab, baricitinib, and supportive therapy showed a decrease in viral load and improvement of clinical symptoms. There is conflicting evidence with tocilizumab, convalescent plasma, and anticoagulant therapy in reducing mortality, ventilator-free days, and clinical improvements. In addition, there was limited evidence and lack of data due to ongoing trials for treatments with sotrovimab and budesonide. Conclusion No agent is known to be effective for preventing COVID-19 after exposure to the virus. Further research is needed to ensure safety and efficacy of each of the reviewed interventions for older adults.
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Affiliation(s)
- Helen Senderovich
- Baycrest, 3560 Bathurst Street, Toronto, ON M6A
2E1, Canada
- Department of Family and Community Medicine,
University of Toronto, Toronto, ON, Canada
- Division of Palliative Care, University of
Toronto, Toronto, ON, Canada
| | - Danusha Vinoraj
- Department of Psychiatry, Faculty of Medicine,
University of Ottawa, Ottawa, ON, Canada
| | | | - Sarah Waicus
- School of Medicine, Trinity College Dublin, The
University of Dublin, Dublin, Ireland
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26
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Gopcsa L, Bobek I, Bekő G, Lakatos B, Molnár E, Réti M, Reményi P, Sinkó J, Szlávik J, Tatai G, Vályi-Nagy I. Common points of therapeutic intervention in COVID-19 and in allogeneic hematopoietic stem cell transplantation associated severe cytokine release syndrome. Acta Microbiol Immunol Hung 2021; 68:240-255. [PMID: 34797216 DOI: 10.1556/030.2021.01620] [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: 10/03/2021] [Accepted: 10/22/2021] [Indexed: 11/19/2022]
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) and coronavirus disease 2019 (COVID-19) infection can both lead to severe cytokine release syndrome (sCRS) resulting in critical illness and death. In this single institution, preliminary comparative case-series study we compared clinical and laboratory co-variates as well as response to tocilizumab (TCZ)-based therapy of 15 allogeneic-HSCT- and 17 COVID-19-associated sCRS patients. Reaction to a TCZ plus posttransplant cyclophosphamide (PTCY) consolidation therapy in the allogeneic-HSCT-associated sCRS group yielded significantly inferior long-term outcome as compared to TCZ-based therapy in the COVID-19-associated group (P = 0.003). We report that a TCZ followed by consolidation therapy with a Janus kinase/signal transducer and activator of transcription (JAK/STAT) inhibitor given to 4 out of 8 critically ill COVID-19 patients resulted in their complete recovery. Non-selective JAK/STAT inhibitors influencing the action of several cytokines exhibit a broader effect than TCZ alone in calming down sCRS. Serum levels of cytokines and chemokines show similar changes in allogeneic-HSCT- and COVID-19-associated sCRS with marked elevation of interleukin-6 (IL-6), regulated upon activation normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein-1 (MCP-1) and interferon γ-induced protein 10 kDa (IP-10) levels. In addition, levels of IL-5, IL-10, IL-15 were also elevated in allogeneic-HSCT-associated sCRS. Our multi-cytokine expression data indicate that the pathophysiology of allogeneic-HSCT and COVID-19-associated sCRS are similar therefore the same clinical grading system and TCZ-based treatment approaches can be applied. TCZ with JAK/STAT inhibitor consolidation therapy might be highly effective in COVID-19 sCRS patients.
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Affiliation(s)
- László Gopcsa
- 1Central Hospital of Southern-Pest, National Institute of Hematology and Infectious Diseases, Department of Hematology and Stem Cell Transplantation, Albert Florian ut 5-7, H-1097, Budapest, Hungary
| | - Ilona Bobek
- 2Central Hospital of Southern-Pest, National Institute of Hematology and Infectious Diseases, Department of Intensive Care Unit, Albert Florian ut 5-7, H-1097, Budapest, Hungary
| | - Gabriella Bekő
- 3Central Hospital of Southern-Pest, National Institute of Hematology and Infectious Diseases, Department of Central Laboratory, Albert Florian ut 5-7, H-1097, Budapest, Hungary
| | - Botond Lakatos
- 4Central Hospital of Southern-Pest, National Institute of Hematology and Infectious Diseases, Department of Infectious Diseases, Albert Florian ut 5-7, H-1097, Budapest, Hungary
| | - Eszter Molnár
- 2Central Hospital of Southern-Pest, National Institute of Hematology and Infectious Diseases, Department of Intensive Care Unit, Albert Florian ut 5-7, H-1097, Budapest, Hungary
| | - Marienn Réti
- 1Central Hospital of Southern-Pest, National Institute of Hematology and Infectious Diseases, Department of Hematology and Stem Cell Transplantation, Albert Florian ut 5-7, H-1097, Budapest, Hungary
| | - Péter Reményi
- 1Central Hospital of Southern-Pest, National Institute of Hematology and Infectious Diseases, Department of Hematology and Stem Cell Transplantation, Albert Florian ut 5-7, H-1097, Budapest, Hungary
| | - János Sinkó
- 1Central Hospital of Southern-Pest, National Institute of Hematology and Infectious Diseases, Department of Hematology and Stem Cell Transplantation, Albert Florian ut 5-7, H-1097, Budapest, Hungary
| | - János Szlávik
- 4Central Hospital of Southern-Pest, National Institute of Hematology and Infectious Diseases, Department of Infectious Diseases, Albert Florian ut 5-7, H-1097, Budapest, Hungary
| | - Gábor Tatai
- 1Central Hospital of Southern-Pest, National Institute of Hematology and Infectious Diseases, Department of Hematology and Stem Cell Transplantation, Albert Florian ut 5-7, H-1097, Budapest, Hungary
| | - István Vályi-Nagy
- 1Central Hospital of Southern-Pest, National Institute of Hematology and Infectious Diseases, Department of Hematology and Stem Cell Transplantation, Albert Florian ut 5-7, H-1097, Budapest, Hungary
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Uemasu K, Yasuda Y, Hirayama Y, Arasawa S, Iwashima D, Takahashi KI. Post-COVID-19 interstitial lung disease presenting with profound hypoxemia: Report of three cases demonstrating a good response to high-dose corticosteroid therapy. J Infect Chemother 2021; 28:321-325. [PMID: 34810106 PMCID: PMC8598950 DOI: 10.1016/j.jiac.2021.11.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/12/2021] [Accepted: 11/04/2021] [Indexed: 12/26/2022]
Abstract
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which leads to critical pneumonia, although the clinical courses vary. In some cases, COVID-19 pneumonia causes secondary pulmonary fibrosis, which can retain radiological changes and prolong respiratory symptoms. Interstitial lung disease (ILD) secondary to COVID-19 is thought to be caused by multiple pathologies, such as excessive cytokines and abnormal repair processes elaborated by lung cells (epithelium, mesenchyme, and alveolar macrophages) after lung injury rather than viral invasion itself. Immunosuppression therapy may improve chronic respiratory symptoms and radiological changes in post-COVID-19 ILD, although the treatment is not yet established. Herein, we report three patients with post-COVID-19 ILD who presented with profound hypoxemia that had a good response to high-dose corticosteroid therapy. Further and larger studies are needed to establish post-COVID-19 ILD.
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Affiliation(s)
- Kiyoshi Uemasu
- Department of Respiratory Medicine, Kishiwada City Hospital, Japan.
| | - Yuto Yasuda
- Department of Respiratory Medicine, Kishiwada City Hospital, Japan
| | - Yutaka Hirayama
- Department of Respiratory Medicine, Kishiwada City Hospital, Japan
| | - Soichi Arasawa
- Department of Gastroenterology, Kishiwada City Hospital, Japan
| | - Daisuke Iwashima
- Department of Respiratory Medicine, Kishiwada City Hospital, Japan
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28
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Felsenstein S, Reiff AO. A hitchhiker's guide through the COVID-19 galaxy. Clin Immunol 2021; 232:108849. [PMID: 34563684 PMCID: PMC8461017 DOI: 10.1016/j.clim.2021.108849] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 09/04/2021] [Indexed: 01/08/2023]
Abstract
Numerous reviews have summarized the epidemiology, pathophysiology and the various therapeutic aspects of Coronavirus disease 2019 (COVID-19), but a practical guide on "how to treat whom with what and when" based on an understanding of the immunological background of the disease stages remains missing. This review attempts to combine the current knowledge about the immunopathology of COVID-19 with published evidence of available and emerging treatment options. We recognize that the information about COVID-19 and its treatment is rapidly changing, but hope that this guide offers those on the frontline of this pandemic an understanding of the host response in COVID-19 patients and supports their ongoing efforts to select the best treatments tailored to their patient's clinical status.
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Affiliation(s)
- Susanna Felsenstein
- University of Liverpool, Faculty of Health and Life Sciences, Brownlow Hill, Liverpool, L69 3GB, United Kingdom.
| | - Andreas Otto Reiff
- Arthritis & Rheumatic Diseases, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, United States.
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29
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Abizanda P, Calbo Mayo JM, Mas Romero M, Cortés Zamora EB, Tabernero Sahuquillo MT, Romero Rizos L, Sánchez‐Jurado PM, Sánchez‐Nievas G, Campayo Escolano C, Ochoa Serrano A, Sánchez‐Flor Alfaro V, López Bru R, Gómez Ballesteros C, Caldevilla Bernardo D, Callejas González FJ, Andrés‐Pretel F, Lauschke VM, Stebbing J. Baricitinib reduces 30-day mortality in older adults with moderate-to-severe COVID-19 pneumonia. J Am Geriatr Soc 2021; 69:2752-2758. [PMID: 34235720 PMCID: PMC8447356 DOI: 10.1111/jgs.17357] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/22/2021] [Accepted: 06/26/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Older adults are at the highest risk of severe disease and death due to COVID-19. Randomized data have shown that baricitinib improves outcomes in these patients, but focused stratified analyses of geriatric cohorts are lacking. Our objective was to analyze the efficacy of baricitinib in older adults with COVID-19 moderate-to-severe pneumonia. METHODS This is a propensity score [PS]-matched retrospective cohort study. Patients from the COVID-AGE and Alba-Score cohorts, hospitalized for moderate-to-severe COVID-19 pneumonia, were categorized in two age brackets of age <70 years old (86 with baricitinib and 86 PS-matched controls) or ≥70 years old (78 on baricitinib and 78 PS-matched controls). Thirty-day mortality rates were analyzed with Kaplan-Meier and Cox proportional hazard models. RESULTS Mean age was 79.1 for those ≥70 years and 58.9 for those <70. Exactly 29.6% were female. Treatment with baricitinib resulted in a significant reduction in death from any cause by 48% in patients aged 70 or older, an 18.5% reduction in 30-day absolute mortality risk (n/N: 16/78 [20.5%] baricitinib, 30/78 [38.5%] in PS-matched controls, p < 0.001) and a lower 30-day adjusted fatality rate (HR 0.21; 95% CI 0.09-0.47; p < 0.001). Beneficial effects on mortality were also observed in the age group <70 (8.1% reduction in 30-day absolute mortality risk; HR 0.14; 95% CI 0.03-0.64; p = 0.011). CONCLUSIONS Baricitinib is associated with an absolute mortality risk reduction of 18.5% in adults older than 70 years hospitalized with COVID-19 pneumonia.
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Affiliation(s)
- Pedro Abizanda
- Department of GeriatricsComplejo Hospitalario Universitario de AlbaceteAlbaceteSpain
- CIBERFESMinisterio de Economía y CompetitividadMadridSpain
- Facultad de MedicinaUniversidad de Castilla‐La ManchaAlbaceteSpain
| | - Juan María Calbo Mayo
- Department of Internal MedicineComplejo Hospitalario Universitario de AlbaceteAlbaceteSpain
| | - Marta Mas Romero
- Department of GeriatricsComplejo Hospitalario Universitario de AlbaceteAlbaceteSpain
| | - Elisa Belén Cortés Zamora
- Department of GeriatricsComplejo Hospitalario Universitario de AlbaceteAlbaceteSpain
- CIBERFESMinisterio de Economía y CompetitividadMadridSpain
| | | | - Luis Romero Rizos
- Department of GeriatricsComplejo Hospitalario Universitario de AlbaceteAlbaceteSpain
- CIBERFESMinisterio de Economía y CompetitividadMadridSpain
- Facultad de MedicinaUniversidad de Castilla‐La ManchaAlbaceteSpain
| | - Pedro Manuel Sánchez‐Jurado
- Department of GeriatricsComplejo Hospitalario Universitario de AlbaceteAlbaceteSpain
- CIBERFESMinisterio de Economía y CompetitividadMadridSpain
- Facultad de MedicinaUniversidad de Castilla‐La ManchaAlbaceteSpain
| | - Ginés Sánchez‐Nievas
- Department of RheumatologyComplejo Hospitalario Universitario de AlbaceteAlbaceteSpain
| | | | - Alba Ochoa Serrano
- Department of Internal MedicineComplejo Hospitalario Universitario de AlbaceteAlbaceteSpain
| | | | - Rita López Bru
- Department of GeriatricsComplejo Hospitalario Universitario de AlbaceteAlbaceteSpain
| | | | | | | | - Fernando Andrés‐Pretel
- Department of StatisticsFoundation of the National Paraplegics Hospital of ToledoToledoSpain
| | | | - Justin Stebbing
- Department of Surgery and Cancer, Imperial CollegeHammersmith Hospital, ICTEM BuildingLondonUK
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Gatti M, Turrini E, Raschi E, Sestili P, Fimognari C. Janus Kinase Inhibitors and Coronavirus Disease (COVID)-19: Rationale, Clinical Evidence and Safety Issues. Pharmaceuticals (Basel) 2021; 14:ph14080738. [PMID: 34451835 PMCID: PMC8401109 DOI: 10.3390/ph14080738] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 02/06/2023] Open
Abstract
We are witnessing a paradigm shift in drug development and clinical practice to fight the novel coronavirus disease (COVID-19), and a number of clinical trials have been or are being testing various pharmacological approaches to counteract viral load and its complications such as cytokine storm. However, data on the effectiveness of antiviral and immune therapies are still inconclusive and inconsistent. As compared to other candidate drugs to treat COVID-19, Janus Kinase (JAK) inhibitors, including baricitinib and ruxolitinib, possess key pharmacological features for a potentially successful repurposing: convenient oral administration, favorable pharmacokinetic profile, multifunctional pharmacodynamics by exerting dual anti-inflammatory and anti-viral effects. Baricitinib, originally approved for rheumatoid arthritis, received Emergency Use Authorization in November 2020 by the Food and Drug Administration in combination with remdesivir for the treatment of COVID-19 in hospitalized patients ≥ 2 years old who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation. By July 2021, the European Medicines Agency is also expected to issue the opinion on whether or not to extend its use in hospitalised patients from 10 years of age who require supplemental oxygen. Ruxolitinib, approved for myelofibrosis, was prescribed in patients with COVID-19 within an open-label Emergency Expanded Access Plan. This review will address key milestones in the discovery and use of JAK inhibitors in COVID-19, from artificial intelligence to current clinical evidence, including real world experience, and critically appraise emerging safety issues, namely infections, thrombosis, and liver injury. An outlook to ongoing studies (ClinicalTrials.gov) and unpublished pharmacovigilance data is also offered.
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Affiliation(s)
- Milo Gatti
- Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum—Università di Bologna, Via Irnerio 48, 40126 Bologna, Italy;
- SSD Clinical Pharmacology, IRCCS Azienda Ospedaliero Universitaria Sant’Orsola, 40126 Bologna, Italy
| | - Eleonora Turrini
- Department for Life Quality Studies, Alma Mater Studiorum—Università di Bologna, C.so D’Augusto 237, 47921 Rimini, Italy;
| | - Emanuel Raschi
- Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum—Università di Bologna, Via Irnerio 48, 40126 Bologna, Italy;
- Correspondence: (E.R.); (C.F.)
| | - Piero Sestili
- Department of Biomolecular Sciences (DISB), Università degli Studi di Urbino Carlo Bo, Via I Maggetti 26, 61029 Urbino, Italy;
| | - Carmela Fimognari
- Department for Life Quality Studies, Alma Mater Studiorum—Università di Bologna, C.so D’Augusto 237, 47921 Rimini, Italy;
- Correspondence: (E.R.); (C.F.)
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31
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Yang L, Xie X, Tu Z, Fu J, Xu D, Zhou Y. The signal pathways and treatment of cytokine storm in COVID-19. Signal Transduct Target Ther 2021; 6:255. [PMID: 34234112 PMCID: PMC8261820 DOI: 10.1038/s41392-021-00679-0] [Citation(s) in RCA: 372] [Impact Index Per Article: 93.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/22/2021] [Accepted: 06/12/2021] [Indexed: 02/07/2023] Open
Abstract
The Coronavirus Disease 2019 (COVID-19) pandemic has become a global crisis and is more devastating than any other previous infectious disease. It has affected a significant proportion of the global population both physically and mentally, and destroyed businesses and societies. Current evidence suggested that immunopathology may be responsible for COVID-19 pathogenesis, including lymphopenia, neutrophilia, dysregulation of monocytes and macrophages, reduced or delayed type I interferon (IFN-I) response, antibody-dependent enhancement, and especially, cytokine storm (CS). The CS is characterized by hyperproduction of an array of pro-inflammatory cytokines and is closely associated with poor prognosis. These excessively secreted pro-inflammatory cytokines initiate different inflammatory signaling pathways via their receptors on immune and tissue cells, resulting in complicated medical symptoms including fever, capillary leak syndrome, disseminated intravascular coagulation, acute respiratory distress syndrome, and multiorgan failure, ultimately leading to death in the most severe cases. Therefore, it is clinically important to understand the initiation and signaling pathways of CS to develop more effective treatment strategies for COVID-19. Herein, we discuss the latest developments in the immunopathological characteristics of COVID-19 and focus on CS including the current research status of the different cytokines involved. We also discuss the induction, function, downstream signaling, and existing and potential interventions for targeting these cytokines or related signal pathways. We believe that a comprehensive understanding of CS in COVID-19 will help to develop better strategies to effectively control immunopathology in this disease and other infectious and inflammatory diseases.
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Affiliation(s)
- Lan Yang
- Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Xueru Xie
- Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Zikun Tu
- Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Jinrong Fu
- General Department, Children's Hospital of Fudan University, Shanghai, China
| | - Damo Xu
- State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen Key Laboratory of Allergy and Immunology, Shenzhen University School of Medicine, Shenzhen, China.
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
| | - Yufeng Zhou
- Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
- National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China.
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32
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Kang S, Kishimoto T. Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms. Exp Mol Med 2021; 53:1116-1123. [PMID: 34253862 PMCID: PMC8273570 DOI: 10.1038/s12276-021-00649-0] [Citation(s) in RCA: 175] [Impact Index Per Article: 43.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 02/06/2023] Open
Abstract
Interleukin-6 (IL-6) plays a crucial role in host defense against infection and tissue injuries and is a bioindicator of multiple distinct types of cytokine storms. In this review, we present the current understanding of the diverse roles of IL-6, its receptors, and its signaling during acute severe systemic inflammation. IL-6 directly affects vascular endothelial cells, which produce several types of cytokines and chemokines and activate the coagulation cascade. Endothelial cell dysregulation, characterized by abnormal coagulation and vascular leakage, is a common complication in cytokine storms. Emerging evidence indicates that a humanized anti-IL-6 receptor antibody, tocilizumab, can effectively block IL-6 signaling and has beneficial effects in rheumatoid arthritis, juvenile systemic idiopathic arthritis, and Castleman's disease. Recent work has also demonstrated the beneficial effect of tocilizumab in chimeric antigen receptor T-cell therapy-induced cytokine storms as well as coronavirus disease 2019 (COVID-19). Here, we highlight the distinct contributions of IL-6 signaling to the pathogenesis of several types of cytokine storms and discuss potential therapeutic strategies for the management of cytokine storms, including those associated with sepsis and COVID-19.
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Affiliation(s)
- Sujin Kang
- Laborabory of Immune Regulation, Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka, Japan.
| | - Tadamitsu Kishimoto
- Laborabory of Immune Regulation, Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka, Japan.
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33
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Assadiasl S, Fatahi Y, Mosharmovahed B, Mohebbi B, Nicknam MH. Baricitinib: From Rheumatoid Arthritis to COVID-19. J Clin Pharmacol 2021; 61:1274-1285. [PMID: 33870531 PMCID: PMC8250677 DOI: 10.1002/jcph.1874] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 04/11/2021] [Indexed: 12/19/2022]
Abstract
Baricitinib is a JAK1/2 inhibitor that was first approved for treating moderate to severe rheumatoid arthritis (RA) but that later showed considerable efficacy in the control of exaggerated inflammatory responses that occur in a wide range of diseases. There is a growing body of evidence, obtained from clinical trials and case reports, demonstrating clinical and paraclinical improvement in patients following administration of baricitinib including RA, systemic lupus erythematosus, psoriasis, atopic dermatitis, alopecia areata, interferon‐mediated autoinflammatory diseases, graft‐versus‐host disease, diabetic kidney disease, and, recently, coronavirus disease‐19. However, despite overall encouraging results, many adverse effects have been observed in baricitinib‐treated patients, ranging from simple infections to increased risk of malignancies, particularly in long‐term use. The significant efficacy of baricitinib, versus the probable adverse effects, urge further investigation before establishing it as a part of standard therapeutic protocols. Here, we have provided a review of the studies that have used baricitinib for treating various inflammatory disorders and summarized the advantages and disadvantages of its administration.
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Affiliation(s)
- Sara Assadiasl
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Yousef Fatahi
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.,Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Banafsheh Mosharmovahed
- Department of Chemical Engineering-Pharmaceutical Engineering, University of Tehran, Tehran, Iran
| | - Bahareh Mohebbi
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Nicknam
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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34
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Nasonov EL. Coronavirus disease 2019 (COVID-19) and autoimmunity. RHEUMATOLOGY SCIENCE AND PRACTICE 2021. [DOI: 10.47360/1995-4484-2021-5-30] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The coronavirus 2019 pandemic (coronavirus disease, COVID-19), etiologically related to the SARS-CoV-2 virus (severe acute respiratory syndrome coronavirus-2), has once again reawakened healthcare professionals’ interest towards new clinical and conceptual issues of human immunology and immunopathology. An unprecedented number of clinical trials and fundamental studies of epidemiology, virology, immunology and molecular biology, of the COVID-19 clinical course polymorphism and pharmacotherapy have been conducted within one year since the outbreak of 2019 pandemic, bringing together scientists of almost all biological and physicians of almost all medical specialties. Their joint efforts have resulted in elaboration of several types of vaccines against SARS-CoV-2 infection and, in general, fashioning of more rational approaches to patient management. Also important for COVID-19 management were all clinical trials of biologics and “targeted” anti-inflammatory drugs modulating intracellular cytokine signaling, which have been specifically developed for treatment immune-mediated inflammatory rheumatic disease (IMIRDs) over the past 20 years. It became obvious after a comprehensive analysis of the entire spectrum of clinical manifestations and immunopathological disorders in COVID-19 is accompanied by a wide range of extrapulmonary clinical and laboratory disorders, some of which are characteristic of IMIRDs and other autoimmune and auto-in-flammatory human diseases. All these phenomena substantiated the practice of anti-inflammatory drugs repurposing with off-label use of specific antirheumatic agents for treatment of COVID-19. This paper discusses potential use of glucocorticoids, biologics, JAK inhibitors, etc., blocking the effects of pro-inflammatory cytokines for treatment of COVID-19.
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Affiliation(s)
- E. L. Nasonov
- V.A. Nasonova Research Institute of Rheumatology; I.M. Sechenov First Moscow State Medical University of the Ministry of Health Care of Russian Federation (Sechenov University)
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35
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Viceconte G, Buonomo AR, Lanzardo A, Pinchera B, Zappulo E, Scotto R, Schiano Moriello N, Vargas M, Iacovazzo C, Servillo G, Gentile I. Pneumocystis jirovecii pneumonia in an immunocompetent patient recovered from COVID-19. Infect Dis (Lond) 2021; 53:382-385. [PMID: 33645461 DOI: 10.1080/23744235.2021.1890331] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
BACKGROUND Several cases of invasive fungal diseases in patients with COVID-19 have been reported, mostly due to Aspergillus spp., with anecdotic reports of Pneumocystis jirovecii pneumonia (PJP) as co-infections in immunocompromised patients. We describe the first case of PJP in an immunocompetent patient who recovered from COVID-19 pneumonia. CASE DESCRIPTION Our patient was hospitalized for 18 d for respiratory failure due to Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pneumonia and successfully treated with continuous positive airway pressure (CPAP) respiratory support, enoxaparin, ceftaroline and intravenous 6 mg of dexamethasone for 10 d, then with oral prednisone tapering. Despite his improved radiological and clinical conditions at discharge, he was admitted again after 18 d for worsening of respiratory conditions. Upon the second admission, a high-resolution CT-scan of the chest showed the development of new ground-glass opacities and P. jirovecii was detected on bronchoalveolar lavage fluid. A therapy with trimethoprim-sulphamethoxazole 20 mg/kg and methylprednisolone 40 mg i.v. bis in die (BID) was started, with improvement of clinical, biochemical and radiological conditions. CONCLUSIONS COVID-19 patients may have multiple risk factors for development of PJP, in particular lymphopaenia and use of steroids. PJP must be ruled out with direct microbiological methods in patients presenting with radiologic and clinical features of possible or probable PJP, even in immunocompetent hosts.
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Affiliation(s)
- Giulio Viceconte
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | | | - Amedeo Lanzardo
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | - Biagio Pinchera
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | - Emanuela Zappulo
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | - Riccardo Scotto
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | - Nicola Schiano Moriello
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
| | - Maria Vargas
- Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, Italy
| | - Carmine Iacovazzo
- Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, Italy
| | - Giuseppe Servillo
- Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, Italy
| | - Ivan Gentile
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy
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36
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Chen CX, Wang JJ, Li H, Yuan LT, Gale RP, Liang Y. JAK-inhibitors for coronavirus disease-2019 (COVID-19): a meta-analysis. Leukemia 2021; 35:2616-2620. [PMID: 33990684 PMCID: PMC8119232 DOI: 10.1038/s41375-021-01266-6] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/21/2021] [Accepted: 04/26/2021] [Indexed: 01/31/2023]
Abstract
We analyzed reports on safety and efficacy of JAK-inhibitors in patients with coronavirus infectious disease-2019 (COVID-19) published between January 1st and March 6th 2021 using the Newcastle-Ottawa and Jadad scales for quality assessment. We used disease severity as a proxy for time when JAK-inhibitor therapy was started. We identified 6 cohort studies and 5 clinical trials involving 2367 subjects treated with ruxolitinib (N = 3) or baricitinib 45 (N = 8). Use of JAK-inhibitors decreased use of invasive mechanical ventilation (RR = 0.63; [95% Confidence Interval (CI), 0.47, 0.84]; P = 0.002) and had borderline impact on rates of intensive care unit (ICU) admission (RR = 0.24 [0.06, 1.02]; P = 0.05) and acute respiratory distress syndrome (ARDS; RR = 0.50 [0.19, 1.33]; P = 0.16). JAK-inhibitors did not decrease length of hospitalization (mean difference (MD) -0.18 [-4.54, 4.18]; P = 0.94). Relative risks of death for both drugs were 0.42 [0.30, 0.59] (P < 0.001), for ruxolitinib, RR = 0.33 (0.13, 0.88; P = 0.03) and for baricitinib RR = 0.44 (0.31, 0.63; P < 0.001). Timing of JAK-inhibitor treatment during the course of COVID-19 treatment may be important in determining impact on outcome. However, these data are not consistently reported.
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Affiliation(s)
- Chong-xiang Chen
- grid.488530.20000 0004 1803 6191Department of Hematologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China ,grid.470124.4State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province China ,grid.488530.20000 0004 1803 6191Department of ICU, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jiao-jiao Wang
- grid.256112.30000 0004 1797 9307Department of Tuberculosis, Fuzhou Pulmonary Hospital, Teaching Hospital of Fujian Medical University, Fuzhou, Fujian Province China
| | - Huan Li
- grid.488530.20000 0004 1803 6191Department of Hematologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China ,grid.488530.20000 0004 1803 6191Department of ICU, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Le-tao Yuan
- grid.12981.330000 0001 2360 039XSchool of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Robert Peter Gale
- grid.7445.20000 0001 2113 8111Department of Immunology and Inflammation, Haematology Research Centre, Imperial College London, London, UK
| | - Yang Liang
- grid.488530.20000 0004 1803 6191Department of Hematologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
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