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Aguareles J, Forné C, García-Casas A, Santamaría-Corral G, Carnevali-Ruiz D, Sotres-Fernández G, Solera JT, Guisado-Vasco P. Influence of anti-Spike protein antibody levels on tocilizumab efficacy in hospitalized patients with severe COVID-19 pneumonia: a post-hoc analysis of the COVACTA trial. BMC Infect Dis 2025; 25:676. [PMID: 40340657 PMCID: PMC12063319 DOI: 10.1186/s12879-025-11001-6] [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: 01/17/2025] [Accepted: 04/17/2025] [Indexed: 05/10/2025] Open
Abstract
BACKGROUND Our aim in this work is to find biomarkers to optimize therapy with IL-6 inhibitors, as not all clinical trials have shown clear benefits on mortality or mechanical ventilation progression. Given the link between delayed seroconversion and higher complication risks, we aim to test if evaluating SARS-CoV-2 spike protein antibody status before treatment could enhance IL-6 inhibitor therapy effectiveness in COVID-19 patients. METHODS We conducted a post hoc analysis of the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial of the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19. Cox and logistic regression analysis were used to assess the tocilizumab's efficacy in severe COVID-19 patients on survival and ICU stay at day 28, based on SARS-CoV-2 S-spike and neutralizing antibody levels. RESULTS Tocilizumab reduced 28-day mortality over placebo in patients with low S-spike antibody titers (20% vs. 29%). No benefit was observed for higher antibody levels. Patients with low S-spike antibody levels treated with tocilizumab exhibited a lower probability of ICU stay at day 28 compared to those treated with placebo (63% vs. 82%). No significant differences were noted in mortality and ICU stay based on whole neutralizing antibody titers. CONCLUSIONS Our findings suggest that using IL-6 inhibitors in severe COVID-19 patients with low S-spike antibody titers may improve clinical outcomes. CLINICAL TRIAL Not applicable.
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Affiliation(s)
- José Aguareles
- Internal Medicine Department, Hospital Universitario Quirónsalud Madrid, Madrid, Spain
- Department of Medicine, Faculty of Medicine, Health and Sports, European University of Madrid, Madrid, Spain
- Research and Clinical Trials Unit, Hospital Universitario Quirónsalud Madrid, Madrid, Spain
| | - Carles Forné
- Heorfy Consulting, Lleida, Spain
- Department of Basic Medical Sciences, University of Lleida, Lleida, Spain
| | - Ana García-Casas
- Internal Medicine Department, Hospital Universitario Quirónsalud Madrid, Madrid, Spain
- Research and Clinical Trials Unit, Hospital Universitario Quirónsalud Madrid, Madrid, Spain
| | - Guillermo Santamaría-Corral
- Internal Medicine Department, Hospital Universitario Quirónsalud Madrid, Madrid, Spain
- Research and Clinical Trials Unit, Hospital Universitario Quirónsalud Madrid, Madrid, Spain
| | - Daniel Carnevali-Ruiz
- Internal Medicine Department, Hospital Universitario Quirónsalud Madrid, Madrid, Spain
- Department of Medicine, Faculty of Medicine, Health and Sports, European University of Madrid, Madrid, Spain
| | - Gabriel Sotres-Fernández
- Internal Medicine Department, Hospital Universitario Quirónsalud Madrid, Madrid, Spain
- Department of Medicine, Faculty of Medicine, Health and Sports, European University of Madrid, Madrid, Spain
| | - Javier T Solera
- Internal Medicine Department, Hospital Universitario Quirónsalud Madrid, Madrid, Spain
- Department of Medicine, Faculty of Medicine, Health and Sports, European University of Madrid, Madrid, Spain
| | - Pablo Guisado-Vasco
- Internal Medicine Department, Hospital Universitario Quirónsalud Madrid, Madrid, Spain.
- Department of Medicine, Faculty of Medicine, Health and Sports, European University of Madrid, Madrid, Spain.
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Ishikawa T, Matsumoto K, Hamada T, Koze H, Baba M, Okamoto M, Sudoh M. In Silico Discovery of SARS-CoV-2 Main Protease Inhibitors Using Docking, Molecular Dynamics, and Fragment Molecular Orbital Calculations. J Phys Chem B 2025; 129:1740-1749. [PMID: 39886917 DOI: 10.1021/acs.jpcb.4c07920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2025]
Abstract
The 3C-like protease of severe acute respiratory syndrome coronavirus 2, known as the main protease (Mpro), is an attractive drug target for the treatment of coronavirus disease 2019. This study reports the discovery of novel Mpro inhibitors using several in silico techniques, including docking, molecular dynamics (MD), and fragment molecular orbital (FMO) calculations. We performed docking calculations on 5950 compounds with bioactivity, and 12 compounds were selected. An enzymatic assay was conducted, revealing that BP-1-102 exhibits significant Mpro inhibitory activity with an IC50 of 11.1 μM. The identification of seed compounds from the experiments on a few compounds demonstrates the effectiveness of our docking calculations. Furthermore, the detailed analyses using MD and FMO calculations suggested an interaction mechanism in which the hydroxyl group of BP-1-102 forms a hydrogen bond with E166 of Mpro. The Mpro inhibitory activity of SH-4-54, a derivative without the aforementioned hydroxyl group, was investigated and observed to be significantly reduced, with an IC50 of 81.5 μM. This result strongly supports the suggested interaction mechanism.
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Affiliation(s)
- Takeshi Ishikawa
- Department of Chemistry, Biotechnology, and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima 890-0065, Japan
| | - Kenji Matsumoto
- Department of Chemistry, Biotechnology, and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University, 1-21-40 Korimoto, Kagoshima 890-0065, Japan
| | - Toshiyuki Hamada
- Department of Chemistry, Graduate School of Science and Engineering, Kagoshima University, 1-21-35 Korimoto, Kagoshima 890-0065, Japan
| | - Hinako Koze
- Department of Chemistry, Graduate School of Science and Engineering, Kagoshima University, 1-21-35 Korimoto, Kagoshima 890-0065, Japan
| | - Masanori Baba
- Division of Infection Control Research, Center for Advanced Science Research and Promotion, Kagoshima University, 1-21-24, Korimoto, Kagoshima 890-8580, Japan
| | - Mika Okamoto
- Division of Infection Control Research, Center for Advanced Science Research and Promotion, Kagoshima University, 1-21-24, Korimoto, Kagoshima 890-8580, Japan
| | - Masayuki Sudoh
- Department of Translational Research, Joint Research Center for Human Retrovirus Infection, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
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Salo JLM, Marcelo LJN, Sanchez ACA, Marcelino CP, Hazel Anne LC, Miranda KJA, Carandang RRZ. Effectiveness of Tocilizumab in COVID-19 Patients with Pneumonia: A Systematic Review. ACTA MEDICA PHILIPPINA 2025; 59:72-80. [PMID: 39967711 PMCID: PMC11831086 DOI: 10.47895/amp.vi0.8188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
Abstract
Background and Objective COVID-19 contributes significantly to global morbidity and mortality. Age-related comorbidities elevate the risk of severe cases. Studies have recently demonstrated that widely available medications, including tocilizumab (TCZ), can manage severe symptoms. However, its effectiveness is unclear, particularly among the older population. Therefore, this review aimed to evaluate TCZ's efficacy in managing severe pneumonia in individuals aged 50 and older. Methods We systematically search several databases and gray literature including Web of Science, CINAHL, Academic Search Complete, PsycINFO, PsycArticles, SocINDEX, CENTRAL/Cochrane Library, PubMed/MEDLINE for original research articles in English across several study designs published in the year 2020-2022. A narrative synthesis was conducted to summarize the evidence. We employed the NIH quality assessment tool for observational cohort studies to evaluate risk of bias. Additionally, we utilized GRADE to appraise the certainty of evidence. Results Among 539 screened articles, only five studies met the selection criteria. Tocilizumab's impact on severe COVID-19 pneumonia revealed a diverse effect on mortality rate, with 29% in the TCZ group, and 40% in the controls died within 30 days of intubation (OR 0.61; 95% CI, 0.27-1.36). It is also reported that TCZ was not associated with mortality, despite faster decline in pulmonary function and prolonged fever. Hospital mortality in the TCZ group was significantly lower than in the controls, and age over 60 was the only significant risk factor. Moreover, administering TCZ reduced mechanical ventilation needs, with 82% extubated compared to 53% in controls. However, 45% in TCZ group was associated with a higher ventilator-associated pneumonia rate than in the untreated group which was 20% (P < 0.001). Despite this, TCZ-treated patients had shorter hospital stays. Conclusions The effects of tocilizumab on reducing mortality risk and improving the survival rate of COVID-19 patients with pneumonia remained inconclusive. Yet, the majority of results suggested that giving tocilizumab leads to shorter hospital stays, lowers the requirement for mechanical ventilation, and decreases the likelihood of ICU transfer. Tocilizumab is linked to the incidence of secondary infections; hence, this medication should be closely monitored for side effects.
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Affiliation(s)
| | | | | | | | | | | | - Rogie Royce Z Carandang
- College of Pharmacy, Adamson University, Manila, Philippines
- Department of Public Health Sciences, University of Connecticut School of Medicine, Connecticut, USA
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Mori N, Nanki T, Hirakawa A, Yamato M, Kaneko Y, Shiokawa R, Ozaki R, Kawabata N, Ohmagari N. Tocilizumab in combination with standard of care in patients with severe COVID-19 pneumonia: Efficacy and safety from a phase 3 clinical trial in Japan. J Infect Chemother 2025; 31:102524. [PMID: 39326494 DOI: 10.1016/j.jiac.2024.09.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 08/21/2024] [Accepted: 09/13/2024] [Indexed: 09/28/2024]
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) is characterized by high interleukin-6 levels. Clinical data supporting tocilizumab, a monoclonal antibody that targets interleukin-6 receptor-alpha, for treating Japanese patients with severe COVID-19 pneumonia are needed. METHODS This single-arm phase 3 study investigated tocilizumab (8 mg/kg) plus standard of care (SOC) in Japanese patients hospitalized with severe COVID-19 pneumonia. Clinical status was assessed using a 7-category ordinal scale on day 28 (primary endpoint) and day 14 (secondary endpoint). Other secondary endpoints were time to improvement (≥2 category improvement) and time to hospital discharge. Safety was assessed as the incidence of adverse events (AEs). RESULTS Among 48 patients enrolled, 44 (91.7 %) scored ≥3 on the 7-category ordinal scale at baseline. At day 28, 35 patients (72.9 %) scored 1 and 5 (10.4 %) scored 7 on the 7-category ordinal scale; 36 (75.0 %, 95 % confidence interval [CI]: 60.40 %-86.36 %) and 39 (81.3 %, 95 % CI: 67.37 %-91.05 %) patients achieved ≥2- and ≥1-category improvement, respectively; 6 patients (12.5 %, 95 % CI: 4.73 %-25.25 %) demonstrated ≥1-category worsening. At day 14, 25 (52.1 %, 95 % CI: 37.19 %-66.71 %) and 33 patients (68.8 %, 95 % CI: 53.75 %-81.34 %) achieved ≥2- and ≥1-category improvement, respectively; 5 patients (10.4 %, 95 % CI: 3.47 %-22.66 %) demonstrated ≥1-category worsening. Median times (95 % CI) to improvement and hospital discharge were 11 (9-15) and 15 (11-18) days, respectively. Forty patients (83.3 %) experienced AEs; the incidence of ≥grade 3 AEs was 25 %. CONCLUSION Tocilizumab plus SOC may provide improved clinical status in Japanese patients with severe COVID-19 pneumonia; no new safety signals were identified.
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Affiliation(s)
- Nobuyoshi Mori
- Division of Infectious Diseases, Department of Medicine, St. Luke's International Hospital, Tokyo, Japan.
| | - Toshihiro Nanki
- Division of Rheumatology, Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan
| | - Akihiro Hirakawa
- Department of Clinical Biostatistics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masaya Yamato
- Division of General Internal Medicine and Infectious Diseases, Rinku General Medical Center, Osaka, Japan
| | - Yuko Kaneko
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | | | - Ryoto Ozaki
- Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
| | | | - Norio Ohmagari
- Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan
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Zhou K, Lu J. Progress in cytokine research for ARDS: A comprehensive review. Open Med (Wars) 2024; 19:20241076. [PMID: 39479463 PMCID: PMC11524396 DOI: 10.1515/med-2024-1076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 09/16/2024] [Accepted: 10/06/2024] [Indexed: 11/02/2024] Open
Abstract
Introduction Acute respiratory distress syndrome (ARDS) is a critical form of acute respiratory failure characterized by diffuse alveolar damage, refractory hypoxemia, and non-cardiogenic pulmonary edema, resulting in high mortality. Dysregulated inflammation, driven by cytokines, is central to ARDS pathogenesis, progression, and prognosis. Objective This review synthesizes current knowledge on the role of cytokines in ARDS and evaluates their potential as therapeutic targets, offering new insights for clinical management. Methods A comprehensive analysis of recent studies was conducted to explore the roles of pro-inflammatory cytokines (e.g., IL-1β, IL-6, IL-8) and anti-inflammatory cytokines (e.g., IL-10, IL-22) in ARDS pathogenesis and to assess current and emerging therapies targeting these cytokines. Results Pro-inflammatory cytokines are crucial in initiating inflammatory responses and lung injury in early ARDS, while anti-inflammatory cytokines help regulate and resolve inflammation. Targeted therapies, such as IL-1 and IL-6 inhibitors, show potential in managing ARDS, particularly in COVID-19, but their clinical efficacy is still debated. Combination therapy strategies may enhance outcomes, but further large-scale, multicenter randomized controlled trials are required to establish their safety and efficacy. Conclusion Understanding cytokine regulation in ARDS could lead to innovative therapeutic approaches. Future research should focus on cytokine roles across ARDS subtypes and stages and develop biomarker-driven, individualized treatments.
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Affiliation(s)
- Kaihuan Zhou
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, China
| | - Junyu Lu
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, No. 166 Daxuedong Road, Nanning, Guangxi 530007, China
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Srisurapanont K, Lerttiendamrong B, Meejun T, Thanakitcharu J, Manothummetha K, Thongkam A, Chuleerarux N, Sanguankeo A, Li LX, Leksuwankun S, Langsiri N, Torvorapanit P, Worasilchai N, Plongla R, Moonla C, Nematollahi S, Kates OS, Permpalung N. Candidemia Following Severe COVID-19 in Hospitalised and Critical Ill Patients: A Systematic Review and Meta-Analysis. Mycoses 2024; 67:e13798. [PMID: 39379339 PMCID: PMC11607781 DOI: 10.1111/myc.13798] [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: 07/28/2024] [Revised: 08/27/2024] [Accepted: 08/30/2024] [Indexed: 10/10/2024]
Abstract
RATIONALE The epidemiology and clinical impact of COVID-19-associated candidemia (CAC) remained uncertain, leaving gaps in understanding its prevalence, risk factors and outcomes. METHODS A systematic review and meta-analysis were conducted by searching PubMed, Embase and Scopus for reports of CAC prevalence, risk factors and clinical outcomes up to June 18, 2024. The generalised linear mixed model was employed to determine the prevalence and 95% confidence intervals (CIs). The risk factors and clinical outcomes were compared between patients with and without CAC using the inverse variance method. RESULTS From 81 studies encompassing 29 countries and involving 351,268 patients, the global prevalence of CAC was 4.33% (95% Cl, 3.16%-5.90%) in intensive care unit (ICU) patients. In ICUs, the pooled prevalence of CAC in high-income countries was significantly higher than that of lower-middle-income countries (5.99% [95% Cl, 4.24%-8.40%] vs. 2.23% [95% Cl, 1.06%-4.61%], p = 0.02). Resistant Candida species, including C. auris, C. glabrata (Nakaseomyces glabratus) and C. krusei (Pichia kudriavzveii), constituted 2% of ICU cases. The mortality rate for CAC was 68.40% (95% Cl, 61.86%-74.28%) among ICU patients. Several risk factors were associated with CAC, including antibiotic use, central venous catheter placement, dialysis, mechanical ventilation, tocilizumab, extracorporeal membrane oxygenation and total parenteral nutrition. Notably, the pooled odds ratio of tocilizumab was 2.59 (95% CI, 1.44-4.65). CONCLUSIONS The prevalence of CAC is substantial in the ICU setting, particularly in high-income countries. Several risk factors associated with CAC were identified, including several that are modifiable, offering the opportunity to mitigate the risk of CAC.
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Affiliation(s)
| | | | - Tanaporn Meejun
- Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Jaedvara Thanakitcharu
- Panyananthaphikkhu Cholprathan Medical Center, Srinakharinwirot University, Nonthaburi, Thailand
| | - Kasama Manothummetha
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Achitpol Thongkam
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Nipat Chuleerarux
- Department of Medicine, University of Miami/Jackson Memorial Hospital, Miami, Florida, USA
| | - Anawin Sanguankeo
- Department of Preventive and Social Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Lucy X. Li
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Surachai Leksuwankun
- Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
- Thai Red Cross Emerging Infectious Diseases Clinical Center, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Nattapong Langsiri
- Panyananthaphikkhu Cholprathan Medical Center, Srinakharinwirot University, Nonthaburi, Thailand
| | - Pattama Torvorapanit
- Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
- Thai Red Cross Emerging Infectious Diseases Clinical Center, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Navaporn Worasilchai
- Department of Transfusion Medicine and Clinical Microbiology, Faculty of Allied Health Sciences, and Research Unit of Medical Mycology Diagnosis, Chulalongkorn University, Bangkok, Thailand
| | - Rongpong Plongla
- Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Chatphatai Moonla
- Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
- Center of Excellence in Translational Hematology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Saman Nematollahi
- Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona, USA
| | - Olivia S. Kates
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Nitipong Permpalung
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Akbari M, Dehghani Y, Shirzadi M, Pourajam S, Hosseinzadeh M, Sajadi M, Alenaseri M, Siavash M, Jafari L, Solgi H. Bacterial infections and outcomes of inpatients with COVID-19 in the intensive care unit during the delta-dominant phase: the worst wave of pandemic in Iran. Front Public Health 2024; 12:1411314. [PMID: 39314786 PMCID: PMC11416957 DOI: 10.3389/fpubh.2024.1411314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 08/26/2024] [Indexed: 09/25/2024] Open
Abstract
Background Epidemiological data regarding the prevalence of bacterial multidrug-resistant (MDR) Gram-negative infections in patients with COVID-19 in Iran are still ambiguous. Thus, in this study we have investigated the epidemiology, risk factors for death, and clinical outcomes of bacterial infections among patients with COVID-19 in the intensive care unit (ICU). Method This retrospective cohort study included patients with COVID-19 hospitalized in the ICU of a university hospital in Iran between June 2021 and December 2021. We evaluated the epidemiological, clinical, and microbiological features, outcomes and risk factors associated with death among all COVID-19 patients. Data and outcomes of these patients with or without bacterial infections were compared. Kaplan-Meier plot was used for survival analyses. Results In total, 505 COVID-19 patients were included. The mean age of the patients was 52.7 ± 17.6 years and 289 (57.2%) were female. The prevalence of bacterial infections among hospitalized patients was 14.9%, most of them being hospital-acquired superinfections (13.3%). MDR Klebsiella pneumoniae and Staphylococcus aureus were the most common pathogens causing respiratory infections. Urinary tract infections were most frequently caused by MDR Escherichia coli and K. pneumoniae. The overall in-hospital mortality rate of COVID-19 patients was 46.9% (237/505), while 78.7% (59/75) of patients with bacterial infections died. Infection was significantly associated with death (OR 6.01, 95% CI = 3.03-11.92, p-value <0.0001) and a longer hospital stay (p < 0.0001). Multivariate logistic regression analysis showed that Age (OR = 1.04, 95% CI = 1.03-1.06, p-value <0.0001), Sex male (OR = 1.70, 95% CI = 1.08-2.70, p-value <0.0001), Spo2 (OR = 1.99, 95% CI = 1.18-3.38, p-value = 0.010) and Ferritin (OR = 2.33, 95% CI = 1.37-3.97, p-value = 0.002) were independent risk factors associated with in-hospital mortality. Furthermore, 95.3% (221/232) of patients who were intubated died. Conclusion Our findings demonstrate that bacterial infection due to MDR Gram-negative bacteria associated with COVID-19 has an expressive impact on increasing the case mortality rate, reinforcing the importance of the need for surveillance and strict infection control rules to limit the expansion of almost untreatable microorganisms.
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Affiliation(s)
- Mojtaba Akbari
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Yeganeh Dehghani
- Amin Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Shirzadi
- Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Samaneh Pourajam
- Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Majid Hosseinzadeh
- Department of Genetics and Molecular Biology, School of Medicine Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahdi Sajadi
- Amin Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Malihe Alenaseri
- Amin Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mansour Siavash
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Leila Jafari
- Amin Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hamid Solgi
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- Amin Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
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Sarikaya ZT, Gucyetmez B, Tuzuner F, Dincer O, Sahan C, Dogan L, Yildirim SA, Zengin R, Kocagoz AS, Telci L, Akinci IO. The usage of immunosuppressant agents and secondary infections in patients with COVID-19 in the intensive care unit: a retrospective study. Sci Rep 2024; 14:20991. [PMID: 39251824 PMCID: PMC11385116 DOI: 10.1038/s41598-024-71912-3] [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: 05/24/2024] [Accepted: 09/02/2024] [Indexed: 09/11/2024] Open
Abstract
Although COVID-19 infection is an immunosuppressant disease, many immunosuppressant agents, such as pulse methylprednisolone (PMP), dexamethasone (DXM), and tocilizumab (TCZ), were used during the pandemic. Secondary infections in patients with COVID-19 have been reported recently. This study investigated these agents' effects on secondary infections and outcomes in patients with COVID-19 in intensive care units (ICUs). This study was designed retrospectively, and all data were collected from the tertiary intensive care units of six hospitals between March 2020 and October 2021. All patients were divided into three groups: Group I [GI, PMP (-), DXM (-) and TCZ (-)], Group II [GII, PMP (+), DXM (+)], and Group III [GIII, PMP (+), DXM (+), TCZ (+)]. Demographic data, PaO/FiO2 ratio, laboratory parameters, culture results, and outcomes were recorded. To compare GI-GII and GI-GIII, propensity score matching (PSM) was used by matching 14 parameters. Four hundred twelve patients with COVID-19 in the ICU were included in the study. The number of patients with microorganisms ≥ 2 was 279 (67.7%). After PSM, in GII and GIII, the number of (+) tracheal cultures and (+) bloodstream cultures detected different microorganisms ≥ 2 during the ICU period, neuropathy, tracheotomized patients, duration of IMV, and length of ICU stay were significantly higher than GI. The mortality rate was similar in GI and GII, whereas it was significantly higher in GIII than in GI. The use of immunosuppressant agents in COVID-19 patients may lead to an increase in secondary infections. In addition, increased secondary infections may lead to prolonged ICU stay, prolonged IMV duration, and increased mortality.
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Affiliation(s)
- Zeynep Tugce Sarikaya
- Department of Anesthesiology and Reanimation, Acibadem Mehmet Ali Aydinlar University School of Medicine, Istanbul, Turkey.
- General Intensive Care Unit, Acibadem Altunizade Hospital, Istanbul, Turkey.
| | - Bulent Gucyetmez
- Department of Anesthesiology and Reanimation, Acibadem Mehmet Ali Aydinlar University School of Medicine, Istanbul, Turkey
- General Intensive Care Unit, Acibadem International Hospital, Istanbul, Turkey
| | - Filiz Tuzuner
- General Intensive Care Unit, Acibadem Taksim Hospital, Istanbul, Turkey
| | - Ozlem Dincer
- General Intensive Care Unit, Acibadem Atakent Hospital, Istanbul, Turkey
- General Intensive Care Unit, Acibadem Bakırköy Hospital, Istanbul, Turkey
| | - Cenk Sahan
- General Intensive Care Unit, Acibadem Atakent Hospital, Istanbul, Turkey
- General Intensive Care Unit, Acibadem Maslak Hospital, Istanbul, Turkey
| | - Lerzan Dogan
- General Intensive Care Unit, Acibadem Altunizade Hospital, Istanbul, Turkey
| | - Serap Aktas Yildirim
- Department of Anesthesiology and Reanimation, Acibadem Mehmet Ali Aydinlar University School of Medicine, Istanbul, Turkey
| | - Rehile Zengin
- Department of Infectious Diseases and Clinical Microbiology, Acibadem Altunizade Hospital, Istanbul, Turkey
| | - Ayse Sesin Kocagoz
- Department of Infectious Disease and Clinical Microbiology, Acibadem Mehmet Ali Aydinlar University School of Medicine, Istanbul, Turkey
| | - Lutfi Telci
- General Intensive Care Unit, Acibadem International Hospital, Istanbul, Turkey
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Bhol NK, Bhanjadeo MM, Singh AK, Dash UC, Ojha RR, Majhi S, Duttaroy AK, Jena AB. The interplay between cytokines, inflammation, and antioxidants: mechanistic insights and therapeutic potentials of various antioxidants and anti-cytokine compounds. Biomed Pharmacother 2024; 178:117177. [PMID: 39053423 DOI: 10.1016/j.biopha.2024.117177] [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: 05/17/2024] [Revised: 07/03/2024] [Accepted: 07/22/2024] [Indexed: 07/27/2024] Open
Abstract
Cytokines regulate immune responses essential for maintaining immune homeostasis, as deregulated cytokine signaling can lead to detrimental outcomes, including inflammatory disorders. The antioxidants emerge as promising therapeutic agents because they mitigate oxidative stress and modulate inflammatory pathways. Antioxidants can potentially ameliorate inflammation-related disorders by counteracting excessive cytokine-mediated inflammatory responses. A comprehensive understanding of cytokine-mediated inflammatory pathways and the interplay with antioxidants is paramount for developing natural therapeutic agents targeting inflammation-related disorders and helping to improve clinical outcomes and enhance the quality of life for patients. Among these antioxidants, curcumin, vitamin C, vitamin D, propolis, allicin, and cinnamaldehyde have garnered attention for their anti-inflammatory properties and potential therapeutic benefits. This review highlights the interrelationship between cytokines-mediated disorders in various diseases and therapeutic approaches involving antioxidants.
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Affiliation(s)
- Nitish Kumar Bhol
- Post Graduate Department of Biotechnology, Utkal University, Bhubaneswar, Odisha 751004, India
| | | | - Anup Kumar Singh
- National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, India
| | - Umesh Chandra Dash
- Environmental Biotechnology Laboratory, KIIT School of Biotechnology, KIIT Deemed to be University, Bhubaneswar, Odisha, India
| | - Rakesh Ranjan Ojha
- Department of Bioinformatics, BJB (A) College, Bhubaneswar, Odisha-751014, India
| | - Sanatan Majhi
- Post Graduate Department of Biotechnology, Utkal University, Bhubaneswar, Odisha 751004, India
| | - Asim K Duttaroy
- Department of Nutrition, Institute of Medical Sciences, Faculty of Medicine, University of Oslo, Norway.
| | - Atala Bihari Jena
- National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, India.
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10
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Merson L, Duque S, Garcia-Gallo E, Yeabah TO, Rylance J, Diaz J, Flahault A, ISARIC Clinical Characterisation Group. Optimising Clinical Epidemiology in Disease Outbreaks: Analysis of ISARIC-WHO COVID-19 Case Report Form Utilisation. EPIDEMIOLOGIA 2024; 5:557-580. [PMID: 39311356 PMCID: PMC11417906 DOI: 10.3390/epidemiologia5030039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 08/09/2024] [Accepted: 08/27/2024] [Indexed: 09/26/2024] Open
Abstract
Standardised forms for capturing clinical data promote consistency in data collection and analysis across research sites, enabling faster, higher-quality evidence generation. ISARIC and the World Health Organization have developed case report forms (CRFs) for the clinical characterisation of several infectious disease outbreaks. To improve the design and quality of future forms, we analysed the inclusion and completion rates of the 243 fields on the ISARIC-WHO COVID-19 CRF. Data from 42 diverse collaborations, covering 1886 hospitals and 950,064 patients, were analysed. A mean of 129.6 fields (53%) were included in the adapted CRFs implemented across the sites. Consistent patterns of field inclusion and completion aligned with globally recognised research priorities in outbreaks of novel infectious diseases. Outcome status was the most highly included (95.2%) and completed (89.8%) field, followed by admission demographics (79.1% and 91.6%), comorbidities (77.9% and 79.0%), signs and symptoms (68.9% and 78.4%), and vitals (70.3% and 69.1%). Mean field completion was higher in severe patients (70.2%) than in all patients (61.6%). The results reveal how clinical characterisation CRFs can be streamlined to reduce data collection time, including the modularisation of CRFs, to offer a choice of data volume collection and the separation of critical care interventions. This data-driven approach to designing CRFs enhances the efficiency of data collection to inform patient care and public health response.
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Affiliation(s)
- Laura Merson
- ISARIC, Pandemic Sciences Institute, University of Oxford, Oxford OX37LF, UK; (S.D.); (E.G.-G.)
- Institute of Global Health, Faculty of Medicine, University of Geneva, 1202 Geneva, Switzerland;
| | - Sara Duque
- ISARIC, Pandemic Sciences Institute, University of Oxford, Oxford OX37LF, UK; (S.D.); (E.G.-G.)
- Infectious Diseases Department, Universidad de La Sabana, Chia 250001, Colombia
| | - Esteban Garcia-Gallo
- ISARIC, Pandemic Sciences Institute, University of Oxford, Oxford OX37LF, UK; (S.D.); (E.G.-G.)
- Infectious Diseases Department, Universidad de La Sabana, Chia 250001, Colombia
| | | | - Jamie Rylance
- Health Emergencies Program, World Health Organization, 1211 Geneva, Switzerland; (J.R.); (J.D.)
| | - Janet Diaz
- Health Emergencies Program, World Health Organization, 1211 Geneva, Switzerland; (J.R.); (J.D.)
| | - Antoine Flahault
- Institute of Global Health, Faculty of Medicine, University of Geneva, 1202 Geneva, Switzerland;
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11
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Merson L, Duque S, Garcia-Gallo E, Yeabah TO, Rylance J, Diaz J, Flahault A, ISARIC Clinical Characterisation Group. Optimising Clinical Epidemiology in Disease Outbreaks: Analysis of ISARIC-WHO COVID-19 Case Report Form Utilisation. EPIDEMIOLOGIA 2024; 5:557-580. [DOI: https:/doi.org/10.3390/epidemiologia5030039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2025] Open
Abstract
Standardised forms for capturing clinical data promote consistency in data collection and analysis across research sites, enabling faster, higher-quality evidence generation. ISARIC and the World Health Organization have developed case report forms (CRFs) for the clinical characterisation of several infectious disease outbreaks. To improve the design and quality of future forms, we analysed the inclusion and completion rates of the 243 fields on the ISARIC-WHO COVID-19 CRF. Data from 42 diverse collaborations, covering 1886 hospitals and 950,064 patients, were analysed. A mean of 129.6 fields (53%) were included in the adapted CRFs implemented across the sites. Consistent patterns of field inclusion and completion aligned with globally recognised research priorities in outbreaks of novel infectious diseases. Outcome status was the most highly included (95.2%) and completed (89.8%) field, followed by admission demographics (79.1% and 91.6%), comorbidities (77.9% and 79.0%), signs and symptoms (68.9% and 78.4%), and vitals (70.3% and 69.1%). Mean field completion was higher in severe patients (70.2%) than in all patients (61.6%). The results reveal how clinical characterisation CRFs can be streamlined to reduce data collection time, including the modularisation of CRFs, to offer a choice of data volume collection and the separation of critical care interventions. This data-driven approach to designing CRFs enhances the efficiency of data collection to inform patient care and public health response.
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Affiliation(s)
- Laura Merson
- ISARIC, Pandemic Sciences Institute, University of Oxford, Oxford OX37LF, UK
- Institute of Global Health, Faculty of Medicine, University of Geneva, 1202 Geneva, Switzerland
| | - Sara Duque
- ISARIC, Pandemic Sciences Institute, University of Oxford, Oxford OX37LF, UK
- Infectious Diseases Department, Universidad de La Sabana, Chia 250001, Colombia
| | - Esteban Garcia-Gallo
- ISARIC, Pandemic Sciences Institute, University of Oxford, Oxford OX37LF, UK
- Infectious Diseases Department, Universidad de La Sabana, Chia 250001, Colombia
| | | | - Jamie Rylance
- Health Emergencies Program, World Health Organization, 1211 Geneva, Switzerland
| | - Janet Diaz
- Health Emergencies Program, World Health Organization, 1211 Geneva, Switzerland
| | - Antoine Flahault
- Institute of Global Health, Faculty of Medicine, University of Geneva, 1202 Geneva, Switzerland
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12
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Liang Y, Quan X, Gu R, Meng Z, Gan H, Wu Z, Sun Y, Pan H, Han P, Liu S, Dou G. Repurposing existing drugs for the treatment ofCOVID-19/SARS-CoV-2: A review of pharmacological effects and mechanism of action. Heliyon 2024; 10:e35988. [PMID: 39247343 PMCID: PMC11379597 DOI: 10.1016/j.heliyon.2024.e35988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 08/05/2024] [Accepted: 08/07/2024] [Indexed: 09/10/2024] Open
Abstract
Following the coronavirus disease-2019 outbreak caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an ongoing need to seek drugs that target COVID-19. First off, novel drugs have a long development cycle, high investment cost, and are high risk. Second, novel drugs must be evaluated for activity, efficacy, safety, and metabolic performance, contributing to the development cycle, investment cost, and risk. We searched the Cochrane COVID-19 Study Register (including PubMed, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and WHO COVID-19 Coronaviral Disease Global Literature to identify completed and ongoing studies as of February 20, 2024. We evaluated the pharmacological effects, in vivo and in vitro data of the 16 candidates in the paper. The difficulty of studying these candidates in clinical trials involving COVID-19 patients, dosage of repurposed drugs, etc. is discussed in detail. Ultimately, Metformin is more suitable for prophylactic administration or mildly ill patients; the combination of Oseltamivir, Tamoxifen, and Dexamethasone is suitable for moderately and severely ill patients; and more clinical trials are needed for Azvudine, Ribavirin, Colchicine, and Cepharanthine to demonstrate efficacy.
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Affiliation(s)
- Yutong Liang
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Xiaoxiao Quan
- Beijing Institute of Radiation Medicine, Beijing, China
- Scientific Experimental Center of Guangxi University of Chinese Medicine, Nanning, China
| | - Ruolan Gu
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Zhiyun Meng
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Hui Gan
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Zhuona Wu
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Yunbo Sun
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Huajie Pan
- General Internal Medicine Department, Jingnan Medical District, PLA General Hospital, Beijing, China
| | - Peng Han
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Shuchen Liu
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Guifang Dou
- Beijing Institute of Radiation Medicine, Beijing, China
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13
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Kilic HH, Gozukucuk R. Comparison of the Results of BAL and ETA Culture in Intubated COVID-19 Patients. Niger J Clin Pract 2024; 27:945-949. [PMID: 39212429 DOI: 10.4103/njcp.njcp_666_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 07/25/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND The isolation of pathogens using bronchoalveolar lavage (BAL) culture or endotracheal aspirate (ETA) culture may enhance the treatment success for secondary pneumonia due to COVID-19, thereby reducing the risk of morbidity and mortality. AIM This study aimed to retrospectively analyze the results of BAL and ETA cultures in intubated COVID-19 patients and to determine whether BAL has an advantage over ETA. METHODS We routinely perform BAL culture via bronchoscopy or ETA culture within the first 48 h after intubation. We retrospectively reviewed cases that underwent BAL and ETA. The patients were divided into two groups: Group B (BAL) and Group E (ETA). Various parameters were evaluated and compared between the two groups. RESULTS The demographic data and blood test results were similar between the two groups. However, ICU stay, duration of intubation, and culture positivity were significantly higher in Group B. Although not statistically significant, the mortality rate was higher in Group E. The most commonly isolated microorganisms were Candida species. CONCLUSION The observed mortality rates were consistent with the existing literature. Since the microorganism isolation rate is higher with BAL, leading to more effective antimicrobial treatment, early deaths were prevented, and ICU stay durations were prolonged. Conversely, these durations were shorter in the ETA group due to higher mortality. In intubated COVID-19 patients, a more effective treatment process can be achieved by clearing the airway with fiberoptic bronchoscopy and tailoring the treatment based on BAL culture results. This approach may positively impact prognosis and mortality rates.
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Affiliation(s)
- H H Kilic
- Department of Anesthesiology, Dogus University, Istanbul, Türkiye
- Anaesthesiology and Reanimation Department, Hisar Intercontinental Hospital, Istanbul, Türkiye
| | - R Gozukucuk
- Clinical Microbiology and Infectious Diseases Department, Hisar Intercontinental Hospital, Istanbul, Türkiye
- Basic Sciences Department, Galata University, Istanbul, Türkiye
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14
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Bhimraj A, Morgan RL, Shumaker AH, Baden L, Cheng VCC, Edwards KM, Gallagher JC, Gandhi RT, Muller WJ, Nakamura MM, O’Horo JC, Shafer RW, Shoham S, Murad MH, Mustafa RA, Sultan S, Falck-Ytter Y. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients With COVID-19 (September 2022). Clin Infect Dis 2024; 78:e250-e349. [PMID: 36063397 PMCID: PMC9494372 DOI: 10.1093/cid/ciac724] [Citation(s) in RCA: 99] [Impact Index Per Article: 99.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 08/30/2022] [Indexed: 02/07/2023] Open
Abstract
There are many pharmacologic therapies that are being used or considered for treatment of coronavirus disease 2019 (COVID-19), with rapidly changing efficacy and safety evidence from trials. The objective was to develop evidence-based, rapid, living guidelines intended to support patients, clinicians, and other healthcare professionals in their decisions about treatment and management of patients with COVID-19. In March 2020, the Infectious Diseases Society of America (IDSA) formed a multidisciplinary guideline panel of infectious disease clinicians, pharmacists, and methodologists with varied areas of expertise to regularly review the evidence and make recommendations about the treatment and management of persons with COVID-19. The process used a living guideline approach and followed a rapid recommendation development checklist. The panel prioritized questions and outcomes. A systematic review of the peer-reviewed and grey literature was conducted at regular intervals. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the certainty of evidence and make recommendations. Based on the most recent search conducted on 31 May 2022, the IDSA guideline panel has made 32 recommendations for the treatment and management of the following groups/populations: pre- and postexposure prophylaxis, ambulatory with mild-to-moderate disease, and hospitalized with mild-to-moderate, severe but not critical, and critical disease. As these are living guidelines, the most recent recommendations can be found online at: https://idsociety.org/COVID19guidelines. At the inception of its work, the panel has expressed the overarching goal that patients be recruited into ongoing trials. Since then, many trials were conducted that provided much-needed evidence for COVID-19 therapies. There still remain many unanswered questions as the pandemic evolved, which we hope future trials can answer.
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Affiliation(s)
- Adarsh Bhimraj
- Division of Infectious Diseases, Houston Methodist Hospital, Houston, Texas
| | - Rebecca L Morgan
- Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
- Department of Medicine, Case Western Reserve University, School of Medicine, Cleveland, Ohio
| | - Amy Hirsch Shumaker
- Department of Medicine, Case Western Reserve University, School of Medicine, Cleveland, Ohio
- VA Northeast Ohio Healthcare System, Cleveland, Ohio
| | | | - Vincent Chi Chung Cheng
- Queen Mary Hospital, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Kathryn M Edwards
- Division of Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center,Nashville, Tennessee
| | - Jason C Gallagher
- Department of Pharmacy Practice, Temple University, Philadelphia, Pennsylvania
| | - Rajesh T Gandhi
- Infectious Diseases Division, Department of Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts
| | - William J Muller
- Division of Pediatric Infectious Diseases, Ann & Robert H. Lurie Children’s Hospital of Chicago and Northwestern University, Chicago, Illinois
| | - Mari M Nakamura
- Antimicrobial Stewardship Program and Division of Infectious Diseases, Boston Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
| | - John C O’Horo
- Division of Infectious Diseases, Joint Appointment Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota
| | - Robert W Shafer
- Division of Infectious Diseases, Department of Medicine, Stanford University, Palo Alto, California
| | - Shmuel Shoham
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - M Hassan Murad
- Division of Public Health, Infectious Diseases and Occupational Medicine, Mayo Clinic, Rochester, Minnesota
| | - Reem A Mustafa
- Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas
| | - Shahnaz Sultan
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis VA Healthcare System, Minneapolis, Minnesota
| | - Yngve Falck-Ytter
- Department of Medicine, Case Western Reserve University, School of Medicine, Cleveland, Ohio
- VA Northeast Ohio Healthcare System, Cleveland, Ohio
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15
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Strelkova D, Kuleshov V, Burmistrova E, Sychev I, Savochkina Y, Danilov D, Yatsyshina S, Glushchenko E, Elkina M, Ananicheva N, Yasneva A, Topolyanskaya S, Rachina S. The significance of monitoring respiratory sample cultures and polymerase chain reaction tests for detecting bacterial pathogens in severely and critically ill patients with COVID-19. Afr J Thorac Crit Care Med 2024; 30:e1293. [PMID: 39544846 PMCID: PMC11561391 DOI: 10.7196/ajtccm.2024.v30i1.1293] [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: 07/20/2023] [Accepted: 01/08/2024] [Indexed: 11/17/2024] Open
Abstract
Background Bacterial superinfection is one of the most common and potentially lethal complications in severely and critically ill patients with COVID-19. Objectives To determine the colonisation time frame and the spectrum of potential bacterial pathogens in respiratory samples from patients with severe and critical COVID-19, using routine culture and polymerase chain reaction (PCR) tests. Methods A prospective observational study was conducted on patients aged ≥18 years with confirmed severe and critical COVID-19 who were admitted to or transferred to the intensive care unit (ICU). Respiratory samples were collected for microbial culture and PCR testing within the first 2 days after ICU admission/transfer, between days 3 and 6, and after 7 days of ICU stay. Results A total of 82 patients, with a median (interquartile range) age of 74.5 (67.3 - 81.0) years and a median Charlson comorbidity index of 4 (3 - 5), were enrolled in the study. Colonisation with any pathogen was observed in 67% of patients, after a median of 4 (2 - 6) days in the ICU. On days 0 - 2 of the ICU stay, micro-organisms were detected in 18% of patients, with Klebsiella pneumoniae (without acquired antibiotic resistance) and methicillin-susceptible Staphylococcus aureus being most frequently identified. Later, A. baumannii and carbapenem-resistant K. pneumoniae became the predominant micro-organisms, identified in nearly half of the patients. In 74% of the samples, the results of microbial culture and PCR tests were identical. In 17%, PCR revealed bacterial pathogens not identified by culture. Conclusion Our study confirms that colonisation of the respiratory tract occurs early in the course of ICU stay. Superinfections are predominantly caused by multidrug-resistant Gram-negative bacteria. Study synopsis What the study adds. This real-world study provides valuable insights into the significance of microbiological monitoring of critically ill COVID-19 patients. It confirms that bacterial colonisation of the respiratory tract occurs early in the course of ICU stay, with nosocomial superinfections caused predominantly by multidrug-resistant Gram-negative pathogens. Polymerase chain reaction (PCR) testing can assist in ruling out colonisation and in early detection of potential bacterial superinfections.Implications of the findings. Bacterial superinfections present a major challenge in critically ill COVID-19 patients, owing to their high prevalence and mortality rates. Their early detection, determination of causative agents, and antibiotic susceptibility profiling are therefore of paramont importance. PCR testing of clinical specimens appears to be a valuable supplement to respiratory culture, enhancing the precision of diagnosis of lower respiratory tract infections.
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Affiliation(s)
- D Strelkova
- I. M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - V Kuleshov
- City Clinical Hospital named after S. S. Yudin, Moscow, Russian Federation
| | - E Burmistrova
- City Clinical Hospital named after S. S. Yudin, Moscow, Russian Federation
| | - I Sychev
- Russian Medical Academy of Continuous Professional Education, Moscow, Russian Federation
| | - Y Savochkina
- Federal State Budgetary Institution, Centre for Strategic Planning and Management of Biomedical Health Risks of the Federal Medical and
Biological Agency, Moscow, Russian Federation
| | - D Danilov
- Federal State Budgetary Institution, Centre for Strategic Planning and Management of Biomedical Health Risks of the Federal Medical and
Biological Agency, Moscow, Russian Federation
| | - S Yatsyshina
- Central Research Institute of Epidemiology (CRIE) of the Federal Service for Surveillance on Consumer Rights Protection and Human
Wellbeing, Moscow, Russian Federation
| | - E Glushchenko
- Federal State Budgetary Institution, Centre for Strategic Planning and Management of Biomedical Health Risks of the Federal Medical and
Biological Agency, Moscow, Russian Federation
| | - M Elkina
- Central Research Institute of Epidemiology (CRIE) of the Federal Service for Surveillance on Consumer Rights Protection and Human
Wellbeing, Moscow, Russian Federation
| | - N Ananicheva
- City Clinical Hospital named after S. S. Yudin, Moscow, Russian Federation
| | - A Yasneva
- I. M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - S Topolyanskaya
- I. M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - S Rachina
- I. M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
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16
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Tong T, Jin YH, Wang M, Gong FQ. Treatment of multisystem inflammatory syndrome in children. World J Pediatr 2024; 20:325-339. [PMID: 38509432 DOI: 10.1007/s12519-024-00798-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 01/29/2024] [Indexed: 03/22/2024]
Abstract
BACKGROUND Multisystem inflammatory syndrome in children (MIS-C), a relatively uncommon but severe pediatric complication, is associated with coronavirus disease 2019 (COVID-19). A variety of treatment approaches, including intravenous immunoglobulins (IVIGs), glucocorticoids (GCs) and biologic agents, such as anakinra and infliximab, have been described for the management of COVID-19-related MIS-C. Anticoagulant therapy is also important. However, a well-developed treatment system has not been established, and many issues remain controversial. Several recently published articles related to the treatment of MIS-C have been released. Hence, in this review, we identified relevant articles published recently and summarized the treatment of MIS-C more comprehensively and systematically. DATA SOURCES We reviewed the literature on the treatment of MIS-C through 20 September 2023. The PubMed/Medline, Web of Science, EMBASE, and Cochrane Library databases were searched with the combination of the terms "multisystem inflammatory syndrome", "MIS-C", "PIMS-TS", "therapy", "treatment", "drug", "IVIG", "GCs", "intravenous immunoglobulin", "corticosteroids", "biological agent", and "aspirin". RESULTS The severity of MIS-C varies, and different treatment schemes should be used according to the specific condition. Ongoing research and data collection are vital to better understand the pathophysiology and optimal management of MIS-C. CONCLUSIONS MIS-C is a disease involving multiple systems and has great heterogeneity. With the accumulation of additional experience, we have garnered fresh insights into its treatment strategies. However, there remains a critical need for greater standardization in treatment protocols, alongside the pressing necessity for more robust and meticulously conducted studies to deepen our understanding of these protocols. Supplementary file1 (MP4 208044 kb).
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Affiliation(s)
- Tong Tong
- Department of Cardiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, China
| | - Yi-Hua Jin
- Department of Cardiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, China
| | - Min Wang
- Department of Cardiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, China
| | - Fang-Qi Gong
- Department of Cardiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, China.
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17
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Berber E, Mulik S, Rouse BT. Meeting the Challenge of Controlling Viral Immunopathology. Int J Mol Sci 2024; 25:3935. [PMID: 38612744 PMCID: PMC11011832 DOI: 10.3390/ijms25073935] [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: 02/14/2024] [Revised: 03/27/2024] [Accepted: 03/29/2024] [Indexed: 04/14/2024] Open
Abstract
The mission of this review is to identify immune-damaging participants involved in antiviral immunoinflammatory lesions. We argue these could be targeted and their activity changed selectively by maneuvers that, at the same time, may not diminish the impact of components that help resolve lesions. Ideally, we need to identify therapeutic approaches that can reverse ongoing lesions that lack unwanted side effects and are affordable to use. By understanding the delicate balance between immune responses that cause tissue damage and those that aid in resolution, novel strategies can be developed to target detrimental immune components while preserving the beneficial ones. Some strategies involve rebalancing the participation of immune components using various approaches, such as removing or blocking proinflammatory T cell products, expanding regulatory cells, restoring lost protective cell function, using monoclonal antibodies (moAb) to counteract inhibitory molecules, and exploiting metabolic differences between inflammatory and immuno-protective responses. These strategies can help reverse ongoing viral infections. We explain various approaches, from model studies and some clinical evidence, that achieve innate and adaptive immune rebalancing, offering insights into potential applications for controlling chronic viral-induced lesions.
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Affiliation(s)
- Engin Berber
- Infection Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA;
| | - Sachin Mulik
- Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA;
| | - Barry T. Rouse
- College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA
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18
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Gao Y, Zhou A, Chen K, Zhou X, Xu Y, Wu S, Ning X. A living neutrophil Biorobot synergistically blocks multifaceted inflammatory pathways in macrophages to effectively neutralize cytokine storm. Chem Sci 2024; 15:2243-2256. [PMID: 38332816 PMCID: PMC10848682 DOI: 10.1039/d3sc03438k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 12/20/2023] [Indexed: 02/10/2024] Open
Abstract
Cytokine storm is a potentially life-threatening immune response typically correlated with lung injury, particularly in people with underlying disease states, such as pneumonia. Therefore, the prompt treatment of cytokine storm is essential for successful recovery from a potentially fatal condition. Herein, a living anti-inflammatory Biorobot (firefighter), composed of neutrophils encapsulating mannose-decorated liposomes of the NF-κB inhibitor TPCA-1 and STING inhibitor H-151 (M-Lip@TH, inflammatory retardant), is developed for alleviating hyperinflammatory cytokine storm through targeting multiple inflammatory pathways in macrophages. Biorobot fully inherits the chemotaxis characteristics of neutrophils, and efficiently delivers and releases therapeutic M-Lip@TH at the inflammatory site. Subsequently, M-Lip@TH selectively targets macrophages and simultaneously blocks the transcription factor NF-κB pathway and STING pathway, thereby preventing the overproduction of cytokines. Animal studies show that Biorobot selectively targets LPS-induced acute lung injury, and not only inhibits the NF-κB pathway to suppress the release of various pro-inflammatory cytokines and chemokines, but also blocks the STING pathway to prevent an overactive immune response, which helps to neutralize cytokine storms. Particularly, Biorobot reduces lung inflammation and injury, improves lung function, and increases the survival rates of pneumonia mice. Therefore, Biorobot represents a rational combination therapy against cytokine storm, and may provide insights into the treatment of diseases involving overactive immune responses.
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Affiliation(s)
- Ya Gao
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University Nanjing 210093 China
| | - Anwei Zhou
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, School of Physics, Nanjing University Nanjing 210093 China
| | - Kerong Chen
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University Nanjing 210093 China
| | - Xinyuan Zhou
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University Nanjing 210093 China
| | - Yurui Xu
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University Nanjing 210093 China
| | - Shuangshuang Wu
- Jiangsu Provincial Key Laboratory of Geriatrics, Department of Geriatrics, The First Affiliated Hospital with Nanjing Medical University Nanjing 210029 China
| | - Xinghai Ning
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University Nanjing 210093 China
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19
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Lacy MG, Filippov E, Nematollahi S. Controlling infections in hospitalized pretransplant candidates. Curr Opin Organ Transplant 2024; 29:56-63. [PMID: 37991047 DOI: 10.1097/mot.0000000000001120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2023]
Abstract
PURPOSE OF REVIEW Infections in hospitalized patients awaiting solid organ transplantation can pose complicated diagnostic and therapeutic challenges. Goals of management include stabilizing the patient, treating or controlling infections, and decreasing the risk of reactivation of infection after transplant. RECENT FINDINGS Groups such as The Organ Procurement and Transplantation Network, American Society of Transplantation Infectious Diseases Community of Practice and the European Society of Clinical Microbiology and Infectious Diseases have updated their guidelines on screening and treatment of infection in transplant candidates. There are also recent developments in therapeutic options for tuberculosis, COVID-19, Clostridioides difficile colitis, bloodstream infections, and other common infections. SUMMARY Ideally, antimicrobial therapy should be complete prior to transplantation. In situations in which completion of therapy prior to transplant is not feasible, therapy may need to be prolonged or modified. In most situations, infections can be managed similarly to the general population, although some infections, particularly fungal and mycobacterial, require a different management approach. We review disease- and organ-specific management.
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Affiliation(s)
- Marian G Lacy
- Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona
| | - Evgenii Filippov
- Department of Medicine, Sinai Hospital of Baltimore, Baltimore, Maryland, USA
| | - Saman Nematollahi
- Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona
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20
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Khan S, Bond SE, Lee-Milner J, Conway BR, Lattyak WJ, Aldeyab MA. Antimicrobial consumption in an acute NHS Trust during the COVID-19 pandemic: intervention time series analysis. JAC Antimicrob Resist 2024; 6:dlae013. [PMID: 38328263 PMCID: PMC10848649 DOI: 10.1093/jacamr/dlae013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 01/11/2024] [Indexed: 02/09/2024] Open
Abstract
Objective To determine the impact of the COVID-19 pandemic on antimicrobial consumption and trends of therapeutic drugs for COVID-19 treatments, including corticosteroids, remdesivir and monoclonal antibodies (tocilizumab) from April 2017 to September 2022 in a secondary care NHS Trust in England. Methods A retrospective intervention time series analysis was conducted for April 2017 to September 2022 at the Mid Yorkshire Teaching NHS Trust. Data were retrieved from the pharmacy dispensing system as defined daily doses (DDDs) monthly and reported per 1000 occupied bed days (OBDs). Antimicrobial consumption and COVID-19 treatment options were measured. DDDs were calculated according to the classification of antimicrobials for systemic use (J01) and for other drugs classification. Trends for antimicrobial consumption and other therapeutic drugs for treating COVID-19 were also determined in each wave in England. Results During the pandemic: total antibiotic consumption decreased from 826.4 to 728.2 DDDs per 1000 OBDs (P = 0.0067); piperacillin/tazobactam use increased (P < 0.0001) and ciprofloxacin use decreased (P < 0.0001); there were no changes in Access, Watch, Reserve antibiotic use, and the proportion of antifungal consumption was consistent throughout the study. The use of total antibiotics (P = 0.024), levofloxacin (P = 0.0007), piperacillin/tazobactam (P = 0.0015) and co-amoxiclav (P = 0.0198) increased during wave one. Consumption of COVID-19 treatment drugs was highest during wave two, with 624.3 DDDs per 1000 OBDs for dexamethasone (P = 0.4441), 6.8 DDDs per 1000 OBDs for remdesivir (P < 0.0001) and 35.01 DDDs per 1000 OBDs for tocilizumab (P = 0.2544). Discussion This study determined the consumption of antimicrobials trends before and during the pandemic. The individual wave antimicrobial consumption indicates maximum consumption in the first wave, advocating for antimicrobial stewardship and preparedness for future pandemics.
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Affiliation(s)
- Sidra Khan
- Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK
| | - Stuart E Bond
- Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK
- Pharmacy Department, Mid Yorkshire Teaching NHS Trust, Wakefield, WF1 4DG, UK
| | - Jade Lee-Milner
- Pharmacy Department, Mid Yorkshire Teaching NHS Trust, Wakefield, WF1 4DG, UK
| | - Barbara R Conway
- Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK
- Institute of Skin Integrity and Infection Prevention, University of Huddersfield, Huddersfield, HD1 3DH, UK
| | - William J Lattyak
- Statistical Consulting Department, Scientific Computing Associates Corp., River Forest, IL 60305, USA
| | - Mamoon A Aldeyab
- Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK
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21
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Hemmati AA, Mojiri-Forushani H. Off-label Use of Medicines in COVID-19: A Lesson For Future. CORONAVIRUSES 2024; 5. [DOI: 10.2174/0126667975271719231107052426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 09/13/2023] [Accepted: 09/18/2023] [Indexed: 01/03/2025]
Abstract
Abstract:
The COVID-19 infection is rapidly spreading worldwide. Treating this new viral infection
is a great challenge worldwide. There is no specific and approved medication for its treatment,
so some medications are considered off-label. Antivirals, corticosteroids, antimalarial agents, and
antibiotics are proposed in different countries to treat COVID-19. This narrative review discussed the
off-label use of medications for COVID-19 and the beneficial and adverse effects of them. Evidence
was collected and sorted from the literature ranging from 2019 to 2022 on scientific databases such
as Web of Science, PubMed, and Scopus with suitable keywords. All papers, namely systematic
reviews, case studies, and clinical guidelines, were evaluated. Antimalarial agents, antivirals, antibiotics,
corticosteroids, NSAIDs, biological medicines, Ivermectin, and melatonin were reviewed in
this study. Some medications have direct antiviral effects, and many can reduce infection symptoms
and hospitalization. In some clinical trial trials, even some of them, such as corticosteroids, can lower
death rates, particularly during the cytokine storm period. However, the effectiveness of some
medications has not been understood. Besides, the side effects of off-label use of these medications
must be considered a serious concern. There are no proven medications for COVID-19 yet. Off-label
use of medications is a double-edged sword that can have advantages outweighing its disadvantages.
The COVID-19 crisis taught us many lessons about dealing with health-related crises and their
treatment management. One of the most important lessons is paying more attention to the discovery
and development of novel drugs and vaccines based on modern technology.
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Affiliation(s)
- Ali Asghar Hemmati
- Department of Pharmacology, Marine Pharmaceutical Science Research Center, School of Pharmacy, Ahvaz
Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hoda Mojiri-Forushani
- Department of Pharmacology, School of Medicine, Abadan
University of Medical Sciences, Abadan, Iran
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22
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Thakur R, Shishodia SK, Sharma A, Chauhan A, Kaur S, Shankar J. Accelerating the understanding of Aspergillus terreus: Epidemiology, physiology, immunology and advances. CURRENT RESEARCH IN MICROBIAL SCIENCES 2024; 6:100220. [PMID: 38303967 PMCID: PMC10831165 DOI: 10.1016/j.crmicr.2024.100220] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2024] Open
Abstract
Aspergillus species encompass a variety of infections, ranging from invasive aspergillosis to allergic conditions, contingent upon the immune status of the host. In this spectrum, Aspergillus terreus stands out due to its emergence as a notable pathogen and its intrinsic resistance to amphotericin-B. The significance of Aspergillus-associated infections has witnessed a marked increase in the past few decades, particularly with the increasing number of immunocompromised individuals. The exploration of epidemiology, morphological transitions, immunopathology, and novel treatment approaches such as new antifungal drugs (PC945, olorofim) and combinational therapy using antifungal drugs and phytochemicals (Phytochemicals: quercetin, shikonin, artemisinin), also using immunotherapies to modulate immune response has resulted in better outcomes. Furthermore, in the context COVID-19 era and its aftermath, fungal infections have emerged as a substantial challenge for both immunocompromised and immunocompetent individuals. This is attributed to the use of immune-suppressing therapies during COVID-19 infections and the increase in transplant cases. Consequently, this review aims to provide an updated overview encompassing the epidemiology, germination events, immunopathology, and novel drug treatment strategies against Aspergillus terreus-associated infections.
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Affiliation(s)
- Raman Thakur
- Department of Medical Laboratory Science, Lovely Professional University, Jalandhar, Punjab, India
| | | | - Ananya Sharma
- Genomic Laboratory, Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat Solan, Himachal Pradesh, India
| | - Arjun Chauhan
- Department of Biotechnology, Institute of Applied Sciences and Humanities, GLA University, Mathura, Uttar Pradesh, India
| | - Sumanpreet Kaur
- Department of Medical Laboratory Science, Lovely Professional University, Jalandhar, Punjab, India
| | - Jata Shankar
- Genomic Laboratory, Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat Solan, Himachal Pradesh, India
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23
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Wei C, Yin W, Hu T, Zhang J, Dan H, Wu B. Agranulocytosis and secondary infection related to JAK inhibitors and IL-6 receptor blockers: a disproportionality analysis using the US Food and drug administration adverse event reporting system. Front Pharmacol 2024; 14:1323240. [PMID: 38264533 PMCID: PMC10803638 DOI: 10.3389/fphar.2023.1323240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 12/22/2023] [Indexed: 01/25/2024] Open
Abstract
Background: Given that the fight against coronavirus disease 2019 (COVID-19) is not over, we aimed to explore the occurrence of agranulocytosis and infectious complications in patients with and without COVID-19 following immunoregulatory therapy based on real-world data. Methods: This was a retrospective disproportionality analysis based on the US Food and Drug Administration Adverse Event Reporting System (FAERS). All cases reported between the first quarter of 2004 and the fourth quarter of 2022 about Janus kinase inhibitors (baricitinib, tofacitinib, ruxolitinib) and interleukin-6 receptor blockers (tocilizumab, sarilumab) were collected. Disproportionality analyses were conducted by reporting odds ratio (ROR) and information component (IC). Results: A total of 211,363 cases were recognized from the FDA Adverse Event Reporting System database. Data analysis showed that tocilizumab (reporting odds ratio: 3.18, 95% CI: 3.18-3.29; information component: 1.37, 95% CI: 1.31-1.42), sarilumab (ROR: 1.64, 95% CI: 1.55-1.73; IC: 0.61, 95% CI: 0.43-0.79), baricitinib (ROR: 3.42, 95% CI: 3.19-3.67; IC: 1.43, 95% CI: 1.21-1.65), tofacitinib (ROR: 2.53, 95% CI: 2.49-2.57; IC: 1.11, 95% CI: 1.05-1.16), and ruxolitinib (ROR: 1.87, 95% CI: 1.83-1.91; IC: 0.77, 95% CI: 0.70-0.84) were all associated with secondary infection. The association in the combination group was higher than that in the monotherapy group (ROR: 4.69, 95% CI: 4.53-4.86; IC: 1.73, 95% CI: 1.62-1.84). As for agranulocytosis, tocilizumab (ROR: 1.61, 95% CI: 1.53-1.69; IC: 0.67, 95% CI: 0.50-0.84) and ruxolitinib (ROR: 2.32, 95% CI: 2.21-2.43; IC: 1.18, 95% CI: 1.02-1.33) showed the significant signals. The association was higher in the combination group than in the monotherapy group (ROR: 2.36, 95% CI: 2.15-2.58; IC: 1.20, 95% CI: 0.90-1.51). Secondary infection after treatment with tofacitinib (ROR: 1.37, 95% CI: 1.02-1.84), tocilizumab (ROR: 1.46, 95% CI: 1.01-2.09), and sarilumab (ROR: 2.46, 95% CI: 1.10-5.50) was reported more frequently in COVID-19 than in non-COVID-19 patients. Conclusion: Both Janus kinase inhibitors and interleukin-6 receptor blockers are significantly associated with secondary infection and agranulocytosis, and the combined treatment further increases the association. The correlation with secondary infection in patients treated with tofacitinib, tocilizumab, and sarilumab is higher in COVID-19 than in non-COVID-19 patients.
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Affiliation(s)
- Chunyan Wei
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Wanhong Yin
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
- West China School of Clinical Medical College, Sichuan University, Chengdu, China
| | - Tingting Hu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Jingyi Zhang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Huifang Dan
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Bin Wu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
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24
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Qidwai T. Cytokine storm in COVID-19 and malaria: Annals of pro-inflammatory cytokines. Cytokine 2024; 173:156420. [PMID: 37976701 DOI: 10.1016/j.cyto.2023.156420] [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: 07/24/2023] [Revised: 10/28/2023] [Accepted: 11/01/2023] [Indexed: 11/19/2023]
Abstract
Infectious diseases are affecting the people worldwide. Mostly, infectious agents activate excessive production of cytokines so called cytokine storm. Among the infectious diseases COVID-19 is one of the deadliest diseases affecting individuals all over the world, moreover, Plasmodium falciparum malaria and HIV are major killers. An excessive pro-inflammatory response is one of the major causes of pathological conditions in these diseases. It is important to investigate the pathophysiology in the infectious diseases such as COVID-19, malaria and HIV as there is no concrete therapy against them so far. Exploration of excessive pro-inflammation could be important for therapeutic intervention. In this article, an attempt has been made to analyze the pathological conditions arise due to excessive inflammatory response in COVID-19, malaria and other infectious diseases. Targeting excessive pro-inflammatory response/cytokine storm in infectious diseases could be a useful strategy.
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Affiliation(s)
- Tabish Qidwai
- Faculty of Biotechnology, Shri Ramswaroop Memorial University, Lucknow Deva Road, Uttar Pradesh 225003, India.
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25
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Howard-Jones AR, Huang S, Orde SR, Branley JM. Risk factors for mortality in severe COVID-19: Exploring the interplay of immunomodulatory therapy and coinfection. Anaesth Intensive Care 2024; 52:52-63. [PMID: 37717183 DOI: 10.1177/0310057x231183451] [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] [Indexed: 09/18/2023]
Abstract
Patients with severe clinical manifestations of coronavirus disease 2019 (COVID-19) present particular diagnostic and management challenges to critical care physicians, including identifying and responding to concurrent bacterial and fungal coinfections. This study evaluates risk factors for in-hospital mortality in patients admitted to the intensive care unit with severe COVID-19 during circulation of the B.1.617.2 (Delta) variant, including the impact of immunomodulators and bacterial and/or fungal coinfection. This retrospective cohort study enrolled patients with severe COVID-19. A Cox proportional hazard ratio analysis identified risk factors for in-hospital mortality. Outcomes were also compared between patients receiving and not receiving immunomodulatory therapy alongside standard care. Ninety patients admitted to the intensive care unit were enrolled. On multivariate analysis, the greatest risk factors for in-hospital mortality were invasive mechanical ventilation (hazard ratio (HR) = 15.27; 95% confidence interval (CI) 3.29-71.0; P < 0.001), elevated body mass index (HR = 1.07 per unit; 95% CI 1.02-1.13; P = 0.007) and older age (HR = 1.53 per decade; 95% CI 1.05-2.24; P = 0.028). Bacterial and/or fungal coinfection occurred at equal frequency in patients receiving and not receiving immunomodulatory therapy. However, in patients receiving immunomodulators, coinfection carried a significantly higher mortality risk (63.0%) compared with those without coinfection (15.4%; P = 0.038). Mortality from severe COVID-19 is significantly higher in older patients and those with elevated body mass index and requiring mechanical ventilation. Immunomodulatory therapy necessitates vigilance towards evolving coinfection in the intensive care setting.
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Affiliation(s)
- Annaleise R Howard-Jones
- New South Wales Health Pathology-Nepean, Nepean Hospital, Kingswood, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Stephen Huang
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia
- Department of Intensive Care Medicine, Nepean Hospital, Kingswood, Australia
| | - Sam R Orde
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia
- Department of Intensive Care Medicine, Nepean Hospital, Kingswood, Australia
| | - James M Branley
- New South Wales Health Pathology-Nepean, Nepean Hospital, Kingswood, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, Australia
- Department of Infectious Diseases and Microbiology, Nepean Hospital, Kingswood, Australia
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26
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Conroy GM, Bauer SR, Pallotta AM, Duggal A, Wang L, Sacha GL. Baricitinib versus tocilizumab in critically ill COVID-19 patients: A retrospective cohort study. Pharmacotherapy 2024; 44:28-38. [PMID: 37593883 PMCID: PMC10961678 DOI: 10.1002/phar.2867] [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: 04/07/2023] [Revised: 07/06/2023] [Accepted: 07/14/2023] [Indexed: 08/19/2023]
Abstract
OBJECTIVES The immunomodulators tocilizumab and baricitinib improve outcomes in severely ill patients with coronavirus disease 2019 (COVID-19); however, comparative analyses of clinical outcomes related to these agents are lacking. A tocilizumab national shortage shifted treatment to baricitinib in critically ill patients, allowing for an outcome comparison in a similar population. The purpose of this study is to compare clinical outcomes in critically ill COVID-19 patients who received tocilizumab and those who received baricitinib. DESIGN Retrospective, observational cohort study using generalized estimating equation models, accounting for clustering by hospital and known confounders, to estimate the proportional odds of the ordinal World Health Organization Clinical Progression Scale (WHO-CPS) score at day 14, the primary outcome. Secondary outcomes included WHO-CPS score at day 7. SETTING Multiple hospitals within the Cleveland Clinic Health System. PATIENTS Adult patients admitted for COVID-19 between January 2021 and November 2021. INTERVENTIONS Receipt of tocilizumab, before its shortage, or baricitinib, during shortage. MEASUREMENTS AND MAIN RESULTS In total, 507 patients were included; 217 received tocilizumab and 290 received baricitinib. Over 96% of patients required ICU admission and 98% received concomitant dexamethasone. Tocilizumab recipients had higher (worse) baseline WHO-CPS scores. After adjustment, tocilizumab use was associated with higher odds of a worse day 14 WHO-CPS score compared with baricitinib (adjusted odds ratio [OR] 1.65 [95% confidence interval (CI) 1.10-2.48]). Similarly, after adjustment, tocilizumab use was associated with higher odds of a worse day 7 WHO-CPS score (adjusted OR 1.65 [95% CI 1.22-2.24]). CONCLUSIONS Baricitinib use was associated with better WHO-CPS scores at day 14 and day 7 compared with tocilizumab in a cohort of critically ill patients with COVID-19. The odds of having a one unit increase in WHO-CPS score at day 14 was 71% higher with tocilizumab than baricitinib. No difference in mortality or adverse effects was noted.
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Affiliation(s)
| | - Seth R. Bauer
- Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio
| | | | - Abhijit Duggal
- Respiratory Institute, Cleveland Clinic, Cleveland, Ohio
| | - Lu Wang
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio
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27
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Herrera S, Aguado JM, Candel FJ, Cordero E, Domínguez-Gil B, Fernández-Ruiz M, Los Arcos I, Len Ò, Marcos MÁ, Muñez E, Muñoz P, Rodríguez-Goncer I, Sánchez-Céspedes J, Valerio M, Bodro M. Executive summary of the consensus statement of the group for the study of infection in transplantation and other immunocompromised host (GESITRA-IC) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) on the treatment of SARS-CoV-2 infection in solid organ transplant recipients. Transplant Rev (Orlando) 2023; 37:100788. [PMID: 37591117 DOI: 10.1016/j.trre.2023.100788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/04/2023] [Accepted: 08/06/2023] [Indexed: 08/19/2023]
Affiliation(s)
- Sabina Herrera
- Department of Infectious Diseases, Hospital Clínic, IDIBAPS (Institut D'Investigacions Biomèdiques Agust Pi I Sunyer), Universitat de Barcelona, Barcelona, Spain
| | - Jose M Aguado
- Infectious Diseases Unit, Hospital Universitario 12 de Octubre (Madrid), Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Francisco Javier Candel
- Clinical Microbiology & Infectious Diseases, Transplant Coordination, Hospital Clínico Universitario San Carlos, Madrid 28040, Spain; Department of Clinical Microbiology and Infectious Diseases, Hospital Clínico San Carlos, Madrid, Spain
| | - Elisa Cordero
- Infectious Diseases Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina Sevilla, Sevilla, Spain
| | | | - Mario Fernández-Ruiz
- Infectious Diseases Unit, Hospital Universitario 12 de Octubre (Madrid), Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Ibai Los Arcos
- Infectious Diseases Department, Hospital Universitari Vall D'Hebron, Barcelona, Spain
| | - Òscar Len
- Infectious Diseases Department, Hospital Universitari Vall D'Hebron, Barcelona, Spain
| | | | - Elena Muñez
- Infectious Diseases Unit, Internal Medicine Department, University Hospital Puerta de Hierro, Majadahonda, Madrid, Spain
| | - Patricia Muñoz
- Department of Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, 9 Madrid, Spain
| | - Isabel Rodríguez-Goncer
- Infectious Diseases Unit, Hospital Universitario 12 de Octubre (Madrid), Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Javier Sánchez-Céspedes
- Infectious Diseases Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina Sevilla, Sevilla, Spain
| | - Maricela Valerio
- Department of Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, 9 Madrid, Spain
| | - Marta Bodro
- Department of Infectious Diseases, Hospital Clínic, IDIBAPS (Institut D'Investigacions Biomèdiques Agust Pi I Sunyer), Universitat de Barcelona, Barcelona, Spain.
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28
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Adzic-Vukicevic T, Markovic D, Reljic A, Brkovic V. What did we learn about tocilizumab use against COVID-19? A single-center observational study from an intensive care unit in Serbia. Front Med (Lausanne) 2023; 10:1253135. [PMID: 38034537 PMCID: PMC10683091 DOI: 10.3389/fmed.2023.1253135] [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: 07/04/2023] [Accepted: 10/24/2023] [Indexed: 12/02/2023] Open
Abstract
Background Selection of effective and safe therapy for management of patients with coronavirus disease is challenging. Tocilizumab (TZB) has emerged as a potential treatment option for COVID-19. Several aspects regarding Tocilizumab treatment remain uncertain, such as the optimal timing for its administration and the safety profile, including the potential risk of infections. The aim of the study is to present the clinical characteristics of patients with COVID-19 following the application of Tocilizumab. Methods This is a retrospective analysis of 121 patients with severe forms of COVID-19 previously treated with Tocilizumab was conducted. All patients were admitted to intensive care units (ICUs). Results Of 121 patients, the majority were men 72 (59.5%) with a median age at presentation of 65 ± 13 years. Only 9 (7.43%) patients were without comorbidities, while the other 112 (92.55%) had two or more comorbidities. Almost all of the 120 patients (99.2%) needed oxygen therapy, such as nasal cannulas in 110 (90.9%) patients, high flow nasal catheter (HFNC) in 4 (3.3%) patients, and continuous positive airway pressure (CPAP) in 5 (4.1%) patients while 1 patient was intubated at the time of hospital admission. The average time from Tocilizumab application to admission to the ICU was 3 days. During clinical deterioration, almost half 57 (47.1%) of the patients were intubated, and 52 (82.5%) of these intubated patients (p < 0.001) had lethal outcomes. The most significant predictors for a lethal outcome according to multivariate analysis were diabetes mellitus (p < 0.001) followed by a subsequent elevation in C-reactive protein levels (CRP; p < 0.002) and ferritin (p < 0.013) after Tocilizumab application. Bloodstream infections were found in 20 (16.5%) patients, most frequently with Gram-negative pathogens like Acinetobacter spp. as in 12 (18.6%) patients, Klebsiella spp. in 6 (8%) patients, and Pseudomonas spp. in 2 (3.2%) patients. Urine culture isolates were found in 9 (7.43%) patients, with Candida spp. being most frequently isolated in 7 (5.8%) patients, followed by Klebsiella spp. and Pseudomonas spp. in 1 patient each (0.8%). Significantly lower survival was seen in patients with proven infection. Conclusion The benefit of tocilizumab was not found in our study. The high mortality rate among intubated patients after Tocilizumab use suggests appropriate patient selection and monitoring and emphasizes the risk of superinfections. Diabetes mellitus, increased levels of CRP, and ferritin were identified as the most significant predictors of poor outcomes in contrast to increased levels of IL-6.
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Affiliation(s)
- Tatjana Adzic-Vukicevic
- Clinic of Pulmonology, University Clinical Center of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Dejan Markovic
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
- Clinic for Anesthesiology, University Clinical Center of Serbia, Belgrade, Serbia
| | - Aleksandar Reljic
- Covid Hospital Batajnica, University Clinical Center of Serbia, Belgrade, Serbia
| | - Voin Brkovic
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
- Clinic for Nephrology, University Clinical Center of Serbia, Belgrade, Serbia
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29
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Fadel RA, Scott A, Parsons A, Murskyj I, Nasiri N, Abu Sayf A, Ouellette D. Tocilizumab Associated With Survival in Patients Hospitalized for COVID-19 Acute Respiratory Distress Syndrome and Low Urine Output. J Intensive Care Med 2023; 38:1042-1050. [PMID: 37306148 PMCID: PMC10261959 DOI: 10.1177/08850666231180528] [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: 01/07/2023] [Revised: 05/09/2023] [Accepted: 05/22/2023] [Indexed: 06/13/2023]
Abstract
BACKGROUND Acute respiratory distress syndrome (ARDS) with oliguria is associated with increased mortality. Interleukin-6 (IL-6) plays an integral role in the pathophysiology of both disease processes. Patients who experience severe COVID-19 have demonstrated higher IL-6 levels compared to baseline, and use of tocilizumab has demonstrated efficacy in such cohorts. We set out to investigate the relationship between tocilizumab use, COVID-19 ARDS, low urine output, and mortality. METHODS Retrospective cohort review of adult patients aged ≥ 18 years with COVID-19 and moderate or severe ARDS, admitted to the intensive care unit (ICU) of a tertiary referral center in metropolitan Detroit. Patients were analyzed based on presence of oliguria (defined as ≤ 0.7 mL/kg/h) on the day of intubation and exposure to tocilizumab while inpatient. The primary outcome was inpatient mortality. RESULTS One hundred and twenty-eight patients were analyzed, 103 (80%) with low urine output, of whom 30 (29%) received tocilizumab. In patients with low urine output, risk factors associated with mortality on univariate analysis included Black race (P = .028), lower static compliance (P = .015), and tocilizumab administration (P = .002). Tocilizumab (odds ratio 0.245, 95% confidence interval 0.079-0.764, P = .015) was the only risk factor independently associated with survival on multivariate logistic regression analysis. CONCLUSION In this retrospective cohort review of patients hospitalized with COVID-19 and moderate or severe ARDS, tocilizumab administration was independently associated with survival in patients with low urine output ≤ 0.7 mL/kg/h on the day of intubation. Prospective studies are needed to investigate the impact of urine output on efficacy of interleukin-targeted therapies in the management of ARDS.
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Affiliation(s)
- Raef Ali Fadel
- Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, MI, USA
| | - Ashley Scott
- Department of Pulmonary and Critical Care Medicine, University of Arizona, Tucson, AZ, USA
| | - Austin Parsons
- Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA
| | - Ivanna Murskyj
- Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, MI, USA
| | - Nour Nasiri
- Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA
| | - Alaa Abu Sayf
- Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, MI, USA
| | - Daniel Ouellette
- Division of Pulmonary and Critical Care Medicine, Henry Ford Hospital, Detroit, MI, USA
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Artaud-Macari E, Le Bouar G, Maris J, Dantoing E, Vatignez T, Girault C. [Ventilatory management of SARS-CoV-2 acute respiratory failure]. Rev Mal Respir 2023; 40:751-767. [PMID: 37865564 DOI: 10.1016/j.rmr.2023.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 09/19/2023] [Indexed: 10/23/2023]
Abstract
COVID-19 pneumonia presents several particularities in its clinical presentation (cytokine storm, silent hypoxemia, thrombo-embolic risk) and may lead to a number of acute respiratory distress syndrome (ARDS) phenotypes. While the optimal oxygenation strategy in cases of hypoxemic acute respiratory failure (ARF) is still under debate, ventilatory management of COVID-19-related ARF has confirmed the efficacy of high-flow oxygen therapy and restored interest in other ventilatory approaches such as continuous positive airway pressure (CPAP) and noninvasive ventilation involving a helmet, which due to patient overflow are sometimes implemented outside of critical care units. However, further studies are still needed to determine which patients should be given which oxygenation technique, and under which conditions they require invasive mechanical ventilation, given that delayed initiation potentially burdens prognosis. During invasive mechanical ventilation, ventral decubitus and extracorporeal membrane oxygenation have become increasingly prevalent. While innovative therapies such as awake prone position or lung transplantation have likewise been developed, their indications, modalities and efficacy remain to be determined.
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Affiliation(s)
- E Artaud-Macari
- Service de pneumologie, oncologie thoracique et soins intensifs respiratoires, CHU de Rouen, 76000 Rouen, France; UNIROUEN, UR-3830, Normandie université, CHU de Rouen, 76000 Rouen, France.
| | - G Le Bouar
- Service de pneumologie, oncologie thoracique et soins intensifs respiratoires, CHU de Rouen, 76000 Rouen, France
| | - J Maris
- Service de pneumologie, oncologie thoracique et soins intensifs respiratoires, CHU de Rouen, 76000 Rouen, France
| | - E Dantoing
- Service de pneumologie, oncologie thoracique et soins intensifs respiratoires, CHU de Rouen, 76000 Rouen, France
| | - T Vatignez
- Service de médecine intensive et réanimation, CHU de Rouen, 76000 Rouen, France
| | - C Girault
- UNIROUEN, UR-3830, Normandie université, CHU de Rouen, 76000 Rouen, France; Service de médecine intensive et réanimation, CHU de Rouen, 76000 Rouen, France
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Morin C, Padki A, Wong A, Miano T, Kane-Gill SL, Cozzi G, Deveau R. Comparison of COVID-19 Preprint and Peer-Reviewed Versions of Studies on Therapies for Critically Ill Patients. J Intensive Care Med 2023; 38:1060-1067. [PMID: 37337731 PMCID: PMC10285362 DOI: 10.1177/08850666231182563] [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: 03/28/2023] [Accepted: 06/01/2023] [Indexed: 06/21/2023]
Abstract
PURPOSE Significant increases in the volume of preprint articles due to the COVID-19 pandemic, we examined the reliability of preprint articles compared to their peer-reviewed publications. MATERIALS AND METHODS Preprint articles evaluating experimental studies of select treatment options (anticoagulation, dexamethasone, hydroxychloroquine, remdesivir, and tocilizumab) for COVID-19 in the critically ill, available in a peer-reviewed publication were screened for inclusion within Altmetric (n = 2040). A total of 40 articles met inclusion criteria, with 21 being randomly selected for evaluation. The primary outcome of this evaluation was a change in a study's reported primary outcome or statistical significance between preprint and peer-reviewed articles. Secondary outcomes included changes in primary/secondary outcome effect size and change in study conclusion. RESULTS One article (4.8%, 95% CI 0.12%-23.8%) had a change in the primary outcome. Seven articles (33.3%, 95% CI 14.6%-57.0%) had a change in the primary outcome's effect measure. Five studies (23.8%, 95% CI 8.2%-47.2%) had changes in statistical significance of at least one secondary outcome. Four studies (19.0%, 95% CI 5.4%-41.9%) had a change in study conclusion. CONCLUSIONS In preprint articles of COVID-19 treatments, the provided primary outcome is generally reliable, while interpretation of secondary outcomes should be made with caution, while awaiting completion of the peer-review process.
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Affiliation(s)
- Conor Morin
- Department of Pharmacy, Providence Alaska Medical Center, Anchorage, AK, USA
| | - Anirudh Padki
- Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA
| | - Adrian Wong
- Department of Pharmacy, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Todd Miano
- Department of Biostatistics, Epidemiology and Statistics, University of Pennsylvania, Philadelphia, PA, USA
- Department of Pharmacy, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Sandra L. Kane-Gill
- Department of Pharmacy and Therapeutics, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Pharmacy, UPMC Presbyterian, Pittsburgh, PA, USA
| | - Gabrielle Cozzi
- Department of Pharmacy, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Robert Deveau
- Department of Pharmacy, Beth Israel Deaconess Medical Center, Boston, MA, USA
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Trifi A, Sellaouti S, Mehdi A, Messaoud L, Seghir E, Tlili B, Abdellatif S. Healthcare-associated infections in critical COVID-19 patients in Tunis: epidemiology, risk factors, and outcomes. Acute Crit Care 2023; 38:425-434. [PMID: 38052509 DOI: 10.4266/acc.2023.00773] [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: 06/02/2023] [Accepted: 09/26/2023] [Indexed: 12/07/2023] Open
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) pandemic disrupted adherences to healthcare-associated infection (HAI) prevention protocols. Herein, we studied the characteristics of all HAIs occurring in critically ill COVID-19 patients. METHODS A retrospective, single-center cohort of critical COVID-19 patients during 2021. Microbiological samples were collected if HAI was suspected. We analyzed all factors that could potentially induce HAI, using septic shock and mortality as endpoints. RESULTS Sixty-four among 161 included patients (39.7%) presented a total of 117 HAIs with an incidence density of 69.2 per 1,000 hospitalization days. Compared to the prior COVID-19 period (2013-2019), the identification of HAI increased in 2021. HAIs were classified into ventilator-associated pneumonia (VAP; n=38), bloodstream infection (n=32), urinary tract infection (n=24), catheter-related infection (n=12), and fungal infection (n=11). All HAIs occurred significantly earlier in the post-COVID-19 period (VAP: 6 vs. 10 days, P=0.045, in 2017 and 2021). Acinetobacter baumannii (39.5%) and Klebsiella pneumoniae (27%) were the most commonly isolated pathogens that exhibited a multidrug-resistant (MDR) profile, observed in 89% and 64.5%, respectively. The HAI factors were laboratory abnormalities (odds ratio [OR], 6.4; 95% confidence interval [CI], 2.3-26.0), cumulative steroid dose (OR, 1.9; 95% CI, 1.3-4.0), and invasive procedures (OR, 20.7; 95% CI, 5.3-64.0). HAI was an independent factor of mortality (OR, 8.5; P=0.004). CONCLUSIONS During the COVID-19 era, the incidence of HAIs increased and MDR isolates remained frequent. A severe biological inflammatory syndrome, invasive devices, and elevated cumulative steroid dosages were related to HAIs. HAI was a significant death factor.
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Affiliation(s)
- Ahlem Trifi
- Medical Intensive Care Unit, La Rabta Hospital, Tunis, Tunisia
| | - Selim Sellaouti
- Medical Intensive Care Unit, La Rabta Hospital, Tunis, Tunisia
| | - Asma Mehdi
- Medical Intensive Care Unit, La Rabta Hospital, Tunis, Tunisia
| | - Lynda Messaoud
- Medical Intensive Care Unit, La Rabta Hospital, Tunis, Tunisia
| | - Eya Seghir
- Medical Intensive Care Unit, La Rabta Hospital, Tunis, Tunisia
| | - Badis Tlili
- Medical Intensive Care Unit, La Rabta Hospital, Tunis, Tunisia
| | - Sami Abdellatif
- Medical Intensive Care Unit, La Rabta Hospital, Tunis, Tunisia
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Skarbinski J, Fischer H, Hong V, Liu L, Yau VM, Incerti D, Qian L, Ackerson BK, Amsden LB, Shaw SF, Tartof SY. Real-World Evidence to Supplement Randomized Clinical Trials: Tocilizumab for Severe COVID-19 Pneumonia vs. a Cohort Receiving Standard of Care. Clin Pharmacol Ther 2023; 114:1073-1081. [PMID: 37571812 DOI: 10.1002/cpt.3020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 08/01/2023] [Indexed: 08/13/2023]
Abstract
Randomized controlled trials (RCTs) remain the gold standard for evaluating treatment efficacy, but real-world evidence can supplement RCT results. Tocilizumab was not found to reduce 28-day mortality in a phase III, double-blind, placebo-controlled trial (COVACTA) among hospitalized patients with severe coronavirus disease 2019 (COVID-19) pneumonia. We created a real-world external comparator arm mirroring the COVACTA trial to confirm findings and assess the feasibility of using an external comparator arm to supplement an RCT. Eligible COVACTA participants in both the tocilizumab treatment and placebo arms were matched 1:1 using propensity score matching to persons without tocilizumab exposure in an external comparator arm. Adjusted Cox proportional hazard models estimated differences in 28-day mortality comparing COVACTA participants to matched external comparator arm participants. Patients in the COVACTA tocilizumab treatment arm had a similar risk of death compared with patients in the external comparator arm (hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.64-1.84) with similar estimated 28-day mortality in the COVACTA tocilizumab treatment arm compared with the external comparator arm (18%, 95% CI: 13-24 vs. 19%, 95% CI: 13-24, P > 0.9). COVACTA placebo treatment arm participants had a similar risk of mortality (adjusted HR: 0.69, 95% CI: 0.32-1.46) compared with the external comparator arm. Using an external comparator arm has the potential to supplement RCT data and support results of primary RCT analyses.
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Affiliation(s)
- Jacek Skarbinski
- Division of Research, Kaiser Permanente Northern California, Oakland, California, USA
- Department of Infectious Diseases, Oakland Medical Center, Kaiser Permanente Northern California, Oakland, California, USA
| | - Heidi Fischer
- Department of Research & Evaluation, Kaiser Permanente Southern California, California, Pasadena, USA
| | - Vennis Hong
- Department of Research & Evaluation, Kaiser Permanente Southern California, California, Pasadena, USA
| | - Liyan Liu
- Division of Research, Kaiser Permanente Northern California, Oakland, California, USA
| | - Vincent M Yau
- Genentech, a Member of the Roche Group, South San Francisco, California, USA
| | - Devin Incerti
- Genentech, a Member of the Roche Group, South San Francisco, California, USA
| | - Lei Qian
- Department of Research & Evaluation, Kaiser Permanente Southern California, California, Pasadena, USA
| | - Bradley K Ackerson
- Southern California Permanente Medical Group, Harbor City, California, USA
| | - Laura B Amsden
- Division of Research, Kaiser Permanente Northern California, Oakland, California, USA
| | - Sally F Shaw
- Department of Research & Evaluation, Kaiser Permanente Southern California, California, Pasadena, USA
| | - Sara Y Tartof
- Department of Research & Evaluation, Kaiser Permanente Southern California, California, Pasadena, USA
- Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, California, USA
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Butt AA, Yan P, Shaikh OS, Omer SB, Mayr FB, Talisa VB. Molnupiravir Use and 30-Day Hospitalizations or Death in a Previously Uninfected Nonhospitalized High-risk Population With COVID-19. J Infect Dis 2023; 228:1033-1041. [PMID: 37260359 PMCID: PMC10582917 DOI: 10.1093/infdis/jiad195] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 05/24/2023] [Accepted: 05/31/2023] [Indexed: 06/02/2023] Open
Abstract
BACKGROUND Clinical benefit of molnupiravir (MPV) in coronavirus disease 2019 (COVID-19)-infected subpopulations is unclear. METHODS We used a matched cohort study design to determine the rate of hospitalization or death within 30 days of COVID-19 diagnosis among MPV treated and untreated controls. Participants were nonhospitalized, previously uninfected Veterans with a first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection between 1 January and 31 August 2022, who were prescribed MPV within 3 days of COVID-19 diagnosis, and matched individuals who were not prescribed MPV. RESULTS Among 1459 matched pairs, the incidence of hospitalization/death was not different among MPV treated versus untreated controls (48 vs 44 cases; absolute risk difference [ARD], 0.27; 95% confidence interval [CI], -.94 to 1.49). No benefit was observed among those >60 or ≤60 years old (ARD, 0.27; 95% CI, -1.25 to 1.79 vs ARD, -0.29; 95% CI, -1.22 to 1.80), those with specific comorbidities, or by vaccination status. A significant benefit was observed in asymptomatic but not in symptomatic persons (ARD, -2.80; 95% CI, -4.74 to -.87 vs ARD, 1.12; 95% CI -.31 to 2.55). Kaplan-Meier curves did not show a difference in proportion of persons who were hospitalized or died among MPV treated compared with untreated controls (logrank P = .7). CONCLUSIONS MPV was not associated with a reduction in hospitalization or death within 30 days of COVID-19 diagnosis. A subgroup of patients presenting without symptoms experienced a benefit.
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Affiliation(s)
- Adeel A Butt
- Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA
- Department of Medicine, Weill Cornell Medicine, New York, New York, USA
- Department of Medicine, Weill Cornell Medicine, Doha, Qatar
- Department of Population Health Sciences, Weill Cornell Medicine, New York, New York, USA
- Department of Population Health Sciences, Weill Cornell Medicine, Doha, Qatar
- Hamad Medical Corporation, Doha, Qatar
| | - Peng Yan
- Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA
| | - Obaid S Shaikh
- Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA
- Department of Medicine, Division of Gastroenterology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Saad B Omer
- Institute for Global Health, Yale University, New Haven, Connecticut, USA
| | - Florian B Mayr
- Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Victor B Talisa
- Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Hsieh MC, Yu WC, Weng CC, Chen WJ, Chen CK, Lee YC, Chen MH. Elevated serum levels of T-cell immunoglobulin and mucin-domain containing molecule 3 in patients with systemic inflammation following COVID-19 vaccination. J Chin Med Assoc 2023; 86:818-825. [PMID: 37481764 DOI: 10.1097/jcma.0000000000000969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/25/2023] Open
Abstract
BACKGROUND ChAdOx1 nCoV-19 vaccine has been widely used. Some unexpected adverse effects such as the development of systemic hyper inflammation with multiorgan involvement after vaccination, in rare cases, have been reported. However, its pathogenesis remains unclear. METHODS This study recruited two cases who suffered from systemic inflammation following ChAdOx1 nCoV-19 vaccine and two 30-year-old male volunteers without underlying disease who have received ChAdOx1 nCoV-19 vaccine as control group. Blood samples were collected from our patients and healthy subjects before and after treatment with anti-inflammatory agent such as glucocorticoid and tocilizumab. The immune profile from our patients and healthy controls were measured using a human XL cytokine Proteome Profiler array (ARY022b, R&D Systems). RESULTS Biochemical parameters revealed leukocytosis with segmented neutrophil dominance and elevated serum levels of C-reactive protein (CRP), erythrocyte sedimentation rate, and ferritin in these two patients. The cytokine array revealed that mean levels of T cell immunoglobulin and mucin-domain containing-3 (TIM-3) (3640.3 vs 1580.5 pixels per inch [ppi]), B-cell activating factor (BAFF) (3036.8 vs 1471.0 ppi), urokinase plasminogen activator surface receptor (uPAR) (1043.1 vs 516.8 ppi), Resistin (1783.7 vs 711.3 ppi), platelet-derived growth factor (PDGF)-AB/BB (1980.7 vs 939.7 ppi), macrophage inflammatory protein-3-beta (MIP-3β) (911.9 vs 346.2 ppi), and interferon-inducible T-cell alpha chemoattractant (I-TAC) (1026.3 vs 419.7 ppi) were 2-fold higher in the patients than in normal subjects who received ChAdOx1 nCoV-19 vaccine. CONCLUSION We demonstrated that systemic inflammation may occur in subjects who have received the ChAdOx1 nCoV-19 vaccination. Moreover, we proposed immune markers, which may be implicated in the pathogenesis of systemic inflammation following COVID-19 vaccination as potential diagnostic biomarkers.
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Affiliation(s)
- Ming-Chieh Hsieh
- Division of Allergy-Immunology-Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Wen-Chung Yu
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chang-Chi Weng
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Wei-Jen Chen
- Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Shu-Tien Urological Institute, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chun-Ku Chen
- Division of Cardiopulmonary Radiology, Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Radiology, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Ying-Chi Lee
- Division of Cardiopulmonary Radiology, Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ming-Han Chen
- Division of Allergy-Immunology-Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
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Bostanghadiri N, Ziaeefar P, Mofrad MG, Yousefzadeh P, Hashemi A, Darban-Sarokhalil D. COVID-19: An Overview of SARS-CoV-2 Variants-The Current Vaccines and Drug Development. BIOMED RESEARCH INTERNATIONAL 2023; 2023:1879554. [PMID: 37674935 PMCID: PMC10480030 DOI: 10.1155/2023/1879554] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 07/07/2023] [Accepted: 08/04/2023] [Indexed: 09/08/2023]
Abstract
The world is presently in crisis facing an outbreak of a health-threatening microorganism known as COVID-19, responsible for causing uncommon viral pneumonia in humans. The virus was first reported in Wuhan, China, in early December 2019, and it quickly became a global concern due to the pandemic. Challenges in this regard have been compounded by the emergence of several variants such as B.1.1.7, B.1.351, P1, and B.1.617, which show an increase in transmission power and resistance to therapies and vaccines. Ongoing researches are focused on developing and manufacturing standard treatment strategies and effective vaccines to control the pandemic. Despite developing several vaccines such as Pfizer/BioNTech and Moderna approved by the U.S. Food and Drug Administration (FDA) and other vaccines in phase 4 clinical trials, preventive measures are mandatory to control the COVID-19 pandemic. In this review, based on the latest findings, we will discuss different types of drugs as therapeutic options and confirmed or developing vaccine candidates against SARS-CoV-2. We also discuss in detail the challenges posed by the variants and their effect on therapeutic and preventive interventions.
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Affiliation(s)
- Narjess Bostanghadiri
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Pardis Ziaeefar
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Morvarid Golrokh Mofrad
- Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| | - Parsa Yousefzadeh
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Hashemi
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Darban-Sarokhalil
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Mulik S, Berber E, Sehrawat S, Rouse BT. Controlling viral inflammatory lesions by rebalancing immune response patterns. Front Immunol 2023; 14:1257192. [PMID: 37671156 PMCID: PMC10475736 DOI: 10.3389/fimmu.2023.1257192] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 08/07/2023] [Indexed: 09/07/2023] Open
Abstract
In this review, we discuss a variety of immune modulating approaches that could be used to counteract tissue-damaging viral immunoinflammatory lesions which typify many chronic viral infections. We make the point that in several viral infections the lesions can be largely the result of one or more aspects of the host response mediating the cell and tissue damage rather than the virus itself being directly responsible. However, within the reactive inflammatory lesions along with the pro-inflammatory participants there are also other aspects of the host response that may be acting to constrain the activity of the damaging components and are contributing to resolution. This scenario should provide the prospect of rebalancing the contributions of different host responses and hence diminish or even fully control the virus-induced lesions. We identify several aspects of the host reactions that influence the pattern of immune responsiveness and describe approaches that have been used successfully, mainly in model systems, to modulate the activity of damaging participants and which has led to lesion control. We emphasize examples where such therapies are, or could be, translated for practical use in the clinic to control inflammatory lesions caused by viral infections.
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Affiliation(s)
- Sachin Mulik
- Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, TX, United States
| | - Engin Berber
- Infection Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Sharvan Sehrawat
- Indian Institute of Science Education and Research, Department of Biological Sciences, Mohali, Punjab, India
| | - Barry Tyrrell Rouse
- College of Veterinary Medicine, University of Tennessee, Knoxville, TN, United States
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Burger BJ, Epps SM, Cardenas VM, Jagana R, Meena NK, Atchley WT. Tocilizumab Is Associated with Increased Risk of Fungal Infections among Critically Ill Patients with COVID-19 and Acute Renal Failure: An Observational Cohort Study. Life (Basel) 2023; 13:1752. [PMID: 37629609 PMCID: PMC10455962 DOI: 10.3390/life13081752] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/09/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
RESEARCH QUESTION Does treatment with tocilizumab increase the risk of a fungal infection in critically ill patients with coronavirus-19? BACKGROUND Numerous therapies have been evaluated as possible treatments for coronavirus-2019 caused by severe acute respiratory syndrome coronavirus-2. Tocilizumab is a humanized monoclonal antibody directed against the interleukin-6 receptor that has found a role as a therapy for patients with severe coronavirus-19 pneumonia. The immunomodulatory effects of tocilizumab may have the unintended consequence of predisposing recipients to secondary infections. We sought to assess the risk of invasive fungal disease and the therapeutic impact of tocilizumab on the hospital length of stay, duration of mechanical ventilation, and intensive-care-unit length of stay in critically ill patients with severe coronavirus-19 pneumonia. METHODS Records of critically ill patients with coronavirus-2019 admitted from March to September 2020 at our institution were reviewed. The risk for fungal infections, intensive-care-unit length of stay, hospital length of stay, and duration of mechanical ventilation in those that received tocilizumab in addition to standard coronavirus-2019 treatments was assessed. RESULTS Fifty-six critically ill patients treated with dexamethasone and remdesivir for coronavirus-2019 were included, of which 16 patients also received tocilizumab. The majority of the cohort was African American, Asian, or of other ethnic minorities (53.6%). Invasive fungal infections occurred in 10.7% of all patients, and infection rates were significantly higher in the tocilizumab group than in the control group (31.2% vs. 2.5%, risk difference [RD] = 28.8%, p < 0.01). The increased risk in the tocilizumab group was strongly associated with renal replacement therapy. There was a dose-response relationship between the risk of fungal infection and number of tocilizumab doses received, with 2.5% of infections occurring with zero doses, 20% with a single dose (RD = 17.5%), and 50% with two doses (RD = 47.5%) (trend test p < 0.001). In addition, ICU LOS (23.4 days vs. 9.0 days, p < 0.01), the duration of mechanical ventilation (18.9 vs. 3.5 days, p = 0.01), and hospital length of stay (LOS) (29.1 vs. 15.5, p < 0.01) were increased in patients that received tocilizumab. CONCLUSIONS Repurposed immunomodulator therapies, such as tocilizumab, are now recommended treatments for severe coronavirus-2019 pneumonia, but safety concerns remain. In this early pandemic cohort, the addition of tocilizumab to dexamethasone was associated with an increased risk of fungal infection in those that were critically ill and received renal replacement therapy. Tocilizumab use was also associated with increased ICU and hospital LOSs and duration of mechanical ventilation.
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Affiliation(s)
- Barrett J. Burger
- Division of Pulmonary and Critical Care Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA; (S.M.E.); (N.K.M.)
| | - Sarenthia M. Epps
- Division of Pulmonary and Critical Care Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA; (S.M.E.); (N.K.M.)
| | - Victor M. Cardenas
- Department of Epidemiology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA
| | - Rajani Jagana
- Division of Pulmonary and Critical Care Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA; (S.M.E.); (N.K.M.)
| | - Nikhil K. Meena
- Division of Pulmonary and Critical Care Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA; (S.M.E.); (N.K.M.)
| | - William T. Atchley
- Division of Pulmonary and Critical Care Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA; (S.M.E.); (N.K.M.)
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Peng R, Yang T, Tong Y, Wang J, Zhou H, Yang M, Zhu J, Yang L, Shi Z, Liu Y. Efficacy and safety of interleukin-6 receptor antagonists in adult patients admitted to intensive care unit with COVID-19: A systematic review and meta-analysis of randomized controlled trials. Prev Med Rep 2023; 34:102276. [PMID: 37309358 PMCID: PMC10247142 DOI: 10.1016/j.pmedr.2023.102276] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/01/2023] [Accepted: 06/03/2023] [Indexed: 06/14/2023] Open
Abstract
The purpose of the systematic review was to evaluate the efficacy and safety of interleukin-6 receptor (IL-6) antagonists (tocilizumab, sarilumab) in adult patients with severe or critical COVID-19. A systematic review of the literature was conducted in Medline, Cochrane and Embase databases, and World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov from the inception dates to10 January 2023. Randomized clinical trials comparing IL-6 receptor antagonists (tocilizumab, sarilumab) with a placebo or usual care treatment for adult patients with severe or critical COVID-19 were identified. Two independent reviewers performed the assessment and selection of eligible studies, assessed study quality and extracted data. Relative risk (RR), mean difference (MD), and 95% confidence interval (CI) with random-effects models was performed in meta-analysis. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the quality of the evidence. The search retrieved a total of 11 RCTs involving 5028 participants were eligible for meta-analysis. Our findings suggest that as the new drug used in adult patients with severe or critical COVID-19, IL-6 antagonists (tocilizumab, sarilumab) may reduce the length of ICU stay and hospital stay. However, they did not significantly increase the risks of serious adverse events and did not reduce all-cause mortality (28-day, 14-day, and 7-day).
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Affiliation(s)
- Rong Peng
- Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, Sichuan, China
| | - Ting Yang
- College of Pharmacy, Zunyi Medical University, Zunyi, Guizhou, China
- Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, Sichuan, China
| | - Yu Tong
- Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, Sichuan, China
| | - Ji Wang
- Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, Sichuan, China
| | - Hui Zhou
- Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, Sichuan, China
| | - Minglong Yang
- Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, Sichuan, China
| | - Junchen Zhu
- Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, Sichuan, China
| | - Lijun Yang
- Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, Sichuan, China
| | - Zheng Shi
- Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, Sichuan, China
| | - Ya Liu
- Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, Sichuan, China
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Chatterjee A, Saha R, Mishra A, Shilkar D, Jayaprakash V, Sharma P, Sarkar B. Molecular Determinants, Clinical Manifestations and Effects of Immunization on Cardiovascular Health During COVID-19 Pandemic Era - A Review. Curr Probl Cardiol 2023; 48:101250. [PMID: 35577079 PMCID: PMC9098920 DOI: 10.1016/j.cpcardiol.2022.101250] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 05/10/2022] [Indexed: 02/08/2023]
Abstract
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has enveloped the world into an unprecedented pandemic since 2019. Significant damage to multiple organs, such as the lungs and heart, has been extensively reported. Cardiovascular injury by ACE2 downregulation, hypoxia-induced myocardial injury, and systemic inflammatory responses complicate the disease. This virus causes multisystem inflammatory syndrome in children with similar symptoms to adult SARS-CoV-2-induced myocarditis. While several treatment strategies and immunization programs have been implemented to control the menace of this disease, the risk of long-term cardiovascular damage associated with the disease has not been adequately assessed. In this review, we surveyed and summarized all the available information on the effects of COVID-19 on cardiovascular health as well as comorbidities. We also examined several case reports on post-immunization cardiovascular complications.
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Affiliation(s)
- Amrita Chatterjee
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Rajdeep Saha
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Arpita Mishra
- SLT Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India
| | - Deepak Shilkar
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Venkatesan Jayaprakash
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Pawan Sharma
- Center for Translational Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Jane & Leonard Korman Respiratory Institute, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA.
| | - Biswatrish Sarkar
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India.
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Osborn R, Alamri M, Tomic R, Ison MG. Infectious Complications of Lung Transplant for Coronavirus Disease 2019-Associated Lung Injury: A Single-Center Case-Control Cohort Study. Clin Infect Dis 2023; 77:220-228. [PMID: 36942560 PMCID: PMC10517091 DOI: 10.1093/cid/ciad160] [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: 01/19/2023] [Revised: 03/12/2023] [Accepted: 03/15/2023] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND Lung transplantation is one of the only options for patients with severe coronavirus disease 2019 (COVID-19)-associated lung injury (CALI). Studies on patients who received a lung transplant for CALI have, to date, not looked at the infectious outcomes. METHODS After institutional review board approval, a retrospective case-control cohort study, matched 1:1, collected data on patients who underwent lung transplantation for CALI (case) and for non-COVID-19 end-stage lung disease (control) between 1 June 2020 and 1 April 2022 at a large academic hospital in Chicago. We assessed infectious complications and other key outcomes pre-transplant and for 1 year post-transplant. RESULTS Among 78 patients (39 CALI and 39 matched control lung transplant patients), those in the CALI cohort were less likely to be vaccinated pre-transplant and were more likely to have diabetes, to be obese, to not be ambulatory, and to require pre-transplant extracorporeal membrane oxygenation and mechanical ventilation. Patients transplanted for CALI had higher rates of infection pre-transplant (66.7% vs 15.4% of patients in the control) and in the first 30 days post-transplant (43.6% vs 20.5%). Numbers and types of infection were similar in both groups at other time points. One-year mortality was similar for CALI and control groups (12.8% vs 10.3%, respectively). CONCLUSIONS Patients who received a lung transplant for CALI are more deconditioned with prolonged hospital stays and experience more infectious complications immediately pre- and post-transplant. Infections due to multidrug-resistant organisms are important contributors to morbidity and mortality in this population. Antimicrobial stewardship is urgently needed.
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Affiliation(s)
- Rebecca Osborn
- Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Maha Alamri
- Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Rade Tomic
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Michael G Ison
- Respiratory Diseases Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, Rockville, Maryland, USA
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Perreault G, Ching C, Nobel YR. COVID-19 in patients with liver disease and liver transplant: clinical implications, prevention, and management. Therap Adv Gastroenterol 2023; 16:17562848231188586. [PMID: 37521085 PMCID: PMC10372508 DOI: 10.1177/17562848231188586] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 07/02/2023] [Indexed: 08/01/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has had enormous implications for the care of patients with chronic liver disease (CLD), cirrhosis, and liver transplant (LT). Clinical outcomes of COVID-19 vary in patients with CLD and cirrhosis compared to healthy controls, and in patients with LT compared to patients without LT. Several special considerations apply to the approach to vaccination and treatment in patients with CLD and LT. The practice of liver transplantation has also been heavily impacted by the pandemic, including persistent reductions in living donor LT and increases in LT for an indication of alcohol-related liver disease. Recent medical society guidelines strive to standardize severe acute respiratory syndrome coronavirus 2 testing in donors and recipients and the approach to transplantation after recovered from COVID-19 infection, but certain controversies remain.
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Affiliation(s)
- Gabriel Perreault
- Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA
| | - Charlotte Ching
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
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Gomon YM, Kolbin AS, Fahrutdinova AM, Usmanova TA, Sultanova FM, Balykina YE. A Systematic Review with Meta-Analysis and Indirect Comparison of the Effectiveness of COVID-19 Anti-Interleukin Therapy. ANTIBIOTICS AND CHEMOTHERAPY 2023; 68:52-65. [DOI: 10.37489/0235-2990-2023-68-3-4-52-65] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Aim. Evaluation of the effectiveness of anti-interleukin drugs used in the pathogenetic therapy of COVID-19 in relation to the relative risks of 28-day mortality and the odds ratio of 14-day improvement of symptoms of the disease. Materials and methods. A systematic review of publications concerning the evaluation of the effectiveness of these drugs recommended for use as COVID-19 pathogenetic therapy, with meta-analysis and indirect comparison of the data obtained, was carried out. Results. The meta-analysis included 15 randomized and 8 non-randomized studies. In direct comparison of anti-interleukin drugs with controls, it was demonstrated that only tocilizumab and anakinra surpass standard therapy in terms of the relative risk of 28-day mortality (RR 0.85 [95% CI 0.74; 0.97] and 0.5 [95% CI 0.32; 0.80], respectively). Statistically reliable data were also obtained in favor of the effectiveness of levilimab in comparison with standard therapy according to the criterion of «improvement by the 14th day of the disease», which was 2.29 [1.31; 4.01]. With an indirect comparison of tocilizumab and anakinra, the latter showed greater effectiveness in reducing the 28-day mortality rate: the RR was 1.2 [95% CI 1.16; 1.25], P=0.0001. Conclusion. The meta-analysis of the results of the systematic review demonstrated the effectiveness of tocilizumab and anakinra in relation to the 28-day mortality rate, and levilimab in relation to the indicator «Improvement by the 14th day of the disease».
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Affiliation(s)
- Yu. M. Gomon
- First St. Petersburg State Medical University named after Academician I. P. Pavlova Ministry of Health of Russia; Hospital of St. George the Great Martyr
| | - A. S. Kolbin
- First St. Petersburg State Medical University named after Academician I. P. Pavlova Ministry of Health of Russia;
St. Petersburg State University
| | | | - T. A. Usmanova
- First St. Petersburg State Medical University named after Academician I. P. Pavlova Ministry of Health of Russia
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Flisiak R, Flisiak-Jackiewicz M, Rzymski P, Zarębska-Michaluk D. Tocilizumab for the treatment of COVID-19. Expert Rev Anti Infect Ther 2023; 21:791-797. [PMID: 37326214 DOI: 10.1080/14787210.2023.2226867] [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: 03/26/2023] [Accepted: 06/14/2023] [Indexed: 06/17/2023]
Abstract
INTRODUCTION Since the beginning of the COVID-19 pandemic, the repurposing of medicines has been pursued to find interventions effective in preventing fatal outcome of the disease. One of these drugs was tocilizumab, an interleukin-6 inhibiting monoclonal antibody, previously used to treat several immune-related disorders. AREAS COVERED In this article, we present the results of the initial observational studies and subsequent randomized clinical trials on the efficacy and safety of tocilizumab in the treatment of COVID-19. Despite conflicting results, possibly due to the heterogeneity of the studied populations, large studies have ultimately proven that preventing IL-6 from attaching to its receptors can effectively reverse the fatal course of the disease. We also discuss the meta-analyses, which mostly supported the validity of tocilizumab therapy. We show how tocilizumab found its place in the most important recommendations on COVID-19 treatment and obtained authorization from the major regulatory authorities. EXPERT OPINION The criteria for optimizing tocilizumab therapy in COVID-19 still need to be established. They are also important considering the existing risks of future zoonotic spillovers and epidemics that may trigger hyperinflammation that could be efficiently blocked. The experience gained with tocilizumab shall be perceived as preparedness for future challenges.
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Affiliation(s)
- Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, Poland
| | - Marta Flisiak-Jackiewicz
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, Bialystok, Poland
| | - Piotr Rzymski
- Department of Environmental Medicine, Poznan University of Medical Sciences, Poznań, Poland
- Integrated Science Association (ISA), Universal Scientific Education and Research Network (USERN), Poznań, Poland
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Athanassiou P, Athanassiou L. Current Treatment Approach, Emerging Therapies and New Horizons in Systemic Lupus Erythematosus. Life (Basel) 2023; 13:1496. [PMID: 37511872 PMCID: PMC10381582 DOI: 10.3390/life13071496] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 06/18/2023] [Accepted: 06/30/2023] [Indexed: 07/30/2023] Open
Abstract
Systemic lupus erythematosus (SLE), the prototype of systemic autoimmune diseases is characterized by extreme heterogeneity with a variable clinical course. Renal involvement may be observed and affects the outcome. Hydroxychloroquine should be administered to every lupus patient irrespective of organ involvement. Conventional immunosuppressive therapy includes corticosteroids, methotrexate, cyclophosphamide, mycophenolate mofetil, azathioprine, cyclosporine and tacrolimus. However, despite conventional immunosuppressive treatment, flares occur and broad immunosuppression is accompanied by multiple side effects. Flare occurrence, target organ involvement, side effects of broad immunosuppression and increased knowledge of the pathogenetic mechanisms involved in SLE pathogenesis as well as the availability of biologic agents has led to the application of biologic agents in SLE management. Biologic agents targeting various pathogenetic paths have been applied. B cell targeting agents have been used successfully. Belimumab, a B cell targeting agent, has been approved for the treatment of SLE. Rituximab, an anti-CD20 targeting agent is also used in SLE. Anifrolumab, an interferon I receptor-targeting agent has beneficial effects on SLE. In conclusion, biologic treatment is applied in SLE and should be further evaluated with the aim of a good treatment response and a significant improvement in quality of life.
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Affiliation(s)
| | - Lambros Athanassiou
- Department of Rheumatology, Asclepeion Hospital, Voula, GR16673 Athens, Greece
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Adzic-Vukicevic T, Mladenovic M, Jovanovic S, Soldatović I, Radovanovic-Spurnic A. Invasive fungal disease in COVID-19 patients: a single-center prospective observational study. Front Med (Lausanne) 2023; 10:1084666. [PMID: 37359005 PMCID: PMC10288186 DOI: 10.3389/fmed.2023.1084666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 05/05/2023] [Indexed: 06/28/2023] Open
Abstract
Background Invasive fungal diseases (IFDs) are caused by fungal infections that manifest as serious secondary infections in patients with COVID-19. The increased morbidity and mortality rates are most frequently observed in patients with COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated candidiasis (CAC). CAPA is the most frequently encountered infection with an incidence rate of 0.7-7.7%, while CAC is a less common and less studied fungal infection in COVID-19 patients. Materials and methods The present article is a prospective observational single-center study that was conducted between 1 September 2021 and 24 December 2021, involving 6,335 patients who were admitted to COVID Hospital "Batajnica," University Clinical Center of Serbia, Belgrade. Results Of the 6,335 patients hospitalized during the four-month period of the study, 120 patients (1.86%) who had a proven diagnosis of IFD were included in the study. These patients were divided into two groups: CAPA patients (n = 63) and CAC patients (n = 56); however, one of the 120 patients was diagnosed with Cryptoccocus neoformans infection. The mean age of the study population was 65.7 ± 13.9 years, and 78 (65.5%) of them were men. The patients were identified to have the following non-malignant comorbidities: arterial hypertension in 62 (52.1%) patients, diabetes mellitus in 34 (28.65), pre-existing lung damage similar to that observed in COPD and asthma in 20 (16.8%), and chronic renal insufficiency in 13 (10.9%) patients. The hematological malignancies were found to be the most prevalent malignancies and were identified in 20 (16.8%) patients, particularly in CAPA patients [11 (17.5%); p < 0.041]. Fiberoptic bronchoscopy with bronchoalveolar lavage fluid (BALF) and microscopic examination confirmed the presence of fungal infections in 17 (14.3%) patients. Serology testing was also performed in the majority of cases. Antibodies against Aspergillus spp. and Candida spp. were predominantly found in CAPA patients (p < 0.001). The patients were also tested for the presence of (1-3)-β-D glucan (p < 0.019), galactomannan, and mannan in the specimens. Blood cultures were found to be positive in 45 (37.8%) patients, mostly in CAC patients. Mechanical ventilation was applied in 41 (34.5%) patients, while a non-invasive technique, such as continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC), was used in 20 (16.8%) patients. The following antifungals were administered: echinocandins in 42 (35.3%), voriconazole in 30 (25.2%), and fluconazole in 27 (22.7%) patients. Most of the patients received systemic corticosteroids (mainly methylprednisolone), while 11 (9.16%) received favipiravir, 32 (26.67%) remdesivir, 8 (6.67%) casirivimab/imdevimab, and 5 (4.16%) sotrovimab. The outcome was lethal in 76 (63.9%) patients, predominantly CAC patients (p < 0.001). Conclusion Invasive fungal disease is a severe complication associated with COVID-19 and accounts for increased mortality in these patients. Early identification and appropriate treatment may provide a favorable outcome.
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Affiliation(s)
- Tatjana Adzic-Vukicevic
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
- Covid Hospital Batajnica, University Clinical Center of Serbia, Belgrade, Serbia
- Clinic for Pulmonology, University Clinical Center of Serbia, Belgrade, Serbia
| | - Milos Mladenovic
- Covid Hospital Batajnica, University Clinical Center of Serbia, Belgrade, Serbia
| | - Snezana Jovanovic
- Covid Hospital Batajnica, University Clinical Center of Serbia, Belgrade, Serbia
- Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Belgrade, Serbia
| | - Ivan Soldatović
- Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Aleksandra Radovanovic-Spurnic
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
- Covid Hospital Batajnica, University Clinical Center of Serbia, Belgrade, Serbia
- Center for Microbiology, University Clinical Center of Serbia, Belgrade, Serbia
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Bello S, Lasierra AB, López-Vergara L, de Diego C, Torralba L, de Gopegui PR, Lahoz R, Abadía C, Godino J, Cebollada A, Jimeno B, Bello C, Tejada A, Torres A. IL-6 and cfDNA monitoring throughout COVID-19 hospitalization are accurate markers of its outcomes. Respir Res 2023; 24:125. [PMID: 37147677 PMCID: PMC10161166 DOI: 10.1186/s12931-023-02426-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 04/18/2023] [Indexed: 05/07/2023] Open
Abstract
BACKGROUND Severe COVID-19 entails a dysregulated immune response, most likely inflammation related to a lack of virus control. A better understanding of immune toxicity, immunosuppression balance, and COVID-19 assessments could help determine whether different clinical presentations are driven by specific types of immune responses. The progression of the immune response and tissular damage could predict outcomes and may help in the management of patients. METHODS We collected 201 serum samples from 93 hospitalised patients classified as moderately, severely, and critically ill. We differentiated the viral, early inflammatory, and late inflammatory phases and included 72 patients with 180 samples in separate stages for longitudinal study and 55 controls. We studied selected cytokines, P-selectin, and the tissue damage markers lactate dehydrogenase (LDH) and cell-free DNA (cfDNA). RESULTS TNF-α, IL-6, IL-8, and G-CSF were associated with severity and mortality, but only IL-6 increased since admission in the critical patients and non-survivors, correlating with damage markers. The lack of a significant decrease in IL-6 levels in the critical patients and non-survivors in the early inflammatory phase (a decreased presence in the other patients) suggests that these patients did not achieve viral control on days 10-16. For all patients, lactate dehydrogenase and cfDNA levels increased with severity, and cfDNA levels increased in the non-survivors from the first sample (p = 0.002) to the late inflammatory phase (p = 0.031). In the multivariate study, cfDNA was an independent risk factor for mortality and ICU admission. CONCLUSIONS The distinct progression of IL-6 levels in the course of the disease, especially on days 10-16, was a good marker of progression to critical status and mortality and could guide the start of IL-6 blockade. cfDNA was an accurate marker of severity and mortality from admission and throughout COVID-19 progression.
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Affiliation(s)
- Salvador Bello
- Department of Pulmonary Medicine, Miguel Servet University Hospital, CIBERES, Instituto de Investigación Sanitaria (ISS) Aragón, Avenida Isabel La Católica 1-9, 50009, Zaragoza, Spain.
| | | | - Lucía López-Vergara
- Department of Pulmonary Medicine, Miguel Servet University Hospital, CIBERES, Instituto de Investigación Sanitaria (ISS) Aragón, Avenida Isabel La Católica 1-9, 50009, Zaragoza, Spain
| | - Cristina de Diego
- Department of Pulmonary Medicine, Miguel Servet University Hospital, CIBERES, Instituto de Investigación Sanitaria (ISS) Aragón, Avenida Isabel La Católica 1-9, 50009, Zaragoza, Spain
| | - Laura Torralba
- Department of Pulmonary Medicine, Miguel Servet University Hospital, CIBERES, Instituto de Investigación Sanitaria (ISS) Aragón, Avenida Isabel La Católica 1-9, 50009, Zaragoza, Spain
| | | | - Raquel Lahoz
- Department of Biochemistry, Miguel Servet University Hospital, Zaragoza, Spain
| | - Claudia Abadía
- Department of Biochemistry, Miguel Servet University Hospital, Zaragoza, Spain
| | - Javier Godino
- Department of Cytometry and Cell Separation, Aragon Institute of Health Sciences (IACS), Zaragoza, Spain
| | - Alberto Cebollada
- Biocomputing Technical Scientific Service, Aragon Institute of Health Sciences (IACS), Zaragoza, Spain
| | - Beatriz Jimeno
- Department of Cytometry and Cell Separation, Aragon Institute of Health Sciences (IACS), Zaragoza, Spain
| | - Carlota Bello
- Department of Radiology, Hospital Clínico Lozano Blesa, Zaragoza, Spain
| | - Antonio Tejada
- Intensive Care Unit, Miguel Servet University Hospital, Zaragoza, Spain
| | - Antoni Torres
- Servei de Pneumologia, Hospital Clinic, Universitat de Barcelona, IDIBAPS, ICREA, CIBERESUCICOVID, Barcelona, Spain
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Mondini L, Salton F, Trotta L, Bozzi C, Pozzan R, Barbieri M, Tavano S, Lerda S, Hughes M, Confalonieri M, Confalonieri P, Ruaro B. Host-Based Treatments for Severe COVID-19. Curr Issues Mol Biol 2023; 45:3102-3121. [PMID: 37185727 PMCID: PMC10136924 DOI: 10.3390/cimb45040203] [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: 03/03/2023] [Revised: 03/29/2023] [Accepted: 04/02/2023] [Indexed: 05/17/2023] Open
Abstract
COVID-19 has been a global health problem since 2020. There are different spectrums of manifestation of this disease, ranging from asymptomatic to extremely severe forms requiring admission to intensive care units and life-support therapies, mainly due to severe pneumonia. The progressive understanding of this disease has allowed researchers and clinicians to implement different therapeutic alternatives, depending on both the severity of clinical involvement and the causative molecular mechanism that has been progressively explored. In this review, we analysed the main therapeutic options available to date based on modulating the host inflammatory response to SARS-CoV-2 infection in patients with severe and critical illness. Although current guidelines are moving toward a personalised treatment approach titrated on the timing of presentation, disease severity, and laboratory parameters, future research is needed to identify additional biomarkers that can anticipate the disease course and guide targeted interventions on an individual basis.
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Affiliation(s)
- Lucrezia Mondini
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of Trieste, 34149 Trieste, Italy
| | - Francesco Salton
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of Trieste, 34149 Trieste, Italy
| | - Liliana Trotta
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of Trieste, 34149 Trieste, Italy
| | - Chiara Bozzi
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of Trieste, 34149 Trieste, Italy
| | - Riccardo Pozzan
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of Trieste, 34149 Trieste, Italy
| | - Mariangela Barbieri
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of Trieste, 34149 Trieste, Italy
| | - Stefano Tavano
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of Trieste, 34149 Trieste, Italy
| | - Selene Lerda
- Graduate School, University of Milan, 20149 Milano, Italy
| | - Michael Hughes
- Division of Musculoskeletal and Dermatological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester & Salford Royal NHS Foundation Trust, Manchester M6 8HD, UK
| | - Marco Confalonieri
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of Trieste, 34149 Trieste, Italy
| | - Paola Confalonieri
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of Trieste, 34149 Trieste, Italy
| | - Barbara Ruaro
- Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of Trieste, 34149 Trieste, Italy
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49
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Niu MM, Jiang Q, Cao Y, Yang Q, Zhang YF, Li DT, Hu P. Tocilizumab in multisystem inflammatory syndrome in children (MIS-C)-summarized experiences. J Eur Acad Dermatol Venereol 2023; 37:e443-e446. [PMID: 36433780 DOI: 10.1111/jdv.18784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 11/21/2022] [Indexed: 11/27/2022]
Affiliation(s)
- Man Man Niu
- Department of Pediatrics, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qi Jiang
- Department of Pediatrics, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yue Cao
- Department of Pediatrics, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qian Yang
- Department of Pediatrics, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yan Fang Zhang
- Department of Pediatrics, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Dao Ting Li
- Department of Pediatrics, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Peng Hu
- Department of Pediatrics, the First Affiliated Hospital of Anhui Medical University, Hefei, China
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50
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Liapman TD, Bormotovs J, Reihmane D. Severe COVID-19 Pneumonia in a Three-Year-Old with Congenital Iron and B12 Deficiency Anemia of Unknown Etiology: A Case Report. CHILDREN (BASEL, SWITZERLAND) 2023; 10:children10040616. [PMID: 37189864 DOI: 10.3390/children10040616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 03/10/2023] [Accepted: 03/21/2023] [Indexed: 05/17/2023]
Abstract
Since COVID-19 first emerged in Wuhan, China, and was declared a global pandemic by the WHO, researchers have been meticulously studying the disease and its complications. Studies of severe COVID-19 disease among pediatric populations are scarce, leading to difficulty in establishing a comprehensive management approach. Case presentation: This report outlines a case of a long-standing combined iron and vitamin B12 deficiency anemia in a three-year-old treated at the Children's Clinical University Hospital due to severe COVID-19 disease. The patient's clinical condition coincided with the derangement of biomarkers described in the literature, including lymphopenia, increased neutrophil/lymphocyte ratio (NLR), decreased lymphocyte/C-reactive protein ratio (LCR), as well as elevated inflammatory markers such as CRP and D-dimers. The patient developed severe bilateral pneumonia requiring invasive ventilation, high-flow oxygen, immunosuppressive therapy with dexamethasone and tocilizumab, and supplementation of anemia deficits with blood transfusion and vitamin B12 administration. Conclusions: Our findings are consistent with the most important biomarkers reported in the literature indicative of severe disease progression. Additionally, poorly controlled anemia may be suggested as a potentially important risk factor for severe COVID-19 disease among children. However, additional quantitative research is required to establish the nature and severity of the risk.
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Affiliation(s)
- Theodore Daniel Liapman
- Department of Human Physiology and Biochemistry, Riga Stradins University, LV-1007 Riga, Latvia
- Altnagelvin Area Hospital, Western Health and Social Care Trust, Derry BT47 6LS, UK
| | | | - Dace Reihmane
- Department of Human Physiology and Biochemistry, Riga Stradins University, LV-1007 Riga, Latvia
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