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Koutalos AA, Koskiniotis A, Rountas C, Konstantinou E, Georgiadou S, Stefos A, Gatselis NK, Dalekos GN, Malizos KN. Osteonecrosis risk after steroids-related treatment of COVID-19 is not negligible: A cross sectional study. Eur J Intern Med 2024; 123:127-131. [PMID: 38281818 DOI: 10.1016/j.ejim.2024.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 12/31/2023] [Accepted: 01/04/2024] [Indexed: 01/30/2024]
Abstract
BACKGROUND & AIMS During the pandemic, steroids use at various dosages and durations for the treatment of COVID-19 patients, especially in hospitalized patients, was a common and effective strategy. However, steroid administration is associated with osteonecrosis as an adverse event. The aim of the study was to examine the prevalence of skeleton osteonecrosis in COVID-19 patients treated with or without steroids. METHODS Eighty randomly selected hospitalized COVID-19 patients were analyzed, of which 40 were managed with a published protocol including steroids and 40 did not receive steroids. Demographics and laboratory measurements including white blood cells count, C-reactive protein and ferritin were retrieved from the medical records. All patients underwent magnetic resonance imaging of the hips, shoulders, and knees. Subsequently, all patients were clinically examined and Oxford hip score (OHS) and EuroQol- 5 Dimension (EQ-5D-5 L) were documented. RESULTS Three patients (3/40; 7.5 %) treated with steroids were diagnosed with femoral head osteonecrosis. None of the patients in the non-steroid-treated group developed osteonecrosis. There were no differences between the two groups regarding OHS and EQ-5D-5 L. Patients with osteonecrosis had higher ferritin levels, received higher doses of corticosteroids (median dose 2200 mg), and had longer hospitalization. CONCLUSIONS COVID-19-related therapy with steroids resulted in lower prevalence of osteonecrosis than that previously recorded in patients with severe acute respiratory syndrome caused by coronavirus-type-1. However, this risk seems not negligible and therefore, high clinical suspicion for early diagnosis is warranted, given the fact that a great proportion of hospitalized patients received steroids during the COVID-19 pandemic.
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Affiliation(s)
- Antonios A Koutalos
- Department of Orthopaedic Surgery and Musculoskeletal Trauma, General University Hospital of Larissa, Greece
| | - Alexandros Koskiniotis
- Department of Orthopaedic Surgery and Musculoskeletal Trauma, General University Hospital of Larissa, Greece
| | - Christos Rountas
- Department of Radiology, Faculty of Medicine, University of Thessaly, Larisa, Greece
| | - Efstathios Konstantinou
- Department of Orthopaedic Surgery and Musculoskeletal Trauma, General University Hospital of Larissa, Greece
| | - Sarah Georgiadou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Aggelos Stefos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Nikolaos K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Konstantinos N Malizos
- Department of Orthopaedic Surgery & Musculoskeletal Trauma, Faculty of Medicine, University of Thessaly, Larissa, Greece.
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Gatselis NK, Lyberopoulou A, Lygoura V, Giannoulis G, Samakidou A, Vaiou A, Antoniou K, Triantafyllou K, Stefos A, Georgiadou S, Sagris D, Sveroni D, Gabeta S, Ntaios G, Norman GL, Dalekos GN. Calprotectin serum levels on admission and during follow-up predict severity and outcome of patients with COVID-19: A prospective study. Eur J Intern Med 2024; 122:78-85. [PMID: 37953124 DOI: 10.1016/j.ejim.2023.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/02/2023] [Accepted: 11/02/2023] [Indexed: 11/14/2023]
Abstract
BACKGROUND & AIMS Calprotectin reflects neutrophil activation and is increased in various inflammatory conditions including severe COVID-19. However, serial serum calprotectin measurements in COVID-19 patients are limited. We assessed prospectively, calprotectin levels as biomarker of severity/outcome of the disease and a COVID-19 monitoring parameter in a large cohort of consecutive COVID-19 patients. METHODS Calprotectin serum levels were measured in 736 patients (58.2 % males; median age 63-years; moderate disease, n = 292; severe, n = 444, intubated and/or died, n = 50). Patients were treated with combined immunotherapies according to our published local algorithm. The endpoint was the composite event of intubation due to severe respiratory failure (SRF)/COVID-19-related mortality. RESULTS Median (interquartile range) calprotectin levels were significantly higher in patients with severe disease [7(8.2) vs. 6.1(8.1)μg/mL, p = 0.015]. Calprotectin on admission was the only independent risk factor for intubation/death (HR=1.473, 95 %CI=1.003-2.165, p = 0.048) even after adjustment for age, sex, body mass index, comorbidities, neutrophils, lymphocytes, neutrophil to lymphocytes ratio, ferritin, and CRP. The area under the curve (AUC, 95 %CI) of calprotectin for prediction of intubation/death was 0.619 (0.531-0.708), with an optimal cut-off at 13 μg/mL (sensitivity: 44 %, specificity: 79 %, positive and negative predictive values: 13 % and 95 %, respectively). For intubated/died patients, paired comparisons from baseline to middle of hospitalization and subsequently to intubation/death showed significant increase of calprotectin (p = 0.009 and p < 0.001, respectively). Calprotectin alteration had the higher predictive ability for intubation/death [AUC (95 %CI):0.803 (0.664-0.943), p < 0.001]. CONCLUSIONS Calprotectin levels on admission and their subsequent dynamic alterations could serve as indicator of COVID-19 severity and predict the occurrence of SRF and mortality.
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Affiliation(s)
- Nikolaos K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Vasiliki Lygoura
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - George Giannoulis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Anna Samakidou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Antonia Vaiou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Katerina Antoniou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Katerina Triantafyllou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Aggelos Stefos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Sarah Georgiadou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Dimitrios Sagris
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Dafni Sveroni
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Stella Gabeta
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - George Ntaios
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Gary L Norman
- Research and Development, Headquarters & Technology Center Autoimmunity, Werfen, San Diego, CA 92131, USA
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece.
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Farina N, Dagna L. Immune regulators for the treatment of COVID-19: A critical appraisal after two years. Eur J Intern Med 2023; 116:34-35. [PMID: 37541923 DOI: 10.1016/j.ejim.2023.07.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 08/06/2023]
Affiliation(s)
- Nicola Farina
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Milan, Italy
| | - Lorenzo Dagna
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
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Bakaros E, Voulgaridi I, Paliatsa V, Gatselis N, Germanidis G, Asvestopoulou E, Alexiou S, Botsfari E, Lygoura V, Tsachouridou O, Mimtsoudis I, Tseroni M, Sarrou S, Mouchtouri VA, Dadouli K, Kalala F, Metallidis S, Dalekos G, Hadjichristodoulou C, Speletas M. Innate Immune Gene Polymorphisms and COVID-19 Prognosis. Viruses 2023; 15:1784. [PMID: 37766191 PMCID: PMC10537595 DOI: 10.3390/v15091784] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 08/19/2023] [Accepted: 08/19/2023] [Indexed: 09/29/2023] Open
Abstract
COVID-19 is characterized by a heterogeneous clinical presentation and prognosis. Risk factors contributing to the development of severe disease include old age and the presence of comorbidities. However, the genetic background of the host has also been recognized as an important determinant of disease prognosis. Considering the pivotal role of innate immunity in the control of SARS-CoV-2 infection, we analyzed the possible contribution of several innate immune gene polymorphisms (including TLR2-rs5743708, TLR4-rs4986790, TLR4-rs4986791, CD14-rs2569190, CARD8-rs1834481, IL18-rs2043211, and CD40-rs1883832) in disease severity and prognosis. A total of 249 individuals were enrolled and further divided into five (5) groups, according to the clinical progression scale provided by the World Health Organization (WHO) (asymptomatic, mild, moderate, severe, and critical). We identified that elderly patients with obesity and/or diabetes mellitus were more susceptible to developing pneumonia and respiratory distress syndrome after SARS-CoV-2 infection, while the IL18-rs1834481 polymorphism was an independent risk factor for developing pneumonia. Moreover, individuals carrying either the TLR2-rs5743708 or the TLR4-rs4986791 polymorphisms exhibited a 3.6- and 2.5-fold increased probability for developing pneumonia and a more severe disease, respectively. Our data support the notion that the host's genetic background can significantly affect COVID-19 clinical phenotype, also suggesting that the IL18-rs1834481, TLR2-rs5743708, and TLR4-rs4986791 polymorphisms may be used as molecular predictors of COVID-19 clinical phenotype.
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Affiliation(s)
- Evangelos Bakaros
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece; (E.B.); (V.P.); (E.A.); (S.A.); (E.B.); (S.S.); (F.K.)
| | - Ioanna Voulgaridi
- Laboratory of Hygiene and Epidemiology, Faculty of Medicine, University of Thessaly, 41222 Larissa, Greece; (I.V.); (V.A.M.); (K.D.); (C.H.)
| | - Vassiliki Paliatsa
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece; (E.B.); (V.P.); (E.A.); (S.A.); (E.B.); (S.S.); (F.K.)
| | - Nikolaos Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, Full Member of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, 41110 Larissa, Greece; (N.G.); (V.L.); (G.D.)
| | - Georgios Germanidis
- First Internal Medicine Department, Infectious Diseases Division, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (G.G.); (O.T.); (I.M.); (S.M.)
| | - Evangelia Asvestopoulou
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece; (E.B.); (V.P.); (E.A.); (S.A.); (E.B.); (S.S.); (F.K.)
| | - Stamatia Alexiou
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece; (E.B.); (V.P.); (E.A.); (S.A.); (E.B.); (S.S.); (F.K.)
| | - Elli Botsfari
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece; (E.B.); (V.P.); (E.A.); (S.A.); (E.B.); (S.S.); (F.K.)
| | - Vasiliki Lygoura
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, Full Member of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, 41110 Larissa, Greece; (N.G.); (V.L.); (G.D.)
| | - Olga Tsachouridou
- First Internal Medicine Department, Infectious Diseases Division, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (G.G.); (O.T.); (I.M.); (S.M.)
| | - Iordanis Mimtsoudis
- First Internal Medicine Department, Infectious Diseases Division, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (G.G.); (O.T.); (I.M.); (S.M.)
| | - Maria Tseroni
- National Public Health Organization, 15123 Athens, Greece;
| | - Styliani Sarrou
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece; (E.B.); (V.P.); (E.A.); (S.A.); (E.B.); (S.S.); (F.K.)
| | - Varvara A. Mouchtouri
- Laboratory of Hygiene and Epidemiology, Faculty of Medicine, University of Thessaly, 41222 Larissa, Greece; (I.V.); (V.A.M.); (K.D.); (C.H.)
| | - Katerina Dadouli
- Laboratory of Hygiene and Epidemiology, Faculty of Medicine, University of Thessaly, 41222 Larissa, Greece; (I.V.); (V.A.M.); (K.D.); (C.H.)
| | - Fani Kalala
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece; (E.B.); (V.P.); (E.A.); (S.A.); (E.B.); (S.S.); (F.K.)
| | - Simeon Metallidis
- First Internal Medicine Department, Infectious Diseases Division, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (G.G.); (O.T.); (I.M.); (S.M.)
| | - George Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, Full Member of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, 41110 Larissa, Greece; (N.G.); (V.L.); (G.D.)
| | - Christos Hadjichristodoulou
- Laboratory of Hygiene and Epidemiology, Faculty of Medicine, University of Thessaly, 41222 Larissa, Greece; (I.V.); (V.A.M.); (K.D.); (C.H.)
| | - Matthaios Speletas
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece; (E.B.); (V.P.); (E.A.); (S.A.); (E.B.); (S.S.); (F.K.)
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Valsamaki A, Xanthoudaki M, Oikonomou KG, Vlachostergios PJ, Papadogoulas A, Katsiafylloudis P, Voulgaridi I, Skoura AL, Komnos A, Papamichalis P. Prevention, diagnostic evaluation, management and prognostic implications of liver disease in critically ill patients with COVID-19. World J Clin Cases 2023; 11:514-527. [PMID: 36793637 PMCID: PMC9923862 DOI: 10.12998/wjcc.v11.i3.514] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 12/05/2022] [Accepted: 01/10/2023] [Indexed: 01/23/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, broke out in December 2019 in Wuhan city of China and spread rapidly worldwide. Therefore, by March 2020, the World Health Organization declared the disease a global pandemic. Apart from the respiratory system, various other organs of the human body are also seriously affected by the virus. Liver injury in patients with a severe form of COVID-19 is estimated to be 14.8%-53.0%. Elevated levels of total bilirubin, aspartate aminotransferase and alanine aminotransferase and low levels of serum albumin and prealbumin are the main laboratory findings. Patients with pre-existing chronic liver disease and cirrhosis are much more prone to develop severe liver injury. This literature review presented the recent scientific findings regarding the pathophysiological mechanisms responsible for liver injury in critically ill patients with COVID-19, the various interactions between drugs used to treat the disease and the function of the liver and the specific tests providing the possibility of early diagnosis of severe liver injury in these patients. Moreover, it highlighted the burden that COVID-19 put on health systems worldwide and its effect on transplant programs and the care provided to critically ill patients in general and particularly to those with chronic liver disease.
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Affiliation(s)
- Asimina Valsamaki
- Intensive Care Unit, General Hospital of Larissa, Larissa 41221, Greece
| | - Maria Xanthoudaki
- Intensive Care Unit, General Hospital of Larissa, Larissa 41221, Greece
| | | | - Panagiotis J Vlachostergios
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, United States
| | | | | | - Ioanna Voulgaridi
- Department of Microbiology, General Hospital of Larissa, Larissa 41221, Greece
| | | | - Apostolos Komnos
- Intensive Care Unit, General Hospital of Larissa, Larissa 41221, Greece
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Valsamaki A, Xanthoudaki M, Oikonomou KG, Vlachostergios PJ, Papadogoulas A, Katsiafylloudis P, Voulgaridi I, Skoura AL, Komnos A, Papamichalis P. Prevention, diagnostic evaluation, management and prognostic implications of liver disease in critically ill patients with COVID-19. World J Clin Cases 2023; 11:514-527. [DOI: 18.valsamaki a, xanthoudaki m, oikonomou kg, vlachostergios pj, papadogoulas a, katsiafylloudis p, voulgaridi i, skoura al, komnos a, papamichalis p.prevention, diagnostic evaluation, management and prognostic implications of liver disease in critically ill patients with covid-19.world j clin cases.2023 jan 26;11(3):514-527.doi: 10.12998/wjcc.v11.i3.514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/17/2025] Open
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Elmekaty EZI, Maklad A, Abouelhassan R, Munir W, Ibrahim MIM, Nair A, Alibrahim R, Iqbal F, Al Bishawi A, Abdelmajid A, Aboukamar M, Hadi HA, Khattab MA, Al Soub H, Al Maslamani M. Evaluation of anakinra in the management of patients with COVID-19 infection: A randomized clinical trial. Front Microbiol 2023; 14:1098703. [PMID: 36778864 PMCID: PMC9910697 DOI: 10.3389/fmicb.2023.1098703] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 01/06/2023] [Indexed: 01/27/2023] Open
Abstract
Background The global COVID-19 pandemic led to substantial clinical and economic outcomes with catastrophic consequences. While the majority of cases has mild to moderate disease, minority of patients progress into severe disease secondary to the stimulation of the immune response. The hyperinflammatory state contributes towards progression into multi-organ failure which necessitates suppressive therapy with variable outcomes. This study aims to explore the safety and efficacy of anakinra in COVID-19 patients with severe disease leading to cytokine release syndromes. Methods In this open-label, multi-center, randomized clinical trial, patients with confirmed COVID-19 infection with evidence of respiratory distress and signs of cytokine release syndrome were randomized in 1:1 ratio to receive either standard of care (SOC) or anakinra (100 mg subcutaneously every 12 h for 3 days then 100 mg subcutaneously once daily for 4 days) in addition to SOC. The primary outcome was treatment success at day 14 as defined by the WHO clinical progression score of ≤3. Primary analysis was based upon intention-to-treat population, with value of p of <0.05. Results Out 327 patients screened for eligibility, 80 patients were recruited for the study. The mean age was 49.9 years (SD = 11.7), with male predominance at 82.5% (n = 66). The primary outcome was not statistically different (87.5% (n = 35) in anakinra group vs. 92.5% (n = 37) in SOC group, p = 0.712; OR = 1.762 (95%CI: 0.39-7.93). The majority of reported adverse events were mild in severity and not related to the study treatment. Elevated aspartate aminotransferase was the only significant adverse event which was not associated with discontinuation of therapy. Conclusion In patients with severe COVID-19 infection, the addition of anakinra to SOC treatment was safe but was not associated with significant improvement according to the WHO clinical progression scale. Further studies are warranted to explore patients' subgroups characteristics that might benefit from administered therapy. Clinical Trial Registration Trial registration at ClinicalTrials.gov, identifier: NCT04643678.
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Affiliation(s)
- Eman Zeyad I. Elmekaty
- Communicable Diseases Center, Hamad Medical Corporation, Doha, Qatar,*Correspondence: Eman Zeyad I. Elmekaty,
| | - Aya Maklad
- College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | | | - Waqar Munir
- Communicable Diseases Center, Hamad Medical Corporation, Doha, Qatar
| | | | - Arun Nair
- Communicable Diseases Center, Hamad Medical Corporation, Doha, Qatar
| | - Rim Alibrahim
- Communicable Diseases Center, Hamad Medical Corporation, Doha, Qatar
| | - Fatima Iqbal
- Communicable Diseases Center, Hamad Medical Corporation, Doha, Qatar
| | - Ahmad Al Bishawi
- Communicable Diseases Center, Hamad Medical Corporation, Doha, Qatar
| | | | - Mohamed Aboukamar
- Communicable Diseases Center, Hamad Medical Corporation, Doha, Qatar
| | - Hamad Abdel Hadi
- Communicable Diseases Center, Hamad Medical Corporation, Doha, Qatar
| | | | - Hussam Al Soub
- Communicable Diseases Center, Hamad Medical Corporation, Doha, Qatar
| | - Muna Al Maslamani
- Communicable Diseases Center, Hamad Medical Corporation, Doha, Qatar
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Tasoudis PT, Arvaniti CK, Adamou AT, Belios I, Stone JH, Horick N, Sagris D, Dalekos GN, Ntaios G. Interleukin-6 inhibitors reduce mortality in coronavirus disease-2019: An individual patient data meta-analysis from randomized controlled trials. Eur J Intern Med 2022; 101:41-48. [PMID: 35422374 PMCID: PMC8986475 DOI: 10.1016/j.ejim.2022.04.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 03/18/2022] [Accepted: 04/05/2022] [Indexed: 12/25/2022]
Abstract
OBJECTIVE To assess the efficacy of IL-6 inhibitors compared to standard of care (SOC) in COVID-19 patients. DATA SOURCES A systematic review of the MEDLINE and Scopus databases (last search: October 8th, 2021) was performed according to the PRISMA statement. STUDY SELECTION Randomized control trials (RCTs) comparing IL-6 inhibitors to SOC in hospitalized COVID-19 patients were deemed eligible. DATA EXTRACTION AND SYNTHESIS Individual patient data were extracted from the Kaplan-Meier curves or were obtained from authors of included studies. Additionally, the reviewers independently abstracted data and assessed study quality of each eligible report. RESULTS Eleven studies were identified, incorporating 7467 patients (IL-6 inhibitors: 4103, SOC: 3364). IL-6 inhibitors were associated with decreased risk for death compared to SOC at the one-stage meta-analysis (Hazard Ratio [HR]: 0.75, 95% Confidence interval [CI]: 0.69-0.82, p<0.0001) and the two-stage meta-analysis (HR: 0.85, 95%CI: 0.77-0.93, p<0.001, I2 = 0.0%). Meta-regression analysis revealed that the difference in OS between the two groups was not influenced by the mean age of patients. At secondary meta-analyses, IL-6 inhibitors were associated with decreased odds for intubation OR:0.74, 95%CI:0.65-0.85, p<0.001, I2=0.0%). IL-6 inhibitors were associated with increased odds for discharge compared to SOC (OR:1.28, 95% CI:1.15-1.42, p<0.001, I2=0.0%). CONCLUSIONS AND RELEVANCE This meta-analysis of individual patient data from randomized trials shows that IL-6 inhibitors significantly reduce the risk of death compared to SOC. IL-6 inhibitors are also associated with better outcomes in terms of intubation and discharge rates compared to SOC.
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Affiliation(s)
- Panagiotis T Tasoudis
- Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Christina K Arvaniti
- Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Anastasia T Adamou
- Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Ioannis Belios
- Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - John H Stone
- Massachusetts General Hospital Rheumatology Unit, Harvard Medical School, 55 Fruit St., Boston, MA 02114, United States
| | - Nora Horick
- Massachusetts General Hospital Rheumatology Unit, Harvard Medical School, 55 Fruit St., Boston, MA 02114, United States
| | - Dimitrios Sagris
- Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - George N Dalekos
- Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - George Ntaios
- Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece.
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9
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Kassianidis G, Siampanos A, Poulakou G, Adamis G, Rapti A, Milionis H, Dalekos GN, Petrakis V, Sympardi S, Metallidis S, Alexiou Z, Gkavogianni T, Giamarellos-Bourboulis EJ, Theoharides TC. Calprotectin and Imbalances between Acute-Phase Mediators Are Associated with Critical Illness in COVID-19. Int J Mol Sci 2022; 23:ijms23094894. [PMID: 35563282 PMCID: PMC9099708 DOI: 10.3390/ijms23094894] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 04/25/2022] [Accepted: 04/26/2022] [Indexed: 12/13/2022] Open
Abstract
The trajectory from moderate and severe COVID-19 into acute respiratory distress syndrome (ARDS) necessitating mechanical ventilation (MV) is a field of active research. We determined serum levels within 24 h of presentation of 20 different sets of mediators (calprotectin, pro- and anti-inflammatory cytokines, interferons) of patients with COVID-19 at different stages of severity (asymptomatic, moderate, severe and ARDS/MV). The primary endpoint was to define associations with critical illness, and the secondary endpoint was to identify the pathways associated with mortality. Results were validated in serial measurements of mediators among participants of the SAVE-MORE trial. Levels of the proinflammatory interleukin (IL)-8, IL-18, matrix metalloproteinase-9, platelet-derived growth factor (PDGF)-B and calprotectin (S100A8/A9) were significantly higher in patients with ARDS and MV. Levels of the anti-inflammatory IL-1ra and IL-33r were also increased; IL-38 was increased only in asymptomatic patients but significantly decreased in the more severe cases. Multivariate ordinal regression showed that pathways of IL-6, IL-33 and calprotectin were associated with significant probability for worse outcome. Calprotectin was serially increased from baseline among patients who progressed to ARDS and MV. Further research is needed to decipher the significance of these findings compared to other acute-phase reactants, such as C-reactive protein (CRP) or ferritin, for the prognosis and development of effective treatments.
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Affiliation(s)
- Georgios Kassianidis
- Intensive Care Unit, Korgialeneion-Benakeion Athens General Hospital, 115 26 Athens, Greece;
| | - Athanasios Siampanos
- 4th Department of Internal Medicine, ATTIKON University General Hospital, Medical School, National and Kapodistrian University of Athens, 1 Rimini Street, 124 62 Athens, Greece; (A.S.); (T.G.)
| | - Garyphalia Poulakou
- 3rd Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece;
| | - George Adamis
- 1st Department of Internal Medicine, G. Gennimatas General Hospital of Athens, 115 27 Athens, Greece;
| | - Aggeliki Rapti
- 2nd Department of Pulmonary Medicine, Sotiria General Hospital of Chest Diseases, 115 27 Athens, Greece;
| | - Haralampos Milionis
- 1st Department of Internal Medicine, Medical School, University of Ioannina, 455 00 Ioannina, Greece;
| | - George N. Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National and European Expertise Center in Autoimmune Liver Diseases, General University Hospital of Larissa, 412 21 Larissa, Greece;
| | - Vasileios Petrakis
- 2nd Department of Internal Medicine, Medical School, Democritus University of Thrace, 681 00 Alexandroupolis, Greece;
| | - Styliani Sympardi
- 1st Department of Internal Medicine, Thriasio General Hospital of Eleusis, 196 00 Magoula, Greece;
| | - Symeon Metallidis
- 1st Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, 546 21 Thessaloniki, Greece;
| | - Zoi Alexiou
- 2nd Department of Internal Medicine, Thriasio General Hospital of Eleusis, 196 00 Magoula, Greece;
| | - Theologia Gkavogianni
- 4th Department of Internal Medicine, ATTIKON University General Hospital, Medical School, National and Kapodistrian University of Athens, 1 Rimini Street, 124 62 Athens, Greece; (A.S.); (T.G.)
| | - Evangelos J. Giamarellos-Bourboulis
- 4th Department of Internal Medicine, ATTIKON University General Hospital, Medical School, National and Kapodistrian University of Athens, 1 Rimini Street, 124 62 Athens, Greece; (A.S.); (T.G.)
- Correspondence: (E.J.G.-B.); (T.C.T.); Tel.: +30-210-58-31-994 (E.J.G.-B.); Fax: +30-210-53-26446 (E.J.G.-B.)
| | - Theoharis C. Theoharides
- Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Immunology, Tufts University School of Medicine, Boston, MA 02111, USA
- School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA
- Department of Internal Medicine, Tufts University School of Medicine and Tufts Medical Center, Boston, MA 02111, USA
- Institute of Neuro-Immune Medicine, Nova Southeastern University, Clearwater, FL 33759, USA
- Correspondence: (E.J.G.-B.); (T.C.T.); Tel.: +30-210-58-31-994 (E.J.G.-B.); Fax: +30-210-53-26446 (E.J.G.-B.)
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10
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Soluble IL-2R Levels at Baseline Predict the Development of Severe Respiratory Failure and Mortality in COVID-19 Patients. Viruses 2022; 14:v14040787. [PMID: 35458517 PMCID: PMC9025750 DOI: 10.3390/v14040787] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 04/02/2022] [Accepted: 04/08/2022] [Indexed: 12/03/2022] Open
Abstract
Risk stratification of coronavirus disease-19 (COVID-19) patients by simple markers is critical to guide treatment. We studied the predictive value of soluble interleukin-2 receptor (sIL-2R) for the early identification of patients at risk of developing severe clinical outcomes. sIL-2R levels were measured in 197 patients (60.9% males; median age 61 years; moderate disease, n = 65; severe, n = 132, intubated and/or died, n = 42). All patients received combined immunotherapies (anakinra ± corticosteroids ± intravenous immunoglobulin ± tocilizumab) according to our local treatment algorithm. The endpoint was the composite event of intubation due to severe respiratory failure (SRF) or mortality. Median (interquartile range) sIL-2R levels were significantly higher in patients with severe disease, compared with those with moderate disease (6 (6.2) vs. 5.2 (3.4) ng/mL, p = 0.017). sIL-2R was the strongest laboratory predictive factor for intubation/death (hazard ratio 1.749, 95%CI 1.041–2.939, p = 0.035) after adjustment for other known risk factors. Youden’s index revealed optimal sIL-2R cut-off for predicting intubation/death at 9 ng/mL (sensitivity: 67%; specificity: 86%; positive and negative predictive value: 57% and 91%, respectively). Delta sIL-2R between the day of event or discharge minus admission date was higher in patients that intubated/died than in those who did not experience an event (2.91 (10.42) vs. 0.44 (2.88) ng/mL; p = 0.08)). sIL-2R on admission and its dynamic changes during follow-up may reflect disease severity and predict the development of SRF and mortality.
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11
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Immunomodulation and Reduction of Thromboembolic Risk in Hospitalized COVID-19 Patients: Systematic Review and Meta-Analysis of Randomized Trials. J Clin Med 2021; 10:jcm10225366. [PMID: 34830648 PMCID: PMC8617689 DOI: 10.3390/jcm10225366] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 11/12/2021] [Indexed: 12/19/2022] Open
Abstract
Background: We aimed to investigate the potential beneficial effect of immunomodulation therapy on the thromboembolic risk in hospitalized COVID-19 patients. Methods: We searched PubMed and Scopus for randomized trials reporting the outcomes of venous thromboembolism (VTE), ischemic stroke or systemic embolism, myocardial infarction, any thromboembolic event, and all-cause mortality in COVID-19 patients treated with immunomodulatory agents. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using the Mantel–Haenszel random effects method. Results: Among 8499 patients hospitalized with COVID-19, 4638 were treated with an immunomodulatory agent, 3861—with usual care only. Among the patients prescribed immunomodulatory agents, there were 1.77 VTEs per 100 patient-months compared to 2.30 among those treated with usual care (OR: 0.84, 95% CI: 0.61–1.16; I2: 0%). Among the patients who received an interleukin 6 (IL-6) antagonist, VTEs were reported in 12 among the 1075 patients compared to 20 among the 848 receiving the usual care (OR: 0.52, 95% CI: 0.22–1.20; I2: 6%). Immunomodulators as an add-on to usual care did not reduce the risk of stroke or systemic embolism (OR: 1.10, 95% CI: 0.50–2.40; I2: 0%) or of myocardial infarction (OR: 1.06, 95% CI: 0.47–2.39; I2: 0%) and there was a nonsignificant reduction in any thromboembolic event (OR: 0.86, 95% CI: 0.65–1.14; I2: 0%). Conclusions: We did not identify a statistically significant effect of immunomodulation on prevention of thromboembolic events in COVID-19. However, given the large effect estimate for VTE prevention, especially in the patients treated with IL-6 antagonists, we cannot exclude a potential effect of immunomodulation.
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12
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Speletas M, Dadouli K, Syrakouli A, Gatselis N, Germanidis G, Mouchtouri VA, Koulas I, Samakidou A, Nikolaidou A, Stefos A, Mimtsoudis I, Hatzianastasiou S, Koureas M, Anagnostopoulos L, Tseroni M, Tsinti G, Metallidis S, Dalekos G, Hadjichristodoulou C. MBL deficiency-causing B allele (rs1800450) as a risk factor for severe COVID-19. Immunobiology 2021; 226:152136. [PMID: 34628288 PMCID: PMC8462051 DOI: 10.1016/j.imbio.2021.152136] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 08/29/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022]
Abstract
The COVID-19 pandemic represents one of the greatest challenges in modern medicine. The disease is characterized by a variable clinical phenotype, ranging from asymptomatic carriage to severe and/or critical disease, which bears poor prognosis and outcome because of the development of severe acute respiratory distress syndrome (SARS) requiring ICU hospitalization, multi-organ failure and death. Therefore, the determination of risk factors predisposing to disease phenotype is of outmost importance. The aim of our study was to evaluate which predisposing factors, including MBL2 genotyping, affected clinical phenotype in 264 COVID-19 patients. We demonstrated that older age along with underlying comorbidities, primarily obesity, chronic inflammatory disorders and diabetes mellitus, represent the most important risk factors related to hospitalization, the development of pneumonia and SARS. Moreover, we found that the presence of the MBL deficiency-causing B allele (rs1800450) was significantly associated with almost 2-fold increased risk for developing pneumonia and requiring hospitalization, suggesting its usage as a molecular predictor of severe disease in SARS-CoV-2 infected individuals.
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Affiliation(s)
- Matthaios Speletas
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, Larissa, Greece.
| | - Katerina Dadouli
- Laboratory of Hygiene and Epidemiology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Argyro Syrakouli
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Nikolaos Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Georgios Germanidis
- First Internal Medicine Department, Infectious Diseases Division, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, Greece
| | - Varvara A Mouchtouri
- Laboratory of Hygiene and Epidemiology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Ioannis Koulas
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Anna Samakidou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Anastasia Nikolaidou
- First Internal Medicine Department, Infectious Diseases Division, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, Greece
| | - Aggelos Stefos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Iordanis Mimtsoudis
- First Internal Medicine Department, Infectious Diseases Division, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, Greece
| | | | - Michalis Koureas
- Laboratory of Hygiene and Epidemiology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Lemonia Anagnostopoulos
- Laboratory of Hygiene and Epidemiology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | | | - Gerasimina Tsinti
- Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Symeon Metallidis
- First Internal Medicine Department, Infectious Diseases Division, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, Greece
| | - George Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
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13
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Gerotziafas GT, Catalano M, Theodorou Y, Dreden PV, Marechal V, Spyropoulos AC, Carter C, Jabeen N, Harenberg J, Elalamy I, Falanga A, Fareed J, Agathaggelou P, Antic D, Antignani PL, Bosch MM, Brenner B, Chekhonin V, Colgan MP, Dimopoulos MA, Douketis J, Elnazar EA, Farkas K, Fazeli B, Fowkes G, Gu Y, Gligorov J, Ligocki MA, Indran T, Kannan M, Kantarcioglu B, Kasse AA, Konstantinidis K, Leivano F, Lewis J, Makatsariya A, Mbaye PM, Mahé I, Panovska-Stavridis I, Olinic DM, Papageorgiou C, Pecsvarady Z, Pillon S, Ramacciotti E, Abdel-Razeq H, Sabbah M, Sassi M, Schernthaner G, Siddiqui F, Shiomura J, Slama-Schwok A, Wautrecht JC, Tafur A, Taher A, Klein-Wegel P, Zhai Z, Zoubida TM. The COVID-19 Pandemic and the Need for an Integrated and Equitable Approach: An International Expert Consensus Paper. Thromb Haemost 2021; 121:992-1007. [PMID: 34169495 PMCID: PMC8322591 DOI: 10.1055/a-1535-8807] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND One year after the declaration of the coronavirus disease 2019 (COVID-19) pandemic by the World Health Organization (WHO) and despite the implementation of mandatory physical barriers and social distancing, humanity remains challenged by a long-lasting and devastating public health crisis. MANAGEMENT Non-pharmacological interventions (NPIs) are efficient mitigation strategies. The success of these NPIs is dependent on the approval and commitment of the population. The launch of a mass vaccination program in many countries in late December 2020 with mRNA vaccines, adenovirus-based vaccines, and inactivated virus vaccines has generated hope for the end of the pandemic. CURRENT ISSUES The continuous appearance of new pathogenic viral strains and the ability of vaccines to prevent infection and transmission raise important concerns as we try to achieve community immunity against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and its variants. The need of a second and even third generation of vaccines has already been acknowledged by the WHO and governments. PERSPECTIVES There is a critical and urgent need for a balanced and integrated strategy for the management of the COVID-19 outbreaks organized on three axes: (1) Prevention of the SARS-CoV-2 infection, (2) Detection and early diagnosis of patients at risk of disease worsening, and (3) Anticipation of medical care (PDA). CONCLUSION The "PDA strategy" integrated into state policy for the support and expansion of health systems and introduction of digital organizations (i.e., telemedicine, e-Health, artificial intelligence, and machine-learning technology) is of major importance for the preservation of citizens' health and life world-wide.
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Affiliation(s)
- Grigoris T Gerotziafas
- Sorbonne Université, INSERM, UMR_S 938, Research Group Cancer, Biology and Therapeutics, Centre de recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie, Paris, France.,Thrombosis Center, Tenon-Saint Antoine, Hôpitaux Universitaires de l'Est Parisien, Assistance Publique Hôpitaux de Paris (APHP), France
| | - Mariella Catalano
- Research Center on Vascular Disease & Angiology Unit, Department of Biomedical Science, L Sacco Hospital, University of Milan, Milan, Italy
| | - Yiannis Theodorou
- Centre d'Immunologie et des Maladies Infectieuses UPMC UMRS CR7, Inserm U1135, CNRS ERL 8255, Paris, France
| | - Patrick Van Dreden
- Sorbonne Université, INSERM, UMR_S 938, Research Group Cancer, Biology and Therapeutics, Centre de recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie, Paris, France
| | - Vincent Marechal
- Sorbonne Université, INSERM, UMR_S 938, Research Group Cancer, Biology and Therapeutics, Centre de recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie, Paris, France
| | - Alex C Spyropoulos
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States.,Department of Obstetrics and Gynecology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia
| | - Charles Carter
- Department of Clinical Research, College of Pharmacy & Health Sciences, Campbell University, Buies Creek, North Carolina, United States
| | - Nusrat Jabeen
- Department of Microbiology, University of Karachi, Karachi, Pakistan
| | - Job Harenberg
- Department for Physical Chemistry, Heidelberg University, Heidelberg, Germany.,DOASENSE GmbH, Heidelberg, Germany
| | - Ismail Elalamy
- Sorbonne Université, INSERM, UMR_S 938, Research Group Cancer, Biology and Therapeutics, Centre de recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie, Paris, France.,Thrombosis Center, Tenon-Saint Antoine, Hôpitaux Universitaires de l'Est Parisien, Assistance Publique Hôpitaux de Paris (APHP), France.,Department of Obstetrics and Gynecology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia
| | - Anna Falanga
- Immunohematology and Transfusion Medicine Department, ASST Papa Giovanni XXIII Hospital, Bergamo, Italy.,School of Medicine, University of Milan Bicocca, Monza, Italy
| | - Jawed Fareed
- Department of Pathology and Laboratory Medicine, Cardiovascular Research Institute, Health Sciences Division, Loyola University Chicago, Maywood, Illinois, United States.,Department of Pharmacology and Neuroscience, Cardiovascular Research Institute, Health Sciences Division, Loyola University Chicago, Maywood, Illinois, United States
| | - Petros Agathaggelou
- Cyprus Department of Interventional Cardiology, American Heart Institute of Cyprus, Nicosia, Cyprus
| | - Darko Antic
- Clinic of Hematology, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | | | - Manuel Monreal Bosch
- Department of Internal Medicine, Hospital Universitario Germans Trias i Pujol de Badalona, Universidad Católica de Murcia, Murcia, Spain
| | - Benjamin Brenner
- Thrombosis and Hemostasis Unit, Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.,Bruce Rappaport Faculty of Medicine, The Technion-Israel Institute of Technology, Haifa, Israel
| | - Vladimir Chekhonin
- Department of Fundamental and Applied Neurobiology, V. P. Serbsky Federal Medical Research Centre of Psychiatry and Narcology, Ministry of Health of the Russian Federation, Moscow, Russia
| | - Mary-Paula Colgan
- Department of Vascular Surgery, St. James's Hospital/Trinity College Dublin, Dublin, Ireland
| | | | - Jim Douketis
- Division of Hematology and Thromboembolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.,Division of Thoracic Surgery, St. Joseph's Healthcare Hamilton, Firestone Institute for Respiratory Health, Hamilton, Ontario, Canada
| | | | - Katalin Farkas
- Department of Angiology, St. Imre University Teaching Hospital, Budapest, Hungary
| | - Bahare Fazeli
- Immunology Department, Avicenna (Bu-Ali) Research Institute, Mashhad University of Medical Sciences, Iran
| | - Gerry Fowkes
- Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom
| | - Yongquan Gu
- Department of Vascular Surgery, Xuan Wu Hospital, Capital Medical University and Institute of Vascular Surgery, Capital Medical University, Beijing, China
| | - Joseph Gligorov
- Sorbonne Université, INSERM, UMR_S 938, Research Group Cancer, Biology and Therapeutics, Centre de recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie, Paris, France.,Medical Oncology Department, CLIP(2) Galilée, Hôpital Tenon, Hôpitaux Universitaires de l'Est Parisien, Assistance Publique Hôpitaux de Paris (APHP), France
| | - Mark A Ligocki
- Department of Pathology and Laboratory Medicine, Cardiovascular Research Institute, Health Sciences Division, Loyola University Chicago, Maywood, Illinois, United States.,Department of Pharmacology and Neuroscience, Cardiovascular Research Institute, Health Sciences Division, Loyola University Chicago, Maywood, Illinois, United States
| | - Tishya Indran
- Australia Department of Haematology, Monash Health, Clayton, Victoria, Australia
| | - Meganathan Kannan
- Division of Blood and Vascular Biology, Department of Life Sciences, School of Life Sciences, Central University of Tamil Nadu, Thiruvarur, India
| | - Bulent Kantarcioglu
- Department of Hematology, Okmeydani Training and Research Hospital, Istanbul, Turkey
| | - Abdoul Aziz Kasse
- Institut du Cancer UCAD, Centre International de Cancérologie de Dakar, Dakar, Senegal
| | - Kostantinos Konstantinidis
- 5th Surgical Department, Group of Vascular Surgery, Hippokrateio General University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Fabio Leivano
- Department of Pharmacology and Neuroscience, Cardiovascular Research Institute, Health Sciences Division, Loyola University Chicago, Maywood, Illinois, United States
| | - Joseph Lewis
- Department of Surgery, Stony Brook Southampton Hospital, Southampton, New York, United States
| | - Alexander Makatsariya
- Department of Obstetrics and Gynecology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia
| | | | - Isabelle Mahé
- Innovative Therapies in Haemostasis, Hôpital Louis Mourier, APHP, Colombes, Université de Paris, INSERM, F-75006 Paris, France
| | | | - Dan-Mircea Olinic
- Medical Clinic No. 1, University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Chryssa Papageorgiou
- Service Anesthésie, Réanimation et Médecine Périopératoire, Hôpital Tenon, Hôpitaux Universitaires de l'Est Parisien, Assistance Publique Hôpitaux de Paris, Faculté de médecine, Sorbonne Université, Paris, France
| | - Zsolt Pecsvarady
- Department of Vascular Medicine, Flor Ferenc Teaching Hospital, Kistarcsa, Hungary
| | - Sergio Pillon
- UOSD Angiology, San Camillo-Forlanini Hospital, National Health Institute ISS, AO San Camillo Forlanini, Rome, Italy
| | - Eduardo Ramacciotti
- Hemostasis & Thrombosis Research Laboratories, Loyola University Medical Center, Maywood, Illinois, United States.,Brazilian Clinical Research Institute, São Paulo, Brazil; Science Valley Research Institute, São Paulo, Brazil
| | - Hikmat Abdel-Razeq
- Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan
| | - Michele Sabbah
- Sorbonne Université, INSERM, UMR_S 938, Research Group Cancer, Biology and Therapeutics, Centre de recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie, Paris, France
| | - Mouna Sassi
- Laboratoire de Biologie, Centre de Maternité et de Néonatologie, Hôpital Fattouma Bourguiba, Monastir, Tunisia
| | - Gerit Schernthaner
- Division of Angiology, Department of Internal Medicine 2, Medical University of Vienna, Vienna, Austria
| | - Fakiha Siddiqui
- Cardiovascular Research Institute, Health Sciences Divisions, Loyola University Chicago, Maywood, Illinois, United States
| | | | - Anny Slama-Schwok
- Sorbonne Université, INSERM, UMR_S 938, Research Group Cancer, Biology and Therapeutics, Centre de recherche Saint-Antoine (CRSA), Institut Universitaire de Cancérologie, Paris, France
| | - Jean Claude Wautrecht
- Service de Pathologie Vasculaire, Hôpital ERASME, Université Libre de Bruxelles, Brussels, Belgium
| | - Alfonso Tafur
- Vascular Medicine, Northshore Cardiovascular Institute, Skokie, Illinois, United States
| | - Ali Taher
- Division of Hematology-Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Peter Klein-Wegel
- Klinik für Angiologie, Zentrum für Innere Medizin II, Ernst von Bergmann Klinikum, Potsdam, Germany
| | - Zenguo Zhai
- Center of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Peking University Health Science Center, Capital Medical University, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Tazi Mezalek Zoubida
- Clinical Hematology - Internal Medicine, Ibn Sina hospital, Mohammed V University, -Rabat, Morocco
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