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1.
Ann Med ; 53(1): 257-266, 2021 12.
Article in English | MEDLINE | ID: covidwho-1574445

ABSTRACT

OBJECTIVES: To appraise effective predictors for COVID-19 mortality in a retrospective cohort study. METHODS: A total of 1270 COVID-19 patients, including 984 admitted in Sino French New City Branch (training and internal validation sets randomly split at 7:3 ratio) and 286 admitted in Optical Valley Branch (external validation set) of Wuhan Tongji hospital, were included in this study. Forty-eight clinical and laboratory features were screened with LASSO method. Further multi-tree extreme gradient boosting (XGBoost) machine learning-based model was used to rank importance of features selected from LASSO and subsequently constructed death risk prediction model with simple-tree XGBoost model. Performances of models were evaluated by AUC, prediction accuracy, precision, and F1 scores. RESULTS: Six features, including disease severity, age, levels of high-sensitivity C-reactive protein (hs-CRP), lactate dehydrogenase (LDH), ferritin, and interleukin-10 (IL-10), were selected as predictors for COVID-19 mortality. Simple-tree XGBoost model conducted by these features can predict death risk accurately with >90% precision and >85% sensitivity, as well as F1 scores >0.90 in training and validation sets. CONCLUSION: We proposed the disease severity, age, serum levels of hs-CRP, LDH, ferritin, and IL-10 as significant predictors for death risk of COVID-19, which may help to identify the high-risk COVID-19 cases. KEY MESSAGES A machine learning method is used to build death risk model for COVID-19 patients. Disease severity, age, hs-CRP, LDH, ferritin, and IL-10 are death risk factors. These findings may help to identify the high-risk COVID-19 cases.


Subject(s)
COVID-19/mortality , Clinical Decision Rules , Hospitalization , Machine Learning , Adult , Aged , Aged, 80 and over , C-Reactive Protein/metabolism , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/physiopathology , Cardiovascular Diseases/epidemiology , China/epidemiology , Cohort Studies , Comorbidity , Diabetes Mellitus/epidemiology , Female , Ferritins/metabolism , Humans , Hypertension/epidemiology , Interleukin-10/metabolism , L-Lactate Dehydrogenase/metabolism , Male , Middle Aged , Prognosis , Reproducibility of Results , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index
2.
Sci Rep ; 11(1): 19618, 2021 10 04.
Article in English | MEDLINE | ID: covidwho-1450293

ABSTRACT

The pathophysiology and the factors determining disease severity in COVID-19 are not yet clear, with current data indicating a possible role of altered iron metabolism. Previous studies of iron parameters in COVID-19 are cross-sectional and have not studied catalytic iron, the biologically most active form of iron. The study was done to determine the role of catalytic iron in the adverse outcomes in COVID-19. We enrolled adult patients hospitalized with a clinical diagnosis of COVID-19 and measured serum iron, transferrin saturation, ferritin, hepcidin and serum catalytic iron daily. Primary outcome was a composite of in-hospital mortality, need for mechanical ventilation, and kidney replacement therapy. Associations between longitudinal iron parameter measurements and time-to-event outcomes were examined using a joint model. We enrolled 120 patients (70 males) with median age 50 years. The primary composite outcome was observed in 25 (20.8%) patients-mechanical ventilation was needed in 21 (17.5%) patients and in-hospital mortality occurred in 21 (17.5%) patients. Baseline levels of ferritin and hepcidin were significantly associated with the primary composite outcome. The joint model analysis showed that ferritin levels were significantly associated with primary composite outcome [HR (95% CI) = 2.63 (1.62, 4.24) after adjusting for age and gender]. Both ferritin and serum catalytic iron levels were positively associated with in-hospital mortality [HR (95% CI) = 3.22 (2.05, 5.07) and 1.73 (1.21, 2.47), respectively], after adjusting for age and gender. The study shows an association of ferritin and catalytic iron with adverse outcomes in COVID-19. This suggests new pathophysiologic pathways in this disease, also raising the possibility of considering iron chelation therapy.


Subject(s)
COVID-19/pathology , Iron/blood , Adult , Aged , COVID-19/mortality , COVID-19/virology , Cross-Sectional Studies , Female , Ferritins/blood , Ferritins/metabolism , Hepcidins/blood , Hepcidins/metabolism , Hospital Mortality , Humans , Iron/chemistry , Male , Middle Aged , Proportional Hazards Models , Respiration, Artificial , SARS-CoV-2/isolation & purification , Severity of Illness Index , Transferrin/chemistry , Transferrin/metabolism
3.
ACS Appl Mater Interfaces ; 13(36): 43696-43707, 2021 Sep 15.
Article in English | MEDLINE | ID: covidwho-1392772

ABSTRACT

Graphene is a two-dimensional semiconducting material whose application for diagnostics has been a real game-changer in terms of sensitivity and response time, variables of paramount importance to stop the COVID-19 spreading. Nevertheless, strategies for the modification of docking recognition and antifouling elements to obtain covalent-like stability without the disruption of the graphene band structure are still needed. In this work, we conducted surface engineering of graphene through heterofunctional supramolecular-covalent scaffolds based on vinylsulfonated-polyamines (PA-VS). In these scaffolds, one side binds graphene through multivalent π-π interactions with pyrene groups, and the other side presents vinylsulfonated pending groups that can be used for covalent binding. The construction of PA-VS scaffolds was demonstrated by spectroscopic ellipsometry, Raman spectroscopy, and contact angle measurements. The covalent binding of -SH, -NH2, or -OH groups was confirmed, and it evidenced great chemical versatility. After field-effect studies, we found that the PA-VS-based scaffolds do not disrupt the semiconducting properties of graphene. Moreover, the scaffolds were covalently modified with poly(ethylene glycol) (PEG), which improved the resistance to nonspecific proteins by almost 7-fold compared to the widely used PEG-monopyrene approach. The attachment of recognition elements to PA-VS was optimized for concanavalin A (ConA), a model lectin with a high affinity to glycans. Lastly, the platform was implemented for the rapid, sensitive, and regenerable recognition of SARS-CoV-2 spike protein and human ferritin in lab-made samples. Those two are the target molecules of major importance for the rapid detection and monitoring of COVID-19-positive patients. For that purpose, monoclonal antibodies (mAbs) were bound to the scaffolds, resulting in a surface coverage of 436 ± 30 ng/cm2. KD affinity constants of 48.4 and 2.54 nM were obtained by surface plasmon resonance (SPR) spectroscopy for SARS-CoV-2 spike protein and human ferritin binding on these supramolecular scaffolds, respectively.


Subject(s)
Biomarkers/analysis , COVID-19/diagnosis , Graphite/chemistry , Immunoassay/methods , Spike Glycoprotein, Coronavirus/analysis , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Ethylenes/chemistry , Ferritins/immunology , Ferritins/metabolism , Humans , Point-of-Care Systems , Polyamines/chemistry , Polyethylene Glycols/chemistry , Pyrenes/chemistry , Quantum Theory , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Semiconductors , Spike Glycoprotein, Coronavirus/immunology , Sulfonic Acids/chemistry , Surface Plasmon Resonance
4.
Stroke ; 52(11): e706-e709, 2021 11.
Article in English | MEDLINE | ID: covidwho-1371922
7.
Sci Rep ; 11(1): 9927, 2021 05 11.
Article in English | MEDLINE | ID: covidwho-1225516

ABSTRACT

Convalescent plasma (CP) therapy in COVID-19 disease may improve clinical outcome in severe disease. This pilot study was undertaken to inform feasibility and safety of further definitive studies. This was a prospective, interventional and randomized open label pilot trial in patients with severe COVID-19. Twenty COVID-19 patients received two 200 ml transfusions of convalescent patient CP over 24-h compared with 20 who received standard of care. The primary outcome was the requirement for ventilation (non-invasive or mechanical ventilation). The secondary outcomes were biochemical parameters and mortality at 28 days. The CP group were a higher risk group with higher ferritin levels (p < 0.05) though respiratory indices did not differ. The primary outcome measure was required in 6 controls and 4 patients on CP (risk ratio 0.67, 95% CI 0.22-2.0, p = 0.72); mean time on ventilation (NIV or MV) did not differ. There were no differences in secondary measures at the end of the study. Two patients died in the control and one patient in the CP arm. There were no significant differences in the primary or secondary outcome measures between CP and standard therapy, although a larger definitive study is needed for confirmation. However, the study did show that CP therapy appears to be safe in hospitalized COVID-19 patients with hypoxia.Clinical trials registration NCT04356534: 22/04/2020.


Subject(s)
COVID-19/therapy , Adult , Aged , COVID-19/mortality , COVID-19/pathology , COVID-19/virology , Female , Ferritins/metabolism , Humans , Immunization, Passive , Male , Middle Aged , Pilot Projects , Prospective Studies , Respiration, Artificial/statistics & numerical data , SARS-CoV-2/isolation & purification , Severity of Illness Index , Survival Rate , Treatment Outcome
8.
Eur J Haematol ; 107(2): 190-201, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1223481

ABSTRACT

BACKGROUND: A high prevalence of pulmonary embolism (PE) has been described during COVID-19. Our aim was to identify predictive factors of PE in non-ICU hospitalized COVID-19 patients. METHODS: Data and outcomes were collected upon admission during a French multicenter retrospective study, including patients hospitalized for COVID-19, with a CT pulmonary angiography (CTPA) performed in the emergency department for suspected PE. Predictive factors significantly associated with PE were identified through a multivariate regression model. RESULTS: A total of 88 patients (median [IQR] age of 68 years [60-78]) were analyzed. Based on CTPA, 47 (53.4%) patients were diagnosed with PE, and 41 were not. D-dimer ≥3000 ng/mL (OR 8.2 [95% CI] 1.3-74.2, sensitivity (Se) 0.84, specificity (Sp) 0.78, P = .03), white blood count (WBC) ≥12.0 G/L (29.5 [2.3-1221.2], Se 0.47, Sp 0.92, P = .02), and ferritin ≥480 µg/L (17.0 [1.7-553.3], Se 0.96, Sp 0.44, P = .03) were independently associated with the PE diagnosis. The presence of the double criterion D-dimer ≥3000 ng/mL and WBC ≥12.0 G/L was greatly associated with PE (OR 21.4 [4.0-397.9], P = .004). CONCLUSION: The white blood count, the D-dimer and ferritin levels could be used as an indication for CTPA to confirm PE on admission in non-ICU COVID-19 patients.


Subject(s)
COVID-19/complications , Ferritins/metabolism , Fibrin Fibrinogen Degradation Products/metabolism , Leukocyte Count , Pulmonary Embolism/blood , Pulmonary Embolism/complications , COVID-19/virology , France , Humans , Patient Admission , Retrospective Studies , SARS-CoV-2/isolation & purification
9.
Bioconjug Chem ; 32(5): 1034-1046, 2021 05 19.
Article in English | MEDLINE | ID: covidwho-1217668

ABSTRACT

SARS-CoV-2 caused the COVID-19 pandemic that lasted for more than a year. Globally, there is an urgent need to use safe and effective vaccines for immunization to achieve comprehensive protection against SARS-CoV-2 infection. Focusing on developing a rapid vaccine platform with significant immunogenicity as well as broad and high protection efficiency, we designed a SARS-CoV-2 spike protein receptor-binding domain (RBD) displayed on self-assembled ferritin nanoparticles. In a 293i cells eukaryotic expression system, this candidate vaccine was prepared and purified. After rhesus monkeys are immunized with 20 µg of RBD-ferritin nanoparticles three times, the vaccine can elicit specific humoral immunity and T cell immune response, and the neutralizing antibodies can cross-neutralize four SARS-CoV-2 strains from different sources. In the challenge protection test, after nasal infection with 2 × 105 CCID50 SARS-CoV-2 virus, compared with unimmunized control animals, virus replication in the vaccine-immunized rhesus monkeys was significantly inhibited, and respiratory pathology observations also showed only slight pathological damage. These analyses will benefit the immunization program of the RBD-ferritin nanoparticle vaccine in the clinical trial design and the platform construction to present a specific antigen domain in the self-assembling nanoparticle in a short time to harvest stable, safe, and effective vaccine candidates for new SARS-CoV-2 isolates.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Nanoparticles/chemistry , Spike Glycoprotein, Coronavirus/metabolism , T-Lymphocytes/immunology , Animals , Antibodies, Neutralizing/immunology , Binding Sites , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Ferritins/chemistry , Ferritins/metabolism , Immunity, Humoral , Macaca mulatta , Male , Nanoparticles/metabolism , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/metabolism , Ultracentrifugation
10.
Turk J Med Sci ; 51(2): 421-427, 2021 04 30.
Article in English | MEDLINE | ID: covidwho-1211944

ABSTRACT

Background/aim: The COVID-19 infection, which started in Wuhan City, China, in December 2019, turned into a pandemic in a very short time, affecting mainly the elderly and those with serious chronic illnesses. COVID-19 infections have been observed to have a high mortality rate, especially in patients undergoing maintenance hemodialysis. Materials and methods: Forty-two patients over 18 years of age who underwent a maintenance hemodialysis program at our unit, who tested positive for COVID-19 by PCR from nasopharyngeal swabs, and/or who were observed to have disease-related signs in their CTs were included in the study. Results: In this study, 23 of 42 patients receiving hemodialysis support in our clinic were included. The median age was 67 years old (min: 35; max: 91 years), and all of our patients had primary hypertension and other comorbidities. Their clinical evaluation showed that dry cough (47.8%) and shortness of breath (47.8%) were the most common symptoms. Fever was less pronounced (30.4%). The median time from the onset of symptoms to hospitalization was 1 day (min: 0; max:), and the time from hospitalization to death was 18 days (min: 1; max: 22). Transfer from the inpatient ward to the ICU took a median of 7 days (min: 1; max: 13). Among the 23 patients, 3 died during follow-up, and 20 were discharged with full recovery. Baseline ferritin, procalcitonin levels, and CRP/albumin rates were higher, and neutrophil/lymphocyte levels were lower in patients who eventually died. In these patients, despite being nonsignificant, there were more diabetic patients, and the D-dimer levels were higher than 1000 ugFEU/L. Conclusion: The COVID-19 infection is associated with increased mortality in chronic kidney diseases patients. Despite being nonsignificant, there was a trend towards increased mortality in patient with diabetes, D-dimer levels >1000 ugFEU/L, higher ferritin and prokalsitonin levels, an increased CRP/albumin ratio, and a lower neutrophil/lymphocyte ratio.


Subject(s)
COVID-19/physiopathology , Kidney Failure, Chronic/therapy , Adult , Aged , Aged, 80 and over , C-Reactive Protein/metabolism , COVID-19/complications , COVID-19/metabolism , COVID-19/mortality , Cough/physiopathology , Cross-Sectional Studies , Dyspnea/physiopathology , Female , Ferritins/metabolism , Fever/physiopathology , Hospital Mortality , Humans , Kidney Failure, Chronic/complications , Length of Stay , Leukocyte Count , Lymphocyte Count , Male , Middle Aged , Neutrophils , Procalcitonin/metabolism , Prognosis , Renal Dialysis , SARS-CoV-2 , Serum Albumin/metabolism , Time Factors
11.
Turk J Med Sci ; 51(2): 440-447, 2021 04 30.
Article in English | MEDLINE | ID: covidwho-1211943

ABSTRACT

Background/aim: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Turkey on March 10, 2020 and the number of the patients are increasing day by day. Coronavirus disease 2019 (Covid-19) has high mortality rates in intensive care units (ICUs). We aimed to describe the demographic characteristics, comorbidities, treatment protocols, and clinical outcomes among the critically ill patients admitted to the ICU of our hospital. Materials and methods: This cohort study included 103 consecutive patients who had laboratory confirmed Covid-19 and admitted to ICU of Sakarya University Training and Research Hospital between March 19 and April 13, 2020. The final date of the follow-up was April 18. Results: The mean age of the patients was 69.6 ± 14.1 years. Most of the patients had increased CRP (99%), serum ferritin (73.8%), d-dimer (82.5%), and hs-troponin levels (38.8%). 34 patients (33%) had lymphocytopenia, 24 patients (23.3%) had thrombocytopenia. 63 patients (61.2%) developed acute respiratory distress syndrome (ARDS), 31 patients (30.1%) had acute kidney injury, and 52 patients (50.5%) had multiple organ dysfunction syndrome (MODS) during follow-up. Sixty-two patients (60.2%) received mechanical ventilation. As of April 18, of the 103 patients, 52 (50.5%) had died, 30 (29.1%) had been discharged from the ICU, 21 (20.4%) were still in the ICU. Conclusions: Covid-19 has high mortality rates in ICU. Patients with elevated procalcitonin, hs-troponin, d-dimer, and CRP levels and lower platelet count at admission have higher mortality.


Subject(s)
Acute Kidney Injury/physiopathology , COVID-19/physiopathology , Multiple Organ Failure/physiopathology , Respiratory Distress Syndrome/physiopathology , Respiratory Insufficiency/physiopathology , Age Factors , Aged , Aged, 80 and over , Antiviral Agents/therapeutic use , C-Reactive Protein/metabolism , COVID-19/metabolism , COVID-19/mortality , COVID-19/therapy , Cohort Studies , Continuous Renal Replacement Therapy , Critical Illness , Female , Ferritins/metabolism , Fibrin Fibrinogen Degradation Products/metabolism , Glucocorticoids/therapeutic use , Hospital Mortality , Humans , Intensive Care Units , Length of Stay , Lymphopenia/blood , Male , Middle Aged , Oxygen Inhalation Therapy , Platelet Count , Procalcitonin/metabolism , Prognosis , Respiration, Artificial , Respiratory Insufficiency/therapy , SARS-CoV-2 , Severity of Illness Index , Thrombocytopenia/blood , Troponin/metabolism , Turkey
12.
J Med Virol ; 93(3): 1832-1836, 2021 03.
Article in English | MEDLINE | ID: covidwho-1196521

ABSTRACT

Coronavirus disease 2019 (COVID-19) has caused a significant impact on all aspects of life, with the number of death cases still increasing. Therefore, identification of potential treatment for reducing the severity of the disease is important. Currently, the data regarding the effectiveness of tocilizumab as treatment agents for COVID-19 infection is still conflicting. This study aims to give clear evidence regarding the potential benefit of tocilizumab in reducing the biomarkers of COVID-19 infection. We systematically searched the PubMed Central database using specific keywords related to our aims until July 24th, 2020. All articles published on COVID-19 and tocilizumab were retrieved. A total of 9 studies with a total of 577 patients were included in our analysis. Our meta-analysis showed that tocilizumab treatment is associated with reduction of C-reactive protein (mean difference [MD]: -106.69 mg/L [95% confidence interval [CI]: -146.90, -66.49 mg/L], p < .00001; I2 = 98%, random-effect modeling), d-dimer (MD: -3.06 mg/L [95% CI: -5.81, -0.31 mg/L], p = .03; I2 = 98%, random-effect modeling), Ferritin (MD: -532.80 ng/ml [95% CI: -810.93, -254.67 ng/ml], p = .0002; I2 = 25%, random-effect modeling), procalcitonin (MD: -0.67 ng/ml [95% CI: -1.13, -0.22 ng/ml], p = .004; I2 = 92%, random-effect modeling], and increment in the levels of lymphocyte count (MD: 0.36 × 103 /µl [95% CI: 0.18, 0.54 × 103 /µl], p < .0001; I2 = 88%, random-effect modeling). Administration of tocilizumab is effective in reducing the biomarkers of the COVID-19 infection.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Biomarkers/metabolism , COVID-19/drug therapy , COVID-19/metabolism , Aged , C-Reactive Protein/metabolism , Ferritins/metabolism , Humans , Middle Aged , Procalcitonin/metabolism , SARS-CoV-2/drug effects , Severity of Illness Index
13.
Metallomics ; 13(5)2021 05 12.
Article in English | MEDLINE | ID: covidwho-1195731

ABSTRACT

Iron is an essential element required by cells and has been described as a key player in ferroptosis. Ferritin operates as a fundamental iron storage protein in cells forming multimeric assemblies with crystalline iron cores. We discuss the latest findings on ferritin structure and activity and its link to cell metabolism and ferroptosis. The chemistry of iron, including its oxidation states, is important for its biological functions, its reactivity, and the biology of ferritin. Ferritin can be localized in different cellular compartments and secreted by cells with a variety of functions depending on its spatial context. Here, we discuss how cellular ferritin localization is tightly linked to its function in a tissue-specific manner, and how impairment of iron homeostasis is implicated in diseases, including cancer and coronavirus disease 2019. Ferritin is a potential biomarker and we discuss latest research where it has been employed for imaging purposes and drug delivery.


Subject(s)
COVID-19/metabolism , Ferritins/chemistry , Ferritins/metabolism , SARS-CoV-2 , Biomarkers/chemistry , Biomarkers/metabolism , Biotechnology , Ceruloplasmin/metabolism , Drug Delivery Systems , Ferritins/genetics , Ferroptosis/physiology , Glycosylation , Homeostasis , Humans , Inflammation/metabolism , Iron/metabolism , Nanotechnology , Neoplasms/diagnosis , Neoplasms/metabolism , Prognosis , Tissue Distribution
14.
Eur J Gastroenterol Hepatol ; 33(5): 695-700, 2021 05 01.
Article in English | MEDLINE | ID: covidwho-1159966

ABSTRACT

BACKGROUND: The data on clinical course and outcome of acute pancreatitis among patients with coronavirus disease 2019 (COVID-19) are sparse. In this study, we analyzed the clinical profiles of patients with COVID 19 and acute pancreatitis. METHODS: This retrospective study was conducted on Research Patient Data Registry data which was pooled from five Mass General Brigham Healthcare Network hospitals. We extracted data on demographics, symptoms, ICU transfer, mechanical ventilation, laboratories' profiles, imaging findings, and patient outcomes. RESULT: Of 985 screened adult patients, 17 were eligible for the study, 9 (52.9%) were admitted primarily for respiratory failure and developed acute pancreatitis after a median of 22.5 days (13-76 days) from the onset of COVID-19 symptoms. On contrary, eight patients presented with typical symptoms and were diagnosed with acute pancreatitis, the majority with mild severity (62.5%) on admission. Patients who were admitted primarily with severe COVID-19 illness were younger (median age 57 vs. 63 years), females (55.6 vs. 25%), of Hispanic ethnicity (55.6 vs. 25%), and obese (88.9 vs. 37.5%). The median peak lipase, C reactive protein, ferritin, lactate dehydrogenase, D-dimer were higher among patients who developed acute pancreatitis later during hospitalization. Patients who developed acute pancreatitis later also experienced higher episodes of necrotizing pancreatitis (11.1% vs. 0), thromboembolic complications (55.6 vs. 12.5%), and higher mortality (37.5 vs. 12.5%). CONCLUSION: Acute pancreatitis is not common among patients with COVID-19. Patients with COVID-19 who had acute pancreatitis on admission had more benign course and overall better outcome as compared to the patients who developed acute pancreatitis during hospitalization.


Subject(s)
COVID-19/physiopathology , Hospital Mortality , Pancreatitis/physiopathology , Respiratory Distress Syndrome/physiopathology , Adult , African Americans , Age Distribution , Aged , C-Reactive Protein/metabolism , COVID-19/complications , COVID-19/metabolism , Female , Ferritins/metabolism , Fibrin Fibrinogen Degradation Products/metabolism , Humans , L-Lactate Dehydrogenase/metabolism , Length of Stay , Lipase/metabolism , Male , Middle Aged , Pancreatitis/complications , Pancreatitis/epidemiology , Pancreatitis/metabolism , Pancreatitis, Acute Necrotizing/epidemiology , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/metabolism , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Sex Distribution , Thromboembolism/epidemiology
15.
Trials ; 22(1): 194, 2021 Mar 08.
Article in English | MEDLINE | ID: covidwho-1123665

ABSTRACT

OBJECTIVES: We investigate the effects of melatonin, compared to the usual therapeutic regimen on clinical symptoms and laboratory signs in severely ill patients with confirmed COVID-19 who are admitted to the Intensive Care Unit (ICU). TRIAL DESIGN: This is a single-center, open-label, randomized, clinical trial with a parallel-group design. This study is being conducted at Shahid Mohammadi Hospital, Bandar Abbas, Iran. PARTICIPANTS: All patients admitted to the ICU of Shahid Mohammadi Hospital, Bandar Abbas, Iran, will be screened for the following criteria. Inclusion criteria 1. Age >20 years 2. Definitive diagnosis of COVID-19 based on RT-PCR or/and serological testing 3. Severe pneumonia and lung involvement in imaging 4. Signing informed consent Exclusion criteria 1. Underlying diseases, including convulsive disorders, chronic hepatic and renal diseases 2. Use of mechanical ventilation 3. History of known allergy to Melatonin 4. Pregnancy and breastfeeding INTERVENTION AND COMPARATOR: Intervention group: The standard treatment regimen for COVID-19, according to the Iranian Ministry of Health and Medical Education's protocol, along with Melatonin soft gelatin capsule (Danna Pharmaceutical Company) at a dose of 5 mg twice a day for a period of seven days. CONTROL GROUP: The standard treatment for COVID-19 based on the Iranian Ministry of Health and Medical Education's protocol for a period of seven days. MAIN OUTCOMES: The primary outcomes are the recovery rate of clinical symptoms and checking arterial blood gas (ABG), C-reactive protein (C-RP), Ferritin, Lactate dehydrogenase (LDH) within seven days of randomization. The secondary outcomes are time to improvement of clinical and paraclinical features and length of stay in the ICU, need for mechanical ventilation, and mortality rate within seven days of randomization. RANDOMIZATION: Included patients will be allocated to one of the study arms using block randomization in a 1:1 ratio (each block consists of 6 patients). This randomization method ensures a balanced allocation between the arms during the study. A web-based system will generate random numbers for the allocation sequence and concealment of participants. Each number relates to one of the study arms. BLINDING (MASKING): This is an open-label trial without blinding and placebo control. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): A total of 60 participants randomizes (30 patients allocated to the intervention group and 30 patients allocated to the control group). TRIAL STATUS: The protocol is Version 1.0, February 16, 2021. Recruitment began February 28, 2021, and is anticipated to be completed by July 31, 2021. TRIAL REGISTRATION: The trial protocol has been registered in the Iranian Registry of Clinical Trials (IRCT). The registration number is " IRCT20200506047323N7 ". The registration date was February 16, 2021. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Antioxidants/therapeutic use , COVID-19/drug therapy , Melatonin/therapeutic use , Blood Gas Analysis , C-Reactive Protein/metabolism , COVID-19/metabolism , COVID-19/physiopathology , Ferritins/metabolism , Humans , Intensive Care Units , Iran , L-Lactate Dehydrogenase/metabolism , Randomized Controlled Trials as Topic , SARS-CoV-2
16.
Biomark Med ; 15(4): 285-293, 2021 03.
Article in English | MEDLINE | ID: covidwho-1105969

ABSTRACT

Background: Troponin levels may be elevated in COVID-19 infection. The aim of this study was to the explore relation between troponin levels and COVID-19 severity. Materials, methods & Results: One hundred and forty consecutive patients with COVID-19 pneumonia were included. Diagnosis of COVID-19 pneumonia was based on positive chest computed tomography (CT) findings. Quantitative PCR test was performed in all patients. Only 74 patients were quantitative PCR-positive. Twenty four patients had severe CT findings and 27 patients had progressive disease. These patients had significantly lower albumin and higher ferritin, D-dimer, lactate dehydrogenase, C-reactive protein, and high-sensitivity cardiac troponin I (hs-cTnI). Conclusion: COVID-19 patients with severe CT findings and progressive disease had higher hs-cTnI levels suggesting the use of hs-cTnI in risk stratification.


Subject(s)
COVID-19 , Real-Time Polymerase Chain Reaction , SARS-CoV-2/metabolism , Tomography, X-Ray Computed , Adult , Aged , Biomarkers/blood , C-Reactive Protein/metabolism , COVID-19/blood , COVID-19/diagnosis , COVID-19/diagnostic imaging , COVID-19 Nucleic Acid Testing , Female , Ferritins/metabolism , Fibrin Fibrinogen Degradation Products/metabolism , Heart Diseases , Humans , L-Lactate Dehydrogenase/blood , Male , Middle Aged , Serum Albumin, Human/metabolism , Thorax/diagnostic imaging , Troponin I/blood
17.
Seizure ; 84: 66-68, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1065590

ABSTRACT

Symptoms of COVID-19, as reported during the SARS-CoV-2 pandemic in 2019-2020, are primarily respiratory and gastrointestinal, with sparse reports on neurological manifestations. We describe the case of a 17-year old female with Cornelia de Lange syndrome and well controlled epilepsy, who sustained significant cortical injury during a COVID-19 associated multi-inflammatory syndrome.


Subject(s)
Brain Diseases/physiopathology , COVID-19/physiopathology , De Lange Syndrome/complications , Epilepsy/physiopathology , Seizures/physiopathology , Systemic Inflammatory Response Syndrome/physiopathology , Acute Kidney Injury/etiology , Adolescent , Airway Extubation , Anticonvulsants/therapeutic use , Blood Coagulation Disorders/etiology , Bone Marrow Failure Disorders , Brain Diseases/diagnostic imaging , Brain Diseases/etiology , Brain Diseases/pathology , Brain Edema/diagnostic imaging , Brain Edema/etiology , C-Reactive Protein/immunology , COVID-19/complications , COVID-19/immunology , COVID-19/therapy , Disease Progression , Electroencephalography , Epilepsy/complications , Epilepsy/drug therapy , Female , Ferritins/metabolism , Humans , Influenza B virus , Influenza, Human/complications , Levetiracetam/therapeutic use , Magnetic Resonance Imaging , Midazolam/therapeutic use , Necrosis , Phenobarbital/therapeutic use , Pseudomonas Infections/complications , Respiration, Artificial , Rhabdomyolysis/complications , Rhabdomyolysis/etiology , SARS-CoV-2 , Seizures/drug therapy , Seizures/etiology , Sepsis/etiology , Sepsis/physiopathology , Sepsis/therapy , Systemic Inflammatory Response Syndrome/complications , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/therapy , Tachycardia, Ventricular/etiology , Tachycardia, Ventricular/physiopathology , Tachycardia, Ventricular/therapy
18.
Clin Appl Thromb Hemost ; 27: 1076029621992128, 2021.
Article in English | MEDLINE | ID: covidwho-1063147

ABSTRACT

Hyperferritinemia is associated with poor outcomes in critically ill patients with sepsis, hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndromes (MAS) and coronavirus disease 19 (COVID-19). Autopsies of hyperferritinemic patients that succumbed to either sepsis, HLH, MAS or COVID-19 have revealed disseminated microvascular thromboses with von Willebrand factor (VWF)-, platelets-, and/or fibrin-rich microthrombi. It is unknown whether high plasma ferritin concentration actively promotes microvascular thrombosis, or merely serves as a prognostic biomarker in these patients. Here, we show that secretion of VWF from human umbilical vein endothelial cells (HUVEC) is significantly enhanced by 100,000 ng/ml of recombinant ferritin heavy chain protein (FHC). Ferritin fraction that was isolated by size exclusion chromatography from the plasma of critically ill HLH patients promoted VWF secretion from HUVEC, compared to similar fraction from non-critically ill control plasma. Furthermore, recombinant FHC moderately suppressed the activity of VWF cleaving metalloprotease ADAMTS-13. These observations suggest that a state of marked hyperferritinemia could promote thrombosis and organ injury by inducing endothelial VWF secretion and reducing the ADAMTS-13 activity.


Subject(s)
ADAMTS13 Protein/metabolism , COVID-19/blood , COVID-19/complications , Ferritins/metabolism , Hyperferritinemia/blood , Hyperferritinemia/complications , von Willebrand Factor/metabolism , ADAMTS13 Protein/antagonists & inhibitors , COVID-19/immunology , Critical Illness , Ferritins/blood , Human Umbilical Vein Endothelial Cells , Humans , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/complications , Oxidoreductases/blood , Oxidoreductases/metabolism , Recombinant Proteins/blood , Recombinant Proteins/metabolism , SARS-CoV-2 , Thrombosis/blood , Thrombosis/etiology
19.
Int Immunopharmacol ; 93: 107390, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1059618

ABSTRACT

BACKGROUND: Exposure to viral or bacterial pathogens increases the number of neutrophils with a relative decrease in lymphocytes, leading to elevated neutrophil to lymphocyte ratio (NLR). This study aimed to investigate whether differences in NLR among real-time polymerase chain reaction (PCR)-positive and -negative patients presenting with a prediagnosis of COVID-19 pneumonia could be useful in the differential diagnosis. METHODS: The study included 174 patients admitted because of suspected COVID-19 infection between March and April 2020. Patients were divided into two groups: PCR-negative and PCR-positive. Hemogram, NLR, urea, creatinine, aspartate aminotransferase, alanine aminotransferase, bilirubin, ferritin, D-dimer, C-reactive protein, procalcitonin, troponin, and coagulation parameters were analyzed. RESULTS: On comparison of laboratory parameters between both groups at presentation, PCR-positive patients were significantly more likely to have leukopenia (p < 0.001), thrombocytopenia (p = 0.006), neutropenia (p < 0.001), lymphopenia (p = 0.001), and increased NLR (p = 0.003). Furthermore, PCR-positive patients showed significant elevations of ferritin (p = 0.012) and procalcitonin (p = 0.038) and significant lower potassium levels (p = 0.05). CONCLUSION: COVID-19 pneumonia has become a major global health problem. Early diagnosis and treatment of these patients are crucial, as COVID-19 pneumonia shows a rapid progression in most cases. Thus, leukopenia, thrombocytopenia, elevated NLR, and elevated ferritin may be useful as supplementary diagnostic tests in these patients, which may allow early initiation of treatment and may contribute to preventing progression in patients with abnormal results.


Subject(s)
COVID-19/blood , COVID-19/diagnosis , Coronavirus Infections/diagnosis , Adult , Aged , Aged, 80 and over , Coronavirus Infections/blood , Female , Ferritins/metabolism , Humans , Leukocyte Count , Leukocytes/pathology , Leukopenia/blood , Leukopenia/virology , Lymphocyte Count , Male , Middle Aged , Neutrophils/pathology , Platelet Count , Polymerase Chain Reaction , Retrospective Studies , SARS-CoV-2/isolation & purification , Thrombocytopenia/blood , Thrombocytopenia/virology
20.
Trials ; 22(1): 43, 2021 Jan 11.
Article in English | MEDLINE | ID: covidwho-1021413

ABSTRACT

OBJECTIVES: The aim of this study is to assess the effectiveness and safety of glucocorticoid infusion pulse therapy to improve the clinical outcomes of patients with COVID-19 pneumonia with elevated inflammatory biomarkers. TRIAL DESIGN: A parallel-group quadruple-blind (participant, intervention provider, outcome assessor and data manager), randomised controlled trial. PARTICIPANTS: All patients admitted to hospital due to COVID-19 pneumonia will be considered eligible. Potential candidates will be identified and consecutively included in the emergency room or in the COVID-19 admission wards of two hospitals in Spain: Complejo Hospitalario de Navarra (Pamplona) and Hospital Moisès Broggi (Sant Joan Despí, Barcelona). Inclusion criteria are: 1) age ≥18 years old; 2) diagnosis of SARS-CoV-2 pneumonia confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) of nasopharyngeal swabs or sputum in accordance with the recommendations of the Spanish Ministry of Health; 3) history of symptoms compatible with COVID-19 ≥7 days; 4) hospital admission; 5) at least one of the following: C-reactive protein (CRP) >60 mg/dL, interleukin-6 (IL-6) >40 pg/mL, and/or ferritin >1000 µg/L; and 6) provision of informed consent. Exclusion criteria are: 1) allergy or contraindication to any of the drugs under study; 2) oxygen saturation (SpO2) <90% (in air ambient) or partial pressure of oxygen in arterial blood (PaO2) <60 mmHg (in ambient air) or PaO2/FiO2 <300 mmHg; 3) ongoing treatment with glucocorticoids, or other immunosuppressants, including biologics for another indication; 4) decompensated diabetes mellitus; 5) uncontrolled hypertension; 6) psychotic or manic disorder; 7) active cancer; 8) pregnancy or breastfeeding; 9) clinical or biochemical suspicion (procalcitonin >0.5 ng/mL) of active infection other than with SARS-CoV-2; 10) management as an outpatient; 11) conservative or palliative management; 12) participation in another clinical trial; or 13) any major uncontrolled medical, psychological, psychiatric, geographic or social problem that contraindicates the patient's participation in the trial or hinders proper follow-up and adherence to the protocol and evaluation of study outcomes. INTERVENTION AND COMPARATOR: Eligible patients will be randomised to receive standard of care plus methylprednisolone (intervention group) or standard of care plus placebo (control group). Intervention group: standard of care at the discretion of the researcher, including lopinavir/ritonavir (200/50 mg, 2 tablets twice daily, per os, for 7 to 14 days) ± remdesivir (a single intravenous loading dose of 200 mg on day 1 followed by once-daily intravenous maintenance doses of 100 mg from day 2 to 5), or no drug treatment, + methylprednisolone (once-daily intravenous infusion of 120 mg on days 1, 2 and 3). CONTROL GROUP: standard of care at the discretion of the researcher, including lopinavir/ritonavir (200/50 mg, 2 tablets every 12 hours, per os, for 7 to 14 days) ± remdesivir (a single intravenous loading dose of 200 mg on day 1 followed by once-daily intravenous maintenance doses of 100 mg from day 2 to 5), or no drug treatment, + placebo (once-daily intravenous infusion of 100 mL of 0.9% saline on days 1, 2 and 3). MAIN OUTCOMES: The primary outcome is the proportion of patients with treatment failure at 14 days after randomisation, defined as: 1) death, 2) need for admission to an intensive care unit (ICU), 3) initiation of mechanical ventilation, 4) SpO2 falling to <90% (in ambient air) or PaO2 <60 mmHg (in ambient air) or PaO2FiO2 <300 mmHg, not explained by a cause other than COVID-19, and/or 5) decrease in PaO2 ≥15% from baseline, together with laboratory and radiological deterioration. RANDOMISATION: Treatment will be allocated by block randomisation stratified by patient age (< or ≥ 75 years of age). For this purpose, we will use the R randomizeR package using two block sizes (4 and 6) with random permutation. The randomisation sequence will be generated by a unit (the Navarrabiomed Clinical Trials Platform) independent from the researchers who will recruit patients and implement the protocol. BLINDING (MASKING): The study will be quadruple-blinded, specifically, with blinding of patients, intervention providers, outcome assessors and data managers. The pharmacy at each participating hospital will prepare indistinguishable bags of methylprednisolone or placebo (0.9% saline) for patients of the experimental and placebo groups, respectively. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The percentage of patients with treatment failure (primary endpoint) is currently unknown. Assuming an absolute difference of 25% in the primary outcome between the two groups (35% in the control group and 10% in the intervention group), we estimate that 60 patients (30 per group) are required to detect this difference with a two-tailed type I error of 0.05 and a type II error of 0.2. Estimating a loss to follow-up of 20%, we should recruit a total sample size of 72 patients (36 per group). TRIAL STATUS: The Spanish Agency of Medicines and Medical Devices (AEMPS) and the Ethics Committee of the University Hospital La Princesa approved version 7.0 of the protocol on 30 April 2020 as a low intervention clinical trial. Subsequently, the protocol has been amended by researchers and re-approved by AEMPS and the same ethics committee on 1 July 2020 (version 8.0) and on 28 August 2020 (version 9.0). Currently, the trial is in the recruitment phase. Recruitment began on 28 May 2020 and is expected to be completed by February 2021. TRIAL REGISTRATION: This study protocol was registered on the eudract.ema.europa.eu on 5 May 2020 (title "Early treatment of COVID-19 pneumonia with glucocorticoids. Randomized controlled clinical trial"; EudraCT Number: 2020-001827-15 ) and on clinicaltrials.gov on 19 June 2020 (title: "Glucocorticoids in COVID-19 (CORTIVID)"; identifier: NCT04438980 ). FULL PROTOCOL: The full protocol (version 9.0) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
COVID-19/drug therapy , Glucocorticoids/therapeutic use , Methylprednisolone/therapeutic use , C-Reactive Protein/metabolism , COVID-19/metabolism , Double-Blind Method , Ferritins/metabolism , Hospitalization , Humans , Infusions, Intravenous , Interleukin-6/metabolism , Pulse Therapy, Drug , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome
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