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1.
Antioxid Redox Signal ; 35(16): 1358-1375, 2021 12.
Article in English | MEDLINE | ID: covidwho-1735498

ABSTRACT

Significance: Both incidence and mortality rates of sepsis significantly increase with advanced age, and the majority of sepsis patients are late middle-aged or older. With the proportion of older adults rapidly increasing in developed countries, age-dependent sepsis vulnerability is an urgent medical issue. Due to an increasing life expectancy, postsepsis complications and health care costs are expected to increase as well. Recent Advances: Older patients suffer from higher sepsis incidence and mortality rates, likely resulting from frequent comorbidities, increased coagulation, dysgylcemia, and altered immune responses. Critical Issues: Despite a large number of ongoing clinical and basic research studies, there is currently no effective therapeutic strategy targeting older patients with severe sepsis. The disparity between clinical and basic studies is a problem, and this is largely due to the use of animal models lacking clinical relevance. Although the majority of sepsis cases occur in older adults, most laboratory animals used for sepsis research are very young. Further, despite the wide use of combination fluid and antibiotic treatment in intensive care unit (ICU) patients, most animal research does not include such treatment. Future Directions: Because sepsis is a systemic disease with multiple organ dysfunction, combined therapy approaches, not those targeting single pathways or single organs, are essential. As for preclinical research, it is critical to confirm new findings using aged animal models with clinically relevant ICU-like medical treatments. Antioxid. Redox Signal. 35, 1358-1375.


Subject(s)
Sepsis/physiopathology , Adult , Humans , Sepsis/drug therapy
2.
Mol Med ; 28(1): 27, 2022 03 03.
Article in English | MEDLINE | ID: covidwho-1724403

ABSTRACT

Acute lung injury (ALI) and acute respiratory distress syndrome, which is a more severe form of ALI, are life-threatening clinical syndromes observed in critically ill patients. Treatment methods to alleviate the pathogenesis of ALI have improved to a great extent at present. Although the efficacy of these therapies is limited, their relevance has increased remarkably with the ongoing pandemic caused by the novel coronavirus disease 2019 (COVID-19), which causes severe respiratory distress syndrome. Several studies have demonstrated the preventive and therapeutic effects of molecular hydrogen in the various diseases. The biological effects of molecular hydrogen mainly involve anti-inflammation, antioxidation, and autophagy and cell death modulation. This review focuses on the potential therapeutic effects of molecular hydrogen on ALI and its underlying mechanisms and aims to provide a theoretical basis for the clinical treatment of ALI and COVID-19.


Subject(s)
Acute Lung Injury/drug therapy , COVID-19/drug therapy , Hydrogen/pharmacology , Protective Agents/pharmacology , Acute Lung Injury/physiopathology , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Humans , Sepsis/drug therapy , Sepsis/physiopathology
3.
Microvasc Res ; 140: 104303, 2022 03.
Article in English | MEDLINE | ID: covidwho-1568955

ABSTRACT

Systemic inflammatory response, as observed in sepsis and severe COVID-19, may lead to endothelial damage. Therefore, we aim to compare the extent of endothelial injury and its relationship to inflammation in both diseases. We included patients diagnosed with sepsis (SEPSIS group, n = 21), mild COVID-19 (MILD group, n = 31), and severe COVID-19 (SEVERE group, n = 24). Clinical and routine laboratory data were obtained, circulating cytokines (INF-γ, TNF-α, and IL-10) and endothelial injury markers (E-Selectin, Tissue Factor (TF) and von Willebrand factor (vWF)) were measured. Compared to the SEPSIS group, patients with severe COVID-19 present similar clinical and laboratory data, except for lower circulating IL-10 and E-Selectin levels. Compared to the MILD group, patients in the SEVERE group showed higher levels of TNF-α, IL-10, and TF. There was no clear relationship between cytokines and endothelial injury markers among the three studied groups; however, in SEVERE COVID-19 patients, there is a positive relationship between INF-γ with TF and a negative relationship between IL-10 and vWF. In conclusion, COVID-19 and septic patients have a similar pattern of cytokines and endothelial dysfunction markers. These findings highlight the importance of endothelium dysfunction in COVID-19 and suggest that endothelium should be better evaluated as a therapeutic target for the disease.


Subject(s)
COVID-19/pathology , Endothelium, Vascular/pathology , SARS-CoV-2 , Sepsis/pathology , Systemic Inflammatory Response Syndrome/blood , Aged , Aged, 80 and over , Biomarkers , Blood Cell Count , C-Reactive Protein/analysis , COVID-19/blood , COVID-19/complications , COVID-19/physiopathology , E-Selectin/blood , Female , Humans , Interferon-gamma/blood , Interleukin-10/blood , Male , Middle Aged , Retrospective Studies , Sepsis/blood , Sepsis/complications , Sepsis/physiopathology , Severity of Illness Index , Systemic Inflammatory Response Syndrome/etiology , Systemic Inflammatory Response Syndrome/physiopathology , Thromboplastin/analysis , Tumor Necrosis Factor-alpha/analysis , von Willebrand Factor/analysis
4.
Cells ; 10(10)2021 10 05.
Article in English | MEDLINE | ID: covidwho-1458308

ABSTRACT

Extracellular vesicles (EVs) have been identified as novel mediators of intercellular communication. They work via delivering the sequestered cargo to cells in the close vicinity, as well as distant sites in the body, regulating pathophysiological processes. Cell death and inflammation are biologically crucial processes in both normal physiology and pathology. These processes are indistinguishably linked with their effectors modulating the other process. For instance, during an unresolvable infection, the upregulation of specific immune mediators leads to inflammation causing cell death and tissue damage. EVs have gained considerable interest as mediators of both cell death and inflammation during conditions, such as sepsis. This review summarizes the types of extracellular vesicles known to date and their roles in mediating immune responses leading to cell death and inflammation with specific focus on sepsis and lung inflammation.


Subject(s)
Apoptosis , COVID-19/therapy , Cell Death , Extracellular Vesicles/metabolism , Inflammation/metabolism , Lung/pathology , SARS-CoV-2 , Sepsis/immunology , Animals , Biomarkers/metabolism , COVID-19/immunology , Cell Communication , Chemokines , Exosomes , Humans , Lung/immunology , Mice , Sepsis/physiopathology
5.
Crit Care ; 25(1): 202, 2021 06 10.
Article in English | MEDLINE | ID: covidwho-1266500

ABSTRACT

BACKGROUND: The mechanisms driving acute kidney injury (AKI) in critically ill COVID-19 patients are unclear. We collected kidney biopsies from COVID-19 AKI patients within 30 min after death in order to examine the histopathology and perform mRNA expression analysis of genes associated with renal injury. METHODS: This study involved histopathology and mRNA analyses of postmortem kidney biopsies collected from patients with COVID-19 (n = 6) and bacterial sepsis (n = 27). Normal control renal tissue was obtained from patients undergoing total nephrectomy (n = 12). The mean length of ICU admission-to-biopsy was 30 days for COVID-19 and 3-4 days for bacterial sepsis patients. RESULTS: We did not detect SARS-CoV-2 RNA in kidney biopsies from COVID-19-AKI patients yet lung tissue from the same patients was PCR positive. Extensive acute tubular necrosis (ATN) and peritubular thrombi were distinct histopathology features of COVID-19-AKI compared to bacterial sepsis-AKI. ACE2 mRNA levels in both COVID-19 (fold change 0.42, p = 0.0002) and bacterial sepsis patients (fold change 0.24, p < 0.0001) were low compared to control. The mRNA levels of injury markers NGAL and KIM-1 were unaltered compared to control tissue but increased in sepsis-AKI patients. Markers for inflammation and endothelial activation were unaltered in COVID-19 suggesting a lack of renal inflammation. Renal mRNA levels of endothelial integrity markers CD31, PV-1 and VE-Cadherin did not differ from control individuals yet were increased in bacterial sepsis patients (CD31 fold change 2.3, p = 0.0006, PV-1 fold change 1.5, p = 0.008). Angiopoietin-1 mRNA levels were downregulated in renal tissue from both COVID-19 (fold change 0.27, p < 0.0001) and bacterial sepsis patients (fold change 0.67, p < 0.0001) compared to controls. Moreover, low Tie2 mRNA expression (fold change 0.33, p = 0.037) and a disturbed VEGFR2/VEGFR3 ratio (fold change 0.09, p < 0.0001) suggest decreased microvascular flow in COVID-19. CONCLUSIONS: In a small cohort of postmortem kidney biopsies from COVID-19 patients, we observed distinct histopathological and gene expression profiles between COVID-19-AKI and bacterial sepsis-AKI. COVID-19 was associated with more severe ATN and microvascular thrombosis coupled with decreased microvascular flow, yet minimal inflammation. Further studies are required to determine whether these observations are a result of true pathophysiological differences or related to the timing of biopsy after disease onset.


Subject(s)
COVID-19/pathology , Gene Expression/genetics , Kidney/pathology , Kidney/physiopathology , Sepsis/pathology , Acute Kidney Injury/etiology , Acute Kidney Injury/physiopathology , Adult , Aged , Aged, 80 and over , Analysis of Variance , COVID-19/genetics , COVID-19/physiopathology , Critical Illness/therapy , Female , Humans , Intensive Care Units/organization & administration , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Sepsis/genetics , Sepsis/physiopathology , Simplified Acute Physiology Score
6.
Crit Care ; 25(1): 95, 2021 03 08.
Article in English | MEDLINE | ID: covidwho-1123662

ABSTRACT

Endothelial cells play a key role in maintaining intravascular patency through their anticoagulant properties. They provide a favorable environment for plasma anticoagulant proteins, including antithrombin, tissue factor pathway inhibitor, and protein C. Under septic conditions, however, the anticoagulant properties of endothelial cells are compromised. Rather, activated/injured endothelial cells can provide a scaffold for intravascular coagulation. For example, the expression of tissue factor, an important initiator of the coagulation pathway, is induced on the surface of activated endothelial cells. Phosphatidylserine, a high-affinity scaffold for gamma-carboxyglutamate domain containing coagulation factors, including FII, FVII, FIX, and FX, is externalized to the outer leaflet of the plasma membrane of injured endothelial cells. Hemodilution decreases not only coagulation factors but also plasma anticoagulant proteins, resulting in unleashed activation of coagulation on the surface of activated/injured endothelial cells. The aberrant activation of coagulation can be suppressed in part by the supplementation of recombinant antithrombin and recombinant thrombomodulin. This review aims to overview the physiological and pathological functions of endothelial cells along with proof-of-concept in vitro studies. The pathophysiology of COVID-19-associated thrombosis is also discussed.


Subject(s)
COVID-19/complications , Disseminated Intravascular Coagulation/physiopathology , Endothelial Cells/pathology , Sepsis/physiopathology , COVID-19/physiopathology , Clinical Trials, Phase III as Topic , Humans , Randomized Controlled Trials as Topic , Thrombosis/physiopathology , Thrombosis/virology
7.
Int J Mol Sci ; 22(4)2021 Feb 16.
Article in English | MEDLINE | ID: covidwho-1085071

ABSTRACT

Despite progress in understanding the pathophysiology of acute lung damage, currently approved treatment possibilities are limited to lung-protective ventilation, prone positioning, and supportive interventions. Various pharmacological approaches have also been tested, with neuromuscular blockers and corticosteroids considered as the most promising. However, inhibitors of phosphodiesterases (PDEs) also exert a broad spectrum of favorable effects potentially beneficial in acute lung damage. This article reviews pharmacological action and therapeutical potential of nonselective and selective PDE inhibitors and summarizes the results from available studies focused on the use of PDE inhibitors in animal models and clinical studies, including their adverse effects. The data suggest that xanthines as representatives of nonselective PDE inhibitors may reduce acute lung damage, and decrease mortality and length of hospital stay. Various (selective) PDE3, PDE4, and PDE5 inhibitors have also demonstrated stabilization of the pulmonary epithelial-endothelial barrier and reduction the sepsis- and inflammation-increased microvascular permeability, and suppression of the production of inflammatory mediators, which finally resulted in improved oxygenation and ventilatory parameters. However, the current lack of sufficient clinical evidence limits their recommendation for a broader use. A separate chapter focuses on involvement of cyclic adenosine monophosphate (cAMP) and PDE-related changes in its metabolism in association with coronavirus disease 2019 (COVID-19). The chapter illuminates perspectives of the use of PDE inhibitors as an add-on treatment based on actual experimental and clinical trials with preliminary data suggesting their potential benefit.


Subject(s)
Acute Lung Injury/drug therapy , Phosphodiesterase Inhibitors/therapeutic use , Acute Lung Injury/metabolism , Acute Lung Injury/physiopathology , Animals , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/physiopathology , Cyclic AMP/metabolism , Disease Models, Animal , Humans , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/physiopathology , Sepsis/drug therapy , Sepsis/metabolism , Sepsis/physiopathology
8.
BMJ Case Rep ; 14(1)2021 Jan 18.
Article in English | MEDLINE | ID: covidwho-1066836

ABSTRACT

This case represents a rare fulminant course of fried-rice associated food poisoning in an immunocompetent person due to pre-formed exotoxin produced by Bacillus cereus, with severe manifestations of sepsis, including multi-organ (hepatic, renal, cardiac, respiratory and neurological) failure, shock, metabolic acidosis, rhabdomyolysis and coagulopathy. Despite maximal supportive measures (continuous renal replacement therapy, plasmapheresis, N-acetylcysteine infusion and blood products, and broad-spectrum antimicrobials) and input from a multidisciplinary team (consisting of infectious diseases, intensive care, gastroenterology, surgery, toxicology, immunology and haematology), mortality resulted. This case is the first to use whole genome sequencing techniques to confirm the toxigenic potential of B. cereus It has important implications for food preparation and storage, particularly given its occurrence in home isolation during the COVID-19 pandemic.


Subject(s)
Bacillus cereus/genetics , Exotoxins/genetics , Foodborne Diseases/diagnosis , Acetylcysteine/therapeutic use , Acidosis/physiopathology , Acidosis/therapy , Adult , Anti-Arrhythmia Agents/therapeutic use , Anti-Bacterial Agents/therapeutic use , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/therapy , Bacillus cereus/isolation & purification , Blood Coagulation Disorders/physiopathology , Blood Coagulation Disorders/therapy , Blood Transfusion , Brain Diseases , Continuous Renal Replacement Therapy , Fatal Outcome , Female , Foodborne Diseases/microbiology , Foodborne Diseases/physiopathology , Foodborne Diseases/therapy , Free Radical Scavengers/therapeutic use , Humans , Immunocompetence , Liver Failure/physiopathology , Liver Failure/therapy , Multiple Organ Failure/physiopathology , Multiple Organ Failure/therapy , Plasmapheresis , Renal Insufficiency/physiopathology , Renal Insufficiency/therapy , Rhabdomyolysis/physiopathology , Rhabdomyolysis/therapy , Sepsis/physiopathology , Sepsis/therapy , Shock/physiopathology , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Whole Genome Sequencing
9.
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
10.
Eur J Clin Microbiol Infect Dis ; 40(7): 1405-1412, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1053011

ABSTRACT

Recent publications on the probable role of heparin-binding protein (HBP) as a biomarker in sepsis prompted us to investigate its diagnostic and prognostic performance in severe COVID-19. HBP and IL-6 were measured by immunoassays at admission and on day 7 in 178 patients with pneumonia by SARS-CoV-2. Patients were classified into non-sepsis and sepsis as per the Sepsis-3 definitions and were followed up for the development of severe respiratory failure (SRF) and for outcome. Results were confirmed by multivariate analyses. HBP was significantly higher in patients classified as having sepsis and was negatively associated with the oxygenation ratio and positively associated with creatinine and lactate. Logistic regression analysis evidenced admission HBP more than 18 ng/ml and IL-6 more than 30 pg/ml as independent risk factors for the development of SRP. Their integration prognosticated SRF with respective sensitivity, specificity, positive predictive value, and negative predictive 59.1%, 96.3%, 83.9%, and 87.8%. Cox regression analysis evidenced admission HBP more than 35 ng/ml and IL-6 more than 30 pg/ml as independent risk factors for 28-day mortality. Their integration prognosticated 28-day mortality with respective sensitivity, specificity, positive predictive value, and negative predictive value 69.2%, 92.7%, 42.9%, and 97.5%. HBP remained unchanged over-time course. A prediction score of the disposition of patients with COVID-19 is proposed taking into consideration admission levels of IL-6 and HBP. Using different cut-offs, the score may predict the likelihood for SRF and for 28-day outcome.


Subject(s)
Antimicrobial Cationic Peptides/blood , COVID-19/blood , Interleukin-6/blood , Respiratory Insufficiency/blood , Adult , Biomarkers/blood , Blood Proteins , COVID-19/diagnosis , COVID-19/mortality , COVID-19/physiopathology , Female , Humans , Male , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Pneumonia, Viral/physiopathology , Predictive Value of Tests , Prognosis , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/mortality , Respiratory Insufficiency/physiopathology , SARS-CoV-2/isolation & purification , Sepsis/blood , Sepsis/diagnosis , Sepsis/mortality , Sepsis/physiopathology
11.
Pharmacol Res ; 167: 105409, 2021 05.
Article in English | MEDLINE | ID: covidwho-1033338

ABSTRACT

Sepsis, caused by the inappropriate host response to infection, is characterized by excessive inflammatory response and organ dysfunction, thus becomes a critical clinical problem. Commonly, sepsis may progress to septic shock and severe complications, including acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), sepsis-induced myocardial dysfunction (SIMD), liver dysfunction, cerebral dysfunction, and skeletal muscle atrophy, which predominantly contribute to high mortality. Additionally, the global pandemic of coronavirus disease 2019 (COVID-19) raised the concern of development of effectve therapeutic strategies for viral sepsis. Renin-angiotensin system (RAS) may represent as a potent therapeutic target for sepsis therapy. The emerging role of RAS in the pathogenesis of sepsis has been investigated and several preclinical and clinical trials targeting RAS for sepsis treatment revealed promising outcomes. Herein, we attempt to review the effects and mechanisms of RAS manipulation on sepsis and its complications and provide new insights into optimizing RAS interventions for sepsis treatment.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Renin-Angiotensin System/drug effects , SARS-CoV-2/drug effects , Sepsis/drug therapy , Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Animals , Antiviral Agents/adverse effects , COVID-19/metabolism , COVID-19/physiopathology , COVID-19/virology , Host-Pathogen Interactions , Humans , SARS-CoV-2/pathogenicity , Sepsis/metabolism , Sepsis/physiopathology , Sepsis/virology , Treatment Outcome
12.
Turk J Med Sci ; 51(2): 428-434, 2021 04 30.
Article in English | MEDLINE | ID: covidwho-922877

ABSTRACT

Background/aim: We aimed to identify clinical settings of renal transplant patients with COVID-19. Materials and methods: In this retrospective study, we included kidney transplant inpatients with laboratory confirmed COVID-19 who had been discharged or had died by October 1st, 2020. Characteristics of the patients, including basal and last outpatient biochemical parameters were recorded. Discontinuation or dosage reduction of immunosuppressives and other treatment information was documented. Results: Twenty patients were included in this study, of whom 18 were discharged and 2 died in hospital. The mean duration of hospitalization and follow-up were 9.7 ± 6.4 days and 4.5 ± 2.0 months, respectively. Fourteen patients (70%) were male and mean age was 48.0 ± 10.3 years. At admission, all had immunosuppression withdrawn and were started on methylprednisolone 16 mg/ day (50%) or dexamethasone (50%). Tacrolimus/m-TOR inhibitors were reduced by 50% and all antimetabolites were discontinued. Hemodialysis was needed for 10% of patients. Acute kidney injury was detected in 25% of the patients. With respect to hospitalization time and complications, there was no significant difference between patients who used dexamethasone and those who did not (P > 0.05). The discontinued immunosuppressives were resumed within 2 to 4 weeks after discharge according to the severity of disease. No rehospitalization or acute rejection was detected during the follow-up of the patients. Conclusion: Renal transplant patients are considered a high risk group for COVID-19. It can be said that discontinuation or reducing dosages of immunosuppressives may be effective and safe in kidney transplant patients.


Subject(s)
COVID-19/physiopathology , Glucocorticoids/therapeutic use , Graft Rejection/prevention & control , Immunocompromised Host , Immunosuppressive Agents/therapeutic use , Kidney Transplantation , Acute Kidney Injury/physiopathology , Acute Kidney Injury/therapy , Adult , COVID-19/immunology , COVID-19/therapy , Deprescriptions , Dexamethasone/therapeutic use , Disease Progression , Everolimus/therapeutic use , Female , Hospital Mortality , Hospitalization , Humans , Length of Stay , Male , Methylprednisolone/therapeutic use , Middle Aged , Mycophenolic Acid/therapeutic use , Renal Dialysis , Respiration, Artificial , Respiratory Insufficiency/physiopathology , Respiratory Insufficiency/therapy , Retrospective Studies , SARS-CoV-2 , Sepsis/physiopathology , Tacrolimus/therapeutic use
13.
Ear Nose Throat J ; 100(2_suppl): 140S-147S, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-913945

ABSTRACT

BACKGROUND: An outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 infection occurred in Wuhan, China, in December 2019. To date, the analysis of fatal cases and the risk factors for death have rarely been reported. METHODS: In this study, 220 adult patients with confirmed and suspected COVID-19 were enrolled. Clinical characteristics, laboratory data, treatments, and complications were compared between 168 survivors and 52 nonsurvivors. Univariable analysis and multivariable logistic regression were used to investigate the risk factors for mortality. RESULTS: A total of 220 patients (168 were discharged and 52 died in the hospital) were enrolled in the study. The median age of all patients was 59.5 (47.0-69.0) years, and the median age of patients who died was significantly older than that of patients who survived (70.5 vs 56.0 years, respectively; P < .001). According to multivariate logistic regression, older age (odds ratio: 1.09, 95% CI: 1.03-1.15; P = .001), initial Sequential Organ Failure Assessment (SOFA) score >2 (37.4, 9.4-148.0; P = .011), and respiratory rate >24 per minute (10.89, 1.47-80.67; P = .019) were independent risk factors for mortality. CONCLUSION: Clinical and laboratory parameters predicting poor prognosis including older age, baseline SOFA score >2, and respiratory rate >24 per minute were identified.


Subject(s)
COVID-19/mortality , Organ Dysfunction Scores , Respiratory Rate , Acute Kidney Injury/etiology , Acute Kidney Injury/physiopathology , Acute Kidney Injury/therapy , Adult , Age Factors , Aged , Anti-Bacterial Agents/therapeutic use , Antiviral Agents/therapeutic use , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/therapy , COVID-19/complications , COVID-19/physiopathology , COVID-19/therapy , Case-Control Studies , China , Comorbidity , Female , Glucocorticoids/therapeutic use , Humans , Liver Diseases/etiology , Liver Diseases/physiopathology , Liver Diseases/therapy , Logistic Models , Male , Middle Aged , Multivariate Analysis , Oxygen Inhalation Therapy , Prognosis , Respiration, Artificial , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/physiopathology , Respiratory Distress Syndrome/therapy , Retrospective Studies , Risk Factors , SARS-CoV-2 , Sepsis/etiology , Sepsis/physiopathology , Sepsis/therapy
14.
JAMA Intern Med ; 181(1): 71-78, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-775497

ABSTRACT

Importance: Lymphopenia is common and correlates with poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19). Objective: To determine whether a therapy that increases peripheral blood leukocyte and lymphocyte cell counts leads to clinical improvement in patients with COVID-19. Design, Setting and Participants: Between February 18 and April 10, 2020, we conducted an open-label, multicenter, randomized clinical trial at 3 participating centers in China. The main eligibility criteria were pneumonia, a blood lymphocyte cell count of 800 per µL (to convert to ×109/L, multiply by 0.001) or lower, and no comorbidities. Severe acute respiratory syndrome coronavirus 2 infection was confirmed with reverse-transcription polymerase chain reaction testing. Exposures: Usual care alone, or usual care plus 3 doses of recombinant human granulocyte colony-stimulating factor (rhG-CSF, 5 µg/kg, subcutaneously at days 0-2). Main Outcomes and Measures: The primary end point was the time from randomization to improvement of at least 1 point on a 7-category disease severity score. Results: Of 200 participants, 112 (56%) were men and the median (interquartile range [IQR]) age was 45 (40-55) years. There was random assignment of 100 patients (50%) to the rhG-CSF group and 100 (50%) to the usual care group. Time to clinical improvement was similar between groups (rhG-CSF group median of 12 days (IQR, 10-16 days) vs usual care group median of 13 days (IQR, 11-17 days); hazard ratio, 1.28; 95% CI, 0.95-1.71; P = .06). For secondary end points, the proportion of patients progressing to acute respiratory distress syndrome, sepsis, or septic shock was lower in the rhG-CSF group (rhG-CSF group, 2% vs usual care group, 15%; difference, -13%; 95%CI, -21.4% to -5.4%). At 21 days, 2 patients (2%) had died in the rhG-CSF group compared with 10 patients (10%) in the usual care group (hazard ratio, 0.19; 95%CI, 0.04-0.88). At day 5, the lymphocyte cell count was higher in the rhG-CSF group (rhG-CSF group median of 1050/µL vs usual care group median of 620/µL; Hodges-Lehmann estimate of the difference in medians, 440; 95% CI, 380-490). Serious adverse events, such as sepsis or septic shock, respiratory failure, and acute respiratory distress syndrome, occurred in 29 patients (14.5%) in the rhG-CSF group and 42 patients (21%) in the usual care group. Conclusion and Relevance: In preliminary findings from a randomized clinical trial, rhG-CSF treatment for patients with COVID-19 with lymphopenia but no comorbidities did not accelerate clinical improvement, but the number of patients developing critical illness or dying may have been reduced. Larger studies that include a broader range of patients with COVID-19 should be conducted. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2000030007.


Subject(s)
COVID-19/drug therapy , Granulocyte Colony-Stimulating Factor/therapeutic use , Hematologic Agents/therapeutic use , Hospital Mortality , Lymphopenia/drug therapy , Adrenal Cortex Hormones/therapeutic use , Adult , Anti-Bacterial Agents/therapeutic use , Antiviral Agents/therapeutic use , B-Lymphocytes , CD4 Lymphocyte Count , COVID-19/blood , COVID-19/complications , COVID-19/physiopathology , China , Disease Progression , Female , Humans , Killer Cells, Natural , Leukocyte Count , Lymphocyte Count , Lymphopenia/blood , Lymphopenia/complications , Male , Middle Aged , Mortality , Noninvasive Ventilation , Oxygen Inhalation Therapy , Recombinant Proteins , Respiratory Distress Syndrome/physiopathology , Respiratory Insufficiency/physiopathology , SARS-CoV-2 , Sepsis/physiopathology , Shock, Septic/physiopathology , Time Factors
15.
Med Hypotheses ; 144: 110180, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-765363

ABSTRACT

We present the AI-discovered aetiology of COVID-19, based on a precise disease model of COVID-19 built under five weeks that best matches the epidemiological characteristics, transmission dynamics, clinical features, and biological properties of COVID-19 and consistently explains the rapidly expanding COVID-19 literature. We present that SARS-CoV-2 implements a unique unbiased survival strategy of balancing viral replication with viral spread by increasing its dependence on (i) ACE2-expressing cells for viral entry and spread, (ii) PI3K signaling in ACE2-expressing cells for viral replication and egress, and (iii) viral- non-structural-and-accessory-protein-dependent immunomodulation to balance viral spread and viral replication. We further propose the combination of irinotecan (an in-market topoisomerase I inhibitor) and etoposide (an in-market topoisomerase II inhibitor) could potentially be an exceptionally effective treatment to protect critically ill patients from death caused by COVID-19-specific cytokine storms triggered by sepsis, ARDS, and other fatal comorbidities.


Subject(s)
COVID-19/drug therapy , COVID-19/etiology , Etoposide/administration & dosage , Irinotecan/administration & dosage , Comorbidity , Critical Illness , Disease Outbreaks , Disease Progression , Drug Discovery , Drug Therapy, Combination , Humans , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Sepsis/physiopathology , Signal Transduction , Topoisomerase I Inhibitors/administration & dosage , Topoisomerase II Inhibitors/administration & dosage , Treatment Outcome , Virus Internalization/drug effects , Virus Replication
16.
Int J Biol Sci ; 16(14): 2479-2489, 2020.
Article in English | MEDLINE | ID: covidwho-721623

ABSTRACT

The emergence of SARS-CoV-2 virus and its associated disease COVID-19 have triggered significant threats to public health, in addition to political and social changes. An important number of studies have reported the onset of symptoms compatible with pneumonia accompanied by coagulopathy and lymphocytopenia during COVID-19. Increased cytokine levels, the emergence of acute phase reactants, platelet activation and immune checkpoint expression are some of the biomarkers postulated in this context. As previously observed in prolonged sepsis, T-cell exhaustion due to SARS-CoV-2 and even their reduction in numbers due to apoptosis hinder the response to the infection. In this review, we synthesized the immune changes observed during COVID-19, the role of immune molecules as severity markers for patient stratification and their associated therapeutic options.


Subject(s)
Coronavirus Infections/immunology , Coronavirus Infections/physiopathology , Pneumonia, Viral/immunology , Pneumonia, Viral/physiopathology , Sepsis/physiopathology , Adrenal Cortex Hormones/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus , Biomarkers , Blood Coagulation Disorders/immunology , COVID-19 , Cytokines/metabolism , Humans , Immune System , Immunity, Innate , Interferons/metabolism , Lymphopenia/immunology , Pandemics , Phenotype , Platelet Activation , SARS-CoV-2
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