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2.
Shock ; 56(5): 667-672, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1470219

ABSTRACT

BACKGROUND: "Cytokine storm" has been used to implicate increased cytokine levels in the pathogenesis of serious clinical conditions. Similarities with Severe Acute Respiratory Syndrome Coronoavirus-2 (SARS CoV-2) and the 2012 Middle Eastern Respiratory Syndrome led early investigators to suspect a "cytokine storm" resulting in an unregulated inflammatory response associated with the significant morbidity and mortality induced by SARS CoV-2. The threshold of blood cytokines necessary to qualify as a "cytokine storm" has yet to be defined. METHODS: A literature review was conducted to identify cytokine levels released during 11 assorted clinical conditions or diseases. Weighted averages for various cytokines were calculated by multiplying the number of patients in the paper by the average concentration of each cytokine. Correlation between cytokine levels for individual conditions or diseases were assessed using Pearson correlation coefficient. RESULTS: The literature was reviewed to determine blood levels of cytokines in a wide variety of clinical conditions. These conditions ranged from exercise and autoimmune disease to septic shock and therapy with chimeric antigen receptor T cells. The most frequently measured cytokine was IL-6 which ranged from 24,123 pg/mL in septic shock to 11 pg/mL after exercise. In patients with severe SARS CoV-2 infections, blood levels of IL-6 were only 43 pg/mL, nearly three magnitudes lower than IL-6 levels in patients with septic shock. The clinical presentations of these different diseases do not correlate with blood levels of cytokines. Additionally, there is poor correlation between the concentrations of different cytokines among the different diseases. Specifically, blood levels of IL-6 did not correlate with levels of IL-8, IL-10, or TNF. Septic shock had the highest concentrations of cytokines, yet multiple cytokine inhibitors have failed to demonstrate improved outcomes in multiple clinical trials. Patients with autoimmune diseases have very low blood levels of cytokines (rheumatoid arthritis, IL-6 = 34 pg/mL; Crohn's disease, IL-6 = 5 pg/mL), yet respond dramatically to cytokine inhibitors. CONCLUSION: The misleading term "cytokine storm" implies increased blood levels of cytokines are responsible for a grave clinical condition. Not all inflammatory conditions resulting in worsened disease states are correlated with significantly elevated cytokine levels, despite an association with the term "cytokine storm". "Cytokine storm" should be removed from the medical lexicon since it does not reflect the mediators driving the disease nor does it predict which diseases will respond to cytokine inhibitors.


Subject(s)
COVID-19/immunology , Coronavirus Infections/immunology , Cytokine Release Syndrome , Cytokines/blood , COVID-19/blood , Coronavirus Infections/blood , Humans , Inflammation , Interleukin-6/blood , Receptors, Chimeric Antigen/immunology , SARS-CoV-2 , Shock, Septic/blood , Shock, Septic/immunology , T-Lymphocytes/immunology
7.
Clin Microbiol Infect ; 26(10): 1380-1385, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-1439953

ABSTRACT

OBJECTIVES: The aim was to determine the clinical characteristics of COVID-19 patients because the SARS-CoV-2 virus continues to circulate in the population. METHODS: This is a retrospective, multicentre, cohort study. Adult COVID-19 cases from four hospitals in Zhejiang were enrolled and clustered into three groups based on epidemiological history. First-generation patients had a travel history to Hubei within 14 days before disease onset; second-generation patients had a contact history with first-generation patients; third-generation patients had a contact history with second-generation patients. Demographic, clinical characteristics, clinical outcomes and duration of viral shedding were analysed. RESULTS: A total of 171 patients were enrolled, with 83, 44 and 44 patients in the first-, second-, and third-generation, respectively. Compared with the first and second generations, third-generation patients were older (61.3 vs. 48.3 and 44.0 years, p < 0.001) and had more coexisting conditions (56.8% vs. 36.1% and 27.3%, p 0.013). At 7 ± 1 days from illness onset, third-generation patients had lower lymphocyte (0.6 vs. 0.8 and 0.8 × 109/L, p 0.007), higher C-reactive protein (29.7 vs. 17.1 and 13.8 mg/L, p 0.018) and D-dimer (1066 vs. 412.5 and 549 µg/L, p 0.002) and more lesions involving the pulmonary lobes (lobes ≥5, 81.8% vs. 53.0% and 34.1%, p < 0.001). The proportions of third-generation patients developing severe illness (72.7% vs. 32.5% and 27.3%, p < 0.001), critical illness (38.6% vs. 10.8% and 6.8%, p < 0.001) and receiving endotracheal intubation (20.5% vs. 3.6% and 2.3%, p 0.002) were higher than in the other two groups. DISCUSSION: Third-generation patients were older, had more underlying comorbidities and had a higher proportion of severe or critical illness than first- and second-generation patients.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/epidemiology , Diabetes Mellitus/epidemiology , Hypertension/epidemiology , Pandemics , Pneumonia, Viral/epidemiology , Pulmonary Disease, Chronic Obstructive/epidemiology , Adult , Biomarkers/blood , C-Reactive Protein/metabolism , COVID-19 , China/epidemiology , Comorbidity , Contact Tracing , Coronavirus Infections/blood , Coronavirus Infections/physiopathology , Coronavirus Infections/transmission , Diabetes Mellitus/blood , Diabetes Mellitus/physiopathology , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Hypertension/blood , Hypertension/physiopathology , Interleukin-6/blood , Intubation, Intratracheal , Lymphocytes/pathology , Lymphocytes/virology , Male , Middle Aged , Pneumonia, Viral/blood , Pneumonia, Viral/physiopathology , Pneumonia, Viral/transmission , Pulmonary Disease, Chronic Obstructive/blood , Pulmonary Disease, Chronic Obstructive/physiopathology , Retrospective Studies , Risk Factors , SARS-CoV-2 , Severity of Illness Index , Travel/statistics & numerical data , Virus Shedding
8.
J Clin Invest ; 130(11): 6151-6157, 2020 11 02.
Article in English | MEDLINE | ID: covidwho-1435146

ABSTRACT

Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition.


Subject(s)
Betacoronavirus , Complement Membrane Attack Complex , Coronavirus Infections , Extracellular Traps , Neutrophils , Pandemics , Pneumonia, Viral , Thromboplastin , Thrombosis , Aged , Betacoronavirus/immunology , Betacoronavirus/metabolism , COVID-19 , Complement Activation/drug effects , Complement Membrane Attack Complex/immunology , Complement Membrane Attack Complex/metabolism , Coronavirus Infections/blood , Coronavirus Infections/immunology , Extracellular Traps/immunology , Extracellular Traps/metabolism , Female , Humans , Male , Middle Aged , Neutrophils/immunology , Neutrophils/metabolism , Peptides, Cyclic/pharmacology , Pneumonia, Viral/blood , Pneumonia, Viral/immunology , Receptor, Anaphylatoxin C5a/antagonists & inhibitors , Receptor, Anaphylatoxin C5a/blood , Receptor, Anaphylatoxin C5a/immunology , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/virology , SARS-CoV-2 , Thrombin/immunology , Thrombin/metabolism , Thromboplastin/immunology , Thromboplastin/metabolism , Thrombosis/blood , Thrombosis/immunology , Thrombosis/virology
11.
Anaesth Crit Care Pain Med ; 39(5): 553-561, 2020 10.
Article in English | MEDLINE | ID: covidwho-1384795

ABSTRACT

PURPOSE: Community transmission of SARS-CoV-2 was detected in Spain in February 2020, with 216% intensive care unit (ICU) capacity expanded in Vitoria by March 18th, 2020. METHODS: We identified patients from the two public hospitals in Vitoria who were admitted to ICU with confirmed infection by SARS-CoV-2. Data reported here were available in April 6th, 2020. Mortality was assessed in those who completed 15-days of ICU stay. RESULTS: We identified 48 patients (27 males) with confirmed SARS-CoV-2. Median [interquartile range (IQR)] age of patients was 63 [51-75] years. Symptoms began a median of 7 [5-12] days before ICU admission. The most common comorbidities identified were obesity (48%), arterial hypertension (44%) and chronic lung disease (37%). All patients were admitted by hypoxemic respiratory failure and none received non-invasive mechanical ventilation. Forty-five (94%) underwent intubation, 3 (6%) high flow nasal therapy (HFNT), 1 (2%) extracorporeal membrane oxygenation (ECMO) and 22 (46%) required prone position. After 15 days, 14/45 (31%) intubated patients died (13% within one week), 10/45 (22%) were extubated, and 21/45 (47%) underwent mechanical ventilation. Six patients had documented super-infection. Procalcitonin plasma above 0.5µg/L was associated with 16% vs. 19% (p=0.78) risk of death after 7 days. CONCLUSION: This early experience with SARS-CoV-2 in Spain suggests that a strategy of right oxygenation avoiding non-invasive mechanical ventilation was life-saving. Seven-day mortality in SARS-CoV-2 requiring intubation was lower than 15%, with 80% of patients still requiring mechanical ventilation. After 15 days of ICU admission, half of patients remained intubated, whereas one third died.


Subject(s)
Betacoronavirus , Coronavirus Infections/mortality , Hospitals, Public/statistics & numerical data , Intensive Care Units/statistics & numerical data , Pandemics , Pneumonia, Viral/mortality , Adult , Aged , Aged, 80 and over , Antiviral Agents/therapeutic use , COVID-19 , Combined Modality Therapy , Comorbidity , Coronavirus Infections/blood , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/therapy , Disease Outbreaks , Female , Hospital Mortality , Humans , Influenza, Human/epidemiology , Kaplan-Meier Estimate , Length of Stay , Male , Middle Aged , Oxygen Inhalation Therapy , Pneumonia, Viral/blood , Pneumonia, Viral/complications , Pneumonia, Viral/therapy , Procalcitonin/blood , Respiration, Artificial , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/mortality , Respiratory Distress Syndrome/therapy , SARS-CoV-2 , Spain/epidemiology
13.
Clin Pharmacol Ther ; 108(4): 775-790, 2020 10.
Article in English | MEDLINE | ID: covidwho-1384148

ABSTRACT

There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, concentration 90% (EC90 ) values recalculated from in vitro anti-SARS-CoV-2 activity data was expressed as a ratio to the achievable maximum plasma concentration (Cmax ) at an approved dose in humans (Cmax /EC90 ratio). Only 14 of the 56 analyzed drugs achieved a Cmax /EC90 ratio above 1. A more in-depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir-boosted), and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (Kp Ulung ) was also simulated to derive a lung Cmax /half-maximal effective concentration (EC50 ) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir-boosted), tipranavir (ritonavir-boosted), ivermectin, azithromycin, and lopinavir (ritonavir-boosted) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50 . Nitazoxanide and sulfadoxine also exceeded their reported EC50 by 7.8-fold and 1.5-fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritizing compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments, such as the lungs, in order to maximize the potential for success of proposed human clinical trials.


Subject(s)
Antiviral Agents/administration & dosage , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Delivery Systems/methods , Drug Repositioning/methods , Pneumonia, Viral/drug therapy , Antiviral Agents/blood , COVID-19 , Coronavirus Infections/blood , Humans , Pandemics , Pneumonia, Viral/blood , SARS-CoV-2
15.
Transfusion ; 60(6): 1119-1122, 2020 06.
Article in English | MEDLINE | ID: covidwho-1388414

ABSTRACT

Oral swabs, sputum, and blood samples from 18 asymptomatic and symptomatic patients with SARS-CoV-2 infection were examined using RT-PCR testing in order to assess the risk of transfusion-related transmission. In asymptomatic patients as well as patients with flu-like symptoms and fever, no SARS-CoV-2 RNA could be detected in the blood or serum despite a clearly positive result in all throat swabs. As patients with symptoms of infectious disease will not be admitted to blood donation, the risk for transfusion transmission of SARS-CoV-2 seems to be negligible.


Subject(s)
Asymptomatic Infections , Betacoronavirus/isolation & purification , Blood Donors , Blood Safety , Coronavirus Infections/transmission , Donor Selection , Pneumonia, Viral/transmission , Transfusion Reaction/prevention & control , Adolescent , Adult , Aged , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Female , Germany , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , SARS-CoV-2 , Transfusion Reaction/virology , Young Adult
18.
Rev. saúde pública (Online) ; 54: 69, 2020. tab, graf
Article in English | LILACS (Americas) | ID: covidwho-1389803

ABSTRACT

ABSTRACT OBJECTIVE To estimate the seroprevalence of antibodies to SARS-CoV-2 among blood donors in the state of Rio de Janeiro, Brazil. METHODS Data were collected on 2,857 blood donors from April 14 to 27, 2020. This study reports crude prevalence of antibodies to SARS-CoV-2, population weighted prevalence for the state, and prevalence adjusted for test sensitivity and specificity. Logistic regression models were used to establish the correlates of SARS-CoV-2 prevalence. For the analysis, we considered collection period and site, sociodemographic characteristics, and place of residence. RESULTS The proportion of positive tests for SARS-Cov-2, without any adjustment, was 4.0% (95%CI 3.3-4.7%), and the weighted prevalence was 3.8% (95%CI 3.1-4.5%). We found lower estimates after adjusting for test sensitivity and specificity: 3.6% (95%CI 2.7-4.4%) for the non-weighted prevalence, and 3.3% (95%CI 2.6-4.1%) for the weighted prevalence. Collection period was the variable most significantly associated with crude prevalence: the later the period, the higher the prevalence. Regarding sociodemographic characteristics, the younger the blood donor, the higher the prevalence, and the lower the education level, the higher the odds of testing positive for SARS-Cov-2 antibody. We found similar results for weighted prevalence. CONCLUSIONS Our findings comply with some basic premises: the increasing trend over time, as the epidemic curve in the state is still on the rise; and the higher prevalence among both the youngest, for moving around more than older age groups, and the less educated, for encountering more difficulties in following social distancing recommendations. Despite the study limitations, we may infer that Rio de Janeiro is far from reaching the required levels of herd immunity against SARS-CoV-2.


Subject(s)
Humans , Male , Female , Adult , Aged , Young Adult , Pneumonia, Viral/immunology , Blood Donors/statistics & numerical data , Coronavirus Infections/immunology , Betacoronavirus/immunology , Antibodies, Viral/blood , Pneumonia, Viral/blood , Pneumonia, Viral/epidemiology , Brazil/epidemiology , Immunoglobulin G/blood , Immunoglobulin M/blood , Seroepidemiologic Studies , Prevalence , Cross-Sectional Studies , Regression Analysis , Sensitivity and Specificity , Coronavirus Infections/blood , Coronavirus Infections/epidemiology , Pandemics , SARS-CoV-2 , COVID-19 , Middle Aged
19.
Pharmacol Res ; 160: 105036, 2020 10.
Article in English | MEDLINE | ID: covidwho-1364401

ABSTRACT

OBJECTIVES: The current diagnosis and medicines approach in coronavirus disease 2019 (COVID-19) does not reflect the heterogeneous characteristics of this disease. This study aims to find a new antiviral combination regimen by investigating the frequency of clinically relevant and objectively identified comorbidities, and the clustering of these clinical syndromes and varying results of treatment with antiviral drugs in patients hospitalized with severe COVID-19. METHODS: This study recruited 151 severe COVID-19 infection cases diagnosed in our hospital examination and illustrated the clinical potential during a consecutive 25-day medication period. Potential differences in disease severity and clinical characteristics, hematological profile, and current pharmacologic treatments (single agent, double or triple combinations, and the combined antiviral drugs plus Lianhua Qingwen) among comorbidity clusters were explored. RESULTS: Although disease severity was comparable among three clusters, it was markedly different in terms of laboratory test status. Coagulable abnormality was mainly present in cluster 1 and cluster 2. Other indicators were normal, except for a significant increase of neutrophils presented in cluster 2. Patients showed the most complicated haematological results in cluster 3, including severe coagulation abnormalities, leukocytosis, neutrophilic granulocytosis, and lymphopenia. Our results for the first time suggest that a quadruple combination therapy (Ribavirin, Lopinavir/ritonavir, Umifenovir, and Lianhua Qingwen) can be considered as a preferred treatment approach to severe COVID-19 patients. After treatment, abnormal coagulation and leukocyte had markedly improved with a better prognosis. CONCLUSION: This study expands the understanding of the co-occurrence of combination therapy in patients with COVID-19, which provides the probability of developing novel combined therapy. Furthermore, explore clinical trials of variable antivirus treatments based on subgroup analyses or on using subgroups in the selection criteria would be the next step.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/blood , Coronavirus Infections/drug therapy , Pneumonia, Viral/blood , Pneumonia, Viral/drug therapy , Adult , Aged , Blood Cell Count , Blood Coagulation , COVID-19 , Comorbidity , Drug Therapy, Combination , Female , Granulocytes , Humans , Leukocyte Count , Leukocytosis/etiology , Lymphopenia/etiology , Male , Middle Aged , Pandemics , Treatment Outcome
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