Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 75
Filter
1.
Cells ; 11(18)2022 09 16.
Article in English | MEDLINE | ID: covidwho-2043594

ABSTRACT

Rationale: Infection with the SARS-CoV2 virus is associated with elevated neutrophil counts. Evidence of neutrophil dysfunction in COVID-19 is based on transcriptomics or single functional assays. Cell functions are interwoven pathways, and understanding the effect across the spectrum of neutrophil function may identify therapeutic targets. Objectives: Examine neutrophil phenotype and function in 41 hospitalised, non-ICU COVID-19 patients versus 23 age-matched controls (AMC) and 26 community acquired pneumonia patients (CAP). Methods: Isolated neutrophils underwent ex vivo analyses for migration, bacterial phagocytosis, ROS generation, NETosis and receptor expression. Circulating DNAse 1 activity, levels of cfDNA, MPO, VEGF, IL-6 and sTNFRI were measured and correlated to clinical outcome. Serial sampling on day three to five post hospitalization were also measured. The effect of ex vivo PI3K inhibition was measured in a further cohort of 18 COVID-19 patients. Results: Compared to AMC and CAP, COVID-19 neutrophils demonstrated elevated transmigration (p = 0.0397) and NETosis (p = 0.0332), and impaired phagocytosis (p = 0.0036) associated with impaired ROS generation (p < 0.0001). The percentage of CD54+ neutrophils (p < 0.001) was significantly increased, while surface expression of CD11b (p = 0.0014) and PD-L1 (p = 0.006) were significantly decreased in COVID-19. COVID-19 and CAP patients showed increased systemic markers of NETosis including increased cfDNA (p = 0.0396) and impaired DNAse activity (p < 0.0001). The ex vivo inhibition of PI3K γ and δ reduced NET release by COVID-19 neutrophils (p = 0.0129). Conclusions: COVID-19 is associated with neutrophil dysfunction across all main effector functions, with altered phenotype, elevated migration and NETosis, and impaired antimicrobial responses. These changes highlight that targeting neutrophil function may help modulate COVID-19 severity.


Subject(s)
COVID-19 , Neutrophils , B7-H1 Antigen , COVID-19/immunology , Cell-Free Nucleic Acids , Deoxyribonucleases , Humans , Interleukin-6/pharmacology , Neutrophils/cytology , Phenotype , Phosphatidylinositol 3-Kinases , Reactive Oxygen Species/metabolism , SARS-CoV-2
2.
Nat Immunol ; 23(5): 679-691, 2022 05.
Article in English | MEDLINE | ID: covidwho-1878539

ABSTRACT

Here we report the identification of human CD66b-CD64dimCD115- neutrophil-committed progenitor cells (NCPs) within the SSCloCD45dimCD34+ and CD34dim/- subsets in the bone marrow. NCPs were either CD45RA+ or CD45RA-, and in vitro experiments showed that CD45RA acquisition was not mandatory for their maturation process. NCPs exclusively generated human CD66b+ neutrophils in both in vitro differentiation and in vivo adoptive transfer experiments. Single-cell RNA-sequencing analysis indicated NCPs fell into four clusters, characterized by different maturation stages and distributed along two differentiation routes. One of the clusters was characterized by an interferon-stimulated gene signature, consistent with the reported expansion of peripheral mature neutrophil subsets that express interferon-stimulated genes in diseased individuals. Finally, comparison of transcriptomic and phenotypic profiles indicated NCPs represented earlier neutrophil precursors than the previously described early neutrophil progenitors (eNePs), proNeus and COVID-19 proNeus. Altogether, our data shed light on the very early phases of neutrophil ontogeny.


Subject(s)
Antigens, CD , Bone Marrow , Cell Adhesion Molecules , Cell Differentiation , Neutrophils , Receptor, Macrophage Colony-Stimulating Factor , Receptors, IgG , Bone Marrow Cells , COVID-19 , GPI-Linked Proteins , Humans , Interferons , Neutrophils/cytology
3.
Nature ; 607(7919): 578-584, 2022 07.
Article in English | MEDLINE | ID: covidwho-1873525

ABSTRACT

The nervous and immune systems are intricately linked1. Although psychological stress is known to modulate immune function, mechanistic pathways linking stress networks in the brain to peripheral leukocytes remain poorly understood2. Here we show that distinct brain regions shape leukocyte distribution and function throughout the body during acute stress in mice. Using optogenetics and chemogenetics, we demonstrate that motor circuits induce rapid neutrophil mobilization from the bone marrow to peripheral tissues through skeletal-muscle-derived neutrophil-attracting chemokines. Conversely, the paraventricular hypothalamus controls monocyte and lymphocyte egress from secondary lymphoid organs and blood to the bone marrow through direct, cell-intrinsic glucocorticoid signalling. These stress-induced, counter-directional, population-wide leukocyte shifts are associated with altered disease susceptibility. On the one hand, acute stress changes innate immunity by reprogramming neutrophils and directing their recruitment to sites of injury. On the other hand, corticotropin-releasing hormone neuron-mediated leukocyte shifts protect against the acquisition of autoimmunity, but impair immunity to SARS-CoV-2 and influenza infection. Collectively, these data show that distinct brain regions differentially and rapidly tailor the leukocyte landscape during psychological stress, therefore calibrating the ability of the immune system to respond to physical threats.


Subject(s)
Brain , Fear , Leukocytes , Motor Neurons , Neural Pathways , Stress, Psychological , Animals , Bone Marrow Cells/cytology , Bone Marrow Cells/immunology , Brain/cytology , Brain/physiology , COVID-19/immunology , Chemokines/immunology , Disease Susceptibility , Fear/physiology , Glucocorticoids/metabolism , Humans , Leukocytes/cytology , Leukocytes/immunology , Lymphocytes/cytology , Lymphocytes/immunology , Lymphoid Tissue/cytology , Lymphoid Tissue/immunology , Mice , Monocytes/cytology , Monocytes/immunology , Motor Neurons/cytology , Motor Neurons/physiology , Neutrophils/cytology , Neutrophils/immunology , Optogenetics , Orthomyxoviridae Infections/immunology , Paraventricular Hypothalamic Nucleus/physiology , SARS-CoV-2/immunology , Stress, Psychological/immunology , Stress, Psychological/physiopathology
4.
Chem Biodivers ; 19(1): e202100668, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1611203

ABSTRACT

Forsyqinlingines C (1) and D (2), two C9 -monoterpenoid alkaloids bearing a rare skeleton, were isolated from the ripe fruits of Forsythia suspensa. Their structures, including absolute configurations, were fully elucidated by extensive spectroscopic data and ECD experiments. The plausible biogenetic pathway for compounds 1 and 2 was also proposed. In vitro, two C9 -monoterpenoid alkaloids showed anti-inflammatory activity performed by the inhibitory effect on the release of ß-glucuronidase in rat polymorphonuclear leukocytes (PMNs), as well as antiviral activity against influenza A (H1N1) virus and respiratory syncytial virus (RSV).


Subject(s)
Alkaloids/chemistry , Anti-Inflammatory Agents/chemistry , Antiviral Agents/chemistry , Forsythia/chemistry , Monoterpenes/chemistry , Alkaloids/isolation & purification , Alkaloids/pharmacology , Animals , Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/pharmacology , Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , Forsythia/metabolism , Fruit/chemistry , Fruit/metabolism , Glucuronidase/metabolism , Influenza A Virus, H1N1 Subtype/drug effects , Magnetic Resonance Spectroscopy , Molecular Conformation , Neutrophils/cytology , Neutrophils/drug effects , Neutrophils/metabolism , Platelet Activating Factor/pharmacology , Rats , Respiratory Syncytial Viruses/drug effects
5.
Rev Assoc Med Bras (1992) ; 67(10): 1498-1502, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1561626

ABSTRACT

OBJECTIVE: This study investigates whether C-reactive protein, platelet-lymphocyte ratio, and neutrophil-lymphocyte ratio could be useful to predict mortality in COVID-19. METHODS: Data of 635 patients with COVID-19 followed up in Sinop Ataturk State Hospital from February to May 2020 were evaluated retrospectively. Diagnosis of COVID-19 was made according to the interim guidance of the World Health Organization. Patients were grouped into two groups based on mortality as survived and non-survived patients. Age, gender, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and C-reactive protein of the groups were investigated and compared. RESULTS: The mean age of the participants was 55.8±22.3 years. Among the patients, 584 survived and 51 patients died. Age was significantly different between the groups, 54.2±22.3 in the survived group and 75.6±11.1 in the dead group (p=0.000). In addition, neutrophil, C-reactive protein, and neutrophil-lymphocyte ratio values were significantly higher in the dead group (p=0.000). platelet-lymphocyte ratio was slightly higher in the dead group, but this difference was not significant (p=0.42). The area under the curve values for age, lymphocyte, platelet, C-reactive protein, and neutrophil-lymphocyte ratio are 0.797, 0.424, 0.485, 0.778, and 0.729, respectively. CONCLUSIONS: Our results showed that neutrophil-lymphocyte ratio and C-reactive protein are significantly higher in patients leading to death and could be effective biomarkers in predicting COVID-19 fatality. Furthermore, C-reactive protein could be used as an independent biomarker to predict death in patients with COVID-19, regardless of gender and age (p=0.000).


Subject(s)
C-Reactive Protein , COVID-19 , Lymphocytes/cytology , Neutrophils/cytology , Adult , Aged , Biomarkers , C-Reactive Protein/analysis , COVID-19/diagnosis , COVID-19/mortality , Humans , Middle Aged , Retrospective Studies
6.
Viruses ; 13(11)2021 11 21.
Article in English | MEDLINE | ID: covidwho-1538550

ABSTRACT

A cytokine storm is an abnormal discharge of soluble mediators following an inappropriate inflammatory response that leads to immunopathological events. Cytokine storms can occur after severe infections as well as in non-infectious situations where inflammatory cytokine responses are initiated, then exaggerated, but fail to return to homeostasis. Neutrophils, macrophages, mast cells, and natural killer cells are among the innate leukocytes that contribute to the pathogenesis of cytokine storms. Neutrophils participate as mediators of inflammation and have roles in promoting homeostatic conditions following pathological inflammation. This review highlights the advances in understanding the mechanisms governing neutrophilic inflammation against viral and bacterial pathogens, in cancers, and in autoimmune diseases, and how neutrophils could influence the development of cytokine storm syndromes. Evidence for the destructive potential of neutrophils in their capacity to contribute to the onset of cytokine storm syndromes is presented across a multitude of clinical scenarios. Further, a variety of potential therapeutic strategies that target neutrophils are discussed in the context of suppressing multiple inflammatory conditions.


Subject(s)
Autoimmune Diseases/immunology , Cytokine Release Syndrome , Cytokines/immunology , Inflammation/immunology , Neoplasms/immunology , Animals , Humans , Immunity, Innate , Neutrophils/cytology , Neutrophils/immunology
7.
Sci Rep ; 11(1): 21519, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1500511

ABSTRACT

A high neutrophil to lymphocyte ratio (NLR) is considered an unfavorable prognostic factor in various diseases, including COVID-19. The prognostic value of NLR in other respiratory viral infections, such as Influenza, has not hitherto been extensively studied. We aimed to compare the prognostic value of NLR in COVID-19, Influenza and Respiratory Syncytial Virus infection (RSV). A retrospective cohort of COVID-19, Influenza and RSV patients admitted to the Tel Aviv Medical Center from January 2010 to October 2020 was analyzed. Laboratory, demographic, and clinical parameters were collected. Two way analyses of variance (ANOVA) was used to compare the association between NLR values and poor outcomes among the three groups. ROC curve analyses for each virus was applied to test the discrimination ability of NLR. 722 COVID-19, 2213 influenza and 482 RSV patients were included. Above the age of 50, NLR at admission was significantly lower among COVID-19 patients (P < 0.001). NLR was associated with poor clinical outcome only in the COVID-19 group. ROC curve analysis was performed; the area under curve of poor outcomes for COVID-19 was 0.68, compared with 0.57 and 0.58 for Influenza and RSV respectively. In the COVID-19 group, multivariate logistic regression identified a high NLR (defined as a value above 6.82) to be a prognostic factor for poor clinical outcome, after adjusting for age, sex and Charlson comorbidity score (odds ratio of 2.9, P < 0.001). NLR at admission is lower and has more prognostic value in COVID-19 patients, when compared to Influenza and RSV.


Subject(s)
COVID-19/pathology , Influenza, Human/pathology , Respiratory Syncytial Virus Infections/pathology , Adult , Aged , Aged, 80 and over , Area Under Curve , COVID-19/immunology , COVID-19/virology , Female , Humans , Influenza, Human/immunology , Lymphocytes/cytology , Lymphocytes/metabolism , Male , Middle Aged , Neutrophils/cytology , Neutrophils/metabolism , Prognosis , ROC Curve , Respiratory Syncytial Virus Infections/immunology , Retrospective Studies , SARS-CoV-2/isolation & purification
8.
J Am Soc Nephrol ; 32(1): 69-85, 2021 01.
Article in English | MEDLINE | ID: covidwho-1496661

ABSTRACT

BACKGROUND: In children, the acute pyelonephritis that can result from urinary tract infections (UTIs), which commonly ascend from the bladder to the kidney, is a growing concern because it poses a risk of renal scarring and irreversible loss of kidney function. To date, the cellular mechanisms underlying acute pyelonephritis-driven renal scarring remain unknown. METHODS: We used a preclinical model of uropathogenic Escherichia coli-induced acute pyelonephritis to determine the contribution of neutrophils and monocytes to resolution of the condition and the subsequent development of kidney fibrosis. We used cell-specific monoclonal antibodies to eliminate neutrophils, monocytes, or both. Bacterial ascent and the cell dynamics of phagocytic cells were assessed by biophotonic imaging and flow cytometry, respectively. We used quantitative RT-PCR and histopathologic analyses to evaluate inflammation and renal scarring. RESULTS: We found that neutrophils are critical to control bacterial ascent, which is in line with previous studies suggesting a protective role for neutrophils during a UTI, whereas monocyte-derived macrophages orchestrate a strong, but ineffective, inflammatory response against uropathogenic, E. coli-induced, acute pyelonephritis. Experimental neutropenia during acute pyelonephritis resulted in a compensatory increase in the number of monocytes and heightened macrophage-dependent inflammation in the kidney. Exacerbated macrophage-mediated inflammatory responses promoted renal scarring and compromised renal function, as indicated by elevated serum creatinine, BUN, and potassium. CONCLUSIONS: These findings reveal a previously unappreciated outcome for neutrophil-macrophage imbalance in promoting host susceptibility to acute pyelonephritis and the development of permanent renal damage. This suggests targeting dysregulated macrophage responses might be a therapeutic tool to prevent renal scarring during acute pyelonephritis.


Subject(s)
Cicatrix/physiopathology , Kidney/physiopathology , Macrophages/cytology , Neutrophils/cytology , Pyelonephritis/metabolism , Animals , Escherichia coli , Female , Fibrosis/microbiology , Fibrosis/physiopathology , Inflammation , Kidney/microbiology , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Neutrophils/metabolism , Phagocytosis , Pyelonephritis/microbiology , Pyelonephritis/physiopathology , Urinary Tract Infections/microbiology , Urinary Tract Infections/physiopathology
9.
Inflamm Res ; 71(1): 57-67, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1491056

ABSTRACT

OBJECTIVE: Severe COVID-19 is characterized by a dysregulated immune response in which neutrophils play a critical role. Calprotectin reflects neutrophil activation and is involved in the self-amplifying thrombo-inflammatory storm in severe COVID-19. We aimed to evaluate the role of calprotectin in early prediction of severity in COVID-19 patients. METHODS: This was a multicenter prospective observational study enrolling consecutive adult COVID-19 patients. On arrival to emergency department, blood samples were collected for laboratory tests, including serum calprotectin. The primary outcome was severe respiratory failure requiring invasive mechanical ventilation and the secondary outcome was need for Intensive Care Unit (ICU) admission. RESULTS: Study population included 395 patients, 57 (14.4%) required invasive mechanical ventilation and 100 (25.3%) were admitted to ICU. Median serum calprotectin levels were significantly higher in intubated (3.73 mg/L vs. 2.63 mg/L; p < 0.001) and ICU patients (3.48 mg/L vs. 2.60 mg/L; p = 0.001). Calprotectin showed a significant accuracy to predict the need for invasive mechanical ventilation (ROC AUC 0.723) and ICU admission (ROC AUC 0.650). In multivariate analysis, serum calprotectin was an independent predictor of invasive mechanical ventilation (OR 1.161) and ICU admission (OR 1.068). CONCLUSION: Serum calprotectin can be used as an early predictor of severity in COVID-19 patients.


Subject(s)
COVID-19/blood , COVID-19/diagnosis , Leukocyte L1 Antigen Complex/blood , Neutrophil Activation , Neutrophils/cytology , Respiration, Artificial , Respiratory Insufficiency/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Area Under Curve , COVID-19/complications , Female , Humans , Immune System , Inflammation , Intensive Care Units , Male , Middle Aged , Multivariate Analysis , Predictive Value of Tests , Prospective Studies , ROC Curve , Respiratory Insufficiency/complications , Treatment Outcome , Young Adult
10.
Front Immunol ; 12: 744799, 2021.
Article in English | MEDLINE | ID: covidwho-1448731

ABSTRACT

Sepsis is a global health emergency, which is caused by various sources of infection that lead to changes in gene expression, protein-coding, and metabolism. Advancements in "omics" technologies have provided valuable tools to unravel the mechanisms involved in the pathogenesis of this disease. In this study, we performed shotgun mass spectrometry in peripheral blood mononuclear cells (PBMC) from septic patients (N=24) and healthy controls (N=9) and combined these results with two public microarray leukocytes datasets. Through combination of transcriptome and proteome profiling, we identified 170 co-differentially expressed genes/proteins. Among these, 122 genes/proteins displayed the same expression trend. Ingenuity Pathway Analysis revealed pathways related to lymphocyte functions with decreased status, and defense processes that were predicted to be strongly increased. Protein-protein interaction network analyses revealed two densely connected regions, which mainly included down-regulated genes/proteins that were related to the transcription of RNA, translation of proteins, and mitochondrial translation. Additionally, we identified one module comprising of up-regulated genes/proteins, which were mainly related to low-density neutrophils (LDNs). LDNs were reported in sepsis and in COVID-19. Changes in gene expression level were validated using quantitative real-time PCR in PBMCs from patients with sepsis. To further support that the source of the upregulated module of genes/proteins found in our results were derived from LDNs, we identified an increase of this population by flow cytometry in PBMC samples obtained from the same cohort of septic patients included in the proteomic analysis. This study provides new insights into a reprioritization of biological functions in response to sepsis that involved a transcriptional and translational shutdown of genes/proteins, with exception of a set of genes/proteins related to LDNs and host-defense system.


Subject(s)
Leukocytes, Mononuclear/metabolism , Neutrophils/metabolism , Sepsis/metabolism , Databases, Factual , Gene Expression Profiling , Gene Expression Regulation , Humans , Leukocytes, Mononuclear/cytology , Myeloid-Derived Suppressor Cells/cytology , Myeloid-Derived Suppressor Cells/metabolism , Neutrophils/cytology , Protein Interaction Maps , Proteomics , Sepsis/genetics , Sepsis/immunology
11.
Cells ; 10(10)2021 09 26.
Article in English | MEDLINE | ID: covidwho-1438528

ABSTRACT

The coronavirus disease 2019 (COVID-19) is related to enhanced production of NETs, and autoimmune/autoinflammatory phenomena. We evaluated the proportion of low-density granulocytes (LDG) by flow cytometry, and their capacity to produce NETs was compared with that of conventional neutrophils. NETs and their protein cargo were quantified by confocal microscopy and ELISA. Antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA) and the degradation capacity of NETs were addressed in serum. MILLIPLEX assay was used to assess the cytokine levels in macrophages' supernatant and serum. We found a higher proportion of LDG in severe and critical COVID-19 which correlated with severity and inflammatory markers. Severe/critical COVID-19 patients had higher plasmatic NE, LL-37 and HMGB1-DNA complexes, whilst ISG-15-DNA complexes were lower in severe patients. Sera from severe/critical COVID-19 patients had lower degradation capacity of NETs, which was reverted after adding hrDNase. Anti-NET antibodies were found in COVID-19, which correlated with ANA and ANCA positivity. NET stimuli enhanced the secretion of cytokines in macrophages. This study unveils the role of COVID-19 NETs as inducers of pro-inflammatory and autoimmune responses. The deficient degradation capacity of NETs may contribute to the accumulation of these structures and anti-NET antibodies are related to the presence of autoantibodies.


Subject(s)
Autoimmunity , COVID-19/blood , COVID-19/immunology , Extracellular Traps/immunology , Immunity, Humoral , Inflammation , Neutrophils/immunology , Antibodies, Antinuclear , Antimicrobial Cationic Peptides/blood , Autoantibodies/metabolism , Cross-Sectional Studies , Cytokines/metabolism , Cytokines/pharmacology , Flow Cytometry , Granulocytes/metabolism , HMGB1 Protein/blood , Healthy Volunteers , Humans , Microscopy, Confocal , Monocytes/cytology , Neutrophils/cytology , SARS-CoV-2 , Ubiquitins/pharmacology
12.
Thyroid ; 31(12): 1766-1775, 2021 12.
Article in English | MEDLINE | ID: covidwho-1429167

ABSTRACT

Background: Thyroid dysfunctions have been reported after Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. However, the biological mechanisms behind these conditions remain unexplored. Herein, we report on changes of the immune transcriptome in autoptic thyroid tissues of people who have died from coronavirus disease 2019 (COVID-19). Methods: Twenty-five autoptic thyroid specimens of subjects dying from COVID-19 were investigated. Eleven autoptic thyroid specimens of subjects dying from causes other than infectious conditions served as controls. RNA transcripts of 770 immune-related genes together with RNA genomes of multiple coronavirus types were measured by the nCounter system. Reverse transcription-polymerase chain reaction for two SARS-CoV-2 genes was used to assess virus positivity. Results were validated by immunohistochemistry. Results: The SARS-CoV-2 genome and antigens were detected in 9 of 25 (36%) thyroid specimens from the COVID-19 cohort. Virus-negative thyroid tissues from COVID-19 subject did not show changes of gene transcription nor significant numbers of infiltrating immune cells. Conversely, SARS-CoV-2-positive thyroid specimens showed marked upregulation of immune genes, especially those proper of the type I and type II interferon (IFN) pathways. In infected tissues, infiltrates of innate immune cells (macrophages and polymorphonuclear neutrophils) were prevalent. Conclusions: The thyroid gland can be directly infected by the SARS-CoV-2. Infection strongly activates IFN pathways. The direct viral insult combined with an intense immune response may trigger or worsen thyroid conditions in predisposed individuals.


Subject(s)
COVID-19/metabolism , Interferon Type I/metabolism , Interferon-gamma/metabolism , SARS-CoV-2 , Thyroid Gland/metabolism , Thyroid Gland/virology , Adult , Aged , Autopsy , COVID-19/mortality , Cohort Studies , Death , Female , Genome, Viral , Humans , Immunity, Innate , Macrophages/cytology , Male , Middle Aged , Neutrophils/cytology , RNA, Messenger/metabolism , Signal Transduction , Thyroid Gland/immunology
13.
BMC Infect Dis ; 21(1): 760, 2021 Aug 05.
Article in English | MEDLINE | ID: covidwho-1403220

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spread around the world. This retrospective study aims to analyze the clinical features of COVID-19 patients with cancer and identify death outcome related risk factors. METHODS: From February 10th to April 15th, 2020, 103 COVID-19 patients with cancer were enrolled. Difference analyses were performed between severe and non-severe patients. A propensity score matching (PSM) analysis was performed, including 103 COVID-19 patients with cancer and 206 matched non-cancer COVID-19 patients. Next, we identified death related risk factors and developed a nomogram for predicting the probability. RESULTS: In 103 COVID-19 patients with cancer, the main cancer categories were breast cancer, lung cancer and bladder cancer. Compared to non-severe patients, severe patients had a higher median age, and a higher proportion of smokers, diabetes, heart disease and dyspnea. In addition, most of the laboratory results between two groups were significantly different. PSM analysis found that the proportion of dyspnea was much higher in COVID-19 patients with cancer. The severity incidence in two groups were similar, while a much higher mortality was found in COVID-19 patients with cancer compared to that in COVID-19 patients without cancer (11.7% vs. 4.4%, P = 0.028). Furthermore, we found that neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) were related to death outcome. And a nomogram based on the factors was developed. CONCLUSION: In COVID-19 patients with cancer, the clinical features and laboratory results between severe group and non-severe group were significantly different. NLR and CRP were the risk factors that could predict death outcome.


Subject(s)
COVID-19 , Neoplasms , Adult , Aged , Aged, 80 and over , C-Reactive Protein/analysis , COVID-19/complications , COVID-19/mortality , Female , Humans , Lymphocytes/cytology , Male , Middle Aged , Neoplasms/complications , Neoplasms/mortality , Neutrophils/cytology , Nomograms , Retrospective Studies , Risk Factors , Young Adult
14.
FASEB J ; 35(10): e21843, 2021 10.
Article in English | MEDLINE | ID: covidwho-1378886

ABSTRACT

Robust inflammatory responses are critical to survival following respiratory infection, with current attention focused on the clinical consequences of the Coronavirus pandemic. Epigenetic factors are increasingly recognized as important determinants of immune responses, and EZH2 is a prominent target due to the availability of highly specific and efficacious antagonists. However, very little is known about the role of EZH2 in the myeloid lineage. Here, we show EZH2 acts in macrophages to limit inflammatory responses to activation, and in neutrophils for chemotaxis. Selective genetic deletion in macrophages results in a remarkable gain in protection from infection with the prevalent lung pathogen, pneumococcus. In contrast, neutrophils lacking EZH2 showed impaired mobility in response to chemotactic signals, and resulted in increased susceptibility to pneumococcus. In summary, EZH2 shows complex, and divergent roles in different myeloid lineages, likely contributing to the earlier conflicting reports. Compounds targeting EZH2 are likely to impair mucosal immunity; however, they may prove useful for conditions driven by pulmonary neutrophil influx, such as adult respiratory distress syndrome.


Subject(s)
Enhancer of Zeste Homolog 2 Protein/immunology , Inflammation/immunology , Macrophages/immunology , Neutrophils/immunology , Animals , Cells, Cultured , Macrophages/cytology , Mice, Inbred C57BL , Neutrophils/cytology
15.
PLoS One ; 16(8): e0256784, 2021.
Article in English | MEDLINE | ID: covidwho-1378138

ABSTRACT

Viral sepsis has been proposed as an accurate term to describe all multisystemic dysregulations and clinical findings in severe and critically ill COVID-19 patients. The adoption of this term may help the implementation of more accurate strategies of early diagnosis, prognosis, and in-hospital treatment. We accurately quantified 110 metabolites using targeted metabolomics, and 13 cytokines/chemokines in plasma samples of 121 COVID-19 patients with different levels of severity, and 37 non-COVID-19 individuals. Analyses revealed an integrated host-dependent dysregulation of inflammatory cytokines, neutrophil activation chemokines, glycolysis, mitochondrial metabolism, amino acid metabolism, polyamine synthesis, and lipid metabolism typical of sepsis processes distinctive of a mild disease. Dysregulated metabolites and cytokines/chemokines showed differential correlation patterns in mild and critically ill patients, indicating a crosstalk between metabolism and hyperinflammation. Using multivariate analysis, powerful models for diagnosis and prognosis of COVID-19 induced sepsis were generated, as well as for mortality prediction among septic patients. A metabolite panel made of kynurenine/tryptophan ratio, IL-6, LysoPC a C18:2, and phenylalanine discriminated non-COVID-19 from sepsis patients with an area under the curve (AUC (95%CI)) of 0.991 (0.986-0.995), with sensitivity of 0.978 (0.963-0.992) and specificity of 0.920 (0.890-0.949). The panel that included C10:2, IL-6, NLR, and C5 discriminated mild patients from sepsis patients with an AUC (95%CI) of 0.965 (0.952-0.977), with sensitivity of 0.993(0.984-1.000) and specificity of 0.851 (0.815-0.887). The panel with citric acid, LysoPC a C28:1, neutrophil-lymphocyte ratio (NLR) and kynurenine/tryptophan ratio discriminated severe patients from sepsis patients with an AUC (95%CI) of 0.829 (0.800-0.858), with sensitivity of 0.738 (0.695-0.781) and specificity of 0.781 (0.735-0.827). Septic patients who survived were different from those that did not survive with a model consisting of hippuric acid, along with the presence of Type II diabetes, with an AUC (95%CI) of 0.831 (0.788-0.874), with sensitivity of 0.765 (0.697-0.832) and specificity of 0.817 (0.770-0.865).


Subject(s)
COVID-19/pathology , Metabolomics , Sepsis/diagnosis , Adult , Area Under Curve , COVID-19/complications , COVID-19/virology , Chemokines/blood , Cytokines/blood , Female , Humans , Kynurenine/blood , Lymphocytes/cytology , Male , Middle Aged , Neutrophils/cytology , ROC Curve , Retrospective Studies , Risk Factors , SARS-CoV-2/isolation & purification , Sepsis/etiology , Severity of Illness Index , Tryptophan/blood
17.
Diabetes Res Clin Pract ; 178: 108955, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1309207

ABSTRACT

AIMS: To create and compare survival models from admission laboratory indices in people hospitalized with coronavirus disease 2019 (COVID-19) with and without diabetes. METHODS: Retrospective observational study of patients with COVID-19 with or without diabetes admitted to Sheffield Teaching Hospitals from 29 February to 01 May 2020. Predictive variables for in-hospital mortality from COVID-19 were explored using Cox proportional hazard models. RESULTS: Out of 505 patients, 156 (30.8%) had diabetes mellitus (DM) of which 143 (91.7%) had type 2 diabetes. There were significantly higher in-hospital COVID-19 deaths in those with DM [DM COVID-19 deaths 54 (34.6%) vs. non-DM COVID-19 deaths 88 (25.2%): P < 0.05]. Activated partial thromboplastin time (APPT) > 24 s without anticoagulants (HR 6.38, 95% CI: 1.07-37.87: P = 0.04), APTT > 24 s with anticoagulants (HR 24.01, 95% CI: 3.63-159.01: P < 0.001), neutrophil-lymphocyte ratio > 8 (HR 6.18, 95% CI: 2.36-16.16: P < 0.001), and sodium > 136 mmol/L (HR 3.27, 95% CI: 1.12-9.56: P = 0.03) at admission, were only associated with in-hospital COVID-19 mortality for those with diabetes. CONCLUSIONS: At admission, elevated APTT with or without anticoagulants, neutrophil-lymphocyte ratio and serum sodium are unique factors that predict in-hospital COVID-19 mortality in patients with diabetes compared to those without. This novel finding may lead to research into haematological and biochemical mechanisms to understand why those with diabetes are more susceptible to poor outcomes when infected with Covid-19, and contribute to identification of those most at risk when admitted to hospital.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Hospital Mortality , Adolescent , Adult , Aged , Aged, 80 and over , Anticoagulants/therapeutic use , COVID-19/diagnosis , COVID-19/mortality , Diabetes Mellitus, Type 2/complications , Female , Hospitalization , Hospitals, University , Humans , Lymphocytes/cytology , Male , Middle Aged , Neutrophils/cytology , Partial Thromboplastin Time , Retrospective Studies , Risk Factors , Sodium/blood , United Kingdom , Young Adult
18.
Cardiovasc Res ; 117(8): 1814-1822, 2021 07 07.
Article in English | MEDLINE | ID: covidwho-1301347

ABSTRACT

2020 has been an extraordinary year. The emergence of COVID-19 has driven urgent research in pulmonary and cardiovascular science and other fields. It has also shaped the way that we work with many experimental laboratories shutting down for several months, while bioinformatics approaches and other large data projects have gained prominence. Despite these setbacks, vascular biology research is stronger than ever. On behalf of the European Society of Cardiology Council for Basic Cardiovascular Science (ESC CBCS), here we review some of the vascular biology research highlights for 2020. This review is not exhaustive and there are many outstanding vascular biology publications that we were unable to cite due to page limits. Notwithstanding this, we have provided a snapshot of vascular biology research excellence in 2020 and identify topics that are in the ascendency and likely to gain prominence in coming years.


Subject(s)
COVID-19/diagnosis , Extracellular Traps/physiology , Neutrophils/cytology , Smartphone , Computational Biology , Humans , SARS-CoV-2/pathogenicity
19.
PLoS One ; 16(6): e0252599, 2021.
Article in English | MEDLINE | ID: covidwho-1285199

ABSTRACT

Inflammation has an important role in the progression of various viral pneumonia, including COVID-19. Circulating biomarkers that can evaluate inflammation and immune status are potentially useful in diagnosing and prognosis of COVID-19 patients. Even more so when they are a part of the routine evaluation, chest CT could have even higher diagnostic accuracy than RT-PCT alone in a suggestive clinical context. This study aims to evaluate the correlation between inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), platelets-to-lymphocytes ratio (PLR), and eosinophils with the severity of CT lesions in patients with COVID-19. The second objective was to seek a statically significant cut-off value for NLR and PLR that could suggest COVID-19. Correlation of both NLR and PLR with already established inflammatory markers such as CRP, ESR, and those specific for COVID-19 (ferritin, D-dimers, and eosinophils) were also evaluated. One hundred forty-nine patients with confirmed COVID-19 disease and 149 age-matched control were evaluated through blood tests, and COVID-19 patients had thorax CT performed. Both NLR and PLR correlated positive chest CT scan severity. Both NLR and PLR correlated positive chest CT scan severity. When NLR value is below 5.04, CT score is lower than 3 with a probability of 94%, while when NLR is higher than 5.04, the probability of severe CT changes is only 50%. For eosinophils, a value of 0.35% corresponds to chest CT severity of 2 (Se = 0.88, Sp = 0.43, AUC = 0.661, 95% CI (0.544; 0.779), p = 0.021. NLR and PLR had significantly higher values in COVID-19 patients. In our study a NLR = 2.90 and PLR = 186 have a good specificity (0.89, p = 0.001, respectively 0.92, p<0.001). Higher levels in NLR, PLR should prompt the clinician to prescribe a thorax CT as it could reveal important lesions that could influence the patient's future management.


Subject(s)
Blood Platelets/cytology , COVID-19/diagnostic imaging , COVID-19/immunology , Eosinophils/cytology , Neutrophils/cytology , Signal-To-Noise Ratio , Tomography, X-Ray Computed , Adult , COVID-19/pathology , Female , Humans , Lymphocyte Count , Male , Middle Aged
20.
Sci Rep ; 11(1): 13026, 2021 06 22.
Article in English | MEDLINE | ID: covidwho-1279902

ABSTRACT

The objective of the study was to develop and validate a prediction model that identifies COVID-19 patients at risk of requiring oxygen support based on five parameters: C-reactive protein (CRP), hypertension, age, and neutrophil and lymphocyte counts (CHANeL). This retrospective cohort study included 221 consecutive COVID-19 patients and the patients were randomly assigned randomly to a training set and a test set in a ratio of 1:1. Logistic regression, logistic LASSO regression, Random Forest, Support Vector Machine, and XGBoost analyses were performed based on age, hypertension status, serial CRP, and neutrophil and lymphocyte counts during the first 3 days of hospitalization. The ability of the model to predict oxygen requirement during hospitalization was tested. During hospitalization, 45 (41.8%) patients in the training set (n = 110) and 41 (36.9%) in the test set (n = 111) required supplementary oxygen support. The logistic LASSO regression model exhibited the highest AUC for the test set, with a sensitivity of 0.927 and a specificity of 0.814. An online risk calculator for oxygen requirement using CHANeL predictors was developed. "CHANeL" prediction models based on serial CRP, neutrophil, and lymphocyte counts during the first 3 days of hospitalization, along with age and hypertension status, provide a reliable estimate of the risk of supplement oxygen requirement among patients hospitalized with COVID-19.


Subject(s)
C-Reactive Protein/analysis , COVID-19/pathology , Hypertension/complications , Lymphocytes/cytology , Neutrophils/cytology , Oxygen Inhalation Therapy , Age Factors , Aged , Area Under Curve , Biomarkers/analysis , Biomarkers/metabolism , COVID-19/complications , COVID-19/virology , Female , Humans , Logistic Models , Lymphocytes/metabolism , Male , Middle Aged , Neutrophils/metabolism , ROC Curve , Retrospective Studies , SARS-CoV-2/isolation & purification , Severity of Illness Index , Support Vector Machine
SELECTION OF CITATIONS
SEARCH DETAIL