scholarly journals Yellow fever disease severity is driven by an acute cytokine storm modulated by an interplay between the human gut microbiome and the metabolome

2021 ◽  
Author(s):  
Adam-Nicolas Pelletier ◽  
Mateus Tomazella ◽  
Karina de Carvalho ◽  
Andre Nicolau ◽  
Marianna Marmoratto ◽  
...  
Keyword(s):  
Disease Severity ◽  
Yellow Fever ◽  
Cytokine Production ◽  
Severe Disease ◽  
Cytokine Storm ◽  
Human Gut ◽  
Proteolytic Bacteria ◽  
Integrated Omics ◽  
Treg Differentiation ◽  
Pro Inflammatory Cytokines

AbstractInfection with Yellow Fever (YF) can lead to multiple outcomes ranging from death from total organ failure to clearance of viremia and survival. The mechanisms underlying these differences in clinical outcomes have yet to be defined. We had access to a cohort of YF infected subjects that showed these range of outcomes. An unbiased integrated OMICs approach was used to identify pathways and effector molecules that drive the severe disease and death as compared to resolution of infection. We used the MELD and SIC score as objective markers of disease severity. We show that a specific signature of upregulated innate pro-inflammatory cytokines significantly demarcates subjects with severe disease leading to death from subjects who clear virus. Pathogen sequencing showed heightened levels of proteolytic bacteria at the i.e Actinobacteria and these were correlated to lower levels of tryptophan and tyrosine amino acids measured by untargeted metabolomics. These two features were significantly associated to MELD scores synonymous of milder disease. Propionate a bacterial metabolite that triggers Treg differentiation that can as well limit the hyperimmune activation associated to severe outcome was also associated to improved outcome. Our results suggest a model whereby proteolytic bacteria limit the availability of the aromatic amino acid pool available for cytokine production thereby preventing the induction of the cytokine storm that is associated to severe disease and death.

scholarly journals Letter to the Editor in response to Chen et al. 2020

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Jaya Ponnampalam ◽  
George Seligmann ◽  
Tanaya Gandhi ◽  
Dilen Parmar
Keyword(s):  
Lung Injury ◽  
Disease Severity ◽  
Inflammatory Cytokines ◽  
Survival Benefit ◽  
Independent Predictor ◽  
Mortality Rates ◽  
Cytokine Storm ◽  
Tnf Α ◽  
Novel Therapeutic ◽  
Pro Inflammatory Cytokines

AbstractWe would like to comment on the article entitled “Association between cytokine profiles and lung injury in COVID-19 pneumonia” by Li-Da Chen and colleagues, with respect to emerging data regarding the immunopathogenesis of COVID-19. Chen et al. demonstrated the relevance of IL-2R, IL-6 and TNF-α in the cytokine storm and IL-6 as an independent predictor for COVID-19 severity. Del Valle et al. corroborated these findings with regard to IL-6 and disease severity, however, they also showed IL-8 to be of significance. This may be explained by the varying techniques used by the two studies to determine severity. Further studies including critically ill patients and the analysis of mortality rates in this patient cohort would greatly enhance the clinical relevance of these findings. As speculated by Chen et al., early studies on the use of tocilizumab in COVID-19 patients were promising, however, full results from ongoing trials are required to confirm a survival benefit in patients treated with tocilizumab. Moreover, investigating the roles of other pro-inflammatory cytokines and their impact on disease severity could potentially inform novel therapeutic targets.

Storm at the Time of Corona: A Glimpse at the Current Understanding and Therapeutic Opportunities of the SARS-CoV-2 Cytokine Storm

2020 ◽  
Vol 26 ◽  
Author(s):  
Monireh Torabi-Rahvar ◽  
Nima Rezaei
Keyword(s):  
Clinical Trials ◽  
Distress Syndrome ◽  
Severe Disease ◽  
Immune Dysregulation ◽  
Cytokine Storm ◽  
Jak Inhibitors ◽  
Severe Phenotype ◽  
Inflammatory Monocytes ◽  
Viral Virulence ◽  
Pro Inflammatory Cytokines

: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may lead to severe disease in some cases, leading to acute respiratory distress syndrome, multi-organ failure, and death. This severe phenotype seems to be associated with a cytokine storm and immune dysregulation. Increased pro-inflammatory cytokines and CD14+CD16+ inflammatory monocytes, lymphopenia, and decreased levels of regulatory T cells are some of the immunological features that are seen in patients with SARS-CoV-2. As the outcome of SARS-CoV-2 is influenced by both viral virulence and dysregulated inflammatory response, a combination therapy approach using antiviral drugs plus anti-inflammatory treatments, such as corticosteroids, monoclonal antibodies against the IL-6 and IL-1β pathways, and JAK inhibitors are under clinical trials

scholarly journals Distinct Effects of Escherichia coli,Pseudomonas aeruginosa and Staphylococcus aureus Cell Wall Component-Induced Inflammation on the Iron Metabolism of THP-1 Cells

2021 ◽  
Vol 22 (3) ◽  
pp. 1497
Author(s):  
Edina Pandur ◽  
Kitti Tamási ◽  
Ramóna Pap ◽  
Gergely Jánosa ◽  
Katalin Sipos
Keyword(s):  
Cell Wall ◽  
Inflammatory Cytokines ◽  
Iron Metabolism ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Storage Proteins ◽  
Iron Storage ◽  
E Coli ◽  
Iron Storage Proteins ◽  
Pro Inflammatory Cytokines

Macrophages are essential immune cells of the innate immune system. They participate in the development and regulation of inflammation. Macrophages play a fundamental role in fighting against bacterial infections by phagocytosis of bacteria, and they also have a specific role in immunomodulation by secreting pro-inflammatory cytokines. In bacterial infection, macrophages decrease the serum iron concentration by removing iron from the blood, acting as one of the most important regulatory cells of iron homeostasis. We examined whether the Gram-positive and Gram-negative cell wall components from various bacterial strains affect the cytokine production and iron transport, storage and utilization of THP-1 monocytes in different ways. We found that S. aureus lipoteichoic acid (LTA) was less effective in activating pro-inflammatory cytokine expression that may related to its effect on fractalkine production. LTA-treated cells increased iron uptake through divalent metal transporter-1, but did not elevate the expression of cytosolic and mitochondrial iron storage proteins, suggesting that the cells maintained iron efflux via the ferroportin iron exporter. E. coli and P. aeruginosa lipopolysaccharides (LPSs) acted similarly on THP-1 cells, but the rates of the alterations of the examined proteins were different. E. coli LPS was more effective in increasing the pro-inflammatory cytokine production, meanwhile it caused less dramatic alterations in iron metabolism. P. aeruginosa LPS-treated cells produced a smaller amount of pro-inflammatory cytokines, but caused remarkable elevation of both cytosolic and mitochondrial iron storage proteins and intracellular iron content compared to E. coli LPS. These results prove that LPS molecules from different bacterial sources alter diverse molecular mechanisms in macrophages that prepossess the outcome of the bacterial infection.

scholarly journals Serum C-Reactive Protein and Interleukin-6 Levels as Biomarkers for Disease Severity and Clinical Outcomes in Patients with Idiopathic Granulomatous Mastitis

2021 ◽  
Vol 10 (10) ◽  
pp. 2077
Author(s):  
Yi-Min Huang ◽  
Chiao Lo ◽  
Chiao-Feng Cheng ◽  
Cheng-Hsun Lu ◽  
Song-Chou Hsieh ◽  
...  
Keyword(s):  
Disease Severity ◽  
Severe Disease ◽  
Linear Regression Analysis ◽  
Multiple Linear Regression Analysis ◽  
Serum Biomarkers ◽  
Healthy Controls ◽  
Granulomatous Mastitis ◽  
C Reactive Protein ◽  
Idiopathic Granulomatous Mastitis ◽  
Reactive Protein

Idiopathic granulomatous mastitis (IGM) is a rare inflammatory breast disease mimicking breast cancer. Limited research has been conducted on the application of serum biomarkers. This study aims to investigate the association of serum biomarkers with disease severity in patients with IGM. From November 2011 to March 2020, medical records of patients with IGM were reviewed. Serum cytokine levels were measured in patients and healthy controls between July 2018 and March 2020. A total of 41 patients with histologically proven IGM were found. Serum interleukin (IL)-6 level was significantly higher in patients with IGM (n = 11) than healthy controls (n = 7). Serum IL-6 and C-reactive protein (CRP) levels were significantly higher in patients with severe disease than mild and moderate disease. Serum IL-6 (Spearman’s ρ = 0.855; p < 0.001) and CRP (Spearman’s ρ = 0.838; p = 0.001) levels were associated with time to resolution. A higher serum CRP level was associated with a longer time to resolution (B = 0.322; p < 0.001) in multiple linear regression analysis. Serum IL-6 and CRP levels can be used as biomarkers for the evaluation of disease severity in IGM. IL-6 may play a crucial role in the immunopathology of IGM.

scholarly journals Obesity as a Risk Factor for Severe COVID-19 and Complications: A Review

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 933
Author(s):  
Fien Demeulemeester ◽  
Karin de Punder ◽  
Marloes van Heijningen ◽  
Femke van Doesburg
Keyword(s):  
Risk Factor ◽  
Disease Severity ◽  
Viral Entry ◽  
Thrombus Formation ◽  
Clinical Findings ◽  
High Risk Group ◽  
Therapeutic Interventions ◽  
Cytokine Storm ◽  
Negative Consequences ◽  
Major Complications

Emerging data suggest that obesity is a major risk factor for the progression of major complications such as acute respiratory distress syndrome (ARDS), cytokine storm and coagulopathy in COVID-19. Understanding the mechanisms underlying the link between obesity and disease severity as a result of SARS-CoV-2 infection is crucial for the development of new therapeutic interventions and preventive measures in this high-risk group. We propose that multiple features of obesity contribute to the prevalence of severe COVID-19 and complications. First, viral entry can be facilitated by the upregulation of viral entry receptors, like angiotensin-converting enzyme 2 (ACE2), among others. Second, obesity-induced chronic inflammation and disruptions of insulin and leptin signaling can result in impaired viral clearance and a disproportionate or hyper-inflammatory response, which together with elevated ferritin levels can be a direct cause for ARDS and cytokine storm. Third, the negative consequences of obesity on blood coagulation can contribute to the progression of thrombus formation and hemorrhage. In this review we first summarize clinical findings on the relationship between obesity and COVID-19 disease severity and then further discuss potential mechanisms that could explain the risk for major complications in patients suffering from obesity.

scholarly journals Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 653
Author(s):  
Seth O. Asiedu ◽  
Samuel K. Kwofie ◽  
Emmanuel Broni ◽  
Michael D. Wilson
Keyword(s):  
Molecular Docking ◽  
P38 Mapk ◽  
Inflammatory Cytokines ◽  
Binding Energies ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Activity ◽  
Computational Techniques ◽  
Cytokine Storm ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19.

scholarly journals Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio and Their Role as Predictors of Disease Severity of Coronavirus Disease 2019 (COVID-19)

2021 ◽  
Author(s):  
Rohit Jain ◽  
Arun Gopal ◽  
Basant Kumar Pathak ◽  
Sourya Sourabh Mohakuda ◽  
TVSVGK Tilak ◽  
...  
Keyword(s):  
Disease Severity ◽  
Complete Blood Count ◽  
Wide Spectrum ◽  
Statistical Significance ◽  
Severe Disease ◽  
Neutrophil To Lymphocyte Ratio ◽  
Screening Tools ◽  
Platelet To Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
Time Of Admission

Abstract Context Due to the wide spectrum of clinical illness in coronavirus disease 2019 (COVID-19) patients, it is important to stratify patients into severe and nonsevere categories. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been evaluated rapidly by a few studies worldwide for its association with severe disease, but practically none have been conducted in the Indian population. This study was undertaken to examine the role of NLR and PLR in predicting severe disease in Indian patients. Objectives The objective was to study the association of NLR and PLR observed at the time of admission with maximum disease severity during hospitalization and to study their role in predicting disease severity. Material and Methods A total of 229 COVID-19 patients were admitted at the center during the study period. After applying inclusion and exclusion criteria, 191 patients were included in the study. The demographic, clinical, and laboratory (complete blood count, NLR, and PLR) data of all patients were obtained at the time of admission. Maximum disease severity of all patients was assessed during hospitalization. Statistical Analysis Chi-square and Mann–Whitney U tests were used to assess statistical significance. Receiver operating characteristic curve (ROC) was plotted for NLR and PLR to estimate the cutoff values and sensitivity and specificity using Youden’s index for predicting severe disease. Logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals. Results Mean NLR and PLR were significantly higher in severe patients (NLR = 7.41; PLR = 204) compared with nonsevere patients (NLR = 3.30; PLR = 121). ROC analysis showed that NLR, in comparison to PLR, had a higher area under the curve (AUC) of 0.779, with a larger OR of 1.237 and cutoff of 4.1, and showed 69% sensitivity and 78% specificity in predicting severe disease. Cut off for PLR was 115.3, which showed 79% sensitivity and 62% specificity in predicting severe disease. Conclusion NLR and PLR, both showing acceptable AUCs, can be used as screening tools to predict disease severity. However, NLR was a better predictor of disease severity.

scholarly journals Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm

Vaccines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 436
Author(s):  
Ali A. Rabaan ◽  
Shamsah H. Al-Ahmed ◽  
Javed Muhammad ◽  
Amjad Khan ◽  
Anupam A Sule ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Markers ◽  
Therapeutic Drug ◽  
Molecular Pathways ◽  
Cytokine Storm ◽  
Immunomodulatory Drugs ◽  
Alveolar Cells ◽  
Systemic Complications ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a severe pandemic of the current century. The vicious tentacles of the disease have been disseminated worldwide with unknown complications and repercussions. Advanced COVID-19 syndrome is characterized by the uncontrolled and elevated release of pro-inflammatory cytokines and suppressed immunity, leading to the cytokine storm. The uncontrolled and dysregulated secretion of inflammatory and pro-inflammatory cytokines is positively associated with the severity of the viral infection and mortality rate. The secretion of various pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6 leads to a hyperinflammatory response by recruiting macrophages, T and B cells in the lung alveolar cells. Moreover, it has been hypothesized that immune cells such as macrophages recruit inflammatory monocytes in the alveolar cells and allow the production of large amounts of cytokines in the alveoli, leading to a hyperinflammatory response in severely ill patients with COVID-19. This cascade of events may lead to multiple organ failure, acute respiratory distress, or pneumonia. Although the disease has a higher survival rate than other chronic diseases, the incidence of complications in the geriatric population are considerably high, with more systemic complications. This review sheds light on the pivotal roles played by various inflammatory markers in COVID-19-related complications. Different molecular pathways, such as the activation of JAK and JAK/STAT signaling are crucial in the progression of cytokine storm; hence, various mechanisms, immunological pathways, and functions of cytokines and other inflammatory markers have been discussed. A thorough understanding of cytokines’ molecular pathways and their activation procedures will add more insight into understanding immunopathology and designing appropriate drugs, therapies, and control measures to counter COVID-19. Recently, anti-inflammatory drugs and several antiviral drugs have been reported as effective therapeutic drug candidates to control hypercytokinemia or cytokine storm. Hence, the present review also discussed prospective anti-inflammatory and relevant immunomodulatory drugs currently in various trial phases and their possible implications.

scholarly journals CD169/SIGLEC1 is expressed on circulating monocytes in COVID-19 and expression levels are associated with disease severity

Infection ◽  
2021 ◽  
Author(s):  
Jan-Moritz Doehn ◽  
Christoph Tabeling ◽  
Robert Biesen ◽  
Jacopo Saccomanno ◽  
Elena Madlung ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Disease Severity ◽  
Clinical Studies ◽  
Viral Infections ◽  
Severe Disease ◽  
Type I Interferons ◽  
Type I ◽  
Interferon Signaling ◽  
Expression Levels

AbstractCoronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons.

scholarly journals Informing the public health response to COVID-19: a systematic review of risk factors for disease, severity, and mortality

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
M. Flook ◽  
C. Jackson ◽  
E. Vasileiou ◽  
C. R. Simpson ◽  
M. D. Muckian ◽  
...  
Keyword(s):  
Public Health ◽  
Risk Factors ◽  
Systematic Review ◽  
At Risk ◽  
Risk Factor ◽  
Disease Severity ◽  
Severe Disease ◽  
Public Health Response ◽  
Wide Range ◽  
Multivariable Analyses

Abstract Background Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) has challenged public health agencies globally. In order to effectively target government responses, it is critical to identify the individuals most at risk of coronavirus disease-19 (COVID-19), developing severe clinical signs, and mortality. We undertook a systematic review of the literature to present the current status of scientific knowledge in these areas and describe the need for unified global approaches, moving forwards, as well as lessons learnt for future pandemics. Methods Medline, Embase and Global Health were searched to the end of April 2020, as well as the Web of Science. Search terms were specific to the SARS-CoV-2 virus and COVID-19. Comparative studies of risk factors from any setting, population group and in any language were included. Titles, abstracts and full texts were screened by two reviewers and extracted in duplicate into a standardised form. Data were extracted on risk factors for COVID-19 disease, severe disease, or death and were narratively and descriptively synthesised. Results One thousand two hundred and thirty-eight papers were identified post-deduplication. Thirty-three met our inclusion criteria, of which 26 were from China. Six assessed the risk of contracting the disease, 20 the risk of having severe disease and ten the risk of dying. Age, gender and co-morbidities were commonly assessed as risk factors. The weight of evidence showed increasing age to be associated with severe disease and mortality, and general comorbidities with mortality. Only seven studies presented multivariable analyses and power was generally limited. A wide range of definitions were used for disease severity. Conclusions The volume of literature generated in the short time since the appearance of SARS-CoV-2 has been considerable. Many studies have sought to document the risk factors for COVID-19 disease, disease severity and mortality; age was the only risk factor based on robust studies and with a consistent body of evidence. Mechanistic studies are required to understand why age is such an important risk factor. At the start of pandemics, large, standardised, studies that use multivariable analyses are urgently needed so that the populations most at risk can be rapidly protected. Registration This review was registered on PROSPERO as CRD42020177714.

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