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1.
Crit Care Med ; 49(10): 1664-1673, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1452743

ABSTRACT

OBJECTIVES: The rapid diagnosis of acute infections and sepsis remains a serious challenge. As a result of limitations in current diagnostics, guidelines recommend early antimicrobials for suspected sepsis patients to improve outcomes at a cost to antimicrobial stewardship. We aimed to develop and prospectively validate a new, 29-messenger RNA blood-based host-response classifier Inflammatix Bacterial Viral Non-Infected version 2 (IMX-BVN-2) to determine the likelihood of bacterial and viral infections. DESIGN: Prospective observational study. SETTING: Emergency Department, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Germany. PATIENTS: Three hundred twelve adult patients presenting to the emergency department with suspected acute infections or sepsis with at least one vital sign change. INTERVENTIONS: None (observational study only). MEASUREMENTS AND MAIN RESULTS: Gene expression levels from extracted whole blood RNA was quantified on a NanoString nCounter SPRINT (NanoString Technologies, Seattle, WA). Two predicted probability scores for the presence of bacterial and viral infection were calculated using the IMX-BVN-2 neural network classifier, which was trained on an independent development set. The IMX-BVN-2 bacterial score showed an area under the receiver operating curve for adjudicated bacterial versus ruled out bacterial infection of 0.90 (95% CI, 0.85-0.95) compared with 0.89 (95% CI, 0.84-0.94) for procalcitonin with procalcitonin being used in the adjudication. The IMX-BVN-2 viral score area under the receiver operating curve for adjudicated versus ruled out viral infection was 0.83 (95% CI, 0.77-0.89). CONCLUSIONS: IMX-BVN-2 demonstrated accuracy for detecting both viral infections and bacterial infections. This shows the potential of host-response tests as a novel and practical approach for determining the causes of infections, which could improve patient outcomes while upholding antimicrobial stewardship.


Subject(s)
Bacterial Infections/diagnosis , RNA, Messenger/analysis , Virus Diseases/diagnosis , Aged , Aged, 80 and over , Area Under Curve , Bacterial Infections/blood , Bacterial Infections/physiopathology , Berlin , Biomarkers/analysis , Biomarkers/blood , Emergency Service, Hospital/organization & administration , Emergency Service, Hospital/statistics & numerical data , Female , Humans , Male , Middle Aged , Prospective Studies , RNA, Messenger/blood , ROC Curve , Virus Diseases/blood , Virus Diseases/physiopathology
2.
Sci Rep ; 10(1): 14186, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-1434143

ABSTRACT

Infections cause varying degrees of haemostatic dysfunction which can be detected by clot waveform analysis (CWA), a global haemostatic marker. CWA has been shown to predict poor outcomes in severe infections with disseminated intravascular coagulopathy. The effect of less severe bacterial and viral infections on CWA has not been established. We hypothesized that different infections influence CWA distinctively. Patients admitted with bacterial infections, dengue and upper respiratory tract viral infections were recruited if they had an activated partial thromboplastin time (aPTT) measured on admission. APTT-based CWA was performed on Sysmex CS2100i automated analyser using Dade Actin FSL reagent. CWA parameters [(maximum velocity (min1), maximum acceleration (min2) and maximum deceleration (max2)] were compared against control patients. Infected patients (n = 101) had longer aPTT than controls (n = 112) (34.37 ± 7.72 s vs 27.80 ± 1.59 s, p < 0.001), with the mean (± SD) aPTT longest in dengue infection (n = 36) (37.99 ± 7.93 s), followed by bacterial infection (n = 52) (33.96 ± 7.33 s) and respiratory viral infection (n = 13) (29.98 ± 3.92 s). Compared to controls (min1; min2; max2) (5.53 ± 1.16%/s; 0.89 ± 0.19%/s2; 0.74 ± 0.16%/s2), bacterial infection has higher CWA results (6.92 ± 1.60%/s; 1.04 ± 0.28%/s2; 0.82 ± 0.24%/s2, all p < 0.05); dengue infection has significantly lower CWA values (3.93 ± 1.32%/s; 0.57 ± 0.17%/s2; 0.43 ± 0.14%/s2, all p < 0.001) whilst respiratory virus infection has similar results (6.19 ± 1.32%/s; 0.95 ± 0.21%/s2; 0.73 ± 0.18%/s2, all p > 0.05). CWA parameters demonstrated positive correlation with C-reactive protein levels (min1: r = 0.54, min2: r = 0.44, max2: r = 0.34; all p < 0.01). Different infections affect CWA distinctively. CWA could provide information on the haemostatic milieu triggered by infection and further studies are needed to better define its application in this area.


Subject(s)
Bacterial Infections/blood , Hemostasis , Partial Thromboplastin Time/methods , Virus Diseases/blood , Aged , Aged, 80 and over , C-Reactive Protein/analysis , Dengue/blood , Disseminated Intravascular Coagulation/blood , Disseminated Intravascular Coagulation/etiology , Elective Surgical Procedures , Female , Humans , Male , Middle Aged , Procalcitonin/blood , Respiratory Tract Infections/blood
3.
Immunity ; 54(4): 753-768.e5, 2021 04 13.
Article in English | MEDLINE | ID: covidwho-1385739

ABSTRACT

Viral infections induce a conserved host response distinct from bacterial infections. We hypothesized that the conserved response is associated with disease severity and is distinct between patients with different outcomes. To test this, we integrated 4,780 blood transcriptome profiles from patients aged 0 to 90 years infected with one of 16 viruses, including SARS-CoV-2, Ebola, chikungunya, and influenza, across 34 cohorts from 18 countries, and single-cell RNA sequencing profiles of 702,970 immune cells from 289 samples across three cohorts. Severe viral infection was associated with increased hematopoiesis, myelopoiesis, and myeloid-derived suppressor cells. We identified protective and detrimental gene modules that defined distinct trajectories associated with mild versus severe outcomes. The interferon response was decoupled from the protective host response in patients with severe outcomes. These findings were consistent, irrespective of age and virus, and provide insights to accelerate the development of diagnostics and host-directed therapies to improve global pandemic preparedness.


Subject(s)
Immunity/genetics , Virus Diseases/immunology , Antigen Presentation/genetics , Cohort Studies , Hematopoiesis/genetics , Humans , Interferons/blood , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Myeloid Cells/immunology , Myeloid Cells/pathology , Prognosis , Severity of Illness Index , Systems Biology , Transcriptome , Virus Diseases/blood , Virus Diseases/classification , Virus Diseases/genetics , Viruses/classification , Viruses/pathogenicity
4.
Front Immunol ; 12: 659419, 2021.
Article in English | MEDLINE | ID: covidwho-1389180

ABSTRACT

Highly pathogenic virus infections usually trigger cytokine storms, which may have adverse effects on vital organs and result in high mortalities. The two cytokines interleukin (IL)-4 and interferon (IFN)-γ play key roles in the generation and regulation of cytokine storms. However, it is still unclear whether the cytokine with the largest induction amplitude is the same under different virus infections. It is unknown which is the most critical and whether there are any mathematical formulas that can fit the changing rules of cytokines. Three coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2), three influenza viruses (2009H1N1, H5N1 and H7N9), Ebola virus, human immunodeficiency virus, dengue virus, Zika virus, West Nile virus, hepatitis B virus, hepatitis C virus, and enterovirus 71 were included in this analysis. We retrieved the cytokine fold change (FC), viral load, and clearance rate data from these highly pathogenic virus infections in humans and analyzed the correlations among them. Our analysis showed that interferon-inducible protein (IP)-10, IL-6, IL-8 and IL-17 are the most common cytokines with the largest induction amplitudes. Equations were obtained: the maximum induced cytokine (max) FC = IFN-γ FC × (IFN-γ FC/IL-4 FC) (if IFN-γ FC/IL-4 FC > 1); max FC = IL-4 FC (if IFN-γ FC/IL-4 FC < 1). For IFN-γ-inducible infections, 1.30 × log2 (IFN-γ FC) = log10 (viral load) - 2.48 - 2.83 × (clearance rate). The clinical relevance of cytokines and their antagonists is also discussed.


Subject(s)
Cytokine Release Syndrome/immunology , Cytokines/blood , Models, Immunological , Virus Diseases/complications , Biomarkers/blood , Biomarkers/metabolism , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/virology , Cytokines/immunology , Cytokines/metabolism , Humans , Viral Load/immunology , Virus Diseases/blood , Virus Diseases/immunology , Virus Diseases/virology
5.
Adv Food Nutr Res ; 96: 417-429, 2021.
Article in English | MEDLINE | ID: covidwho-1265623

ABSTRACT

Selenium (Se) is an element commonly found in the environment at different levels. Its compounds are found in soil, water, and air. This element is also present in raw materials of plant and animal origin, so it can be introduced into human organisms through food. Selenium is a cofactor of enzymes responsible for the antioxidant protection of the body and plays an important role in regulating inflammatory processes in the body. A deficiency in selenium is associated with a number of viral diseases, including COVID-19. This element, taken in excess, may have a toxic effect in the form of joint diseases and diseases of the blood system. Persistent selenium deficiency in the body may also impact infertility, and in such cases supplementation is needed.


Subject(s)
COVID-19/blood , Nutritional Status , Selenium/blood , COVID-19/etiology , Female , Humans , Infertility/blood , Infertility/drug therapy , Infertility/etiology , Male , Selenium/deficiency , Selenium/therapeutic use , Selenium/toxicity , Virus Diseases/blood , Virus Diseases/etiology
6.
Front Immunol ; 11: 575074, 2020.
Article in English | MEDLINE | ID: covidwho-1256374

ABSTRACT

Combined cellular and humoral host immune response determine the clinical course of a viral infection and effectiveness of vaccination, but currently the cellular immune response cannot be measured on simple blood samples. As functional activity of immune cells is determined by coordinated activity of signaling pathways, we developed mRNA-based JAK-STAT signaling pathway activity assays to quantitatively measure the cellular immune response on Affymetrix expression microarray data of various types of blood samples from virally infected patients (influenza, RSV, dengue, yellow fever, rotavirus) or vaccinated individuals, and to determine vaccine immunogenicity. JAK-STAT1/2 pathway activity was increased in blood samples of patients with viral, but not bacterial, infection and was higher in influenza compared to RSV-infected patients, reflecting known differences in immunogenicity. High JAK-STAT3 pathway activity was associated with more severe RSV infection. In contrast to inactivated influenza virus vaccine, live yellow fever vaccine did induce JAK-STAT1/2 pathway activity in blood samples, indicating superior immunogenicity. Normal (healthy) JAK-STAT1/2 pathway activity was established, enabling assay interpretation without the need for a reference sample. The JAK-STAT pathway assays enable measurement of cellular immune response for prognosis, therapy stratification, vaccine development, and clinical testing.


Subject(s)
Dengue Virus/immunology , Immunity, Cellular , Orthomyxoviridae/immunology , Respiratory Syncytial Virus, Human/immunology , Rotavirus/immunology , Viral Vaccines/therapeutic use , Virus Diseases/immunology , Yellow fever virus/immunology , Biomarkers/blood , Dengue/blood , Dengue/immunology , Dengue/prevention & control , Dengue/virology , Dengue Vaccines/therapeutic use , Dengue Virus/pathogenicity , Diagnosis, Differential , Host-Pathogen Interactions , Humans , Immunogenicity, Vaccine , Influenza Vaccines/therapeutic use , Influenza, Human/blood , Influenza, Human/immunology , Influenza, Human/prevention & control , Influenza, Human/virology , Oligonucleotide Array Sequence Analysis , Orthomyxoviridae/pathogenicity , Predictive Value of Tests , RNA, Messenger/blood , RNA, Messenger/genetics , Respiratory Syncytial Virus Infections/blood , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Virus, Human/pathogenicity , Rotavirus/pathogenicity , Rotavirus Infections/blood , Rotavirus Infections/immunology , Rotavirus Infections/prevention & control , Rotavirus Infections/virology , Rotavirus Vaccines , Signal Transduction/genetics , Virus Diseases/blood , Virus Diseases/prevention & control , Virus Diseases/virology , Yellow Fever/blood , Yellow Fever/immunology , Yellow Fever/prevention & control , Yellow Fever/virology , Yellow Fever Vaccine/therapeutic use , Yellow fever virus/pathogenicity
7.
EBioMedicine ; 67: 103352, 2021 May.
Article in English | MEDLINE | ID: covidwho-1205123

ABSTRACT

BACKGROUND: Precise differential diagnosis between acute viral and bacterial infections is important to enable appropriate therapy, avoid unnecessary antibiotic prescriptions and optimize the use of hospital resources. A systems view of host response to infections provides opportunities for discovering sensitive and robust molecular diagnostics. METHODS: We combine blood transcriptomes from six independent datasets (n = 756) with a knowledge-based human protein-protein interaction network, identifies subnetworks capturing host response to each infection class, and derives common response cores separately for viral and bacterial infections. We subject the subnetworks to a series of computational filters to identify a parsimonious gene panel and a standalone diagnostic score that can be applied to individual samples. We rigorously validate the panel and the diagnostic score in a wide range of publicly available datasets and in a newly developed Bangalore-Viral Bacterial (BL-VB) cohort. FINDING: We discover a 10-gene blood-based biomarker panel (Panel-VB) that demonstrates high predictive performance to distinguish viral from bacterial infections, with a weighted mean AUROC of 0.97 (95% CI: 0.96-0.99) in eleven independent datasets (n = 898). We devise a new stand-alone patient-wise score (VB10) based on the panel, which shows high diagnostic accuracy with a weighted mean AUROC of 0.94 (95% CI 0.91-0.98) in 2996 patient samples from 56 public datasets from 19 different countries. Further, we evaluate VB10 in a newly generated South Indian (BL-VB, n = 56) cohort and find 97% accuracy in the confirmed cases of viral and bacterial infections. We find that VB10 is (a) capable of accurately identifying the infection class in culture-negative indeterminate cases, (b) reflects recovery status, and (c) is applicable across different age groups, covering a wide spectrum of acute bacterial and viral infections, including uncharacterized pathogens. We tested our VB10 score on publicly available COVID-19 data and find that our score detected viral infection in patient samples. INTERPRETATION: Our results point to the promise of VB10 as a diagnostic test for precise diagnosis of acute infections and monitoring recovery status. We expect that it will provide clinical decision support for antibiotic prescriptions and thereby aid in antibiotic stewardship efforts. FUNDING: Grand Challenges India, Biotechnology Industry Research Assistance Council (BIRAC), Department of Biotechnology, Govt. of India.


Subject(s)
Bacterial Infections/diagnosis , Biomarkers/blood , Computational Biology/methods , Virus Diseases/diagnosis , Adult , Bacterial Infections/blood , Bacterial Infections/genetics , Databases, Factual , Decision Support Systems, Clinical , Diagnosis, Differential , Female , Gene Expression Profiling , Humans , India , Male , Middle Aged , Observational Studies as Topic , Predictive Value of Tests , Protein Interaction Maps , Virus Diseases/blood , Virus Diseases/genetics
9.
Blood Rev ; 46: 100745, 2021 03.
Article in English | MEDLINE | ID: covidwho-726418

ABSTRACT

COVID-19 is a new pandemic, caused by Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-Cov2) infection and characterized by a broad spectrum of clinical manifestations. Inflammation and the innate immune system have been recently recognized as pivotal players in the most severe forms, characterized by significantly elevated levels of pro-inflammatory cytokines. In this setting, several studies have also reported the presence of abnormalities in coagulation parameters and platelets count, possibly identifying a subgroup of patients with poor prognosis. Some reports of full-blown thromboembolic events are emerging. Among the possible mechanisms underlying coagulation dysfunction, the so-called "cytokine storm" seems to play a pivotal role. Other candidate factors include virus-specific mechanisms, related to the virus interaction with renin angiotensin system (RAS) and the fibrinolytic pathway, but also comorbidities affecting these patients. Coagulation dysfunction is therefore a candidate risk factor for adverse outcomes in COVID-19 and should be carefully addressed in clinical practice.


Subject(s)
Blood Coagulation Disorders/virology , COVID-19/blood , Aged , Blood Coagulation , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/immunology , COVID-19/immunology , Female , Humans , Immune System , Inflammation/blood , Inflammation/immunology , Male , Middle Aged , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Virus Diseases/blood , Virus Diseases/immunology
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