Cytokine Storm—Definition, Causes, and Implications

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(19), P. 11740 - 11740

Published: Oct. 3, 2022

The human innate and adaptive immune systems consist of effector cells producing cytokines (interleukins, interferons, chemokines, numerous other mediators). Usually, a fragile equilibrium pro- anti-inflammation effects is maintained by complex regulatory mechanisms. Disturbances this homeostasis can lead to intricate chain reactions resulting in massive release cytokines. This may result drastic self-reinforcement various feedback mechanisms, which ultimately systemic damage, multi-organ failure, or death. Not only pathogens initiate such disturbances, but also congenital diseases immunomodulatory therapies. Due the diverse interactions within systems, understanding important clinical syndrome incomplete date effective therapeutic approaches remain scarce.

Language: Английский

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Profiling the dysregulated immune response in sepsis: overcoming challenges to achieve the goal of precision medicine

The Lancet Respiratory Medicine, Journal Year: 2023, Volume and Issue: 12(4), P. 305 - 322

Published: Dec. 21, 2023

Language: Английский

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Deciphering sepsis: transforming diagnosis and treatment through systems immunology

Frontiers in Science, Journal Year: 2025, Volume and Issue: 2

Published: Jan. 30, 2025

Sepsis is an abnormal, life-threatening response to infection that leads (multi-)organ dysfunction and failure. It causes ~20% of deaths worldwide each year, most related severe COVID-19 share various molecular features with sepsis. Current treatment approaches (antimicrobials supportive care) do not address the complexity sepsis or its mechanistic heterogeneity between within patients over time. Systems immunology methods, including multiomics (notably RNA sequencing transcriptomics), machine learning, network biology analysis, have potential transform management paradigm toward precision approaches. Immune dysfunctions evident very early in drive development novel diagnostic gene expression signatures (e.g., cellular reprogramming) could inform therapy. can now be categorized into “endotypes” based on unique immune mechanisms corresponding varying severity mortality rates, raising prospect endotype-specific diagnostics patient-specific immune-directed Longitudinal within-patient analyses also reveal (including epigenetics) differential trajectories time, enabling disease stage-specific therapy during after hospitalization, for post-sepsis long COVID syndromes. Achieving this transformation will require addressing barriers systems research, cost resource-intensiveness, relatively low volume available data, lack suitable animal models; it a change mindset healthcare providers This should prioritized multistakeholder collaborations involving research communities, providers/systems, patients, governments reduce current high burden from mitigate against future pandemics.

Language: Английский

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Leveraging transcriptomics for precision diagnosis: Lessons learned from cancer and sepsis

Frontiers in Genetics, Journal Year: 2023, Volume and Issue: 14

Published: March 10, 2023

Diagnostics require precision and predictive ability to be clinically useful. Integration of multi-omic with clinical data is crucial our understanding disease pathogenesis diagnosis. However, interpretation overwhelming amounts information at the individual level requires sophisticated computational tools for extraction meaningful outputs. Moreover, evolution technical analytical methods often outpaces standardisation strategies. RNA most dynamic component all -omics technologies carrying an abundance regulatory that least harnessed use in diagnostics. Gene expression-based tests capture genetic non-genetic heterogeneity have been implemented certain diseases. For example patients early breast cancer are spared toxic unnecessary treatments scores based on expression a set genes (e.g., Oncotype DX). The transcriptomics portray transcriptional status moment time has also used diagnosis diseases such as sepsis. profiles identify endotypes sepsis prognostic value potential discriminate between viral bacterial infection. application patient stratification environments trials thus holds promise. In this review, we discuss current fields We these paradigms highlight impediments identifying useful diagnostic biomarkers propose approaches overcome them aid efforts towards implementation.

Language: Английский

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Host gene expression signatures to identify infection type and organ dysfunction in children evaluated for sepsis: a multicentre cohort study

The Lancet Child & Adolescent Health, Journal Year: 2024, Volume and Issue: 8(5), P. 325 - 338

Published: March 19, 2024

Background Sepsis is defined as dysregulated host response to infection that leads life-threatening organ dysfunction. Biomarkers characterising the in sepsis are lacking. We aimed develop gene expression signatures predict dysfunction children with bacterial or viral infection. Methods This cohort study was done emergency departments and intensive care units of four hospitals Queensland, Australia, recruited aged 1 month 17 years who, upon admission, underwent a diagnostic test, including blood cultures, for suspected sepsis. Whole-blood RNA sequencing performed Illumina NovaSeq (San Diego, CA, USA). Samples completed phenotyping, monitoring, extraction by March 31, 2020, were included discovery cohort; samples collected thereafter Oct 27, 2021, constituted Rapid Paediatric Infection Diagnosis (RAPIDS) internal validation cohort. An external assembled from count data observational European Childhood Life-threatening Infectious Disease Study (EUCLIDS), which severe nine countries between 2012 2016. Feature selection approaches applied derive novel disease class (bacterial vs infection) severity (presence absence 24 h post-sampling). The primary endpoint presence after sampling confirmed versus Gene signature performance reported area under receiver operating characteristic curves (AUCs) 95% CI. Findings Between Sept 25, 2017, 907 patients enrolled. Blood 595 cohort, 312 RAPIDS derived ten-gene achieved an AUC 94·1% (95% CI 90·6–97·7) distinguishing infections A 82·2% 76·3–88·1) predicting within Used tandem, predicted 90·5% 83·3–97·6) 94·7% (87·8–100·0) In EUCLIDS dataset (n=362), at time 70·1% 44·1–96·2) 69·6% (53·1–86·0) Interpretation evaluated sepsis, transcriptomic specific can identify leading Funding Australian Government Medical Research Future Fund Genomic Health Futures Mission, Children's Hospital Foundation Brisbane Diamantina Partners, Emergency Medicine Foundation, Gold Coast Far North Queensland Townsville Services SERTA Grant, Diseases Centre.

Language: Английский

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Validation of SeptiCyte RAPID to Discriminate Sepsis from Non-Infectious Systemic Inflammation

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(5), P. 1194 - 1194

Published: Feb. 20, 2024

(1) Background: SeptiCyte RAPID is a molecular test for discriminating sepsis from non-infectious systemic inflammation, and estimating probabilities. The objective of this study was the clinical validation RAPID, based on testing retrospectively banked prospectively collected patient samples. (2) Methods: cartridge-based accepts PAXgene blood RNA sample provides sample-to-answer processing in ~1 h. output (SeptiScore, range 0–15) falls into four interpretation bands, with higher scores indicating probabilities sepsis. Retrospective (N = 356) prospective 63) samples were tested adult patients ICU who either had inflammatory response syndrome (SIRS), or suspected having/diagnosed Patients clinically evaluated by panel three expert physicians blinded to results. Results interpreted under Sepsis-2 Sepsis-3 framework. (3) Results: Under framework, performance combined retrospective cohorts Areas ROC Curve (AUCs) ranging 0.82 0.85, negative predictive value 0.91 (sensitivity 0.94) SeptiScore Band 1 (score 0.1–5.0; lowest risk sepsis), positive 0.81 (specificity 0.90) 4 7.4–15; highest sepsis). Performance estimates cohort ranged AUC 0.86–0.95. For physician-adjudicated cases that culture (+) blood, urine (+)(+), 43/48 (90%) fell Bands 3 4. In multivariable analysis up 14 additional variables, most important variable diagnosis. A comparable obtained majority reanalyzed definition, although subgroup 16 identified called septic but not Sepsis-3. (4) Conclusions: This validates probability, both frameworks, hospitalized their first day admission.

Language: Английский

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DNA-based molecular classifiers for the profiling of gene expression signatures

Journal of Nanobiotechnology, Journal Year: 2024, Volume and Issue: 22(1)

Published: April 17, 2024

Abstract Although gene expression signatures offer tremendous potential in diseases diagnostic and prognostic, but massive caused challenges for experimental detection computational analysis clinical setting. Here, we introduce a universal DNA-based molecular classifier profiling generating immediate outcomes. The begins with feature transformation, modular programmable strategy was used to capture relative relationships of low-concentration RNAs convert them general coding inputs. Then, competitive inhibition the DNA catalytic reaction enables strict weight assignment different inputs according their importance, followed by summation, annihilation reporting accurately implement mathematical model classifier. We validated entire workflow utilizing miRNA levels diagnosis hepatocellular carcinoma (HCC) samples an accuracy 85.7%. results demonstrate provides solution explore correlation between patterns disease diagnostics, monitoring, prognosis, supports personalized healthcare primary care.

Language: Английский

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Biomarkers in pulmonary infections: a clinical approach

Annals of Intensive Care, Journal Year: 2024, Volume and Issue: 14(1)

Published: July 17, 2024

Abstract Severe acute respiratory infections, such as community-acquired pneumonia, hospital-acquired and ventilator-associated constitute frequent lethal pulmonary infections in the intensive care unit (ICU). Despite optimal management with early appropriate empiric antimicrobial therapy adequate supportive care, mortality remains high, part attributable to aging, growing number of comorbidities, rising rates multidrug resistance pathogens. Biomarkers have potential offer additional information that may further improve outcome infections. Available pathogen-specific biomarkers, for example, Streptococcus pneumoniae urinary antigen test galactomannan, can be helpful microbiologic diagnosis infection ICU patients, improving timing appropriateness since these tests a short turnaround time comparison classic microbiology. On other hand, host-response C-reactive protein procalcitonin, used conjunction clinical data, useful prediction monitoring response treatment, guiding duration therapy. The assessment serial measurements overtime, kinetics is more informative than single value. utilization accurate biomarkers benefit decision-making at bedside optimize stewardship.

Language: Английский

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Future applications of host direct therapies for infectious disease treatment

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Oct. 1, 2024

New and emerging pathogens, such as SARS-CoV2 have highlighted the requirement for threat agnostic therapies. Some antibiotics or antivirals can demonstrate broad-spectrum activity against pathogens in same family genus but efficacy quickly reduce due to their specific mechanism of action ability disease causing agent evolve. This has led generation antimicrobial resistant strains, making infectious diseases more difficult treat. Alternative approaches therefore need be considered, which include exploring utility Host-Directed Therapies (HDTs). is a growing area with huge potential difficulties arise complexity profiles. For example, HDT given early during infection may not appropriate effective when become chronic patient intensive care. With understanding immune function, new treatment could allow targeting pathways augment diminish host response, dependent upon profile, bespoke therapeutic management plans. review highlights promising approved HDTs that manipulate system throughout spectrum disease, particular viral bacterial demonstrates how advantages will soon outweigh side effects.

Language: Английский

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Gene score to quantify systemic inflammation in patients with acutely decompensated cirrhosis

Gut, Journal Year: 2025, Volume and Issue: unknown, P. gutjnl - 333876

Published: Feb. 26, 2025

Background and aims Quantifying systemic inflammation (SI) in acutely decompensated cirrhosis (ADC) is of major importance because SI a driver the most severe forms ADC, including acute-on-chronic liver failure (ACLF). Blood biomarkers already evaluated ADC failed to appropriately assess ADC. We aimed investigate whether gene expression related circulating immune cells could quantify Methods Standard (white cell count, C reactive protein, cytokines) genome-wide RNA (RNA-sequencing) were obtained blood from 700 patients with at time their hospital admission. A composite score based on standard (Chronic Liver Failure-Standard Biomarkers Composite (CLIF-SBC) score) (CLIF-Systemic Inflammation Gene (SIG) composed 28 top differentially expressed cell-related genes comparison between high-severity low-severity clinical phenotypes computed. Among patients, CLIF-SIG was repeated once during follow-up 375 3 times or more 46 patients. Results The accurate reflecting severity induced by than CLIF-SBC (area under curve 0.803 vs 0.658). 0.386 (Youden Index) best cut-off level discriminating poor outcomes others, all scenarios. Sequential measurement showed that 78% admitted peak descending part SI-wave. ACLF developed hospitalisation 80% >0.386 Conclusions In an estimator SI, course prognosis.

Language: Английский

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