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Sepsis is a complex syndrome triggered by infection and characterized by systemic deregulation of immune and inflammatory pathways. It is a major cause of death worldwide and results in the widespread use of antibiotics and substantial health care costs. In a vicious circle, sepsis treatment promotes the emergence of highly virulent and resistant p...
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... genetic variations have to be approached as a global phenomenon with regional peculiarities that do not support the definition of "race" in a taxonomic sense, because interindividual genetic variability is very large even among indi- viduals from the same population. In fact, several studies suggest that ancestral African populations were genetically differentiated even before the expansion of modern humans from Africa approximately 70,000 years ago [22][23][24][25] (Figure 1). ...
Citations
... O advento das tecnologias de alto rendimento permitem uma melhor compreensão da sepse como a soma de múltiplas interações microbianas com o metagenoma. Nesse âmbito, a medicina personalizada é provavelmente uma estratégia capaz de desconstruir e atualizar nosso conhecimento sobre sepse, permitindo o entendimento da sepse como um fenômeno amplo, interconectado, cominúmeras variáveis e peculiaridades[11][12][13] . ...
A fisiopatologia das respostas imunológicas e cardiovasculares têm sido amplamente investigadas e estudos sugerem que os hormônios são críticos em pacientes sépticos e atuam de forma diferente na resposta de infecção em homens e mulheres. A partir do presente estudo, nota-se que pacientes do sexo masculino possuem maiores taxas de óbito após internação por sepse em UTI do que pacientes do sexo feminino, se comparados dentro dos mesmos grupos etários. A descoberta da diferença na mortalidade da sepse entre os sexos permite modificar o manejo destes pacientes e melhorar desfechos clínicos, além de impactar em uma melhor compreensão da doença, com maior desenvolvimento de terapia personalizada.
... Sepsis is a complex disease characterized by a different inflammatory response in every patient of sepsis. The most successful way to facilitate the treatment of sepsis is through a personalized approach, as individual patients have a unique profile of immune activation against particular pathogens [101]. A personalized approach is used to prevent, diagnose and treat individual patient characteristics and is based on "omics" based data (genomics, transcriptomics, proteomics, metabolomics, epigenomics, pharmacogenomics, interactomics and microbiomic). ...
Sepsis is a life-threatening condition that causes a global health burden associated with high mortality and morbidity. Often life-threatening, sepsis can be caused by bacteria, viruses, parasites or fungi. Sepsis management primarily focuses on source control and early broad-spectrum antibiotics, plus organ function support. Comprehensive changes in the way we manage sepsis patients include early identification, infective focus identification and immediate treatment with antimicrobial therapy, appropriate supportive care and hemodynamic optimization. Despite all efforts of clinical and experimental research over thirty years, the capacity to positively influence the outcome of the disease remains limited. This can be due to limited studies available on sepsis in developing countries, especially in Southeast Asia. This review summarizes the progress made in the diagnosis and time associated with sepsis, colistin resistance and chloramphenicol boon, antibiotic abuse, resource constraints and association of sepsis with COVID-19 in Southeast Asia. A personalized approach and innovative therapeutic alternatives such as CytoSorb® are highlighted as potential options for the treatment of patients with sepsis in Southeast Asia.
... Over the last few decades, the diagnostic criteria for sepsis have being updated periodically, but the primary pathophysiology remains constant-the presence of inflammation during disease (Nedeva et al., 2019). However, patients with sepsis may have distinct inflammatory responses and unique profile of immune activation against the pathogen (Pinheiro da Silva and César Machado, 2015). Therefore, the desirable way to decipher the heterogeneity and advance the treatment of sepsis may be identifying companion biomarkers for better assessing immune status and stratifying patients (Venet and Monneret, 2018). ...
Sepsis is a heterogeneous disease state triggered by an uncontrolled inflammatory host response with high mortality and morbidity in severely ill patients. Unfortunately, the treatment effectiveness varies among sepsis patients and the underlying mechanisms have yet to be elucidated. The present aim is to explore featured metabolism-related genes that may become the biomarkers in patients with sepsis. In this study, differentially expressed genes (DEGs) between sepsis and non-sepsis in whole blood samples were identified using two previously published datasets (GSE95233 and GSE54514). A total of 66 common DEGs were determined, namely, 52 upregulated and 14 downregulated DEGs. The Gene Set Enrichment Analysis (GSEA) results indicated that these DEGs participated in several metabolic processes including carbohydrate derivative, lipid, organic acid synthesis oxidation reduction, and small-molecule biosynthesis in patients with sepsis. Subsequently, a total of 8 hub genes were screened in the module with the highest score from the Cytoscape plugin cytoHubba. Further study showed that these hub DEGs may be robust markers for sepsis with high area under receiver operating characteristic curve (AUROC). The diagnostic values of these hub genes were further validated in myocardial tissues of septic rats and normal controls by untargeted metabolomics analysis using liquid chromatography-mass spectrometry (LC-MS). Immune cell infiltration analysis revealed that different infiltration patterns were mainly characterized by B cells, T cells, NK cells, monocytes, macrophages, dendritics, eosinophils, and neutrophils between sepsis patients and normal controls. This study indicates that metabolic hub genes may be hopeful biomarkers for prognosis prediction and precise treatment in sepsis patients.
... [2][3][4] It is a heterogeneous illness affecting males more often than females. 5 Evaluating if outcomes differ by sex is a recognised health research priority. 6 It has been hypothesised that sex may have a prognostic effect on sepsis outcomes. ...
Objective
To assess the role of sex as an independent prognostic factor for mortality in patients with sepsis admitted to intensive care units (ICUs).
Design
Systematic review and meta-analysis.
Data sources
MEDLINE, Embase, Web of Science, ClinicalTrials.gov and the WHO Clinical Trials Registry from inception to 17 July 2020.
Study selection
Studies evaluating independent associations between sex and mortality in critically ill adults with sepsis controlling for at least one of five core covariate domains prespecified following a literature search and consensus among experts.
Data extraction and synthesis
Two authors independently extracted and assessed the risk of bias using Quality In Prognosis Studies tool. Meta-analysis was performed by pooling adjusted estimates. The Grades of Recommendations, Assessment, Development and Evaluation approach was used to rate the certainty of evidence.
Results
From 14 304 records, 13 studies (80 520 participants) were included. Meta-analysis did not find sex-based differences in all-cause hospital mortality (OR 1.02, 95% CI 0.79 to 1.32; very low-certainty evidence) and all-cause ICU mortality (OR 1.19, 95% CI 0.79 to 1.78; very low-certainty evidence). However, females presented higher 28-day all-cause mortality (OR 1.18, 95% CI 1.05 to 1.32; very low-certainty evidence) and lower 1-year all-cause mortality (OR 0.83, 95% CI 0.68 to 0.98; low-certainty evidence). There was a moderate risk of bias in the domain adjustment for other prognostic factors in six studies, and the certainty of evidence was further affected by inconsistency and imprecision.
Conclusion
The prognostic independent effect of sex on all-cause hospital mortality, 28-day all-cause mortality and all-cause ICU mortality for critically ill adults with sepsis was uncertain. Female sex may be associated with decreased 1-year all-cause mortality.
PROSPERO registration number
CRD42019145054.
... Personalized therapy optimizes the safety-toefficacy ratio by selecting patients with higher response rates based on specific biomarkers [1][2][3] and is becoming an important modality for improving patient care by enabling the use of optimized therapies for selected groups of patients. [4][5][6][7] Inflammation plays a key role in the pathogenesis of non-alcoholic steatohepatitis (NASH), a common liver disorder. [8][9][10] Currently, there are no approved therapies for NASH, and several of the drugs tested over the last few years have shown efficacy only in a subset of patients. ...
Personalized therapies are designed to optimize the safety-to-efficacy ratio by selecting patients with higher response rates based on specific biomarkers. Inflammation plays a vital role in the pathogenesis of non-alcoholic steatohepatitis (NASH), a common liver disorder. Eotaxin-1 plays a role in innate and adaptive immune responses. High eotaxin-1 levels are associated with diabetes and fatty liver disease and, therefore, serves as a biomarker for patient selection. The anti-eotaxin-1 monoclonal antibody is tailored for the personalized therapy of patients with inflammatory conditions due to high levels of eotaxin-1. To evaluate the biological activity and immunomodulatory effect of orally administered anti-eotaxin-1. C57B1/6 mice were treated with either oral or intra-peritoneal anti-eotaxin-1 antibody before induction of immune-mediated hepatitis using an injection of concanavalin A (ConA) and checked for liver injury and eotaxin-1 serum levels. Oral administration of anti-eotaxin-1 alleviated the immune-mediated liver injury. Serum alanine aminotransferase levels decreased to 1807 U/L, compared with 19025 U/L in untreated controls and 3657 U/L in mice treated with parenteral anti-eotaxin-1 ( P < 0.005). A trend toward reduced serum eotaxin-1 levels was observed in treated mice, ranging from 594 pg/mL in the controls to 554 and 561 pg/mL in mice treated orally and intraperitoneally ( P = 0.08, P = 0.06, respectively). Oral administration of anti-eotaxin-1 antibody shows biological activity in the gut and exerts a systemic immunomodulatory effect to alleviate immune-mediated hepatitis. The data suggest that testing for eotaxin-1 serum levels may enable screening patients with high-eotaxin-1 levels-associated NASH.
... Sepsis, accounting for one of year ve deaths worldwide and leading cause of death in intensive care units (ICUs), remains to be a global health problem [2][3][4]. Sepsis is a heterogeneous illness affecting both male and female individuals [5]. Prior evidence suggests sex-related risk differences for developing sepsis. ...
Background: Incidence and sepsis-related mortality are failing, but sepsis continues to be a leading cause of admission and death in intensive care units (ICUs). Although the preceding evidence suggests sex-related risk differences for developing sepsis, the influence of sex on mortality outcomes remains unclear as previous studies showed discordant results. This systematic review assesed the independent effect of sex for mortality among critically ill patients with sepsis.
Methods: Electronic databases were searched up to 17th July 2020 for studies that examined independent associations between sex and mortality outcomes in critically ill adults with sepsis while controlling for covariates. Primary meta-analyses were performed by pooling adjusted estimates for a pre-specified core set of adjustment factors. The primary outcomes included all-cause hospital mortality and 28-day all-cause hospital mortality. The secondary outcomes included 7-day all-cause hospital mortality, 1-year all-cause mortality, and all-cause ICU mortality.
Results: Among the 14304 records identified, 12 studies (71850 participants) were included. Meta-analysis showed inconclusive results on sex-based differences in hospital mortality (OR 0.95, 95% CI 0.55 to 1.64; very low-certainty evidence) and ICU mortality (OR 1.19, 95% CI 0.79 to 1.78; very low-certainty evidence). Meta-analysis found higher 28-day hospital mortality in the female group (OR 1.18, 95% CI 1.05 to 1.32; very low-certainty evidence). No studies reported on 7-day hospital mortality. A single study provided adjusted estimates on 1-year mortality reporting lower risk in the female group (OR 0.83 95% CI 0.68 to 0.98; low-certainty of evidence). The main reasons for assessing the certainty of evidence as very low were inconsistency and imprecision while downgrading to low-certainty was risk of bias and imprecision.
Conclusions: The prognostic independent effect of sex on hospital mortality, 28-day hospital mortality, and ICU mortality for critically ill adults with sepsis is uncertain. Female sex may be associated with decreased 1-year mortality. No included studies reported on 7-day all-cause hospital mortality.
... According to the current state of knowledge, the identification of a suitable target population for IgGAM therapy is important. In particular, the idea of "one size fits all" therapy must be critically examined under the current concept of "personalised medicine" and also the lack of cost-effectiveness data [100][101][102][103][104]. ...
Sepsis is a life-threatening organ dysfunction, defined by a dysregulated host immune response to infection. During sepsis, the finely tuned system of immunity, inflammation and anti-inflammation is disturbed in a variety of ways. Both pro-inflammatory and anti-inflammatory pathways are upregulated, activation of the coagulation cascade and complement and sepsis-induced lymphopenia occur. Due to the manifold interactions in this network, the use of IgM-enriched intravenous immunoglobulins seems to be a promising therapeutic approach. Unfortunately, there is still a lack of evidence-based data to answer the important questions of appropriate patient populations, optimal timing and dosage of intravenous immunoglobulins. With this review, we aim to provide an overview of the role of immunoglobulins, with emphasis on IgM-enriched formulations, in the therapy of adult patients with sepsis and septic shock.
... [4][5][6] Sepsis is a heterogeneous disease affecting both male and female individuals. 7 Recently, it has been recognised that sex may contribute to a differential risk for developing sepsis; and it remains uncertain if the prognosis of sepsis varies between the sexes. [8][9][10][11][12][13][14] Prognosis factors are relevant in clinical care as they can identify risk groups in which clinical practice may be tailored to the aim of reducing morbidity and mortality. ...
Introduction
Sepsis is a leading cause of mortality in critically ill patients. Recently, it has been recognised that sex may contribute to a differential risk for developing sepsis and it remains uncertain if the prognosis of sepsis varies between the sexes. The aim of this systematic review is to summarise the available evidence to assess the role of sex as a prognostic factor in patients with sepsis managed in the intensive care unit (ICU).
Methods and analysis
This is a systematic review protocol of prognostic studies of sex in patients with sepsis managed in the ICU. The primary outcomes include all-cause hospital mortality and all-cause hospital mortality during the first 28 days. The secondary outcomes include all-cause hospital mortality during the first 7 days and all-cause mortality at 1 year. We will conduct a search strategy based on the population (sepsis), the prognostic factor (sex), the outcome of interest (mortality) and prognostic study methods. We will search in the following databases up to December 2019: MEDLINE Ovid (from 1976), Embase Elsevier (from 1974), Web of Science and two trial registries. We will impose no language restrictions. Two authors will independently screen titles, abstracts and full-text articles for eligibility of studies, and subsequently extract data. Two authors will independently assess the risk of bias of each study using the Quality in Prognostic Studies (QUIPS) tool. If possible, we will carry out a meta-analysis to provide a pooled prognostic effect estimate for each outcome. We will use the Grading of Recommendations Assessment, Development and Evaluation system to assess the quality of evidence.
Ethics and dissemination
Ethical approval will not be required. Findings from this review will be reported in a peer-reviewed scientific journal. Additionally, the results will be disseminated at conferences and in the mass media.
PROSPERO registration number
CRD42019145054.
... Merely a few interventions in the management of sepsis have strong supporting data (Rhodes et al., 2017). Deleterious prognosis in these patients might be partly related to the lack of methods for personalizing the therapies in a highly dynamic system (Pinheiro da Silva and Cesar machado, 2015). ...
Sepsis remains a major therapeutic challenge and is associated with a high rate of morbidity and mortality. It is a dynamic condition in which multiple parameters change over time, rendering it difficult to overcome the various injurious responses, which worsen the prognosis in these patients. The prognosis of sepsis is associated with a disbalance of compensatory responses to infectious triggers, part of which can be deleterious. Marked inter- and intra-patient variability characterizes the mechanisms that underlie sepsis progression and determine the response to therapy. In this paper, we review some of the data on the use of chronopharmacological approaches for the treatment of patients with sepsis and discuss the role of the autonomic nervous system in the mechanisms associated with immune response and chronotherapy in these patients. We describe the implementation of an individualized platform that is based on the personalized autonomic nervous system, immune, and chronobiology-derived parameters for generating a patient-tailored therapeutic regimen. The notion of overcoming the deleterious compensatory response in a highly dynamic system in sepsis is presented to ensure an improved response to current therapies.
... Given individual variations in responses to pathogens and the complexity of the host response, there may be multiple mechanisms, as yet not all understood, which lead to sepsis. Immuno-therapy to prevent severe sepsis against a variety of pathogens has universally failed to meet expectations [52], and the recognition of the diverse nature of sepsis requires stratification not only of the causative microbe but aspects of the host [53] so that therapy may have to be tailored to the individual [54]. Nonetheless, the science resulting from the sepsis field may still present new therapeutic options for severe melioidosis. ...
Introduction: Melioidosis is a significant health problem within endemic areas such as Southeast Asia and Northern Australia. The varied presentation of melioidosis and the intrinsic antibiotic resistance of Burkholderia pseudomallei, the causative organism, make melioidosis a difficult infection to manage. Often prolonged courses of antibiotic treatments are required with no guarantee of clinical success.
Areas covered: B. pseudomallei is able to enter phagocytic cells, affect immune function, and replicate, via manipulation of the caspase system. An examination of this mechanism, and a look at other factors in the pathogenesis of melioidosis, shows that there are multiple potential points of therapeutic intervention, some of which may be complementary. These include the directed use of antimicrobial compounds, blocking virulence mechanisms, balancing or modulating cytokine responses, and ameliorating sepsis.
Expert commentary: There may be therapeutic options derived from drugs in clinical use for unrelated conditions that may have benefit in melioidosis. Key compounds of interest primarily affect the disequilibrium of the cytokine response, and further preclinical work is needed to explore the utility of this approach and encourage the clinical research needed to bring these into beneficial use.
