Burden Of Sepsis Research Articles

Association of Omega-3 Status With Long-Term Risk of Hospitalization for Sepsis.

Sepsis is a life-threatening condition characterized by a dysregulated host response to infection. Despite decades of clinical trials, there are no specific treatments; care of the nearly 50 million annual cases worldwide is limited to antimicrobials and supportive measures. A primary prevention strategy may therefore be of value. We hypothesized that higher premorbid omega-3 fatty acid levels would be associated with a reduced incidence of sepsis. Population-based cohort study. Retrospective data from the United Kingdom (U.K. Biobank). Two hundred seventy-three thousand three hundred twenty-five participants from the U.K. Biobank. None. Our exposure was baseline estimated omega-3 index (eO3I), modeled both categorically in quartiles, and continuously with restricted cubic splines. Our outcome measure was hospital admission with an International Classification of Diseases, 10th Edition code consistent with sepsis. The median (interquartile range) baseline eO3I was 6.0% (4.8-7.3%). Over a mean follow-up period of 13 years, 9241 participants experienced hospitalization with sepsis. In our adjusted model, compared with the lowest eO3I quartile, participants had lower risks of sepsis incidence in the second quartile (hazard ratio [HR], 0.88; 95% CI, 0.86-0.91; p < 0.001), third quartile (HR, 0.80; 95% CI, 0.78-0.83; p < 0.001), and fourth quartile (HR, 0.75; 95% CI, 0.73-0.77; p < 0.001). When analyzed as a continuous variable, increasing eO3I was associated with a decreasing risk of sepsis (p < 0.001). In this population-based cohort study, baseline eO3I was inversely associated with subsequent sepsis incidence. Given that omega-3 levels can be increased with dietary supplementation, primary prevention should be explored to mitigate the burden of sepsis.

Sepsis in Northern Tanzania: A Prospective Observational Study of Clinical Characteristics, Management, and Outcomes for Adolescents and Adults With Sepsis.

Despite a high burden of sepsis in Sub-Saharan Africa, clinical data for adolescent and adult sepsis in this setting are limited. We sought to describe clinical characteristics, management, and outcomes in adolescents and adults with sepsis in northern Tanzania. We also assessed for clinical associations with in-hospital mortality. We conducted a prospective observational cohort study at Kilimanjaro Christian Medical Centre in Moshi, Tanzania, 2019-2020. Data were collected on demographics, clinical characteristics, and management primarily from hours 0-6 after arrival at the emergency department. We calculated bivariable risk ratios (RRs) for associations between demographic and clinical factors and in-hospital death. A multivariable-adjusted analysis was performed for associations between antimicrobial and intravenous fluid administration and in-hospital death. Of 86 participants with sepsis, 25 (29.1%) died in the hospital. Baseline characteristics associated with in-hospital mortality included inability to drink unassisted (RR, 3.15; 95% CI, 1.58-6.30), altered mentation (RR, 3.94; 95% CI, 2.12-7.33), quick Sequential Organ Failure Assessment (qSOFA) score ≥2 (RR, 2.86; 95% CI, 1.42-5.72), and Universal Vital Assessment score ≥5 (RR, 6.33; 95% CI, 2.36-17.02). Twenty-nine (33.7%) received an antimicrobial by hour 6. HIV antibody testing was performed for 4 (4.7%) participants by hour 6. On multivariable analysis, neither antimicrobial administration nor intravenous fluids >1L by hour 6 was associated with in-hospital mortality. Sepsis at our center in northern Tanzania carried a high risk of in-hospital mortality. Further research is needed to establish the highest-yield interventions suited to the unique characteristics of sepsis in Sub-Saharan Africa.

Trend in sepsis burden among hospitalized non-child cancer patients in China, 2017–2019: A nationwide cross-sectional study

BackgroundThe trend in sepsis burden among cancer patients, along with geographic variation and the impact of healthcare resource availability, remains underexplored in China. This study was conducted to evaluate the in-hospital incidence, case fatality, and mortality rates of sepsis among cancer patients in China during the period from 2017 to 2019. MethodsA nationwide cross-sectional study was conducted using data from the National Data Center for Medical Service. Cancer patients aged ≥15 years hospitalized with sepsis across 3975 hospitals from 2017 to 2019 were included. Sepsis cases were identified using ICD-10 diagnosis and ICD-9 procedure codes. Sepsis incidence, case fatality, and mortality rates were estimated, and multivariable regression was used to analyze associations between sepsis outcomes and healthcare resource factors, including intensive care unit (ICU) bed supply and human development index (HDI). ResultsFrom 2017 to 2019, the in-hospital sepsis incidence among cancer patients increased by 35.3%, from 4111.20 to 5564.42 per 100,000 admissions. The case fatality rate declined from 17.94% to 14.08%, while sepsis-related mortality rose from 512.06 to 783.46 per 100,000. Significant geographic disparities were observed, with healthcare resources like HDI and cancer mortality associated with sepsis outcomes. ConclusionsSepsis remains a significant burden on hospitalized cancer patients in China, with considerable geographic disparities. Reducing sepsis incidence through enhanced infection control and improving healthcare resource distribution, especially in regions with limited resources, are critical to lowering sepsis-related mortality among cancer patients.

Unsupervised Classification of the Host Response Identifies Dominant Pathobiological Signatures of Sepsis in Sub-Saharan Africa.

The global burden of sepsis is concentrated in sub-Saharan Africa, where inciting pathogens are diverse and HIV co-infection is a major driver of poor outcomes. Biological heterogeneity inherent to sepsis in this setting is poorly defined. To identify dominant pathobiological signatures of sepsis in sub-Saharan Africa and their relationship to clinical phenotypes, patient outcomes, and biological classifications of sepsis identified in high-income-countries (HICs). We analyzed two prospective cohorts of adults hospitalized with sepsis (severe infection with qSOFA score≥1) at disparate settings in Uganda (discovery cohort [Entebbe,urban], N=242; validation cohort [Tororo,rural], N=253). To identify pathobiological signatures in the discovery cohort, we applied unsupervised clustering to 173 soluble proteins reflecting key domains of the host response to severe infection. A random forest-derived classifier was used to predict signature assignment in the validation cohort. Two signatures (Uganda Sepsis Signature [USS]-1 and USS-2) were identified in the discovery cohort, distinguished by expression of proteins involved in myeloid cell and inflammasome activation, T cell co-stimulation and exhaustion, and endothelial barrier dysfunction. A five-protein classifier (AUROC 0.97) reproduced two signatures in the validation cohort with similar biological profiles. In both cohorts, USS-2 mapped to a more severe clinical phenotype associated with HIV and related immunosuppression, severe tuberculosis, and increased risk of 30-day mortality. Substantial biological overlap was observed between USS-2 and hyperinflammatory and reactive sepsis phenotypes identified in HICs. We identified prognostically-enriched pathobiological signatures among sepsis patients with diverse infections and high HIV prevalence in Uganda. Globally inclusive investigations are needed to define generalizable and context-specific mechanisms of sepsis pathobiology, with the goal of improving access to precision medicine treatment strategies.

The burden of sepsis in Italy: an analysis of treatable mortality trends

Abstract Background The burden of sepsis, a life-threatening condition triggered by the body’s extreme response to infection, remains a critical global healthcare concern. Sepsis-related deaths often result from delayed recognition, insufficient treatment, or gaps in healthcare delivery. The study aims to analyze treatable mortality for sepsis in Italy and its regions. Methods A retrospective study was conducted on data of treatable mortality for sepsis in Italy and its regions. According to joint OECD/Eurostat list, we included sepsis deaths with the ICD-10 codes A40 (excl. A40.3 [sepsis due to Streptococcus pneumoniae]) and A41 (excl. A41.3 [sepsis due to Hemophilus influenzae]) from 2006 to 2019. Through data on the resident population two-year age-standardized rates by region were calculated. Results From 2006/7 to 2018/9 an overall increase was observed in Italy, from 1.6 to 2.2 age-standardized mortality rates with a maximum peak in 2014/5 (+46.7%). This trend was confirmed for Lombardy (+47.8%), Veneto (+48.8%), Emilia-Romagna (+49.3%), Tuscany (52.0%), Marche (+58.4%%), Abruzzo (39.4%), Molise (26.7%), Apulia (+57.0%), Sicily (+57.2%), and Sardinia (+46.8%). Aosta Valley (+72,5%) had a maximum peak in 2010/1, while Piedmont (+42.5%), Autonomous Province (A.P.) of Bolzano (+27.8%), A.P. of Trento (+45.0%), Friuli-Venezia Giulia (+23.3%) in 2012/3, Calabria (+46.4%) in 2016/7 and lastly Campania (+52.9%) and Basilicata (+73.0%) in 2018/9. Liguria (+49.8%), Latium (47.2%) and Umbria (49.3%) showed two maximum values, one in the 2012/3 and the other in the 2014/5. Conclusions We observed an overall increase in age-standardized mortality rates throughout Italy, with a peak in 2014/5. This trend was resumed in ten regions, while three regions showed multiple peaks, indicating fluctuations in mortality rates. These findings underline the importance of targeted health interventions and policy initiatives to address region-specific health challenges. Key messages • Regional disparities in mortality rates highlight the necessity for customized health interventions and policy measures between Italian regions. • Recognizing fluctuating mortality trends in specific regions is crucial to effectively address various health challenges.

Targeting Sepsis: Disease Tolerance, Immune Resilience, and Compartmentalized Immunity.

Introduction: Sepsis remains a major contributor to critical care mortality and morbidity worldwide. Despite advances in understanding its complex immunopathology, the compartmentalized nature of immune responses across different organs has yet to be fully translated into targeted therapies. This review explores the burden of sepsis on organ-specific immune dysregulation, immune resilience, and epigenetic reprogramming, emphasizing translational challenges and opportunities. Methods: We implemented a systematic literature search strategy, incorporating data from studies published between 2010 and 2024, to evaluate the role of molecular profiling techniques, including transcriptomics and epigenetic markers, in assessing the feasibility of targeted therapies. Results: Sepsis-induced immune dysregulation manifests differently in various organs, with lung, heart, liver, and kidney responses driven by unique local immune environments. Organ-specific biomarkers, such as the Spns2/S1P axis in lung macrophages, mitochondrial dysfunction in the heart, proenkephalin for early acute kidney injury (AKI), and adrenomedullin for predicting multi-organ failure, offer promising avenues for timely intervention. Furthermore, immune resilience, particularly through regulatory T-cell modulation and cytokine targeting (e.g., IL-18), is crucial for long-term recovery. Epigenetic mechanisms, including histone modification and trained immunity, present opportunities for reprogramming immune responses but require more precision to avoid unintended inflammatory sequelae. Conclusions: A deeper understanding of compartmentalized immune responses and the dynamic immune landscape in sepsis is critical for developing precision therapies. Real-time immune monitoring and organ-targeted interventions could revolutionize sepsis management, although significant barriers remain in clinical translation. Further research is required to establish biomarkers and treatment timing that optimize therapeutic efficacy while minimizing systemic risks.

Whole genome analysis of Pantoea species identified from sepsis patients in selected Ethiopian referral hospitals: emerging pathogens

BackgroundThe burden of sepsis worsens due to the continuation of emerging pathogens such as multidrug-resistant Pantoea species.MethodsA multicenter study was conducted between October 2019 and September 2020 at four hospitals located in central, southern, and northern parts of Ethiopia. A total of 1416 sepsis patients were recruited and blood cultures were performed. At each study site, positive cultures were characterized by their colony characteristics, gram stain, and conventional biochemical tests. All Pantoea species were identified using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI TOF) and subjected to whole genome sequencing (WGS) using Illumina HiSeq 2500. The phylogeny structure of Pantoea isolates was calculated using IQ-TREE v1.6.12 from single-nucleotide polymorphisms detected by Snippy v.4.6.0 and filtered by Gubbins v.2.3.4. Average nucleotide identity was estimated by using OrthoANI v.0.93.1 on Shovill v.1.1.0 assemblies. Antimicrobial resistance genes and plasmid replicons were detected using ARIBA v.2.14.6. Phylogenetic trees were visualized using iTOLv.6.5.2.ResultsMultiple Pantoea species include: P. dispersa (n = 19), P. septica (n = 1), and a novel Pantoea spp. (n = 1), were identified among sepsis patients. All P. dispersa isolates and the novel Pantoea species were isolated at Dessie Referral Hospital and displayed phylogenetic clonality, including the ubiquity of an IncM1 plasmid and identical antimicrobial resistance (AMR) gene profiles, encoding blaCTX−M−15, blaTEM−1D, blaSCO−1, and aac(3)-lla. The novel Pantoea spp. isolate harboured blaCTX−M−9 and blaTEM−1D and carried an IncN3 plasmid replicon. The P. septica was isolated at Tikur Anbessa Specialized Hospital in Addis Ababa and carried no detectable acquired AMR genes.ConclusionThe emerging Pantoea spp. carrying multiple AMR genes were identified from sepsis patients. Implementation of strong infection prevention strategies and building surveillance capacity with advanced bacteriology laboratories capable of identifying multidrug-resistant emerging pathogens is strongly recommended.

The Global Burden of Sepsis and Septic Shock.

A dysregulated host response to infection causes organ dysfunction in sepsis and septic shock, two potentially fatal diseases. They continue to be major worldwide health burdens with high rates of morbidity and mortality despite advancements in medical care. The goal of this thorough review was to present a thorough summary of the current body of knowledge about the prevalence of sepsis and septic shock worldwide. Using widely used computerized databases, a comprehensive search of the literature was carried out, and relevant studies were chosen in accordance with predetermined inclusion and exclusion criteria. A narrative technique was used to synthesize the data that were retrieved. The review's conclusions show how widely different locations and nations differ in terms of sepsis and septic shock's incidence, prevalence, and fatality rates. Compared to high-income countries (HICs), low- and middle-income countries (LMICs) are disproportionately burdened more heavily. We talk about risk factors, comorbidities, and difficulties in clinical management and diagnosis in a range of healthcare settings. The review highlights the need for more research, enhanced awareness, and context-specific interventions in order to successfully address the global burden of sepsis and septic shock.

Gene expression signatures in blood from a West African sepsis cohort define host response phenotypes

Our limited understanding of the pathophysiological mechanisms that operate during sepsis is an obstacle to rational treatment and clinical trial design. There is a critical lack of data from low- and middle-income countries where the sepsis burden is increased which inhibits generalized strategies for therapeutic intervention. Here we perform RNA sequencing of whole blood to investigate longitudinal host response to sepsis in a Ghanaian cohort. Data dimensional reduction reveals dynamic gene expression patterns that describe cell type-specific molecular phenotypes including a dysregulated myeloid compartment shared between sepsis and COVID-19. The gene expression signatures reported here define a landscape of host response to sepsis that supports interventions via targeting immunophenotypes to improve outcomes.

HETEROGENEOUS EXPANSION OF POLYMORPHONUCLEAR MYELOID-DERIVED SUPPRESSOR CELLS DISTINGUISHES HIGH-RISK SEPSIS IMMUNOPHENOTYPES IN UGANDA.

Background: Understanding of immune cell phenotypes associated with inflammatory and immunosuppressive host responses in sepsis is imprecise, particularly in low- and middle-income countries, where the global sepsis burden is concentrated. In these settings, elucidation of clinically relevant immunophenotypes is necessary to determine the relevance of emerging therapeutics and refine mechanistic investigations of sepsis immunopathology. Methods: In a prospective cohort of adults hospitalized with suspected sepsis in Uganda (N = 43; median age 46 years [IQR 36-59], 24 [55.8%] living with HIV, 16 [37.2%] deceased at 60 days), we combined high-dimensional flow cytometry with unsupervised machine learning and manual gating to define peripheral immunophenotypes associated with increased risk of 60-day mortality. Results: Patients who died showed heterogeneous expansion of polymorphonuclear myeloid-derived suppressor cells, with increased and decreased abundance of CD16 - PD-L1 dim and CD16 bright PD-L1 bright subsets, respectively, significantly associated with mortality. While differences between CD16 - PD-L1 dim cell abundance and mortality risk appeared consistent throughout the course of illness, those for the CD16 bright PD-L1 bright subset were more pronounced early after illness onset. Independent of HIV co-infection, depletion of CD4 + T cells, dendritic cells, and CD56 - CD16 bright NK cells were significantly associated with mortality risk, as was expansion of immature, CD56 + CD16 - CD11c + NK cells. Abundance of T cells expressing inhibitory checkpoint proteins (PD-1, CTLA-4, LAG-3) was similar between patients who died versus those who survived. Conclusions: This is the first study to define high-risk immunophenotypes among adults with sepsis in sub-Saharan Africa, an immunologically distinct region where biologically informed treatment strategies are needed. More broadly, our findings highlight the clinical importance and complexity of myeloid derived suppressor cell expansion during sepsis and support emerging data that suggest a host-protective role for PD-L1 myeloid checkpoints in acute critical illness.

Reducing the burden of preventable deaths from sepsis in Canada: A need for a national sepsis action plan.

Sepsis is a global health threat with significant morbidity and mortality. Despite clinical practice guidelines and developed health systems, sepsis is often unrecognized or misdiagnosed, leading to preventable harm. In Canada, sepsis is responsible for 1 in 20 deaths and is a significant driver of health system costs. Despite being a signatory to the World Health Organization's Resolution WHA 70.7, adopted in 2017, Canada has not lived up to its commitment. Many existing sepsis policies were developed in response to a specific tragedy, and there is no national sepsis action plan. In this article, we describe the burden of sepsis, provide examples of existing, context-specific, reactionary sepsis policies, and urge a coordinated, proactive Canadian sepsis action plan to reduce the burden of sepsis.

Burden of sepsis in critically ill children with cancer: A retrospective study

Burden of sepsis in critically ill children with cancer: A retrospective study

Associations of educational attainment with Sepsis mediated by metabolism traits and smoking: a Mendelian randomization study.

Sepsis constitutes a significant global healthcare burden. Studies suggest a correlation between educational attainment and the likelihood of developing sepsis. Our goal was to utilize Mendelian randomization (MR) in order to examine the causal connection between educational achievement (EA) and sepsis, while measuring the mediating impacts of adjustable variables. We collected statistical data summarizing educational achievement (EA), mediators, and sepsis from genome-wide association studies (GWAS). Employing a two-sample Mendelian randomization (MR) approach, we calculated the causal impact of education on sepsis. Following this, we performed multivariable MR analyses to assess the mediation proportions of various mediators, including body mass index (BMI), smoking, omega-3 fatty acids, and apolipoprotein A-I(ApoA-I). Genetic prediction of 1-SD (4.2 years) increase in educational attainment (EA) was negatively correlated with sepsis risk (OR = 0.83, 95% CI 0.71 to 0.96). Among the four identified mediators, ranked proportionally, they including BMI (38.8%), smoking (36.5%), ApoA-I (6.3%) and omega-3 (3.7%). These findings remained robust across a variety of sensitivity analyses. The findings of this study provided evidence for the potential preventive impact of EA on sepsis, which may be influenced by factors including and metabolic traits and smoking. Enhancing interventions targeting these factors may contribute to reducing the burden of sepsis.

Societal costs of sepsis in the Netherlands

BackgroundSepsis is a life-threatening syndrome characterized by acute loss of organ function due to infection. Sepsis survivors are at risk for long-term comorbidities, have a reduced Quality of Life (QoL), and are prone to increased long-term mortality. The societal impact of sepsis includes its disease burden and indirect economic costs. However, these societal costs of sepsis are not fully understood. This study assessed sepsis’s disease-related and indirect economic costs in the Netherlands.MethodsSepsis prevalence, incidence, sepsis-related mortality, hospitalizations, life expectancy, QoL population norms, QoL reduction after sepsis, and healthcare use post-sepsis were obtained from previous literature and Statistics Netherlands. We used these data to estimate annual Quality-adjusted Life Years (QALYs), productivity loss, and increase in healthcare use post-sepsis. A sensitivity analysis was performed to analyze the burden and indirect economic costs of sepsis under alternative assumptions, resulting in a baseline, low, and high estimated burden. The results are presented as a baseline (low–high burden) estimate.ResultsThe annual disease burden of sepsis is approximately 57,304 (24,398–96,244; low–high burden) QALYs. Of this, mortality accounts for 26,898 (23,166–31,577) QALYs, QoL decrease post-sepsis accounts for 30,406 (1232–64,667) QALYs. The indirect economic burden, attributed to lost productivity and increased healthcare expenditure, is estimated at €416.1 (147.1–610.7) million utilizing the friction cost approach and €3.1 (0.4–5.7) billion using the human capital method. Cumulatively, the combined disease and indirect economic burdens range from €3.8 billion (friction method) to €6.5 billion (human capital method) annually within the Netherlands.ConclusionsSepsis and its complications pose a substantial disease and indirect economic burden to the Netherlands, with an indirect economic burden due to production loss that is potentially larger than the burden due to coronary heart disease or stroke. Our results emphasize the need for future studies to prevent sepsis, saving downstream costs and decreasing the economic burden.

Indigenous Australians critically ill with sepsis: Characteristics, outcomes, and areas for improvement

BackgroundAboriginal and Torres Strait Islander Australians have amongst the highest incidence of sepsis globally. ObjectiveThe objective of this study was to describe the characteristics, short- and long-term outcomes of non-Indigenous, Aboriginal Australian and Torres Strait Islander Australians admitted with sepsis to an intensive care unit (ICU) to inform healthcare outcome improvement. MethodsA retrospective cohort study of 500 consecutive sepsis admissions to the Cairns Hospital ICU compared clinical characteristics, short-term (before ICU discharge) and long-term (2000 days posthospital discharge) outcomes. Cohort stratification was done by voluntary disclosure of Indigenous status. ResultsOf the 442 individual admissions, 145 (33%) identified as Indigenous Australian. Indigenous and non-Indigenous Australians had similar admission Acute Physiology and Chronic Health Evaluation-3 scores (median [interquartile range]: 70 [52–87] vs. 69 [53–87], P = 0.87), but Indigenous patients were younger (53 [43–60] vs. 62 [52–73] years, P < 0.001) and were more likely to have chronic comorbidities such as type 2 diabetes (58% vs. 23%, P < 0.001), cardiovascular disease (40% vs 28%, P = 0.01), and renal disease (39% vs. 10%, P < 0.001). They also had more hazardous healthcare behaviours such as smoking (61% vs. 45%, P = 0.002) and excess alcohol consumption (40% vs. 18%, P < 0.001). Despite this, the case-fatality rate of Indigenous and non-Indigenous Australians before ICU discharge (13% vs. 12%, P = 0.75) and 2000 days post hospital discharge (25 % vs. 28 %, P = 0.40) was similar. Crucially, however, Indigenous Australians died younger both in the ICU (median [interquartile range] 54 (50–60) vs. 70 [61–76], P < 0.0001) and 2000 days post hospital discharge (58 [53–63] vs. 70 [63–77] years, P < 0.0001). ConclusionsAlthough Indigenous Australians critically ill with sepsis have similar short and long-term mortality rates, they present to hospital, die in-hospital, and die post-discharge significantly younger. Unique cohort characteristics may explain these outcomes, and assist clinicians, researchers and policy-makers in targeting interventions to these characteristics to best reduce the burden of sepsis in this cohort and improve their healthcare outcomes.

Understanding health care pathways of patients with sepsis: protocol of a mixed-methods analysis of health care utilization, experiences, and needs of patients with and after sepsis

BackgroundSepsis is associated with about 20% of deaths worldwide. It often presents with non-specific initial symptoms, making its emergency treatment an interdisciplinary and cross-sectoral challenge. Three in four sepsis survivors suffers from new cognitive, psychological, or physical sequelae for which specific treatment concepts are scarce. The AVENIR project aims to improve the understanding of patient pathways, and subjective care experiences and needs along the entire healthcare pathway before, with and after sepsis. Based on this, concrete recommendations for the organization of care and patient information materials will be developed with close patient participation.MethodsMixed-methods study including (1) analysis of anonymized nationwide health claims data from Germany, (2) linkage of health claims data with patient care reports (PCR) of emergency medical services from study regions in two federal states within Germany, and (3) qualitative exploration of the patient, relative, and care provider perspective on sepsis care. In (1), we analyze inpatient and outpatient health care utilization until 30 days pre-sepsis; clinical sepsis care including intra- and inter-hospital transfers; and rehabilitation, inpatient and outpatient aftercare of sepsis survivors as well as costs for health care utilization until 24 months post-sepsis. We attempt to identify survivor classes with similar health care utilization by Latent Class Analyses. In (2), PCR are linked with health claims data to establish a comprehensive database outlining care pathways for sepsis patients from pre-hospital to follow-up. We investigate e.g., whether correct initial assessment is associated with acute (e.g., same-day lethality) and long-term (e.g., new need for care, long-term mortality) outcomes of patients. We compare the performance of sepsis-specific screening tools such as qSOFA, NEWS-2 or PRESEP in the pre-clinical setting. In (3), semi-structured interviews as well as synchronous and asynchronous online focus groups are conducted and analyzed using qualitative content analyses techniques.DiscussionThe results of the AVENIR study will contribute to a deeper understanding of sepsis care pathways in Germany. They may serve as a base for improvements and innovations in sepsis care, that in the long-term can contribute to reduce the personal, medical, and societal burden of sepsis and its sepsis sequelae.Trial registrationRegistered at German Clinical Trial Register (ID: DRKS00031302, date of registration: 5th May 2023).

Multidrug-Resistant Sepsis: A Critical Healthcare Challenge.

Sepsis globally accounts for an alarming annual toll of 48.9 million cases, resulting in 11 million deaths, and inflicts an economic burden of approximately USD 38 billion on the United States healthcare system. The rise of multidrug-resistant organisms (MDROs) has elevated the urgency surrounding the management of multidrug-resistant (MDR) sepsis, evolving into a critical global health concern. This review aims to provide a comprehensive overview of the current epidemiology of (MDR) sepsis and its associated healthcare challenges, particularly in critically ill hospitalized patients. Highlighted findings demonstrated the complex nature of (MDR) sepsis pathophysiology and the resulting immune responses, which significantly hinder sepsis treatment. Studies also revealed that aging, antibiotic overuse or abuse, inadequate empiric antibiotic therapy, and underlying comorbidities contribute significantly to recurrent sepsis, thereby leading to septic shock, multi-organ failure, and ultimately immune paralysis, which all contribute to high mortality rates among sepsis patients. Moreover, studies confirmed a correlation between elevated readmission rates and an increased risk of cognitive and organ dysfunction among sepsis patients, amplifying hospital-associated costs. To mitigate the impact of sepsis burden, researchers have directed their efforts towards innovative diagnostic methods like point-of-care testing (POCT) devices for rapid, accurate, and particularly bedside detection of sepsis; however, these methods are currently limited to detecting only a few resistance biomarkers, thus warranting further exploration. Numerous interventions have also been introduced to treat MDR sepsis, including combination therapy with antibiotics from two different classes and precision therapy, which involves personalized treatment strategies tailored to individual needs. Finally, addressing MDR-associated healthcare challenges at regional levels based on local pathogen resistance patterns emerges as a critical strategy for effective sepsis treatment and minimizing adverse effects.

Clinical prognostic models in children with sepsis in low- and middle-income countries: a systematic review and meta-analysis.

Sepsis is the leading cause of child death worldwide, with the majority of these deaths occurring in low- and middle-income countries (LMICs). The aim of this systematic review and meta-analysis was to describe clinical prognostic scores and models for pediatric sepsis outcomes and assess the performance of these scores for predicting mortality in LMICs. Ovid Medline, CINAHL, Cochrane Library, EBSCO Global Health, and Web of Science, were searched through September 2022 for citations related to the development or validation of a clinical prognostic score or model among children with sepsis, conducted in LMIC. Titles, abstracts, and full texts were screened by two independent reviewers and data extracted included population characteristics, variables included, outcomes, and model performance. Risk of bias was assessed with the Prediction Model Risk of Bias Assessment Tool (PROBAST). 4,251 titles/abstracts and 315 full-text studies were screened, with 12 studies meeting inclusion criteria. Study countries included India, China, Egypt, Indonesia, Tanzania, and a multi-site study in Latin America. Prognostic scores/models included existing scores such as PELOD-2, pSOFA, PRISM, P-MODS, refractory shock criteria. There was high risk of bias in all studies. Meta-analysis was possible for pSOFA, PELOD-2, PRISM, and P-MODS, with pooled area under the receiver-operator characteristic curve of 0.86 (95%CI 0.78-0.94), 0.83 (95% CI 0.76-0.91), respectively. Relatively few clinical scores and models have been externally validated for prognostication and risk-stratification among children with sepsis in diverse LMIC settings. Notably there were no studies from low-income countries. Some potentially relevant studies were excluded due to lack of clarity regarding the presence of sepsis in the study populations. More widespread and standardized use of sepsis criteria may aid in better understanding the burden of sepsis and prognostic model performance at the bedside among children in LMICs. Further research to externally validate, implement and adapt these models is needed to account for challenges in use of these scores in resource-limited settings. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022340126, PROSPERO [CRD42022340126].

Clinical evaluation of a multiplex droplet digital PCR for pathogen detection in critically ill COVID-19 patients with bloodstream infections

BackgroundNosocomial bloodstream infections (nBSI) have emerged as a clinical concern for physicians treating COVID-19 patients. In this study, we aimed to evaluate the effectiveness of a multiplex ddPCR in detecting bacterial pathogens in the blood of COVID-19 critically ill patients.MethodsThis prospective diagnostic study included RT-PCR-confirmed COVID-19 patients admitted to our hospital from December 2022 to February 2023. A multiplex ddPCR assay was used to detect common bacterial pathogens and AMR genes in blood samples of the patients, along with antimicrobial susceptibility testing (AST). The diagnostic performance of the ddPCR assay was evaluated by comparing the results with those obtained through blood culture and clinical diagnosis. Additionally, the ability of ddPCR in detecting bacterial resistance was compared with the AST results.ResultsOf the 200 blood samples collected from 184 patients, 45 (22.5%) were positive using blood culture, while 113 (56.5%) were positive for bacterial targets using the ddPCR assay. The ddPCR assay outperformed blood culture in pathogen detection rate, mixed infection detection rate, and fungal detection rate. Acinetobacter baumannii and Klebsiella pneumoniae were the most commonly detected pathogens in COVID-19 critically ill patients, followed by Enterococcus and Streptococcus. Compared to blood culture, ddPCR achieved a sensitivity of 75.5%, specificity of 51.0%, PPV of 30.9%, and NPV of 87.8%, respectively. However, there were significant differences in sensitivity among different bacterial species, where Gram-negative bacteria have the highest sensitivity of 90.3%. When evaluated on the ground of clinical diagnosis, the sensitivity, specificity, PPV and NPV of ddPCR were 78.1%, 90.5%, 94.7%, and 65.5%, respectively. In addition, the ddPCR assay detected 23 cases of blaKPC, which shown a better consistent with clinical test results than other detected AMR genes. Compared to blaKPC, there were few other AMR genes detected, indicating that the application of other AMR gene detection in the COVID-19 critically ill patients was limited.ConclusionThe multiplex ddPCR assay had a significantly higher pathogen detection positivity than the blood culture, which could be an effective diagnostic tool for BSIs in COVID-19 patients and to improve patient outcomes and reduce the burden of sepsis on the healthcare system, though there is room for optimization of the panels used.- Adjusting the targets to include E. faecalis and E. faecium as well as Candida albicans and Candida glabrata could improve the ddPCR' s effectiveness. However, further research is needed to explore the potential of ddPCR in predicting bacterial resistance through AMR gene detection.

A Pilot Feasibility Randomized Controlled Trial of Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit: The Lessening Organ Dysfunction with Vitamin C-India (LOVIT-India) Trial.

The burden of sepsis is high in India and is associated with substantial morbidity and mortality. Vitamin C, an endogenous antioxidant, may improve patient outcomes. This was a parallel-group pilot feasibility randomized controlled trial conducted at 2 intensive care units in India. Adult patients (≥18 years) with proven or suspected infection as the main diagnosis and needing a continuous intravenous vasopressor infusion were randomized to intravenous vitamin C (50 mg/kg every 6 hours for a maximum of 16 doses) or matching placebo. Primary outcomes were related to protocol adherence and feasibility (enrollment per month). The key secondary outcome was the composite of mortality or persistent organ dysfunction (POD) at day 28 after randomization. 60 patients were screened, 51 were eligible, 32 were randomized, and 30 were included in the analysis (randomized/eligible ratio: 0.63). The overall rate of enrollment was 1.5 patients per month. The median (IQR) age was 63.5 (51.0, 70.0) and 70.0% of the patients were male. In both arms, all patients received ≥90% of scheduled doses of the study drug. No patient received open-label vitamin C and there were no deviations from the glucose monitoring protocol. The composite outcome of mortality or POD at day 28 occurred in 56.3% (9/16) in the vitamin C arm as compared to 42.9% (6/14) in the placebo arm [RR: 1.31 (95% CI: 0.62, 2.76), p = 0.47]. In this pilot feasibility randomized controlled trial of vitamin C for adult patients with sepsis, protocol adherence was excellent and feasibility endpoints were met. CTRI/2020/03/024371. Vijayaraghavan BKT, Venkataraman R, Ramanathan Y, Margabandhu S, Jayakumar D, Ramachandran P, et al. A Pilot Feasibility Randomized Controlled Trial of Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit: The Lessening Organ Dysfunction with Vitamin C-India (LOVIT-India) Trial. Indian J Crit Care Med 2023;27(12):910-916.