Molecular microbiological methods in the diagnosis of neonatal sepsis.
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ABSTRACT:
SUBMITTER: Venkatesh M
PROVIDER: S-EPMC2956278 | biostudies-literature | 2010 Sep
REPOSITORIES: biostudies-literature
Publications
Molecular microbiological methods in the diagnosis of neonatal sepsis.
Venkatesh Mohan M Flores Angela A Luna Ruth Ann RA Versalovic James J
Expert review of anti-infective therapy 20100901 9
Neonatal sepsis is a major cause of neonatal mortality and morbidity. The current gold standard for diagnosis of sepsis, namely blood culture, suffers from low sensitivity and a reporting delay of approximately 48-72 h. Rapid detection of sepsis and institution of antimicrobial therapy may improve patient outcomes. Rapid and sensitive tests that can inform clinicians regarding the institution or optimization of antimicrobial therapy are urgently needed. The ideal diagnostic test should have adeq ...[more]
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Project description:What’s known on this subjectNeonates are at increased risk for developing sepsis, but this population often exhibits ambiguous clinical signs that complicate the diagnosis of infection. No biomarker has yet shown enough diagnostic accuracy to rule out sepsis at the time of clinical suspicion.What this study addsWe show that a gene-expression-based signature is an accurate objective measure of the risk of sepsis in a neonate or preterm infant, and it substantially improves diagnostic accuracy over that of commonly used laboratory-based testing. Implementation might decrease inappropriate antibiotic use.BackgroundNeonatal sepsis can have devastating consequences, but accurate diagnosis is difficult. As a result, up to 200 neonates with suspected sepsis are treated with empiric antibiotics for every 1 case of microbiologically confirmed sepsis. These unnecessary antibiotics enhance bacterial antibiotic resistance, increase economic costs, and alter gut microbiota composition. We recently reported an 11-gene diagnostic test for sepsis (Sepsis MetaScore) based on host whole-blood gene expression in children and adults, but this test has not been evaluated in neonates.MethodsWe identified existing gene expression microarray-based cohorts of neonates with sepsis. We then tested the accuracy of the Sepsis MetaScore both alone and in combination with standard diagnostic laboratory tests in diagnosing sepsis.ResultsWe found 3 cohorts with a total of 213 samples from control neonates and neonates with sepsis. The Sepsis MetaScore had an area under the receiver operating characteristic curve of 0.92-0.93 in all 3 cohorts. We also found that, as a diagnostic test for sepsis, it outperformed standard laboratory measurements alone and, when used in combination with another test(s), resulted in a significant net reclassification index (0.3-0.69) in 5 of 6 comparisons. The mean point estimates for sensitivity and specificity were 95% and 60%, respectively, which, if confirmed prospectively and applied in a high-risk cohort, could reduce inappropriate antibiotic usage substantially.ConclusionsThe Sepsis MetaScore had excellent diagnostic accuracy across 3 separate cohorts of neonates from 3 different countries. Further prospective targeted study will be needed before clinical application.
| S-EPMC5954302 | biostudies-literature
Project description:Neonatal sepsis remains difficult to diagnose due to its non-specific signs and symptoms. Traditional scoring systems help to discriminate between septic or not patients, but they do not consider every single patient particularity. Thus, the purpose of this study was to develop an early- and late-onset neonatal sepsis diagnosis model, based on clinical maternal and neonatal data from electronic records, at the time of clinical suspicion. A predictive model was obtained by training and validating an artificial Neural Networks (ANN) algorithm with a balanced dataset consisting of preterm and term non-septic or septic neonates (early- and late-onset), with negative and positive culture results, respectively, using 25 maternal and neonatal features. The outcome of the model was sepsis or not. The performance measures of the model, evaluated with an independent dataset, outperformed physician's diagnosis using the same features based on traditional scoring systems, with a 93.3% sensitivity, an 80.0% specificity, a 94.4% AUROC, and a regression coefficient of 0.974 between actual and simulated results. The model also performed well-relative to the state-of-the-art methods using similar maternal/neonatal variables. The top 10 factors estimating sepsis were maternal age, cervicovaginitis and neonatal: fever, apneas, platelet counts, gender, bradypnea, band cells, catheter use, and birth weight.
| S-EPMC7518045 | biostudies-literature
Project description:BackgroundNeonatal sepsis (NS) is a life-threatening disorder and an important cause of morbidity and mortality in neonates. Previous studies showed that interleukin 8 (IL-8) may effectively and rapidly diagnose NS.ObjectiveWe conducted the systematic review and meta-analysis to investigate the diagnostic value of the IL-8 in NS.MethodsThe literature was searched in PUBMED, EMBASE, Cochrane Library, CNKI, VIP and other Chinese Medical Databases during October 1998 to January 2014 using set search criteria. Each included study was evaluated by quality assessment of diagnostic accuracy studies tool. Two investigators independently extracted the data and study characteristics, and disagreements, if any, were resolved by consensus. Meta-disc software was used to calculate the pooled sensitivity, specificity and summary diagnostic odds ratio (SDOR), I² or Cochrane Q to test heterogeneity, and meta-regression to investigate the source of heterogeneity. Funnel plots were used to test the potential presence of publication bias. False-positive report probability (FPRP) was calculated to confirm the significance of the results.ResultsEight studies (548 neonates) were included in this meta-analysis. The pooled sensitivity and specificity of IL-8 were 0.78 and 0.84, respectively, which had moderate accuracy in the diagnosis of NS. The pooled diagnostic odds ratio (DOR) and area under curve (AUC) was 21.64 and 0.8908 (Q*=0.8215), respectively. The diagnostic threshold analysis showed that there was no threshold effect. The meta-regression analysis showed the cut-off, QUADAS and onset time have no effect on the heterogeneity. The funnel plots showed the existence of publication bias.ConclusionMeta-analysis showed IL-8 had a moderate accuracy (AUC=0.8908) for the diagnosis of NS. IL-8 is a helpful biomarker for early diagnosis of NS. However, we should combine the results with clinical symptoms and signs, laboratory and microbial results.
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Project description:Neonatal sepsis continues to be a major cause of morbidity and mortality in India. To aid the diagnosis several direct and indirect methods are available. Sepsis screen has resulted in decrease in indiscriminate use of antibiotics. C-reactive protein can be easily estimated and is a useful indicator for favourable outcome or complication. The bacterial flora causing sepsis has changed over the years. Antimicrobial chemotherapy should be based on the prevalent organisms in the neonatal ICU. Outcome can be improved by judicious use of newer antibiotics and exchange transfusion when indicated.
| S-EPMC5531238 | biostudies-other
Project description:Given the long-life expectancy of the newborn, research aimed at improving sepsis diagnosis and management in this population has been recognized as cost-effective, which at early stages continues to be a tremendous challenge. Despite there is not an ideal-specific biomarker, the simultaneous detection of biomarkers with different behavior during an infection such as procalcitonin (PCT) as high specificity biomarker with one of the earliest biomarkers in sepsis as interleukin-6 (IL-6) increases diagnostic performance. This is not only due to their high positive predictive value but also, since it can also help the clinician to rule out infection and thus avoid the use of antibiotics, due to their high negative predictive value. To this end, we explore a cutting-edge micromotor (MM)-based OFF-ON dual aptassay for simultaneous determination of both biomarkers in 15 min using just 2 μL of sample from low-birth-weight neonates with gestational age less than 32 weeks and birthweight below 1000 g with clinical suspicion of late-onset sepsis. The approach reached the high sensitivities demanded in the clinical scenario (LODPCT = 0.003 ng/mL, LODIL6 = 0.15 pg/mL) with excellent correlation performance (r > 0.9990, p < 0.05) of the MM-based approach with the Hospital method for both biomarkers during the analysis of diagnosed samples and reliability (Er < 6% for PCT, and Er < 4% for IL-6). The proposed approach also encompasses distinctive technical attributes in a clinical scenario since its minimal sample volume requirements and expeditious results compatible with few easy-to-obtain drops of heel stick blood samples from newborns admitted to the neonatal intensive care unit. This would enable the monitoring of both sepsis biomarkers within the initial hours after the manifestation of symptoms in high-risk neonates as a valuable tool in facilitating prompt and well-informed decisions about the initiation of antibiotic therapy.These results revealed the asset behind micromotor technology for multiplexing analysis in diagnosing neonatal sepsis, opening new avenues in low sample volume-based diagnostics.
| S-EPMC10798920 | biostudies-literature
Project description:Purpose of Review:Neonatal sepsis is a diagnosis made in infants less than 28 days of life and consists of a clinical syndrome that may include systemic signs of infection, circulatory shock, and multisystem organ failure. Recent Findings:Commonly involved bacteria include Staphylococcus aureus and Escherichia coli. Risk factors include central venous catheter use and prolonged hospitalization. Neonates are at significant risk of delayed recognition of sepsis until more ominous clinical findings and vital sign abnormalities develop. Blood culture remains the gold standard for diagnosis. Summary:Neonatal sepsis remains an important diagnosis requiring a high index of suspicion. Immediate treatment with antibiotics is imperative.
| S-EPMC7100521 | biostudies-literature
Project description:BackgroundDespite the necessity of early recognition for an optimal outcome, sepsis often remains unrecognized. Available tools for early recognition are rarely evaluated in low- and middle-income countries. In this study, we analyzed the spectrum, treatment and outcome of sepsis at an Ethiopian tertiary hospital and evaluated recommended sepsis scores.MethodsPatients with an infection and ≥2 SIRS criteria were screened for sepsis by SOFA scoring. From septic patients, socioeconomic and clinical data as well as blood cultures were collected and they were followed until discharge or death; 28-day mortality was determined.ResultsIn 170 patients with sepsis, the overall mortality rate was 29.4%. The recognition rate by treating physicians after initial clinical assessment was low (12.4%). Increased risk of mortality was significantly associated with level of SOFA and qSOFA score, Gram-negative bacteremia (in comparison to Gram-positive bacteremia; 42.9 versus 16.7%), and antimicrobial regimen including ceftriaxone (35.7% versus 19.2%) or metronidazole (43.8% versus 25.0%), but not with an increased respiratory rate (≥22/min) or decreased systolic blood pressure (≤100mmHg). In Gram-negative isolates, extended antimicrobial resistance with expression of extended-spectrum beta-lactamase and carbapenemase genes was common. Among adult patients, sensitivity and specificity of qSOFA score for detection of sepsis were 54.3% and 66.7%, respectively.ConclusionSepsis is commonly unrecognized and associated with high mortality, showing the need for reliable and easy-applicable tools to support early recognition. The established sepsis scores were either of limited applicability (SOFA) or, as in the case of qSOFA, were significantly impaired in their sensitivity and specificity, demonstrating the need for further evaluation and adaptation to local settings. Regional factors like malaria endemicity and HIV prevalence might influence the performance of different scores. Ineffective empirical treatment due to antimicrobial resistance is common and associated with mortality. Local antimicrobial resistance statistics are needed for guidance of calculated antimicrobial therapy to support reduction of sepsis mortality.
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Project description:Familial hypercholesterolemia (FH) is considered the genetic cause of coronary heart disease and ischemic stroke. FH is mainly an autosomal codominant pattern-based disorder and is primarily determined by point mutations within the low-density lipoprotein receptor, apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 genes, causing increased low-density lipoprotein cholesterol levels in the serum of untreated individuals. The accumulation will eventually lead to atherosclerotic cardiovascular disease. Although clinical criteria comprising several prognosis scores, such as the Simon Broome, Dutch Lipid Clinic Network, Make Early Diagnosis to Prevent Early Death, and the recently proposed Montreal-FH-SCORE, are the conventional basis of diagnosing FH, the genetic diagnosis made by single nucleotide polymorphism genotyping, multiplex ligation-dependent probe amplification analysis, and sequencing (both Sanger and Next-Generation sequencing) offers unequivocal diagnosis. Given the heterogeneity of known mutations, the genetic diagnosis of FH is often difficult to establish, despite the growing evidence of the causative mutations, as well as the polygenic aspect of this pathology and the importance of cascade screening of the FH patient‚s healthy family members. This review article details different genetic techniques that can be used in FH identification when there is a clinical FH suspicion based on criteria comprised in prognosis scores, knowing that none of these are exhaustive in the diagnosis, yet they efficaciously overlap and complement each other for confirming the disease at the molecular level.
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Project description:BackgroundCurrently, there is a lack of clear definition for neonatal sepsis. The Pediatric Committee of the European Medicines Agency (EMA) developed consensus criteria to ensure a standardization for neonatal sepsis definition. However, there is no evidence supporting the accuracy of the EMA sepsis criteria in neonatal sepsis diagnosis. The main objective of this study was to evaluate the diagnostic accuracy of EMA sepsis criteria for proven neonatal sepsis.MethodsA multicenter prospective cohort study was conducted from October 2015 to November 2018. Infants with a gestational age over 34th weeks, diagnosed with clinical sepsis and received antibiotics according to the EMA criteria or experienced neonatologists' opinion were included. Blood culture or multiplex real time-PCR or 16S-rRNA positive infants were accepted as "proven sepsis". The predictive performance of EMA criteria for proven sepsis was evaluated by sensitivity, specificity, accuracy, and area under the curve measures of receiver operator characteristic curves. Data-mining methods were used for further analysis.ResultsAmong the 245 included infants, the EMA criteria were positive in 97 infants (39.6%), while proven sepsis was diagnosed in 113 infants (46.1%). The sensitivity, specificity, and accuracy of the EMA criteria for proven sepsis were 44.2% (95%CI: 34.9-53.9), 64.4% (95%CI: 55.6-72.5), 55.1% (95%CI: 46.6-59.4) respectively. None of the clinical and laboratory parameters had sufficient performance individually in terms of sensitivity, specificity and accuracy measures. The diagnostic performance was similar when different clinical findings were added to the EMA sepsis criteria or assessment of the score was interpreted in different ways.ConclusionsResults highlighted that clinician opinion and standard laboratory tests are limited in the neonatal sepsis diagnosis. The EMA criteria also did not efficiently meet the diagnostic accuracy measures for neonatal sepsis. A predictive sepsis definition and rapid bedside point-of care tests are urgently needed.
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Project description:Analysis of the failure of cell signaling networks is an important topic in systems biology and has applications in target discovery and drug development. In this paper, some advanced methods for fault diagnosis in signaling networks are developed and then applied to a caspase network and an SHP2 network. The goal is to understand how, and to what extent, the dysfunction of molecules in a network contributes to the failure of the entire network. Network dysfunction (failure) is defined as failure to produce the expected outputs in response to the input signals. Vulnerability level of a molecule is defined as the probability of the network failure, when the molecule is dysfunctional. In this study, a method to calculate the vulnerability level of single molecules for different combinations of input signals is developed. Furthermore, a more complex yet biologically meaningful method for calculating the multi-fault vulnerability levels is suggested, in which two or more molecules are simultaneously dysfunctional. Finally, a method is developed for fault diagnosis of networks based on a ternary logic model, which considers three activity levels for a molecule instead of the previously published binary logic model, and provides equations for the vulnerabilities of molecules in a ternary framework. Multi-fault analysis shows that the pairs of molecules with high vulnerability typically include a highly vulnerable molecule identified by the single fault analysis. The ternary fault analysis for the caspase network shows that predictions obtained using the more complex ternary model are about the same as the predictions of the simpler binary approach. This study suggests that by increasing the number of activity levels the complexity of the model grows; however, the predictive power of the ternary model does not appear to be increased proportionally.
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