Diagnostic markers for early sepsis diagnosis in children with systemic inflammatory response syndrome

Sepsis caused by infection remains a major cause of mortality among children. One of the main reasons for high sepsis mortality rates is the inability to obtain early diagnosis. Sensitive and specific biomarkers are greatly needed in rapid diagnosis of sepsis. The main aim of study was to investigate the ability of high-mobility group box-1 protein (HMGB1), lipopolysaccharide-binding protein (LBP), Interleukin-6 (IL-6), procalcitonin (PCT) and C reactive protein (CRP) to differentiate sepsis patients. Eighty-four children with Systemic Inflammatory Response Syndrome (SIRS) were included in the prospective study. Sepsis was recognised in 23% (n = 19) of them. LBP, IL-6, CRP and PCT levels were significantly higher among the sepsis group (P < 0.05). HMGB1 levels in the sepsis patients did not significantly differ from SIRS patients. In ROC analysis in sepsis patients, identification markers LBP, IL6 and CRP performed quite similarly (P < 0.001), with the best result being for IL6. Our data suggest that in early sepsis diagnosis in children, LBP, IL-6, PCT and CRP are probably the superior diagnostic markers, with the best performance by IL6. LBP and IL-6 are superior markers for sepsis patients' disease process monitoring. HMGB1 does not have a diagnostic value for sepsis patient identification.publishersversionPeer reviewe

Levels of Inflammatory Cytokines and Chemokines in Hospitalized Children with Sepsis and Pneumonia

Introduction. Pneumonia is a common childhood lower respiratory tract infection, which accounts for large number of hospitalization and death among children; its diagnosis is based mainly on clinical signs.Aim of the study was to measure inflammatory cytokine panels in children with pneumonia, and their correlation with clinically used inflammatory markers. Materials and methods. We included 20 patients, hospitalized in Children’s Clinical University hospital, with systemic inflammatory response syndrome (SIRS) and radiologically confirmed pneumonia from October 2011 to January 2013. In all patients cytokine and chemokine panels and clinical inflammatory markers were measured at the time of admission, after 24 hours and on the time of discharge.Results. 12 different inflammatory cytokines were measured. sFAS, sVCAM1, IL-8, IL-10, TNF alpha, Eotaxin, G-CSF, IL1ra, IP10 and MCP1 showed statistically significant changes between levels of inclusion in the study and levels after 24 hours. G-CSF, IL-8, IFN gamma, TNF alpha and IL-10 showed also medium strong correlation with clinically used inflammatory markers (PCT, CRO, and IL-6).Conclusions. Inflammatory cytokines show statistically significant changes during course of treatment, thus they could be used in diagnostics in septic patients with pneumonia, and also could show patients response to therapy.publishersversionPeer reviewe

Health-related quality of life of the parents of children hospitalized due to acute rotavirus infection : A cross-sectional study in Latvia

Funding Information: Financial competing interests: Project was granted by Riga Stradins University (Grant No. RSU ZP 06/2013/2–3/155). Manuscript was drafted as part of a project. Non-financial competing interests: This manuscript is part of the doctoral Thesis of the corresponding author Gunta Laizane. Publisher Copyright: © 2018 The Author(s).Background: Rotavirus is the leading cause of severe diarrhea in young children and infants worldwide, representing a heavy public health burden. Limited information is available regarding the impact of rotavirus gastroenteritis on the quality of life of affected children and their families. The objectives of study were to estimate the impact of rotavirus infection on health-related quality of life (HRQL), to assess the social and emotional effects on the families of affected children. Methods: This study enrolled all (n=527) RotaStrip®-positive (with further PCR detection) cases (0-18 years of age) hospitalized from April 2013 to December 2015 and their caregivers. A questionnaire comprising clinical (filled-in by the medical staff) and social (filled by the caregivers) sections was completed per child. Results: Main indicators of emotional burden reported by caregivers were compassion (reported as severe/very severe by 91.1% of parents), worry (85.2%), stress/anxiety (68.0%). Regarding social burden, 79.3% of caregivers reported the need to introduce changes into their daily routine due to rotavirus infection of their child. Regarding economic burden, 55.1% of parents needed to take days off work because of their child's sickness, and 76.1% of parents reported additional expenditures in the family's budget. Objective measures of their child's health status were not associated with HRQL of the family, as were the parent's subjective evaluation of their child's health and some sociodemographic factors. Parents were significantly more worried if their child was tearful (p=0.006) or irritable (p<0.001). Parents were more stressful/anxious if their child had a fever (p=0.003), was tearful (p<0.001), or was irritable (p<0.001). Changes in parents' daily routines were more often reported if the child had a fever (p=0.02) or insufficient fluid intake (p=0.04). Conclusion: Objective health status of the child did not influence the emotional, social or economic burden, whereas the parents' subjective perception of the child's health status and sociodemographic characteristics, were influential. A better understanding of how acute episodes affect the child and family, will help to ease parental fears and advise parents on the characteristics of rotavirus infection and the optimal care of an infected child.publishersversionPeer reviewe

Clinical characterisation of rota virus infection associated with most commonly circulating genotypes in children hospitalised in children's university hospital : A cross-sectional study in Latvia

In developed and developing countries, most cases of acute gastroenteritis in children are caused by viruses, and rotaviruses are known as the leading cause. The aim of our study was to estimate the main circulating serotypes of rotavirus before the introduction of routine immunisation in Latvia, and to search for their possible correlation with clinical symptoms and circulating genotypes. A cross-sectional study was carried out among children who had been hospitalised in the Children's Clinical University Hospital from April 2013 to December 2015. Genotyping was done for 462 stool samples. Among G/P combinations, the most predominant genotypes were G4P[8] (61.3%), G9P[8] (12.4%) and G2P[4] (10.0%) in children of age 5 years. There was a statistically significant correlation (p < 0.05) between clinical signs (vomiting, dehydration, chronic diseases) and G1P[8] and G8P[8] genotypes. Infants infected with genotype G4P[4] had a statistically significant negative correlation with severity of acute gastroenteritis episodes (p < 0.05). We detected nine different rotavirus G genotypes, and two different P genotypes. G4P[8], G9P[8], and G2P[8] were predominant. We observed correlation between the dominant genotypes and clinical manifestations of rotavirus infection.publishersversionPeer reviewe

Biomarker combinations in predicting sepsis in hospitalized children with fever

Funding Information: This study was conducted as a part of the Republic of Latvia “State Research Program VPP BIOMEDICINE” Project No 8.2 „Clinical, molecular-biological and morpho-functional research of diagnostics and treatment of inherited and acquired diseases of childhood”. Funding Information: This study was also partially funded by “The Latvian National Research Program BIOMEDICINE FOR PUBLIC HEALTH”, project No 6. Publisher Copyright: © 2022, The Author(s).Sepsis is among the leading causes of critical illness worldwide. It includes physiologic, pathologic, and biochemical abnormalities, induced by infection. Novel methods for recognizing a dysregulated inflammatory response and predicting associated mortality must be developed. Our aim was to investigate biomarkers that characterize a pro-inflammatory and anti-inflammatory response in patients with fever by comparing predictive validity for sepsis. 165 patients with fever were enrolled in this study, 55 of them had sepsis according to pSOFA criteria. All patients had blood samples drawn at the time of inclusion and after 24 h. CRP, PCT and also IL-6, IL-8 and sFAS levels were significantly higher in patients with sepsis. The AUC of CRP to predict sepsis was 0.799, all the other biomarkers had AUC’s lower than that. Cytokines, when used as a single marker, did not show a significant diagnostic performance We analyzed various models of biomarker combinations. CRP combined with sFAS showed increase in sensitivity in predicting sepsis (88% vs. 83%). The highest AUC was achieved, when CRP, IL-6, sFAS and sVCAM-1 markers were combined 0.830 (95% CI 0.762–0.884) with a sensitivity of 70% and specificity of 84%. vs. 0.799 for CRP alone.publishersversionPeer reviewe

Assessment of ADAMTS-13 Level in Hospitalized Children with Serious Bacterial Infections as a Possible Prognostic Marker

Background and objectives: In children, acute infection is the most common cause of visits in the primary care or emergency department. In 2002, criteria for diagnostics of pediatric sepsis were published, and then revised in 2016 as life-threatening organ dysfunction due to a dysregulated host response to infection. In the pathophysiology of sepsis endothelial dysfunction plays a very important role. Deficient proteolysis of von Willebrand factor, due to reduced ADAMTS-13 activity, results in disseminated platelet-rich thrombi in the microcirculation. ADAMTS-13 deficiency has been detected in systemic inflammation. The clinical relevance of ADAMTS-13 during sepsis is still unclear. We aimed to investigate the possible use of ADAMTS-13 as a prognostic marker in children with serious bacterial infection (SBI). Materials and Methods: Inclusion criteria were hospitalized children with SBI, aged from 1 month to 17 years. SBI was defined based on available clinical, imaging, and later also on microbiological data. Sepsis was diagnosed using criteria by The International Consensus Conference. In all the patients, the levels of ADAMTS-13 were measured at the time of inclusion. Results: Data from 71 patients were analyzed. A total of 47.9% (34) had sepsis, 21.1% (15) were admitted to the ICU, 8.5% (6) had mechanical ventilator support, and 4.2% (3) patients had a positive blood culture. The median level of ADAMTS-13 in this study population was 689.43 ng/mL. Patients with sepsis, patients admitted to the Intensive Care Unit, and patients in need of mechanical ventilator support had significantly lower levels of ADAMTS-13. None of the patients had ADAMTS-13 deficiency. In patients with SBI, the area under the curve (AUC) to predict sepsis was 0.67. A cut-off ADAMTS-13 level of <= 730.49 had 82% sensitivity and 60% specificity for sepsis in patients with SBI. Conclusions: ADATMS-13 levels were lower in patients with SBI and sepsis, but AUC and sensitivity were too low to accept it as a prognostic markerPeer reviewe

Invasive pneumococcal disease in Latvia in PCV10 vaccination era, 2012-2018

Funding Information: This work was supported by the Hepatologu asociacija. Publisher Copyright: © Copyright © 2021 Savrasova, Krumina, Cupeca, Zeltina, Villerusha, Grope, Viksna, Dimina and Balasegaram.In 2010 in Latvia, invasive pneumococcal disease (IPD) became a cause for concern and vaccination of infants with four doses of 7–valent pneumococcal conjugate vaccine (PCV7) commenced. In 2012, 10–valent pneumococcal conjugate vaccine (PCV10) (three doses at 2, 4, and 12–15 month of age) vaccination was introduced. We described incidence and serotype distribution of IPD in Latvia and investigated serotypes associated with death from IPD based on surveillance data. Adult vaccination against pneumococcal infection is not included in the national immunization program. Laboratory confirmed IPD cases are passively notified to the Center for Disease Prevention and Control of Latvia (CDPC) by laboratories and clinicians. We calculated incidence by age, sex, case fatality, and trend in serotypes by conducting a retrospective population-based cross-sectional study based on national IPD surveillance data. From 2012 to 2018 466 cases of IPD were reported. The highest notified incidence was in 2015 at 4.4/100,000, which fell to 3.9 in 2018. The highest mean annual IPD incidence was in infants (4.8) and in the elderly (6.0). PCV10 vaccine serotypes were the most prevalent in IPD cases up to 2015 with a decreasing trend from 50% (20/40) in 2012 to 19% (14/74) in 2018 (chi2 test for trend of odds = 0.000). PCV23nonPCV13 vaccine serotypes had an increasing trend and rose from 18% (7/40) to 34% (25/74) (chi2 test for trend of odds = 0.000). Non-Vaccine serotypes had an increasing trend and rose from 13% (5/40) to 27% (20/74) (chi2 test for trend of odds = 0.038). Reported total case fatality was 19% (87/466). The highest, at 36% (20/56), was reported in 2013. After adjusting for age, Streptococcus pneumoniae serotype 3 was associated with death from IPD (adjusted OR 2.3 95%CI 1.25–4.12 p 0.007). Surveillance data indicate evidence of serotype replacement with an increasing trend of serotype 19A and PPV23nonPCV13 and Non-Vaccine serotypes. Serotype 3 and age were associated with fatal IPD outcome. Further studies of S. pneumoniae carriage would be useful in providing more evidence to characterize serotypes' circulation.publishersversionPeer reviewe

Impact of infection on proteome-wide glycosylation revealed by distinct signatures for bacterial and viral pathogens

Funding Information: This research, part of the PERFORM project, has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 668303 . The samples collected previously were funded by: the European Seventh Framework Programme for Research and Technological Development ( FP7 ) under EUCLIDS Grant Agreement No. 279185 . Funding Information: This research, part of the PERFORM project, has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 668303. The samples collected previously were funded by: the European Seventh Framework Programme for Research and Technological Development (FP7) under EUCLIDS Grant Agreement No. 279185. We would like to thank all the patients and the healthy controls for donating their blood for the EUCLIDS, IRIS, and Westra studies. We would like to thank the Radboud Consortium for Glycoscience for their advice for data interpretation. We also thank the PERFORM consortium (see supplemental material for all participants) for their collaboration and fruitful discussions. Conceptualization, E.W. H.W. and M.J.; Methodology, E.W. M.D. H.W. and M.J.; Investigation, E.W.; Software, A.S. and H.W.; Formal Analysis, E.W. and H.W.; Visualization, E.W. and H.W.; Resources, M.F. L.H. N.K. R.P. M.K. V.W. J.H. and F.M.; Writing – Original Draft, E.W. and M.J.; Writing – Review & Editing, E.W. J.G. A.S. M.F. L.H. N.K. R.P. M.D. M.K. V.W. J.H. F.M. M.L. R.G. A.G. D.L. H.W. and M.J.; Funding Acquisition, M.J. R.G. and M.L.; Supervision, H.W. D.L. and M.J. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: © 2023 The Author(s)Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection.Peer reviewe

A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM) : a multi-cohort machine learning study

Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.BACKGROUND: Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h. METHODS: In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores. FINDINGS: 376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma samples for the MS-A dataset, and 150 plasma samples for the MS-B dataset. Differential abundance analysis, and the first round of feature selection using FS-PLS identified 35 protein biomarker candidates, of which 13 had commercial ELISA or Luminex tests available. 16 proteins with ELISA or Luminex tests available were identified by literature review. Further evaluation via Luminex and ELISA and the second round of feature selection using FS-PLS revealed a six-protein signature: three of the included proteins are elevated in bacterial infections (SELE, NGAL, and IFN-γ), and three are elevated in viral infections (IL18, NCAM1, and LG3BP). Performance testing of the signature using Luminex assays revealed area under the receiver operating characteristic curve values between 89·4% and 93·6%. INTERPRETATION: This study has led to the identification of a protein signature that could be ultimately developed into a blood-based point-of-care diagnostic test for rapidly diagnosing bacterial and viral infections in febrile children. Such a test has the potential to greatly improve care of children who are febrile, ensuring that the correct individuals receive antibiotics. FUNDING: European Union's Horizon 2020 research and innovation programme, the European Union's Seventh Framework Programme (EUCLIDS), Imperial Biomedical Research Centre of the National Institute for Health Research, the Wellcome Trust and Medical Research Foundation, Instituto de Salud Carlos III, Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Grupos de Refeencia Competitiva, Swiss State Secretariat for Education, Research and Innovation.Peer reviewe

Guideline adherence in febrile children below 3 months visiting European Emergency Departments : an observational multicenter study

Funding Information: This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 848196. The Research was supported by the National Institute for Health Research Biomedical Research Centres at Imperial College London, Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. For the remaining authors, no sources of funding were declared. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Publisher Copyright: © 2022, The Author(s).Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment. There is practice variation in management due to differences in guidelines and their usage and adherence. We aimed to assess whether management in febrile children below 3 months attending European Emergency Departments (EDs) was according to the guidelines for fever. This study is part of the MOFICHE study, which is an observational multicenter study including routine data of febrile children (0–18 years) attending twelve EDs in eight European countries. In febrile children below 3 months (excluding bronchiolitis), we analyzed actual management compared to the guidelines for fever. Ten EDs applied the (adapted) NICE guideline, and two EDs applied local guidelines. Management included diagnostic tests, antibiotic treatment, and admission. We included 913 children with a median age of 1.7 months (IQR 1.0–2.3). Management per ED varied as follows: use of diagnostic tests 14–83%, antibiotic treatment 23–54%, admission 34–86%. Adherence to the guideline was 43% (374/868) for blood cultures, 29% (144/491) for lumbar punctures, 55% (270/492) for antibiotic prescriptions, and 67% (573/859) for admission. Full adherence to these four management components occurred in 15% (132/868, range 0–38%), partial adherence occurred in 56% (484/868, range 35–77%). Conclusion: There is large practice variation in management. The guideline adherence was limited, but highest for admission which implies a cautious approach. Future studies should focus on guideline revision including new biomarkers in order to optimize management in young febrile children.What is Known:• Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment.• There is practice variation in management of young febrile children due to differences in guidelines and their usage and adherence.What is New:• Full guideline adherence is limited, whereas partial guideline adherence is moderate in febrile children below 3 months across Europe.• Guideline revision including new biomarkers is needed to improve management in young febrile children.publishersversionPeer reviewe