Project description:BACKGROUND:Health-workers in developing countries rely on clinical algorithms, such as the Integrated Management of Childhood Illnesses (IMCI), for the management of patients, including diagnosis of serious bacterial infections (SBI). The diagnostic accuracy of IMCI in detecting children with SBI is unknown. Prediction rules and guidelines for SBI from well-resourced countries at outpatient level may help to improve current guidelines; however, their diagnostic performance has not been evaluated in resource-limited countries, where clinical conditions, access to care, and diagnostic capacity differ. The aim of this study was to estimate the diagnostic accuracy of existing prediction rules and clinical guidelines in identifying children with SBI in a cohort of febrile children attending outpatient health facilities in Tanzania. METHODS:Structured literature review to identify available prediction rules and guidelines aimed at detecting SBI and retrospective, external validation on a dataset containing 1005 febrile Tanzanian children with acute infections. The reference standard, SBI, was established based on rigorous clinical and microbiological criteria. RESULTS:Four prediction rules and five guidelines, including IMCI, could be validated. All examined rules and guidelines had insufficient diagnostic accuracy for ruling-in or ruling-out SBI with positive and negative likelihood ratios ranging from 1.04-1.87 to 0.47-0.92, respectively. IMCI had a sensitivity of 36.7% (95% CI 29.4-44.6%) at a specificity of 70.3% (67.1-73.4%). Rules that use a combination of clinical and laboratory testing had better performance compared to rules and guidelines using only clinical and or laboratory elements. CONCLUSIONS:Currently applied guidelines for managing children with febrile illness have insufficient diagnostic accuracy in detecting children with SBI. Revised clinical algorithms including simple point-of-care tests with improved accuracy for detecting SBI targeting in tropical resource-poor settings are needed. They should undergo careful external validation against clinical outcome before implementation, given the inherent limitations of gold standards for SBI.

Project description:Viral infections are among the most common causes for fever without an apparent source (FWS) in young children; however, many febrile children are treated with antibiotics despite the absence of bacterial infection. Adenovirus, human herpesvirus 6 (HHV-6) and enterovirus are detected in children with FWS more often than other viral species. Virus and bacteria interact with pattern recognition receptors in circulating blood leukocytes and trigger specific host transcriptional programs that mediate immune response, and unique transcriptional signatures may be ascertained to discriminate between viral and bacterial causes for children with FWS. Microarray analyses were conducted on peripheral blood samples obtained from 51 pediatric patients with confirmed adenovirus, human herpesvirus 6 (HHV-6), enterovirus or bacterial infection. Whole blood transcriptional profiles could clearly distinguish febrile children from healthy controls, and febrile children with viral infections from afebrile children carrying the same virus. Molecular pathways regulating host immune response were the most affected in febrile children with infection. Pattern recognition programs were prominently activated in all febrile children with infection, while differential activation of transcriptional programs was observed among viral species. Interferon signaling pathway was uniquely activated in children with febrile viral infection, while a different set of pathways was uniquely activated in children with bacterial infection. Transcriptional signatures were identified and classified febrile children with viral or bacterial infection with 87% overall accuracy, an improvement from the current clinical practice of deducing from white blood cell (WBC) count status. Similar degree of accuracy was observed when we validated the signature probes on data sets from an independent study with different microarray platforms. The current study confirms the clinical utility of blood transcriptional analysis, suggests the composition of transcriptional signatures which can be used to ascertain the infectious etiology of febrile young children without an apparent source, thus limit the overuse of antibiotics on febrile children presenting with this common clinical complaint.

Project description:Viral infections are among the most common causes for fever without an apparent source (FWS) in young children; however, many febrile children are treated with antibiotics despite the absence of bacterial infection. Adenovirus, human herpesvirus 6 (HHV-6) and enterovirus are detected in children with FWS more often than other viral species. Virus and bacteria interact with pattern recognition receptors in circulating blood leukocytes and trigger specific host transcriptional programs that mediate immune response, and unique transcriptional signatures may be ascertained to discriminate between viral and bacterial causes for children with FWS. Microarray analyses were conducted on peripheral blood samples obtained from 51 pediatric patients with confirmed adenovirus, human herpesvirus 6 (HHV-6), enterovirus or bacterial infection. Whole blood transcriptional profiles could clearly distinguish febrile children from healthy controls, and febrile children with viral infections from afebrile children carrying the same virus. Molecular pathways regulating host immune response were the most affected in febrile children with infection. Pattern recognition programs were prominently activated in all febrile children with infection, while differential activation of transcriptional programs was observed among viral species. Interferon signaling pathway was uniquely activated in children with febrile viral infection, while a different set of pathways was uniquely activated in children with bacterial infection. Transcriptional signatures were identified and classified febrile children with viral or bacterial infection with 87% overall accuracy, an improvement from the current clinical practice of deducing from white blood cell (WBC) count status. Similar degree of accuracy was observed when we validated the signature probes on data sets from an independent study with different microarray platforms. The current study confirms the clinical utility of blood transcriptional analysis, suggests the composition of transcriptional signatures which can be used to ascertain the infectious etiology of febrile young children without an apparent source, thus limit the overuse of antibiotics on febrile children presenting with this common clinical complaint. Total RNA samples extracted from whole blood of young children were processed for hybridization onto Illumina Human-HT12 version 4 beadchips, and differential expression of the transcripts was analyzed between sick children with either viral or bacterial infection and healthy children.

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Blood virosphere in febrile Tanzanian children.

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