Publications
143 results found
Herberg J, Huang H, Thezenas M, et al., 2019, Lipocalin-2 is a sensitive and specific marker of bacterial iInfection in children, Publisher: bioRxiv
Abstract Introduction Bacterial infection is the leading cause of death in children globally. Clinical algorithms to identify children who are likely to benefit from antimicrobial treatment remain suboptimal. Biomarkers that accurately identify serious bacterial infection (SBI) could improve diagnosis and clinical management. Lipocalin 2 (LCN2) and neutrophil collagenase (MMP-8) are neutrophil-derived biomarkers associated with bacterial infection. Methods We evaluated LCN2 and MMP-8 as candidate biomarkers in 40 healthy controls and 151 febrile children categorised confirmed SBI, probable SBI, or viral infection. The diagnostic performance of LCN2 and MMP-8 to predict SBI was estimated by the area under the receiver operating characteristic curve (AUROC) and compared to the performance of C-reactive protein (CRP). Results Plasma LCN2 and MMP-8 concentration were predictive of SBI. The AUROC (95% CI) for LCN2, MMP8 and CRP to predict SBI was 0.88 (0.82-0.94); 0.80 (0.72-0.87) and 0.89 (0.84-0.94), respectively. The diagnostic performance of LCN2 in combination with CRP was significantly superior to either marker alone: AUROC 0.92 (95% CI: 0.88-0.96). Conclusion LCN2 is a sensitive and specific predictor of SBI in children which could be used to improve clinical management and antimicrobial stewardship. LCN2 should be further evaluated in prospective clinical studies.
Dunning J, Blankley S, Hoang LT, et al., 2019, Author Correction: Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza., Nature Immunology, Vol: 20, Pages: 373-373, ISSN: 1529-2908
In the version of this article initially published, a source of funding was not included in the Acknowledgements section. That section should include the following: P.J.M.O. was supported by EU FP7 PREPARE project 602525. The error has been corrected in the HTML and PDF version of the article.
Montaldo P, Kaforou M, Pollara G, et al., 2019, Whole blood gene expression reveals specific transcriptome changes in neonatal encephalopathy, Neonatology, Vol: 115, Pages: 68-76, ISSN: 1661-7800
BackgroundVariable responses to hypothermic neuroprotection are related to the clinical heterogeneity of encephalopathic babies, hence better disease stratification may facilitate the development of individualized neuroprotective therapies.ObjectivesWe examined if whole blood gene expression analysis can identify specific transcriptome profiles in neonatal encephalopathy. Material and MethodsWe performed next generation sequencing on whole blood RNA from twelve babies with neonatal encephalopathy, and six time-matched healthy term babies. The significantly differentially expressed genes between encephalopathic and control babies were identified. This set of genes was then compared to the host RNA response in septic neonates and subjected to pathway analysis. ResultsWe identified 950 statistically significant genes discriminating perfectly between the healthy controls and neonatal encephalopathy. The major pathways in neonatal encephalopathy were axonal guidance signaling (p =0.0009), granulocyte adhesion and diapedesis (p = 0.003), IL-12 Signaling and Production in Macrophages (p= 0.003) and hypoxia-inducible factor 1α signaling (p = 0.004). There were only 137 genes in common between neonatal encephalopathy and bacterial sepsis sets. ConclusionBabies with neonatal encephalopathy have striking differences in gene expression profiles compared with healthy control and septic babies. Gene expression profile may be useful for disease stratification based and for developing personalized neuroprotective therapies.
Feinstein Y, Walker JC, Peters MJ, et al., 2018, Cohort profile of the Biomarkers of Acute Serious Illness in Children (BASIC) study: a prospective multicentre cohort study in critically ill children, BMJ Open, Vol: 8, ISSN: 2044-6055
Purpose Despite significant progress, challenges remain in the management of critically ill children, including early identification of infection and organ failure and robust early risk stratification to predict poor outcome. The Biomarkers of Acute Serious Illness in Children study aims to identify genetic and biological pathways underlying the development of critical illness in infections and organ failure and those leading to poor outcome (death or severe disability) in children requiring emergency intensive care.Participants We recruited a prospective cohort of critically ill children undergoing emergency transport to four paediatric intensive care units (PICUs) in Southeast England between April 2014 and December 2016.Findings to date During the study period, 1017 patients were recruited by the regional PICU transport team, and blood and urine samples were obtained at/around first contact with the patient by the transport team. Consent for participation in the study was deferred until after PICU admission and 674 parents/carers were consented. Further samples (blood, urine, stool and throat swabs) were collected after consent. Samples were processed and stored for genomic, transcriptomic, proteomic and metabolomic analyses. Demographic, clinical and laboratory data at first contact, during PICU stay and at discharge, were collected, as were detailed data regarding infectious or non-infectious aetiology. In addition, 115 families have completed 12-month validated follow-up questionnaires to assess quality of life and child behaviour.The first phase of sample analyses (transcriptomic profiling) is currently in progress.Future plans Stored samples will be analysed using genomic, proteomic and metabolic profiling. Advanced bioinformatics techniques will be used to identify biomarkers for early diagnosis of infection, identification of organ failure and risk stratification to predict poor outcome (death/severe disability).Trial registration number NCT03238040.
Wright V, Herberg J, Kaforou M, et al., 2018, Diagnosis of Kawasaki disease using a minimal whole blood gene expression signature, JAMA Pediatrics, Vol: 172, Pages: 1-10, ISSN: 2168-6203
Importance There is no diagnostic test for Kawasaki disease (KD). Diagnosis is based on clinical features shared with other febrile conditions, frequently resulting in delayed or missed treatment and an increased risk of coronary artery aneurysms. Objective To identify a whole blood gene expression signature that distinguishes children with KD in the first week of illness from other febrile conditions.Design Case-control discovery study groups comprising training, test, and validation groups of children with KD or comparator febrile illness. Setting Hospitals in the UK, Spain, Netherlands and USA.Participants The training and test discovery group comprised 404 children with infectious and inflammatory conditions (78 KD, 84 other inflammatory diseases, 242 bacterial or viral infections) and 55 healthy controls. The independent validation group included 130 febrile children and 102 KD patients, including 72 in the first 7 days of illness.Exposures Whole blood gene expression was evaluated using microarrays, and minimal transcript sets distinguishing KD were identified using a novel variable selection method (Parallel Deterministic Model Search).Main outcomes and measures The ability of transcript signatures - implemented as Disease Risk Scores - to discriminate KD cases from controls, was assessed by Area Under the Curve (AUC), sensitivity, and specificity at the optimal cut-point according to Youden’s index. Results A 13-transcript signature identified in the discovery training set distinguished KD from other infectious and inflammatory conditions in the discovery test set with AUC, sensitivity, and specificity (95% confidence intervals (CI)) of 96.2% (92.5-99.9), 81.7% (60.0-94.8), and 92.1% (84.0-97.0), respectively. In the validation set, the signature distinguished KD from febrile controls with AUC, sensitivity, and specificity (95% CI) of 94.6% (91.3-98.0), 85.9% (76.8-92.6), and 89.1% (83.0-93.7) respectively. The signature was applied to clinically defin
Kone-Paut I, Cimaz R, Herberg J, et al., 2018, The use of interleukin 1 receptor antagonist (anakinra) in Kawasaki disease: A retrospective cases series, Autoimmunity Reviews, Vol: 17, Pages: 768-774, ISSN: 1568-9972
ObjectivesTo identify the clinical characteristics, reasons for use and response to treatment with anakinra in a series of patients with Kawasaki Disease (KD).Study designA retrospective chart review of patients treated with anakinra for KD diagnosed according to the AHA criteria. We compared clinical, biological and echocardiographic characteristics of KD before and after anakinra use. We analysed reasons for use of anakinra, and compared treatment regimens used in 7 European KD referral centres.ResultsEight boys and 3 girls with treatment-refractory KD, aged 4 months to 9 years old, received at least 2 different KD treatments prior to anakinra, which was given on mean at 25 days after disease onset (8 to 87 days). The main reasons for use of anakinra were clinical and biological inflammation, progression of coronary dilatations, and severe myocarditis with cardiac failure. Doses of anakinra ranged from 2 to 8 mg/kg and duration varied from 6 to 81 days. Efficacy of anakinra was judged in terms of fever resolution (100%), decrease of CRP (100%), and in terms of its effect on coronary artery dilatation Z scores, which decreased in 10/11 patients and increased in one who died suddenly of pericardial hemorrhage.ConclusionAnakinra used late in the disease course led to a rapid and sustained improvement in clinical and biological inflammation. Our retrospective analysis did show neither a striking nor a rapid decrease of coronary dilatations and we cannot determine if anakinra itself had an effect on coronary artery dimensions.
Martinón-Torres F, Salas A, Rivero-Calle I, et al., 2018, Life-threatening infections in children in Europe (the EUCLIDS Project): a prospective cohort study, Lancet Child and Adolescent Health, Vol: 2, Pages: 404-414, ISSN: 2352-4642
Background: Sepsis and severe focal infections represent a substantial disease burden in children admitted to hospital. We aimed to understand the burden of disease and outcomes in children with life-threatening bacterial infections in Europe. Methods: The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS) was a prospective, multicentre, cohort study done in six countries in Europe. Patients aged 1 month to 18 years with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 participating hospitals in the UK, Austria, Germany, Lithuania, Spain, and the Netherlands were prospectively recruited between July 1, 2012, and Dec 31, 2015. To assess disease burden and outcomes, we collected demographic and clinical data using a secured web-based platform and obtained microbiological data using locally available clinical diagnostic procedures. Findings: 2844 patients were recruited and included in the analysis. 1512 (53·2%) of 2841 patients were male and median age was 39·1 months (IQR 12·4–93·9). 1229 (43·2%) patients had sepsis and 1615 (56·8%) had severe focal infections. Patients diagnosed with sepsis had a median age of 27·6 months (IQR 9·0–80·2), whereas those diagnosed with severe focal infections had a median age of 46·5 months (15·8–100·4; p < 0·0001). Of 2844 patients in the entire cohort, the main clinical syndromes were pneumonia (511 [18·0%] patients), CNS infection (469 [16·5%] ), and skin and soft tissue infection (247 [8·7%]). The causal microorganism was identified in 1359 (47·8%) children, with the most prevalent ones being Neisseria meningitidis (in 259 [9·1%] patients), followed by Staphylococcus aureus (in 222 [7·8%]), Streptococcus pneumoniae (in 219 [7·7%] ), and group A streptococcus (in 162 [5·7%]). 1070 (37·6%) patients required admis
Dunning J, Blankley S, Hoang LT, et al., 2018, Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza, Nature Immunology, Vol: 19, Pages: 625-635, ISSN: 1529-2916
Transcriptional profiles and host-response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole-blood mRNA signatures and concentrations of local and systemic immunological mediators in 131 adults hospitalized with influenza, from whom extensive clinical and investigational data were obtained by MOSAIC investigators. Signatures reflective of interferon-related antiviral pathways were common up to day 4 of symptoms in patients who did not require mechanical ventilator support; in those who needed mechanical ventilation, an inflammatory, activated-neutrophil and cell-stress or death (‘bacterial’) pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this ‘bacterial’ signature but was able to enhance its development while attenuating the early ‘viral’ signature. Our findings emphasize the importance of timing and severity in the interpretation of host responses to acute viral infection and identify specific patterns of immune-system activation that might enable the development of novel diagnostic and therapeutic tools for severe influenza.
Boeddha NP, Schlapbach LJ, Driessen GJ, et al., 2018, Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS), Critical Care, Vol: 22, ISSN: 1364-8535
BACKGROUND: Sepsis is one of the main reasons for non-elective admission to pediatric intensive care units (PICUs), but little is known about determinants influencing outcome. We characterized children admitted with community-acquired sepsis to European PICUs and studied risk factors for mortality and disability. METHODS: Data were collected within the collaborative Seventh Framework Programme (FP7)-funded EUCLIDS study, which is a prospective multicenter cohort study aiming to evaluate genetic determinants of susceptibility and/or severity in sepsis. This report includes 795 children admitted with community-acquired sepsis to 52 PICUs from seven European countries between July 2012 and January 2016. The primary outcome measure was in-hospital death. Secondary outcome measures were PICU-free days censured at day 28, hospital length of stay, and disability. Independent predictors were identified by multivariate regression analysis. RESULTS: Patients most commonly presented clinically with sepsis without a source (n = 278, 35%), meningitis/encephalitis (n = 182, 23%), or pneumonia (n = 149, 19%). Of 428 (54%) patients with confirmed bacterial infection, Neisseria meningitidis (n = 131, 31%) and Streptococcus pneumoniae (n = 78, 18%) were the main pathogens. Mortality was 6% (51/795), increasing to 10% in the presence of septic shock (45/466). Of the survivors, 31% were discharged with disability, including 24% of previously healthy children who survived with disability. Mortality and disability were independently associated with S. pneumoniae infections (mortality OR 4.1, 95% CI 1.1-16.0, P = 0.04; disability OR 5.4, 95% CI 1.8-15.8, P < 0.01) and illness severity as measured by Pediatric Index of Mortality (PIM2) score (mortality OR 2.8, 95% CI 1.3-6.1, P < 0.01; disability OR 3.4, 95% CI 1.8-6.4, P < 0.001). CONCLUSIONS: Despite wide
Mashbat B, Bellos E, Bidmos F, et al., 2018, Whole exome sequencing identifies BPIFA1 mutation underlying invasive meningococcal disease, Human Genome Meeting 2018, Publisher: BIOMED CENTRAL LTD, ISSN: 1473-9542
Bellos E, Herberg J, Wright V, et al., 2018, The genetic basis of invasive meningococcal disease revealed thorough whole exome sequencing, Human Genome Meeting 2018, Publisher: BioMed Central, ISSN: 1479-7364
BackgroundInvasive meningococcal disease (IMD) is a rare condition affectingchildren and young adults due to infection with Neisseria meningitidis, resulting in meningitis or sepsis. Although the majority of thegeneral population is colonized by N. meningitidis, only a small minority go on to develop IMD, suggesting that those that succumb toinvasive disease may possess an underlying genetic susceptibility.The notion of a genetic contribution to disease manifestation is supported by the finding that patients with congenital complement deficiencies are susceptible to recurrent IMD, yet these conditions arerare. With the aim of identifying other genetic factors underlying IMD, we carried out whole exome sequencing (WES) of approximately 300 IMD patients from an extensive and well characterizedcohort of >2,000 childhood IMD patients.Materials and MethodsThe WES analysis focused on rare variants (MAF<0.01) predicted tohave a detrimental effect on protein function. We undertook analysisof seven multiplex families identifying IBD variants. The rest of theindex cases were analysed as a cohort and put through gene andpathway burden tests to identify any genes/pathways that wereenriched in the collection of patients.ResultsThese analyses revealed a number of patients harbouring mutationsin known primary immunodeficiency genes (approx. 10%) as well asa novel configuration of mutations underlying the complementgenes. Furthermore, novel mutations in the coagulation pathway andmucosal immunity genes were identified and functionally confirmed.ConclusionsThe identification of genes involved in IMD through WES has demonstrated the complex genetic architecture of meningococcal immunityrevealed some novel and unexpected genes/pathways that modulatedisease susceptibility and severity. The results from this studyprovide us with a more comprehensive understanding of IMDpathogenesis.
Sabatino J, Josen M, Paredes J, et al., 2017, Cardiac Mechanics in Children and Young Patients With a History of Kawasaki Disease: A CMR and Speckle Tracking Echocardiographic Study, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Gliddon HD, Herberg JA, Levin M, et al., 2017, Genome-wide host RNA signatures of infectious diseases: discovery and clinical translation., Immunology, Vol: 153, Pages: 171-178, ISSN: 0019-2805
The use of whole blood gene expression to derive diagnostic biomarkers capable of distinguishing between phenotypically similar diseases holds great promise but remains a challenge. Differential gene expression analysis is used to identify the key genes that undergo changes in expression relative to healthy individuals, as well as to patients with other diseases. These key genes can act as diagnostic, prognostic and predictive markers of disease. Gene expression 'signatures' in the blood hold potential to be used for the diagnosis of infectious diseases, where current diagnostics are unreliable, ineffective or of limited potential. For diagnostic tests based on RNA signatures to be useful clinically, the first step is to identify the minimum set of gene transcripts that accurately identify the disease in question. The second requirement is rapid and cost effective detection of the gene expression levels. Whilst signatures have been described for a number of infectious diseases, 'clinic-ready' technologies for RNA detection from clinical samples are limited, though existing methods such as reverse transcription-polymerase chain reaction (RT-PCR) are likely to be superseded by a number of emerging technologies, which may form the basis of the translation of gene expression signatures into routine diagnostic tests for a range of disease states.
Thayyil S, Oliveira V, Lally PJ, et al., 2017, Hypothermia for encephalopathy in low and middle-income countries (HELIX): study protocol for a randomised controlled trial., Trials, Vol: 18, ISSN: 1745-6215
BACKGROUND: Therapeutic hypothermia reduces death and disability after moderate or severe neonatal encephalopathy in high-income countries and is used as standard therapy in these settings. However, the safety and efficacy of cooling therapy in low- and middle-income countries (LMICs), where 99% of the disease burden occurs, remains unclear. We will examine whether whole body cooling reduces death or neurodisability at 18-22 months after neonatal encephalopathy, in LMICs. METHODS: We will randomly allocate 408 term or near-term babies (aged ≤ 6 h) with moderate or severe neonatal encephalopathy admitted to public sector neonatal units in LMIC countries (India, Bangladesh or Sri Lanka), to either usual care alone or whole-body cooling with usual care. Babies allocated to the cooling arm will have core body temperature maintained at 33.5 °C using a servo-controlled cooling device for 72 h, followed by re-warming at 0.5 °C per hour. All babies will have detailed infection screening at the time of recruitment and 3 Telsa cerebral magnetic resonance imaging and spectroscopy at 1-2 weeks after birth. Our primary endpoint is death or moderate or severe disability at the age of 18 months. DISCUSSION: Upon completion, HELIX will be the largest cooling trial in neonatal encephalopathy and will provide a definitive answer regarding the safety and efficacy of cooling therapy for neonatal encephalopathy in LMICs. The trial will also provide important data about the influence of co-existent perinatal infection on the efficacy of hypothermic neuroprotection. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02387385 . Registered on 27 February 2015.
de Graaf H, Sukhtankar P, Arch B, et al., 2017, Duration of intravenous antibiotic therapy for children with acute osteomyelitis or septic arthritis: a feasibility study, HEALTH TECHNOLOGY ASSESSMENT, Vol: 21, Pages: 1-+, ISSN: 1366-5278
BackgroundThere is little current consensus regarding the route or duration of antibiotic treatment for acute osteomyelitis (OM) and septic arthritis (SA) in children.ObjectiveTo assess the overall feasibility and inform the design of a future randomised controlled trial (RCT) to reduce the duration of intravenous (i.v.) antibiotic use in paediatric OM and SA.Design(1) A prospective service evaluation (cohort study) to determine the current disease spectrum and UK clinical practice in paediatric OM/SA; (2) a prospective cohort substudy to assess the use of targeted polymerase chain reaction (PCR) in diagnosing paediatric OM/SA; (3) a qualitative study to explore families’ views and experiences of OM/SA; and (4) the development of a core outcome set via a systematic review of literature, Delphi clinician survey and stakeholder consensus meeting.SettingForty-four UK secondary and tertiary UK centres (service evaluation).ParticipantsChildren with OM/SA.InterventionsPCR diagnostics were compared with culture as standard of care. Semistructured interviews were used in the qualitative study.ResultsData were obtained on 313 cases of OM/SA, of which 218 (61.2%) were defined as simple disease and 95 (26.7%) were defined as complex disease. The epidemiology of paediatric OM/SA in this study was consistent with existing European data. Children who met oral switch criteria less than 7 days from starting i.v. antibiotics were less likely to experience treatment failure (9.6%) than children who met oral switch criteria after 7 days of i.v. therapy (16.1% when switch was between 1 and 2 weeks; 18.2% when switch was > 2 weeks). In 24 out of 32 simple cases (75%) and 8 out of 12 complex cases (67%) in which the targeted PCR was used, a pathogen was detected. The qualitative study demonstrated the importance to parents and children of consideration of short- and long-term outcomes meaningful to families themselves. The consensus meeting agreed on the following outcome
Kaforou M, Herberg JA, Wright VJ, et al., 2017, Diagnosis of bacterial infection using a 2-transcript host RNA signature in febrile infants 60 days or younger, JAMA: Journal of the American Medical Association, Vol: 317, Pages: 1577-1578, ISSN: 0098-7484
Israel L, Wang Y, Bulek K, et al., 2017, Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity, CELL, Vol: 168, Pages: 789-800, ISSN: 0092-8674
The molecular basis of the incomplete penetrance of monogenic disorders is unclear. We describe here eight related individuals with autosomal recessive TIRAP deficiency. Life-threatening staphylococcal disease occurred during childhood in the proband, but not in the other seven homozygotes. Responses to all Toll-like receptor 1/2 (TLR1/2), TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes of all TIRAP-deficient individuals. However, the whole-blood response to the TLR2/6 agonist staphylococcal lipoteichoic acid (LTA) was abolished only in the index case individual, the only family member lacking LTA-specific antibodies (Abs). This defective response was reversed in the patient, but not in interleukin-1 receptor-associated kinase 4 (IRAK-4)-deficient individuals, by anti-LTA monoclonal antibody (mAb). Anti-LTA mAb also rescued the macrophage response in mice lacking TIRAP, but not TLR2 or MyD88. Thus, acquired anti-LTA Abs rescue TLR2-dependent immunity to staphylococcal LTA in individuals with inherited TIRAP deficiency, accounting for incomplete penetrance. Combined TIRAP and anti-LTA Ab deficiencies underlie staphylococcal disease in this patient.
Herberg JA, Kaforou M, Wright VJ, 2017, Correction: Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children (vol 316, pg 835, 2016), JAMA: Journal of the American Medical Association, Vol: 317, Pages: 538-538, ISSN: 0098-7484
MacDermott N, Herberg JA, 2016, Ebola: lessons learned, Paediatrics and Child Health, Vol: 27, Pages: 128-134, ISSN: 1918-1485
Ebola virus disease (EVD) is a viral haemorrhagic fever caused by the filovirus, Ebola virus. In humans clinical disease results from infection with any of four species of Ebola virus (Zaire, Sudan, Bundibugyo, Tai Forest). EVD recently held the world's attention as the international community united to tackle the largest Ebola virus epidemic in history. Focussed in West Africa and caused by the Makona strain of Zaire ebolavirus, there were over 28,000 cases with over 11,000 deaths. This article provides an overview of the epidemiology, pathophysiology and clinical signs and symptoms of EVD, with emphasis on the data arising from the 2013–2016 West African epidemic. Paediatric features, experimental therapies, survivor sequelae and preventive strategies are highlighted providing further information for the clinician on approaches to managing this disease either as individual cases or in an epidemic setting.
Walker J, Peters M, Nadel S, et al., 2016, THE ABILITY OF SEPSIS CRITERIA TO PREDICT SERIOUS BACTERIAL INFECTION IN CRITICALLY ILL CHILDREN, 46th Critical Care Congress of the Society-of-Critical-Care-Medicine, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0090-3493
Martinón-Torres F, Png E, Khor CC, et al., 2016, Natural resistance to Meningococcal Disease related to CFH loci: Meta-analysis of genome-wide association studies, Scientific Reports, Vol: 6, ISSN: 2045-2322
Meningococcal disease (MD) remains an important infectious cause of life threatening infection in both industrialized and resource poor countries. Genetic factors influence both occurrence and severity of presentation, but the genes responsible are largely unknown. We performed a genome-wide association study (GWAS) examining 5,440,063 SNPs in 422 Spanish MD patients and 910 controls. We then performed a meta-analysis of the Spanish GWAS with GWAS data from the United Kingdom (combined cohorts: 897 cases and 5,613 controls; 4,898,259 SNPs). The meta-analysis identified strong evidence of association (P-value ≤ 5 × 10(-8)) in 20 variants located at the CFH gene. SNP rs193053835 showed the most significant protective effect (Odds Ratio (OR) = 0.62, 95% confidence interval (C.I.) = 0.52-0.73; P-value = 9.62 × 10(-9)). Five other variants had been previously reported to be associated with susceptibility to MD, including the missense SNP rs1065489 (OR = 0.64, 95% C.I.) = 0.55-0.76, P-value = 3.25 × 10(-8)). Theoretical predictions point to a functional effect of rs1065489, which may be directly responsible for protection against MD. Our study confirms the association of CFH with susceptibility to MD and strengthens the importance of this link in understanding pathogenesis of the disease.
Herberg JA, Kaforou M, Wright VJ, et al., 2016, Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children, Journal of the American Medical Association, Vol: 316, Pages: 835-845, ISSN: 0002-9955
IMPORTANCE: Because clinical features do not reliably distinguish bacterial from viral infection, many children worldwide receive unnecessary antibiotic treatment, while bacterial infection is missed in others. OBJECTIVE: To identify a blood RNA expression signature that distinguishes bacterial from viral infection in febrile children. DESIGN, SETTING, AND PARTICIPANTS: Febrile children presenting to participating hospitals in the United Kingdom, Spain, the Netherlands, and the United States between 2009-2013 were prospectively recruited, comprising a discovery group and validation group. Each group was classified after microbiological investigation as having definite bacterial infection, definite viral infection, or indeterminate infection. RNA expression signatures distinguishing definite bacterial from viral infection were identified in the discovery group and diagnostic performance assessed in the validation group. Additional validation was undertaken in separate studies of children with meningococcal disease (n = 24) and inflammatory diseases (n = 48) and on published gene expression datasets. EXPOSURES: A 2-transcript RNA expression signature distinguishing bacterial infection from viral infection was evaluated against clinical and microbiological diagnosis. MAIN OUTCOMES AND MEASURES: Definite bacterial and viral infection was confirmed by culture or molecular detection of the pathogens. Performance of the RNA signature was evaluated in the definite bacterial and viral group and in the indeterminate infection group. RESULTS: The discovery group of 240 children (median age, 19 months; 62% male) included 52 with definite bacterial infection, of whom 36 (69%) required intensive care, and 92 with definite viral infection, of whom 32 (35%) required intensive care. Ninety-six children had indeterminate infection. Analysis of RNA expression data identified a 38-transcript signature distinguishing bacterial from viral infection. A smaller
Mcdonald J, Kaforou M, Clare S, et al., 2016, A Simple Screening Approach To Prioritize Genes for Functional Analysis Identifies a Role for Interferon Regulatory Factor 7 in the Control of Respiratory Syncytial Virus Disease, mSystems, Vol: 1, ISSN: 2379-5077
Greater understanding of the functions of host gene products in response to infection is required. While many of these genes enable pathogen clearance, some enhance pathogen growth or contribute to disease symptoms. Many studies have profiled transcriptomic and proteomic responses to infection, generating large data sets, but selecting targets for further study is challenging. Here we propose a novel data-mining approach combining multiple heterogeneous data sets to prioritize genes for further study by using respiratory syncytial virus (RSV) infection as a model pathogen with a significant health care impact. The assumption was that the more frequently a gene is detected across multiple studies, the more important its role is. A literature search was performed to find data sets of genes and proteins that change after RSV infection. The data sets were standardized, collated into a single database, and then panned to determine which genes occurred in multiple data sets, generating a candidate gene list. This candidate gene list was validated by using both a clinical cohort and in vitro screening. We identified several genes that were frequently expressed following RSV infection with no assigned function in RSV control, including IFI27, IFIT3, IFI44L, GBP1, OAS3, IFI44, and IRF7. Drilling down into the function of these genes, we demonstrate a role in disease for the gene for interferon regulatory factor 7, which was highly ranked on the list, but not for IRF1, which was not. Thus, we have developed and validated an approach for collating published data sets into a manageable list of candidates, identifying novel targets for future analysis.
Cebey-López M, Herberg J, Pardo-Seco J, et al., 2016, Does viral co-infection influence the severity of acute respiratory infection in children?, PLOS One, Vol: 11, Pages: e0152481-e0152481, ISSN: 1932-6203
BACKGROUND: Multiple viruses are often detected in children with respiratory infection but the significance of co-infection in pathogenesis, severity and outcome is unclear. OBJECTIVES: To correlate the presence of viral co-infection with clinical phenotype in children admitted with acute respiratory infections (ARI). METHODS: We collected detailed clinical information on severity for children admitted with ARI as part of a Spanish prospective multicenter study (GENDRES network) between 2011-2013. A nested polymerase chain reaction (PCR) approach was used to detect respiratory viruses in respiratory secretions. Findings were compared to an independent cohort collected in the UK. RESULTS: 204 children were recruited in the main cohort and 97 in the replication cohort. The number of detected viruses did not correlate with any markers of severity. However, bacterial superinfection was associated with increased severity (OR: 4.356; P-value = 0.005), PICU admission (OR: 3.342; P-value = 0.006), higher clinical score (1.988; P-value = 0.002) respiratory support requirement (OR: 7.484; P-value < 0.001) and longer hospital length of stay (OR: 1.468; P-value < 0.001). In addition, pneumococcal vaccination was found to be a protective factor in terms of degree of respiratory distress (OR: 2.917; P-value = 0.035), PICU admission (OR: 0.301; P-value = 0.011), lower clinical score (-1.499; P-value = 0.021) respiratory support requirement (OR: 0.324; P-value = 0.016) and oxygen necessity (OR: 0.328; P-value = 0.001). All these findings were replicated in the UK cohort. CONCLUSION: The presence of more than one virus in hospitalized children with ARI is very frequent but it does not seem to have a major clinical impact in terms of severity. However bacterial superinfection increases the severity of the disease course. On the contrary, pneumococcal vaccination plays a protective role.
MacDermott NE, De S, Herberg JA, 2016, Viral haemorrhagic fever in children., Archives of Disease in Childhood, Vol: 101, Pages: 461-468, ISSN: 0003-9888
Viral haemorrhagic fevers (VHFs) are currently at the forefront of the world's attention due to the recent Zaire ebolavirus epidemic in West Africa. This epidemic has highlighted the frailty of the world's public health response mechanisms and demonstrated the potential risks to nations around the world of imported cases of epidemic diseases. While imported cases in children are less likely, the potential for such a scenario remains. It is therefore essential that paediatricians are aware of and prepared for potential imported cases of tropical diseases, VHFs being of particular importance due to their propensity to cause nosocomial spread. Examining the four families of viruses-Filoviridae, Arenaviridae, Bunyaviridae and Flaviviridae, we describe the different types of VHFs, with emphasis on differentiation from other diseases through detailed history-taking, their presentation and management from a paediatric perspective.
Muthuri SG, Venkatesan S, Myles PR, et al., 2015, Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09-related pneumonia: an IPD meta-analysis., Influenza and Other Respiratory Viruses, Vol: 10, Pages: 192-204, ISSN: 1750-2659
BACKGROUND: The impact of neuraminidase inhibitors (NAIs) on Influenza-related pneumonia (IRP) is not established. Our objective was to investigate the association between NAI treatment and IRP incidence and outcomes in patients hospitalised with A(H1N1)pdm09 virus infection. METHODS: A worldwide meta-analysis of individual participant data (IPD) from 20,634 hospitalised patients with laboratory confirmed A(H1N1)pdm09 (n=20,021) or clinically diagnosed (n=613) 'pandemic influenza'. The primary outcome was radiologically confirmed influenza-related pneumonia (IRP). Odds ratios (OR) were estimated using generalized linear mixed modelling, adjusting for NAI treatment propensity, antibiotics and corticosteroids. RESULTS: Among 20,634 included participants, 5,978 (29.0%) had IRP; conversely, 3,349 (16.2%) had confirmed absence of radiographic pneumonia (the comparator). Early NAI treatment (within 2 days of symptom onset) versus no NAI was not significantly associated with IRP [adj. OR 0.83 (95%CI 0.64 - 1.06; p=0.136)]. Among the 5,978 patients with IRP, early NAI treatment versus none did not impact on mortality [adj. OR=0.72 (0.44-1.17; p=0.180)] or likelihood of requiring ventilatory support [adj. OR=1.17 (0.71-1.92; p=0.537)]; but early treatment versus later significantly reduced mortality [adj. OR=0.70 (0.55-0.88; p=0.003)] and likelihood of requiring ventilatory support [adj. OR=0.68 (0.54-0.85; p=0.001)]. CONCLUSIONS: Early NAI treatment of patients hospitalised with A(H1N1)pdm09 virus infection versus no treatment did not reduce the likelihood of IRP. However, in patients who developed IRP early NAI treatment versus later reduced the likelihood of mortality and needing ventilatory support. This article is protected by copyright. All rights reserved.
Cebey-Lopez M, Herberg J, Pardo-Seco J, et al., 2015, Viral Co-Infections in Pediatric Patients Hospitalized with Lower Tract Acute Respiratory Infections, PLOS One, Vol: 10, ISSN: 1932-6203
BackgroundMolecular techniques can often reveal a broader range of pathogens in respiratory infections.We aim to investigate the prevalence and age pattern of viral co-infection in children hospitalizedwith lower tract acute respiratory infection (LT-ARI), using molecular techniques.MethodsA nested polymerase chain reaction approach was used to detect Influenza (A, B), metapneumovirus,respiratory syncytial virus (RSV), parainfluenza (1–4), rhinovirus, adenovirus(A—F), bocavirus and coronaviruses (NL63, 229E, OC43) in respiratory samples of childrenwith acute respiratory infection prospectively admitted to any of the GENDRES networkhospitals between 2011–2013. The results were corroborated in an independent cohort collectedin the UK.ResultsA total of 204 and 97 nasopharyngeal samples were collected in the GENDRES and UKcohorts, respectively. In both cohorts, RSV was the most frequent pathogen (52.9% and36.1% of the cohorts, respectively). Co-infection with multiple viruses was found in 92 samples(45.1%) and 29 samples (29.9%), respectively; this was most frequent in the 12–24months age group. The most frequently observed co-infection patterns were RSV—Rhinovirus (23 patients, 11.3%, GENDRES cohort) and RSV—bocavirus / bocavirus—influenza(5 patients, 5.2%, UK cohort).ConclusionThe presence of more than one virus in pediatric patients admitted to hospital with LT-ARI isvery frequent and seems to peak at 12–24 months of age. The clinical significance of thesefindings is unclear but should warrant further analysis.
Le Doare K, Menson E, Patel D, et al., 2015, Fifteen minute consultation: Managing neonatal and childhood herpes encephalitis, Archives of Disease in Childhood-Education and Practice Edition, Vol: 100, Pages: 58-63, ISSN: 1743-0593
Herpes simplex encephalitis (HSE) is the mostcommon single cause of viral encephalitis ininfants and children. Treated or untreated, itcan be associated with considerable morbidityand mortality, and its presentation is usuallyinsidious and non-specific. Prompt and carefulinvestigation is important in order to establishthe diagnosis so that treatment can beoptimised. We address some commonquestions arising when diagnosingand treating presumed HSE throughoutchildhood.
Davies S, Sutton N, Blackstock S, et al., 2015, Predicting IVIG resistance in UK Kawasaki disease, ARCHIVES OF DISEASE IN CHILDHOOD, Vol: 100, Pages: 366-368, ISSN: 0003-9888
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Herberg JA, Emonts M, Jacobs M, et al., 2015, UK preparedness for children with Ebola infection, Archives of Disease in Childhood, Vol: 100, Pages: 421-423, ISSN: 0003-9888
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