341 results found
Morfopoulou S, Buddle S, Torres Montaguth OE, et al., 2023, Genomic investigations of unexplained acute hepatitis in children., Nature, Vol: 617, Pages: 564-573
Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.
Nijman RG, Tan CD, Hagedoorn NN, et al., 2023, Are children with prolonged fever at a higher risk for serious illness? A prospective observational study., Arch Dis Child
OBJECTIVES: To describe the characteristics and clinical outcomes of children with fever ≥5 days presenting to emergency departments (EDs). DESIGN: Prospective observational study. SETTING: 12 European EDs. PATIENTS: Consecutive febrile children <18 years between January 2017 and April 2018. INTERVENTIONS: Children with fever ≥5 days and their risks for serious bacterial infection (SBI) were compared with children with fever <5 days, including diagnostic accuracy of non-specific symptoms, warning signs and C-reactive protein (CRP; mg/L). MAIN OUTCOME MEASURES: SBI and other non-infectious serious illness. RESULTS: 3778/35 705 (10.6%) of febrile children had fever ≥5 days. Incidence of SBI in children with fever ≥5 days was higher than in those with fever <5 days (8.4% vs 5.7%). Triage urgency, life-saving interventions and intensive care admissions were similar for fever ≥5 days and <5 days. Several warning signs had good rule in value for SBI with specificities >0.90, but were observed infrequently (range: 0.4%-17%). Absence of warning signs was not sufficiently reliable to rule out SBI (sensitivity 0.92 (95% CI 0.87-0.95), negative likelihood ratio (LR) 0.34 (0.22-0.54)). CRP <20 mg/L was useful for ruling out SBI (negative LR 0.16 (0.11-0.24)). There were 66 cases (1.7%) of non-infectious serious illnesses, including 21 cases of Kawasaki disease (0.6%), 28 inflammatory conditions (0.7%) and 4 malignancies. CONCLUSION: Children with prolonged fever have a higher risk of SBI, warranting a careful clinical assessment and diagnostic workup. Warning signs of SBI occurred infrequently but, if present, increased the likelihood of SBI. Although rare, clinicians should consider important non-infectious causes of prolonged fever.
Channon-Wells S, Vito O, McArdle AJ, et al., 2023, Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study, The Lancet Rheumatology, Vol: 5, Pages: e184-e199, ISSN: 2665-9913
BackgroundMultisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments.MethodsThe Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370.FindingsWe enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2–11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologica
Ho A, Orton R, Tayler R, et al., 2023, Adeno-associated virus 2 infection in children with non-A-E hepatitis., Nature
An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10-12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a 'helper virus' to support AAV2 replication) and disease susceptibility related to HLA class II status.
Kohlmaier B, Leitner M, Hagedoorn NN, et al., 2023, European study confirms the combination of fever and petechial rash as an important warning sign for childhood sepsis and meningitis, Acta Paediatrica, ISSN: 0803-5253
Moradi Marjaneh M, Challenger J, Salas A, et al., 2023, Analysis of blood and nasal epithelial transcriptomes to identify mechanisms associated with control of SARS-CoV-2 viral load in the upper respiratory tract
Kuiper R, Wright VJ, Habgood-Coote D, et al., 2023, Bridging a diagnostic Kawasaki disease classifier from a microarray platform to a qRT-PCR assay, Pediatric Research, Vol: 93, Pages: 559-569, ISSN: 0031-3998
BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis that mainly affects children under 5 years of age. Up to 30% of patients develop coronary artery abnormalities, which are reduced with early treatment. Timely diagnosis of KD is challenging but may become more straightforward with the recent discovery of a whole-blood host response classifier that discriminates KD patients from patients with other febrile conditions. Here, we bridged this microarray-based classifier to a clinically applicable quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay: the Kawasaki Disease Gene Expression Profiling (KiDs-GEP) classifier. METHODS: We designed and optimized a qRT-PCR assay and applied it to a subset of samples previously used for the classifier discovery to reweight the original classifier. RESULTS: The performance of the KiDs-GEP classifier was comparable to the original classifier with a cross-validated area under the ROC curve of 0.964 [95% CI: 0.924-1.00] vs 0.992 [95% CI: 0.978-1.00], respectively. Both classifiers demonstrated similar trends over various disease conditions, with the clearest distinction between individuals diagnosed with KD vs viral infections. CONCLUSION: We successfully bridged the microarray-based classifier into the KiDs-GEP classifier, a more rapid and more cost-efficient qRT-PCR assay, bringing a diagnostic test for KD closer to the hospital clinical laboratory. IMPACT: A diagnostic test is needed for Kawasaki disease and is currently not available. We describe the development of a One-Step multiplex qRT-PCR assay and the subsequent modification (i.e., bridging) of the microarray-based host response classifier previously described by Wright et al. The bridged KiDs-GEP classifier performs well in discriminating Kawasaki disease patients from febrile controls. This host response clinical test for Kawasaki disease can be adapted to the hospital clinical laboratory.
Boeddha NP, Atkins L, de Groot R, et al., 2023, Correction to: Group A streptococcal disease in paediatric inpatients: a European perspective., Eur J Pediatr, Vol: 182
van der Velden FJS, de Vries G, Martin A, et al., 2023, Correction to: Febrile illness in high-risk children: a prospective, international observational study., Eur J Pediatr, Vol: 182, Pages: 555-556
Eleftheriou D, Moraes YC, Purvis C, et al., 2023, Multi-centre, randomised, open-label, blinded endpoint assessed, trial of corticosteroids plus intravenous immunoglobulin (IVIG) and aspirin, versus IVIG and aspirin for prevention of coronary artery aneurysms (CAA) in Kawasaki disease (KD): the KD CAA prevention (KD-CAAP) trial protocol, TRIALS, Vol: 24
Dewez JE, Pembrey L, Nijman RG, et al., 2022, Availability and use of rapid diagnostic tests for the management of acute childhood infections in Europe: A cross-sectional survey of paediatricians., PLoS One, Vol: 17, Pages: 1-22, ISSN: 1932-6203
BACKGROUND: Point-of-care-tests (POCTs) have been advocated to optimise care in patients with infections but their actual use varies. This study aimed to estimate the variability in the adoption of current POCTs by paediatricians across Europe, and to explore the determinants of variability. METHODS AND FINDINGS: A cross-sectional survey was conducted of hospital and primary care paediatricians, recruited through professional networks. Questions focused on the availability and use of currently available POCTs. Data were analysed descriptively and using Median Odds Ratio (MOR) to measure variation between countries. Multilevel regression modelling using changes in the area under the receiver operating characteristic curve of models were used to assess the contribution of individual or workplace versus country level factors, to the observed variation. The commonest POCT was urine dipsticks (UD) which were available to >80% of primary care and hospital paediatricians in 68% (13/19) and 79% (23/29) countries, respectively. Availability of all POCTs varied between countries. In primary care, the country (MOR) varied from 1.61 (95%CI: 1.04-2.58) for lactate to 7.28 (95%CI: 3.04-24.35) for UD. In hospitals, the country MOR varied from 1.37 (95%CI:1.04-1.80) for lactate to 11.93 (95%CI:3.35-72.23) for UD. Most paediatricians in primary care (69%, 795/1154) and hospital (81%, 962/1188) would use a diagnostic test in the case scenario of an infant with undifferentiated fever. Multilevel regression modelling showed that the country of work was more important in predicting both the availability and use of POCTs than individual or workplace characteristics. CONCLUSION: There is substantial variability in the adoption of POCTs for the management of acute infections in children across Europe. To inform future implementation of both existing and innovative tests, further research is needed to understand what drives the variation between countries, the needs of frontline clinicia
Hagedoorn NN, Boeddha NP, Kohlfuerst DS, et al., 2022, Hemostasis proteins in invasive meningococcal and nonmeningococcal infections: a prospective multicenter study., Pediatric Critical Care Medicine, Vol: 23, Pages: e543-e554, ISSN: 1529-7535
OBJECTIVES: We aimed to describe the variation of hemostasis proteins in children with bacterial infections due to different pathogens (Neisseria meningitidis, Streptococcus pneumoniae, Staphylococcus aureus, and group A streptococcus [GAS]) and to study hemostasis proteins in relation to mortality. DESIGN: Preplanned analysis in prospective cohort study. SETTING: Hospitals in five European countries (Austria, The Netherlands, Spain, Switzerland, and the United Kingdom). PATIENTS: Admitted children (2012-2016) with community-acquired infections due to meningococci (n = 83), pneumococci (n = 64), S. aureus (n = 50), and GAS (n = 44) with available serum samples collected less than 48 hours after admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fibronectin, plasminogen activator inhibitor type 1 (PAI-1), thrombomodulin, and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) were measured in serum in 2019-2020. Additionally, von Willebrand factor, protein C, protein S, and factor IX were measured in citrate plasma available from a subset of patients. Outcome measures included in-hospital mortality and disease severity (need for ventilation/inotropes, Pediatric Index of Mortality score). Of 241 children, 21 (8.7%) died and 177 (73.5%) were admitted to PICU. Mortality rate was similar for the pathogen groups. Levels of fibronectin and thrombomodulin differed for the different pathogens (p < 0.05). Fibronectin levels were lower in GAS infections than in S. pneumoniae and S. aureus infections but did not differ from meningococcal infections. Thrombomodulin levels in meningococcal infections were higher than in S. aureus and pneumococcal infections. Overall, the area under the curve for mortality was 0.81 (95% CI, 0.70-0.92) for thrombomodulin and 0.78 (95% CI, 0.69-0.88) for ADAMTS-13. The association of each hemostasis protein did not vary across pathogens for any of the outcome measures. CONCLUSIONS: Hemostatic
Boeddha NPP, Atkins L, de Groot R, et al., 2022, Group A streptococcal disease in paediatric inpatients: a European perspective, EUROPEAN JOURNAL OF PEDIATRICS, ISSN: 0340-6199
Tan CD, van der Walle EEPL, Vermont CL, et al., 2022, Correction to: Guideline adherence in febrile children below 3 months visiting European Emergency Departments: an observational multicenter study, European Journal of Pediatrics, Vol: 181, Pages: 4211-4214, ISSN: 0340-6199
Bachanová P, Cheyne A, Broderick C, et al., 2022, Comparative transcriptomic analysis of whole blood mycobacterial growth assays and tuberculosis patients’ blood RNA profiles, Scientific Reports, Vol: 12
<jats:title>Abstract</jats:title><jats:p>In vitro whole blood infection models are used for elucidating the immune response to <jats:italic>Mycobacterium tuberculosis</jats:italic> (<jats:italic>Mtb</jats:italic>). They exhibit commonalities but also differences, to the in vivo blood transcriptional response during natural human <jats:italic>Mtb</jats:italic> disease. Here, we present a description of concordant and discordant components of the immune response in blood, quantified through transcriptional profiling in an in vitro whole blood infection model compared to whole blood from patients with tuberculosis disease. We identified concordantly and discordantly expressed gene modules and performed in silico cell deconvolution. A high degree of concordance of gene expression between both adult and paediatric in vivo<jats:italic>–</jats:italic>in vitro tuberculosis infection was identified. Concordance in paediatric in vivo vs in vitro comparison is largely characterised by immune suppression, while in adults the comparison is marked by concordant immune activation, particularly that of inflammation, chemokine, and interferon signalling. Discordance between in vitro and in vivo increases over time and is driven by T-cell regulation and monocyte-related gene expression, likely due to apoptotic depletion of monocytes and increasing relative fraction of longer-lived cell types, such as T and B cells. Our approach facilitates a more informed use of the whole blood in vitro model, while also accounting for its limitations.</jats:p>
Bachanová P, Cheyne A, Broderick C, et al., 2022, Comparative transcriptomic analysis of whole blood mycobacterial growth assays and tuberculosis patients’ blood RNA profiles, Scientific Reports, Vol: 12, Pages: 1-13, ISSN: 2045-2322
In vitro whole blood infection models are used for elucidating the immune response to Mycobacterium tuberculosis (Mtb). They exhibit commonalities but also differences, to the in vivo blood transcriptional response during natural human Mtb disease. Here, we present a description of concordant and discordant components of the immune response in blood, quantified through transcriptional profiling in an in vitro whole blood infection model compared to whole blood from patients with tuberculosis disease. We identified concordantly and discordantly expressed gene modules and performed in silico cell deconvolution. A high degree of concordance of gene expression between both adult and paediatric in vivo-in vitro tuberculosis infection was identified. Concordance in paediatric in vivo vs in vitro comparison is largely characterised by immune suppression, while in adults the comparison is marked by concordant immune activation, particularly that of inflammation, chemokine, and interferon signalling. Discordance between in vitro and in vivo increases over time and is driven by T-cell regulation and monocyte-related gene expression, likely due to apoptotic depletion of monocytes and increasing relative fraction of longer-lived cell types, such as T and B cells. Our approach facilitates a more informed use of the whole blood in vitro model, while also accounting for its limitations.
van der Velden FJS, de Vries G, Martin A, et al., 2022, Febrile illness in high-risk children: a prospective, international observational study, EUROPEAN JOURNAL OF PEDIATRICS, ISSN: 0340-6199
Tan CD, van der Walle EEPL, Vermont CL, et al., 2022, Guideline adherence in febrile children below 3 months visiting European Emergency Departments: an observational multicenter study, European Journal of Pediatrics, Vol: 181, Pages: 4199-4209, ISSN: 0340-6199
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 guideline
Pennisi I, Moniri A, Miscourides N, et al., 2022, Discrimination of bacterial and viral infection using host-RNA signatures integrated in a lab-on-chip platform, BIOSENSORS & BIOELECTRONICS, Vol: 216, ISSN: 0956-5663
Kumar V, Pouw RB, Autio M, et al., 2022, Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 109, Pages: 1680-1691, ISSN: 0002-9297
Tan CD, El Ouasghiri S, von Both U, et al., 2022, Sex differences in febrile children with respiratory symptoms attending European emergency departments: An observational multicenter study., PLoS One, Vol: 17, Pages: 1-11, ISSN: 1932-6203
OBJECTIVE: To assess sex differences in presentation and management of febrile children with respiratory symptoms attending European Emergency Departments. DESIGN AND SETTING: An observational study in twelve Emergency Departments in eight European countries. PATIENTS: Previously healthy children aged 0-<18 years with fever (≥ 38°C) at the Emergency Department or in the consecutive three days before Emergency Department visit and respiratory symptoms were included. MAIN OUTCOME MEASURES: The main outcomes were patient characteristics and management defined as diagnostic tests, treatment and admission. Descriptive statistics were used for patient characteristics and management stratified by sex. Multivariable logistic regression analyses were performed for the association between sex and management with adjustment for age, disease severity and Emergency Department. Additionally, subgroup analyses were performed in children with upper and lower respiratory tract infections and in children below five years. RESULTS: We included 19,781 febrile children with respiratory symptoms. The majority were boys (54%), aged 1-5 years (58%) and triaged as low urgent (67%). Girls presented less frequently with tachypnea (15% vs 16%, p = 0.002) and increased work of breathing (8% vs 12%, p<0.001) compared with boys. Girls received less inhalation medication than boys (aOR 0.82, 95% CI 0.74-0.90), but received antibiotic treatment more frequently than boys (aOR 1.09, 95% CI 1.02-1.15), which is associated with a higher prevalence of urinary tract infections. Amongst children with a lower respiratory tract infection and children below five years girls received less inhalation medication than boys (aOR 0.77, 95% CI 0.66-0.89; aOR 0.80, 95% CI 0.72-0.90). CONCLUSIONS: Sex differences concerning presentation and management are present in previously healthy febrile children with respiratory symptoms presenting to the Emergency Department. Future research should focus on whethe
Pennisi I, Moniri A, Miscourides N, et al., 2022, Discrimination of bacterial and viral infection using host-RNA signatures integrated in a lab-on-a-chip technology, Publisher: MedRxiv
<h4>ABSTRACT</h4> The unmet clinical need for accurate point-of-care (POC) diagnostic tests able to discriminate bacterial from viral infection demands a solution that can be used both within healthcare settings and in the field and that can also stem the tide of antimicrobial resistance. Our approach to solve this problem is to combine the use of Host-gene signatures with our Lab-on-a-chip (LoC) technology enabling low-cost LoC expression analysis to detect Infectious Disease.Host-gene expression signatures have been extensively study as a potential tool to be implemented in the diagnosis of infectious disease. On the other hand LoC technologies using Ion-sensitive field-effect transistor (ISFET) arrays, in conjunction with isothermal chemistries, are offering a promising alternative to conventional lab-based nucleic acid amplification instruments, owing to their portable and affordable nature. Currently, the data analysis of ISFET arrays are restricted to established methods by averaging the output of every sensor to give a single time-series. This simple approach makes unrealistic assumptions, leading to insufficient performance for applications that require accurate quantification such as RNA host transcriptomics. In order to reliably quantify host-gene expression on our LoC platform enabling the classification of bacterial and viral infection on chip, we propose a novel data-driven algorithm for extracting time-to-positive values from ISFET arrays. The algorithm proposed is based on modelling sensor drift with adaptive signal processing and clustering sensors based on their behaviour with unsupervised learning methods. Results show that the approach correctly outputs a time-to-positive for all the reactions, with a high correlation to RT-qLAMP (0.85, R2 = 0.98, p < 0.01), resulting in a classification accuracy of 100 % (CI, 95 - 100). By leveraging more advanced data processing methods for ISFET arrays, this work aims to bridge the gap between tr
Jackson H, Calle IR, Broderick C, et al., 2022, Characterisation of the blood RNA host response underpinning severity in COVID-19 patients, Scientific Reports, Vol: 12, ISSN: 2045-2322
Infection with SARS-CoV-2 has highly variable clinical manifestations, ranging from asymptomatic infection through to life-threatening disease. Host whole blood transcriptomics can offer unique insights into the biological processes underpinning infection and disease, as well as severity. We performed whole blood RNA Sequencing of individuals with varying degrees of COVID-19 severity. We used differential expression analysis and pathway enrichment analysis to explore how the blood transcriptome differs between individuals with mild, moderate, and severe COVID-19, performing pairwise comparisons between groups. Increasing COVID-19 severity was characterised by an abundance of inflammatory immune response genes and pathways, including many related to neutrophils and macrophages, in addition to an upregulation of immunoglobulin genes. Our insights into COVID-19 severity reveal the role of immune dysregulation in the progression to severe disease and highlight the need for further research exploring the interplay between SARS-CoV-2 and the inflammatory immune response.
Kaforou M, Broderick C, Vito O, et al., 2022, Transcriptomics for child and adolescent tuberculosis, Immunological Reviews, Vol: 309, ISSN: 0105-2896
Tuberculosis (TB) in humans is caused by Mycobacterium tuberculosis (Mtb). It is estimated that 70 million children (<15 years) are currently infected with Mtb, with 1.2 million each year progressing to disease. Of these, a quarter die. The risk of progression from Mtb infection to disease and from disease to death is dependent on multiple pathogen and host factors. Age is a central component in all these transitions. The natural history of TB in children and adolescents is different to adults, leading to unique challenges in the development of diagnostics, therapeutics, and vaccines. The quantification of RNA transcripts, encoded in the genome in specific cells or in the peripheral blood, using high-throughput methods, such as microarray analysis or RNA sequencing, are emerging technologies. RNA sequencing can shed light into the host immune response to Mtb during infection and disease, as well as understanding treatment response, disease severity and vaccination, in a global hypothesis-free manner. Additionally, gene expression profiling can be used for biomarker discovery, to diagnose disease, predict future disease progression and to monitor response to treatment. Here, we review the role of transcriptomics in children and adolescents, focussed mainly on work done in blood, to understand disease biology and to discriminate disease states to assist clinical decision-making. In recent years, studies with a specific paediatric and adolescent focus have identified blood gene expression markers with diagnostic or prognostic potential that meet or exceed the current sensitivity and specificity targets for diagnostic tools. Diagnostic and prognostic gene expression signatures identified through high-throughput methods are currently being translated into diagnostic tests.
Borensztajn DM, Hagedoorn NN, Carrol ED, et al., 2022, Febrile children with comorbidities at the emergency department - a multicentre observational study, European Journal of Pediatrics, Vol: 181, Pages: 3491-3500, ISSN: 0340-6199
We aimed to describe characteristics and management of children with comorbidities attending European emergency departments (EDs) with fever. MOFICHE (Management and Outcome of Fever in children in Europe) is a prospective multicentre study (12 European EDs, 8 countries). Febrile children with comorbidities were compared to those without in terms of patient characteristics, markers of disease severity, management, and diagnosis. Comorbidity was defined as a chronic underlying condition that is expected to last > 1 year. We performed multivariable logistic regression analysis, displaying adjusted odds ratios (aOR), adjusting for patient characteristics. We included 38,110 patients, of whom 5906 (16%) had comorbidities. Most common comorbidities were pulmonary, neurologic, or prematurity. Patients with comorbidities more often were ill appearing (20 versus 16%, p < 0.001), had an ED-Paediatric Early Warning Score of > 15 (22 versus 12%, p < 0.001), or a C-reactive protein > 60 mg/l (aOR 1.4 (95%CI 1.3–1.6)). They more often required life-saving interventions (aOR 2.7, 95% CI 2.2–3.3), were treated with intravenous antibiotics (aOR 2.3, 95%CI 2.1–2.5), and were admitted to the ward (aOR 2.2, 95%CI 2.1–2.4) or paediatric intensive care unit (PICU) (aOR 5.5, 95% CI 3.8–7.9). They were more often diagnosed with serious bacterial infections (aOR 1.8, 95%CI 1.7–2.0), including sepsis/meningitis (aOR 4.6, 95%CI 3.2–6.7). Children most at risk for sepsis/meningitis were children with malignancy/immunodeficiency (aOR 14.5, 8.5–24.8), while children with psychomotor delay/neurological disease were most at risk for life-saving interventions (aOR 5.3, 4.1–6.9) or PICU admission (aOR 9.7, 6.1–15.5).
Melgar M, Seaby EG, McArdle AJ, et al., 2022, Treatment of Multisystem Inflammatory Syndrome in Children: Understanding Differences in Results of Comparative Effectiveness Studies, ACR OPEN RHEUMATOLOGY, Vol: 4, Pages: 804-810
Takele Y, Adem E, Franssen SU, et al., 2022, Impaired in vitro Interferon-gamma production in patients with visceral leishmaniasis is improved by inhibition of PD1/PDL-1 ligation, PLoS Neglected Tropical Diseases, Vol: 16, Pages: 1-12, ISSN: 1935-2727
Visceral leishmaniasis (VL) is a neglected tropical disease that causes substantial morbidity and mortality and is a growing health problem in Ethiopia, where this study took place. Most individuals infected with Leishmania donovani parasites will stay asymptomatic, but some develop VL that, if left untreated, is almost always fatal. This stage of the disease is associated with a profound immunosuppression, characterised by impaired production of Interferonγ (IFNγ), a cytokine that plays a key role in the control of Leishmania parasites, and high expression levels of an inhibitory receptor, programmed cell death 1 (PD1) on CD4+ T cells. Here, we tested the contribution of the interaction between the immune checkpoint PD1 and its ligand PDL-1 on the impaired production of IFNγ in VL patients. Our results show that in the blood of VL patients, not only CD4+, but also CD8+ T cells express high levels of PD1 at the time of VL diagnosis. Next, we identified PDL-1 expression on different monocyte subsets and neutrophils and show that PDL-1 levels were significantly increased in VL patients. PD1/PDL-1 inhibition resulted in significantly increased production of IFNγ, suggesting that therapy using immune checkpoint inhibitors might improve disease control in these patients.
Levin M, Whittaker E, 2022, Balancing risk and benefit of SARS-CoV-2 vaccines in children Comment, LANCET REGIONAL HEALTH-EUROPE, Vol: 18, ISSN: 2666-7762
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Broderick C, Calle IR, Gómez Carballa A, et al., 2022, Pseudotemporal whole blood transcriptional profiling of COVID-19 patients stratified by clinical severity reveals differences in immune responses and possible role of monoamine oxidase B
<jats:title>Abstract</jats:title><jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with highly variable clinical outcomes. Studying the temporal dynamics of host whole blood gene expression during SARS-CoV-2 infection can elucidate the biological processes that underlie these diverse clinical phenotypes. We employed a novel pseudotemporal approach using MaSigPro to model and compare the trajectories of whole blood transcriptomic responses in patients with mild, moderate and severe COVID-19 disease. We identified 5,267 genes significantly differentially expressed (SDE) over pseudotime and between severity groups and clustered these genes together based on pseudotemporal trends. Pathway analysis of these gene clusters revealed upregulation of multiple immune, coagulation, platelet and senescence pathways with increasing disease severity and downregulation of T cell, transcriptional and cellular metabolic pathways. The gene clusters exhibited differing pseudotemporal trends. Monoamine oxidase B was the top SDE gene, upregulated in severe>moderate>mild COVID-19 disease. This work provides new insights into the diversity of the host response to SARS-CoV-2 and disease severity and highlights the utility of pseudotemporal approaches in studying evolving immune responses to infectious diseases.</jats:p>
van Beek AE, Pouw RB, Wright VJ, et al., 2022, Low levels of factor H family proteins during meningococcal disease indicate systemic processes rather than specific depletion by neisseria meningitidis, Frontiers in Immunology, Vol: 13, ISSN: 1664-3224
Neisseria meningitidis, the causative agent of meningococcal disease (MD), evades complement-mediated clearance upon infection by ‘hijacking’ the human complement regulator factor H (FH). The FH protein family also comprises the homologous FH-related (FHR) proteins, hypothesized to act as antagonists of FH, and FHR-3 has recently been implicated to play a major role in MD susceptibility. Here, we show that the circulating levels of all FH family proteins, not only FH and FHR-3, are equally decreased during the acute illness. We did neither observe specific consumption of FH or FHR-3 by N. meningitidis, nor of any of the other FH family proteins, suggesting that the globally reduced levels are due to systemic processes including dilution by fluid administration upon admission and vascular leakage. MD severity associated predominantly with a loss of FH rather than FHRs. Additionally, low FH levels associated with renal failure, suggesting insufficient protection of host tissue by the active protection by the FH protein family, which is reminiscent of reduced FH activity in hemolytic uremic syndrome. Retaining higher levels of FH may thus limit tissue injury during MD.
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