Abstract
Background
Discriminating viral from bacterial lower respiratory tract infections (LRTIs) in children is challenging thus commonly resulting in antibiotic overuse. The Feverkidstool, a ...validated clinical decision rule including clinical symptoms and C-reactive protein, safely reduced antibiotic use in children at low/intermediate risk for bacterial LRTIs in a multicentre trial at emergency departments (EDs) in the Netherlands.
Objectives
Using routine data from an observational study, we simulated the impact of the Feverkidstool on antibiotic prescriptions compared with observed antibiotic prescriptions in children with suspected LRTIs at 12 EDs in eight European countries.
Methods
We selected febrile children aged 1 month to 5 years with respiratory symptoms and excluded upper respiratory tract infections. Using the Feverkidstool, we calculated individual risks for bacterial LRTI retrospectively. We simulated antibiotic prescription rates under different scenarios: (1) applying effect estimates on antibiotic prescription from the trial; and (2) varying both usage (50%–100%) and compliance (70%–100%) with the Feverkidstool’s advice to withhold antibiotics in children at low/intermediate risk for bacterial LRTI (≤10%).
Results
Of 4938 children, 4209 (85.2%) were at low/intermediate risk for bacterial LRTI. Applying effect estimates from the trial, the Feverkidstool reduced antibiotic prescription from 33.5% to 24.1% pooled risk difference: 9.4% (95% CI: 5.7%–13.1%). Simulating 50%–100% usage with 90% compliance resulted in risk differences ranging from 8.3% to 15.8%. Our simulations suggest that antibiotic prescriptions would be reduced in EDs with high baseline antibiotic prescription rates or predominantly (>85%) low/intermediate-risk children.
Conclusions
Implementation of the Feverkidstool could reduce antibiotic prescriptions in children with suspected LRTIs in European EDs.
Antibody replacement therapy for patients with antibody deficiencies contains only IgG. As a result, concurrent IgM and IgA deficiency present in a large proportion of antibody deficient patients ...persists. Especially patients with IgM deficiency remain at risk for recurrent infections of the gastrointestinal and respiratory tract. The lack of IgM in the current IgG replacement therapy is likely to contribute to the persistence of these mucosal infections because this antibody class is especially important for complement activation on the mucosal surface. We evaluated whether supplementation with IgM increased serum bactericidal capacity in vitro. Serum was collected from a patient with agammaglobulinemia and supplemented with purified serum IgM to normal levels. Antibody and complement deposition on the bacterial surface was determined by multi-color flow cytometry. Bacterial survival in serum was determined by colony-forming unit counts. We present a patient previously diagnosed with agammaglobulinemia due to
CD79A
(Igα) deficiency revealing a novel pathogenic insertion variant in the
CD79a
gene (NM_001783.3:c.353_354insT). Despite IgG replacement therapy and antibiotic prophylaxis, this patient developed a
Campylobacter jejuni
spondylodiscitis of lumbar vertebrae L4–L5. We found that serum IgM significantly contributes to complement activation on the bacterial surface of
C. jejuni
. Furthermore, supplementation of serum IgM augmented serum bactericidal activity significantly. In conclusion, supplementation of intravenous IgG replacement therapy with IgM may potentially offer greater protection against bacterial infections, also in the context of increasing antibiotic resistance.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Streptococcus pneumoniae is a major cause of life-threatening infections. Complement activation plays a vital role in opsonophagocytic killing of pneumococci in blood. Initial complement activation ...via the classical and lectin pathways is amplified through the alternative pathway amplification loop. Alternative pathway activity is inhibited by complement factor H (FH). Our study demonstrates the functional consequences of the variability in human serum FH levels on host defense. Using an in vivo mouse model combined with human in vitro assays, we show that the level of serum FH correlates with the efficacy of opsonophagocytic killing of pneumococci. In summary, we found that FH levels determine a delicate balance of alternative pathway activity, thus affecting the resistance to invasive pneumococcal disease. Our results suggest that variation in FH expression levels, naturally occurring in the human population, plays a thus far unrecognized role in the resistance to invasive pneumococcal disease.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
•Pneumococcal induced cytokine production is enhanced through C5aR crosstalk.•Alternative pathway inhibition by exogenous factor H strongly reduces C5aR crosstalk.•Variation in factor H levels may ...affect cytokine responses during infection.
Bacterial pathogens not only stimulate innate immune receptors, but also activate the complement system. Crosstalk between complement C5a receptor (C5aR) and other innate immune receptors is known to enhance the proinflammatory cytokine response. An important determinant of the magnitude of complement activation is the activity of the alternative pathway, which serves as an amplification mechanism for complement activation. Both alternative pathway activity as well as plasma levels of factor H, a key inhibitor of the alternative pathway, show large variation within the human population. Here, we studied the effect of factor H-mediated regulation of the alternative pathway on bacterial-induced proinflammatory cytokine responses. We used the human pathogen Streptococcus pneumoniae as a model stimulus to induce proinflammatory cytokine responses in human peripheral blood mononuclear cells. Serum containing active complement enhanced pneumococcal induced proinflammatory cytokine production through C5a release and C5aR crosstalk. We found that inhibition of the alternative pathway by factor H, with a concentration equivalent to a high physiological level, strongly reduced C5a levels and decreased proinflammatory cytokine production in human peripheral blood mononuclear cells. This suggests that variation in alternative pathway activity due to variation in factor H plasma levels affects individual cytokine responses during infection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
BACKGROUND:Tuberculous meningitis (TBM) is characterized by disruption of the blood-brain barrier (BBB), cerebral edema and increased intracranial pressure (ICP). Vascular endothelial growth factor ...(VEGF) is a potent vascular permeability factor and a mediator of brain edema.
AIMS:To investigate whether in children with TBM disruption of the BBB relates to VEGF production and to assess the effect of corticosteroids on Mycobacterium tuberculosis-induced VEGF production by mononuclear leukocytes.
METHODS:Blood and CSF samples were collected from 26 children with stage 2–3 TBM and 20 controls. All patients received antituberculous and adjuvant corticosteroid therapy. Children were evaluated by ICP recording, computerized tomography scanning and outcome assessment at 6 months follow-up. BBB disruption was quantified by cerebrospinal fluid (CSF)-serum albumin ratios. VEGF concentrations were measured by enzyme-linked immunosorbent assay. In vitro human monocytic THP-1 cells were stimulated with M. tuberculosis sonicate or culture supernatant, and VEGF production was measured in the presence or absence of corticosteroids.
RESULTS:CSF VEGF concentrations were significantly higher in TBM patients than in the controls and correlated with mononuclear cell counts (r = 0.64; P = 0.001) and CSF-serum albumin ratio (r = 0.49; P = 0.015). CSF VEGF did not significantly correlate with elevated ICP. In vitro induction of VEGF production by M. tuberculosis sonicate or culture supernatant could be completely abrogated by corticosteroid treatment.
CONCLUSIONS:Inflammatory cells secrete VEGF during TBM. CSF VEGF correlates with BBB disruption. Inhibition of VEGF may explain part of the clinical effect of adjuvant corticosteroid therapy in TBM.
In this multicenter pharmacokinetic study in HIV-infected children (6–12 years of age), we validated the approved once-daily darunavir/ritonavir dosing recommendations. The geometric mean darunavir ...area under the plasma concentration-time curve was 63.1 h·mg/L, substantially lower than the mean value observed in adults. However, all trough levels were adequate, and short-term virologic outcome was good. These data support the use of the darunavir/ritonavir once-daily dosing recommendations.
Biobanking biospecimens and consent are common practice in paediatric research. We need to explore children and young people's (CYP) knowledge and perspectives around the use of and consent to ...biobanking. This will ensure meaningful informed consent can be obtained and improve current consent procedures.
We designed a survey, in co-production with CYP, collecting demographic data, views on biobanking, and consent using three scenarios: 1) prospective consent, 2) deferred consent, and 3) reconsent and assent at age of capacity. The survey was disseminated via the Young Person's Advisory Group North England (YPAGne) and participating CYP's secondary schools. Data were analysed using a qualitative thematic approach by three independent reviewers (including CYP) to identify common themes. Data triangulation occurred independently by a fourth reviewer.
One hundred two CYP completed the survey. Most were between 16-18 years (63.7%, N = 65) and female (66.7%, N = 68). 72.3% had no prior knowledge of biobanking (N = 73). Acceptability of prospective consent for biobanking was high (91.2%, N = 93) with common themes: 'altruism', 'potential benefits outweigh individual risk', 'frugality', and '(in)convenience'. Deferred consent was also deemed acceptable in the large majority (84.3%, N = 86), with common themes: 'altruism', 'body integrity' and 'sample frugality'. 76.5% preferred to reconsent when cognitively mature enough to give assent (N = 78), even if parental consent was previously in place. 79.2% wanted to be informed if their biobanked biospecimen is reused (N = 80).
Prospective and deferred consent acceptability for biobanking is high among CYP in the UK. Altruism, frugality, body integrity, and privacy are the most important themes. Clear communication and justification are paramount to obtain consent. Any CYP with capacity should be part of the consenting procedure, if possible.
Appropriate treatment and management of children presenting with fever depend on accurate and timely diagnosis, but current diagnostic tests lack sensitivity and specificity and are frequently too ...slow to inform initial treatment. As an alternative to pathogen detection, host gene expression signatures in blood have shown promise in discriminating several infectious and inflammatory diseases in a dichotomous manner. However, differential diagnosis requires simultaneous consideration of multiple diseases. Here, we show that diverse infectious and inflammatory diseases can be discriminated by the expression levels of a single panel of genes in blood.
A multi-class supervised machine-learning approach, incorporating clinical consequence of misdiagnosis as a “cost” weighting, was applied to a whole-blood transcriptomic microarray dataset, incorporating 12 publicly available datasets, including 1,212 children with 18 infectious or inflammatory diseases. The transcriptional panel identified was further validated in a new RNA sequencing dataset comprising 411 febrile children.
We identified 161 transcripts that classified patients into 18 disease categories, reflecting individual causative pathogen and specific disease, as well as reliable prediction of broad classes comprising bacterial infection, viral infection, malaria, tuberculosis, or inflammatory disease. The transcriptional panel was validated in an independent cohort and benchmarked against existing dichotomous RNA signatures.
Our data suggest that classification of febrile illness can be achieved with a single blood sample and opens the way for a new approach for clinical diagnosis.
European Union’s Seventh Framework no. 279185; Horizon2020 no. 668303 PERFORM; Wellcome Trust (206508/Z/17/Z); Medical Research Foundation (MRF-160-0008-ELP-KAFO-C0801); NIHR Imperial BRC.
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•Multi-class supervised machine learning for infectious and inflammatory diseases•Host-blood RNA expression can discriminate multiple pediatric diseases simultaneously•Eighteen specific diseases or causative pathogens are distinguished using 161 transcripts
Infectious and inflammatory diseases are the most common causes of children seeking medical care in both hospital and community settings. It is a considerable challenge for clinical teams to reliably distinguish common viral infections, bacterial infections (which are potentially serious), and less common inflammatory diseases, with existing tests when children initially present at healthcare settings. Habgood-Coote et al. describe an approach for simultaneously distinguishing between 18 infectious and inflammatory diseases using the differences in the levels of expression of 161 genes in patients' blood. A future diagnostic test based on this approach could help provide the right treatment, to the right patient, at the right time, while optimizing antibiotic use and reducing lengthy time to diagnosis for inflammatory diseases.
A multi-class supervised machine-learning approach applied to whole-blood transcriptomics can classify 18 categories of pediatric infectious and inflammatory diseases, reflecting individual causative pathogen or specific disease. Habgood-Coote et al. identify a panel of 161 RNA transcripts in blood using gene expression microarrays, validate using RNA-sequencing, and benchmark against existing dichotomous RNA signatures.
Vascular endothelial growth factor (VEGF) is a potent vascular permeability factor. The development of capillary leak is common in septic patients, and several sepsis-associated mediators may induce ...VEGF production. The potential role of VEGF during sepsis has not been studied to date. The aim of the study was first to assess whether circulating VEGF levels increase during sepsis, and second, to examine whether plasma VEGF levels are associated with disease severity. VEGF levels were measured in serial plasma samples of 18 patients with severe sepsis and in 40 healthy controls. VEGF levels were correlated to clinical signs and symptoms. VEGF levels were significantly elevated in sepsis patients compared with healthy controls (134 vs. 55 pg/mL; P <0.001). Serum albumin levels used as an indirect measure of vascular leak were decreased in septic patients. Increased plasma VEGF levels at study entry were correlated to severity of multiple organ dysfunction during the course of disease (Pearson correlation coefficient r=0.75; P=0.001). Moreover, maximum VEGF levels in nonsurvivors were significantly higher than those in survivors (P=0.018). These data show that plasma VEGF levels are elevated during severe sepsis. Furthermore, our data indicate that plasma VEGF levels are associated with disease severity and mortality. Further study of the potential role of VEGF in the development of sepsis-associated capillary leak is indicated.
Patients with syndromic features frequently suffer from recurrent respiratory infections, but little is known about the spectrum of immunological abnormalities associated with their underlying ...chromosomal aberrations outside the well-known examples of Down and DiGeorge syndromes. Therefore, we performed this retrospective, observational survey study.
All members of the European Society for Immunodeficiencies (ESID) were invited to participate by reporting their patients with chromosomal aberration (excluding Down and DiGeorge syndromes) in combination with one or more identified immunological abnormalities potentially relating to primary immunodeficiency. An online questionnaire was used to collect the patient data.
Forty-six patients were included from 16 centers (24 males, 22 females; median age 10.4 years range 1.0-69.2 years; 36 pediatric, 10 adult patients). A variety of chromosomal aberrations associated with immunological abnormalities potentially relating to primary immune deficiency was reported. The most important clinical presentation prompting the immunological evaluation was 'recurrent ear-nose-throat (ENT) and airway infections'. Immunoglobulin isotype and/or IgG-subclass deficiencies were the most prevalent immunological abnormalities reported.
Our survey yielded a wide variety of chromosomal aberrations associated with immunological abnormalities potentially relating to primary immunodeficiency. Although respiratory tract infections can often also be ascribed to other causes (e.g. aspiration or structural abnormalities), we show that a significant proportion of patients also have an antibody deficiency requiring specific treatment (e.g. immunoglobulin replacement, antibiotic prophylaxis). Therefore, it is important to perform immunological investigations in patients with chromosomal aberrations and recurrent ENT or airway infections, to identify potential immunodeficiency that can be specifically treated.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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