Publications by authors named "Federico Martinón-Torres"

180 Publications

Recent advances in meningococcal B disease prevention: real-world evidence from 4CMenB vaccination: Real-world effectiveness of MenB vaccination.

J Infect 2021 Apr 29. Epub 2021 Apr 29.

GSK, Rockville, MD, USA.

Objectives: 4CMenB is a broadly protective vaccine against invasive meningococcal capsular group B disease (MenB IMD). Licensed worldwide based on immunogenicity and safety data, effectiveness and impact data are now available. We comprehensively reviewed all available real-world evidence gathered from use of 4CMenB since licensure.

Results: Data from 7 countries provide evidence of effectiveness and impact across different healthcare settings and age-groups, including national/regional immunization programs, observational studies and outbreak control. At least 2 4CMenB doses reduced MenB IMD by 50%-100% in 2-month to 20-year-olds depending on length of follow-up. Estimates of vaccine effectiveness in fully vaccinated cohorts ranged from 59%-100%. The safety profile of 4CMenB administered in real-world settings was consistent with pre-licensure clinical trial data.

Conclusion: MenB IMD is an uncommon but life-threatening disease with unpredictable epidemiology. The substantial body of data demonstrating 4CMenB effectiveness and impact supports its use in IMD prevention. The results reinforce the importance of direct protection of the highest risk groups; infants/young children and adolescents. Direct protection via routine infant immunization with catch-up in young children and routine adolescent vaccination could be the preferred option for MenB disease control. A Video Abstract linked to this article is available on Figshare: [Link to be added once available].
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http://dx.doi.org/10.1016/j.jinf.2021.04.031DOI Listing
April 2021

Identification of a Minimal 3-Transcript Signature to Differentiate Viral from Bacterial Infection from Best Genome-Wide Host RNA Biomarkers: A Multi-Cohort Analysis.

Int J Mol Sci 2021 Mar 19;22(6). Epub 2021 Mar 19.

Translational Pediatrics and Infectious Diseases, Department of Pediatrics, Hospital Clínico Universitario de Santiago de Compostela, 15706 Galicia, Spain.

The fight against the spread of antibiotic resistance is one of the most important challenges facing health systems worldwide. Given the limitations of current diagnostic methods, the development of fast and accurate tests for the diagnosis of viral and bacterial infections would improve patient management and treatment, as well as contribute to reducing antibiotic misuse in clinical settings. In this scenario, analysis of host transcriptomics constitutes a promising target to develop new diagnostic tests based on the host-specific response to infections. We carried out a multi-cohort meta-analysis of blood transcriptomic data available in public databases, including 11 different studies and 1209 samples from virus- ( = 695) and bacteria- ( = 514) infected patients. We applied a Parallel Regularized Regression Model Search (PReMS) on a set of previously reported genes that distinguished viral from bacterial infection to find a minimum gene expression bio-signature. This strategy allowed us to detect three genes, namely , and , that clearly differentiate groups of infection with high accuracy (training set: area under the curve (AUC) 0.86 (sensitivity: 0.81; specificity: 0.87); testing set: AUC 0.87 (sensitivity: 0.82; specificity: 0.86)). and are involved in processes related to immune response, while is related to the preservation of methylation patterns, and its expression is modulated by pathogen infections. We successfully tested this three-transcript signature in the 11 independent studies, demonstrating its high performance under different scenarios. The main advantage of this three-gene signature is the low number of genes needed to differentiate both groups of patient categories.
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http://dx.doi.org/10.3390/ijms22063148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003556PMC
March 2021

BCG vaccination improves DTaP immune responses in mice and is associated with lower pertussis incidence in ecological epidemiological studies.

EBioMedicine 2021 Mar 9;65:103254. Epub 2021 Mar 9.

Translational Pediatrics and Infectious Diseases, Pediatrics Department, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain; GENVIP Research Group (www.genvip.org), Instituto de Investigación Sanitaria de Santiago (SERGAS), University of Santiago de Compostela, Galicia, Spain.

Background: The Bacillus Calmette-Guérin (BCG), the only vaccine against tuberculosis (TB) currently in use, has shown beneficial effects against unrelated infections and to enhance immune responses to vaccines. However, there is little evidence regarding the influence of BCG vaccination on pertussis.

Methods: Here, we studied the ability of BCG to improve the immune responses to diphtheria, tetanus, and acellular (DTaP) or whole-cell pertussis (DTwP) vaccination in a mouse model. We included MTBVAC, an experimental live-attenuated vaccine derived from Mycobacterium tuberculosis, in our studies to explore if it presents similar heterologous immunity as BCG. Furthermore, we explored the potential effect of routine BCG vaccination on pertussis incidence worldwide.

Findings: We found that both BCG and MTBVAC when administered before DTaP, triggered Th1 immune responses against diphtheria, tetanus, and pertussis in mice. Immunization with DTaP alone failed to trigger a Th1 response, as measured by the production of IFN-γ. Humoral responses against DTaP antigens were also enhanced by previous immunization with BCG or MTBVAC. Furthermore, exploration of human epidemiological data showed that pertussis incidence was 10-fold lower in countries that use DTaP and BCG compared to countries that use only DTaP.

Interpretation: BCG vaccination may have a beneficial impact on the protection against pertussis conferred by DTaP. Further randomized controlled trials are needed to properly define the impact of BCG on pertussis incidence in a controlled setting. This could be a major finding that would support changes in immunization policies.

Funding: This work was supported by the Ministry of "Economía y Competitividad"; European Commission H2020 program, "Gobierno de Aragón"; CIBERES; "Fundação Butantan"; Instituto de Salud Carlos III and "Fondo FEDER".
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http://dx.doi.org/10.1016/j.ebiom.2021.103254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960937PMC
March 2021

Acute onset supraclavicular lymphadenopathy coinciding with intramuscular mRNA vaccination against COVID-19 may be related to vaccine injection technique, Spain, January and February 2021.

Euro Surveill 2021 03;26(10)

Genetics, Vaccines and Pediatric Infectious Diseases Research Group (GENVIP), Instituto de Investigación Sanitaria de Santiago and Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.

Monitoring adverse reactions following immunisation is essential, particularly for new vaccines such as those against COVID-19. We describe 20 cases of acute onset of a single supraclavicular lymphadenopathy manifesting between 24 h and 9 days after ipsilateral intramuscular administration of an mRNA-based COVID-19 vaccine, referred to our WHO Collaborating Centre for Vaccine Safety. Our results indicate that the swelling of supraclavicular lymph nodes following immunisation may constitute a benign and self-limited condition, related to a higher than recommended injection site.
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http://dx.doi.org/10.2807/1560-7917.ES.2021.26.10.2100193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953532PMC
March 2021

CAPPRIC Study-Characterization of Community-Acquired Pneumonia in Spanish Adults Managed in Primary Care Settings.

Microorganisms 2021 Feb 28;9(3). Epub 2021 Feb 28.

Primary Health Care Center Algeciras-Norte, 11205 Algeciras, Spain.

The real burden of community-acquired pneumonia (CAP) in non-hospitalized patients is largely unknown. This is a 3-year prospective, observational study of ambulatory CAP in adults, conducted in 24 Spanish primary care centers between 2016-2019. Sociodemographic and clinical variables of patients with radiographically confirmed CAP were collected. Pneumococcal etiology was assessed using the Binax Now test. Patients were followed up for 10 ± 3 days. A total of 456 CAP patients were included in the study. Mean age was 56.6 (±17.5) years, 53.5% were female, and 53.9% had ≥1 comorbidity. Average incidence of CAP was 1.2-3.5 cases per 1000 persons per year. Eighteen patients (3.9%) were classified as pneumococcal CAP. Cough was present in 88.1% of patients at diagnosis and fever in 70.8%. Increased pulmonary density (63.3%) and alveolar infiltrates with air bronchogram (16.6%) were the most common radiographic findings. After 14.6 ± 6.0 days (95% CI = 13.9-15.3), 65.4% of patients had recovered. Hospitalization rate was 2.8%. The most frequently prescribed antibiotics were quinolones (58.7%) and β-lactams (31.1%). In conclusion, one-third of CAP patients did not fully recover after two weeks of empiric antibiotic therapy and 2.8% required hospitalization, highlighting the significant burden associated with non-hospitalized CAP in Spain.
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http://dx.doi.org/10.3390/microorganisms9030508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997465PMC
February 2021

Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye.

JAMA 2021 02;325(8):753-764

Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.

Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function.

Design, Setting, And Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.

Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function.

Main Outcomes And Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses.

Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome.

Conclusions And Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.
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http://dx.doi.org/10.1001/jama.2021.0507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903258PMC
February 2021

Impact of maternal diphtheria-tetanus-acellular pertussis vaccination on pertussis booster immune responses in toddlers: Follow-up of a randomized trial.

Vaccine 2021 Mar 19;39(11):1598-1608. Epub 2021 Feb 19.

GSK, Vaccines, 1300 Wavre, Belgium.

Background: Transplacentally transferred antibodies induced by maternal pertussis vaccination interfere with infant immune responses to pertussis primary vaccination. We evaluated whether this interference remains in toddlers after booster vaccination.

Methods: In a prior phase IV, observer-blind, placebo-controlled, randomized study (NCT02377349), pregnant women in Australia, Canada and Europe received intramuscular tetanus-reduced-antigen-content diphtheria-three-component acellular pertussis vaccine (Tdap group) or placebo (control group) at 27-36 weeks' gestation, with crossover immunization postpartum. Their infants were primed (study NCT02422264) and boosted (at 11-18 months; current study NCT02853929) with diphtheria-tetanus-three-component acellular pertussis-hepatitis B virus-inactivated poliovirus/Haemophilus influenzae type b vaccine (DTaP-HepB-IPV/Hib) and 13-valent pneumococcal conjugate vaccine. Immunogenicity before and after booster vaccination, and reactogenicity and safety of the booster were evaluated descriptively.

Results: 263 (Tdap group) and 277 (control group) toddlers received a DTaP-HepB-IPV/Hib booster. Pre-booster vaccination, observed geometric mean concentrations (GMCs) for the three pertussis antigens and diphtheria were 1.4-1.5-fold higher in controls than in the Tdap group. No differences were observed for the other DTaP-HepB-IPV/Hib antigens. One month post-booster vaccination, booster response rates for pertussis antigens were ≥ 92.1% and seroprotection rates for the other DTaP-HepB-IPV/Hib antigens were ≥ 99.2% in both groups (primary objective). Higher post-booster GMCs were observed in controls versus the Tdap group for anti-filamentous hemagglutinin (1.2-fold), anti-pertussis toxoid (1.5-fold) and anti-diphtheria (1.4-fold). GMCs for the other DTaP-HepB-IPV/Hib antigens were similar between groups. Serious adverse events were reported for three toddlers (controls, not vaccination-related). One death occurred pre-booster (Tdap group, not vaccination-related).

Conclusions: As a consequence of interference of maternal pertussis antibodies with infant immune responses to pertussis primary vaccination, pertussis antibody concentrations were still lower in toddlers from Tdap-vaccinated mothers before DTaP-HepB-IPV/Hib booster vaccination. After the booster, antibody concentrations were lower for filamentous hemagglutinin and pertussis toxoid but not for pertactin. The clinical significance of this interference requires further evaluation.

Clinical Trial Registration: ClinicalTrials.gov: NCT02853929.
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http://dx.doi.org/10.1016/j.vaccine.2021.02.001DOI Listing
March 2021

Review of clinical studies comparing meningococcal serogroup C immune responses induced by MenACWY-TT and monovalent serogroup C vaccines.

Hum Vaccin Immunother 2021 Feb 19:1-11. Epub 2021 Feb 19.

Vaccine Medical, Development, Scientific and Clinical Affairs, Pfizer Ltd, Tadworth, UK.

Many countries are replacing meningococcal serogroup C (MenC) conjugate vaccines (MCCV) with quadrivalent conjugate (MenACWY) vaccines, such as MenACWY-TT (Nimenrix®). This review examined eight studies comparing MenC immune responses induced by MenACWY-TT and MCCV to determine if these data support these changes. MenC serum bactericidal antibody levels using human (hSBA) or rabbit complement (rSBA) were evaluated at ~1 month postvaccination. Overall, ≥98.4% of infants administered 2 + 1 MenACWY-TT or MCCV schedules had rSBA titers ≥1:8 postprimary and postbooster vaccination; hSBA titers ≥1:8 were similar. In toddlers administered single MenACWY-TT or MCCV doses, ≥97.3% had rSBA titers ≥1:8 postvaccination; percentages with hSBA titers ≥1:8 were higher post-MenACWY-TT. Of children and adolescents receiving primary and booster MenACWY-TT and MCCV, ≥98.6% had rSBA titers ≥1:8; all children receiving MenACWY-TT or MCCV booster had hSBA titers ≥1:8 postdosing. MenC immune responses induced by MenACWY-TT are robust and generally comparable/superior to MCCV, supporting changes to recommendations.
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http://dx.doi.org/10.1080/21645515.2020.1855952DOI Listing
February 2021

Impact of a clinical decision rule on antibiotic prescription for children with suspected lower respiratory tract infections presenting to European emergency departments: a simulation study based on routine data.

J Antimicrob Chemother 2021 Apr;76(5):1349-1357

Department of General Paediatrics, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.

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.
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http://dx.doi.org/10.1093/jac/dkab023DOI Listing
April 2021

Host Transcriptomic Response Following Administration of Rotavirus Vaccine in Infants' Mimics Wild Type Infection.

Front Immunol 2020 21;11:580219. Epub 2021 Jan 21.

Genetics, Vaccines and Pediatric Infectious Diseases Research Group (GENVIP), Instituto de Investigación Sanitaria de Santiago (IDIS) and Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.

Background: Rotavirus (RV) is an enteric pathogen that has devastating impact on childhood morbidity and mortality worldwide. The immunologic mechanism underlying the protection achieved after RV vaccination is not yet fully understood.

Methods: We compared the transcriptome of children affected by community-acquired RV infection and children immunized with a live attenuated RV vaccine (RotaTeq).

Results: RV vaccination mimics the wild type infection causing similar changes in children's transcriptome, including transcripts associated with cell cycle, diarrhea, nausea, vomiting, intussusception, and abnormal morphology of midgut. A machine learning approach allowed to detect a combination of nine-transcripts that differentiates vaccinated from convalescent-naturally infected children (AUC: 90%; 95%CI: 70-100) and distinguishes between acute-infected and healthy control children (in both cases, AUC: 100%; 95%CI: 100-100). We identified a miRNA hsa-mir-149 that seems to play a role in the host defense against viral pathogens and may have an antiviral role.

Discussion: Our findings might shed further light in the understanding of RV infection, its functional link to intussusception causes, as well as guide development of antiviral treatments and safer and more effective vaccines. The nine-transcript signature may constitute a marker of vaccine protection and helps to differentiate vaccinated from naturally infected or susceptible children.
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http://dx.doi.org/10.3389/fimmu.2020.580219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859632PMC
January 2021

Changes in epigenetic profiles throughout early childhood and their relationship to the response to pneumococcal vaccination.

Clin Epigenetics 2021 Feb 4;13(1):29. Epub 2021 Feb 4.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and The NIHR Oxford Biomedical Research Centre, Oxford, UK.

Background: Pneumococcal infections are a major cause of morbidity and mortality in young children and immaturity of the immune system partly underlies poor vaccine responses seen in the young. Emerging evidence suggests a key role for epigenetics in the maturation and regulation of the immune system in health and disease. The study aimed to investigate epigenetic changes in early life and to understand the relationship between the epigenome and antigen-specific antibody responses to pneumococcal vaccination.

Methods: The epigenetic profiles from 24 healthy children were analyzed at 12 months prior to a booster dose of the 13-valent pneumococcal conjugate vaccine (PCV-13), and at 24 months of age, using the Illumina Methylation 450 K assay and assessed for differences over time and between high and low vaccine responders.

Results: Our analysis revealed 721 significantly differentially methylated positions between 12 and 24 months (FDR < 0.01), with significant enrichment in pathways involved in the regulation of cell-cell adhesion and T cell activation. Comparing high and low vaccine responders, we identified differentially methylated CpG sites (P value < 0.01) associated with HLA-DPB1 and IL6.

Conclusion: These data imply that epigenetic changes that occur during early childhood may be associated with antigen-specific antibody responses to pneumococcal vaccines.
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http://dx.doi.org/10.1186/s13148-021-01012-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860179PMC
February 2021

Variation in hospital admission in febrile children evaluated at the Emergency Department (ED) in Europe: PERFORM, a multicentre prospective observational study.

PLoS One 2021 7;16(1):e0244810. Epub 2021 Jan 7.

Department of General Paediatrics, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.

Objectives: Hospitalisation is frequently used as a marker of disease severity in observational Emergency Department (ED) studies. The comparison of ED admission rates is complex in potentially being influenced by the characteristics of the region, ED, physician and patient. We aimed to study variation in ED admission rates of febrile children, to assess whether variation could be explained by disease severity and to identify patient groups with large variation, in order to use this to reduce unnecessary health care utilization that is often due to practice variation.

Design: MOFICHE (Management and Outcome of Fever in children in Europe, part of the PERFORM study, www.perform2020.org), is a prospective cohort study using routinely collected data on febrile children regarding patient characteristics (age, referral, vital signs and clinical alarming signs), diagnostic tests, therapy, diagnosis and hospital admission.

Setting And Participants: Data were collected on febrile children aged 0-18 years presenting to 12 European EDs (2017-2018).

Main Outcome Measures: We compared admission rates between EDs by using standardised admission rates after adjusting for patient characteristics and initiated tests at the ED, where standardised rates >1 demonstrate higher admission rates than expected and rates <1 indicate lower rates than expected based on the ED patient population.

Results: We included 38,120 children. Of those, 9.695 (25.4%) were admitted to a general ward (range EDs 5.1-54.5%). Adjusted standardised admission rates ranged between 0.6 and 1.5. The largest variation was seen in short admission rates (0.1-5.0), PICU admission rates (0.2-2.2), upper respiratory tract infections (0.4-1.7) and fever without focus (0.5-2.7). Variation was small in sepsis/meningitis (0.9-1.1).

Conclusions: Large variation exists in admission rates of febrile children evaluated at European EDs, however, this variation is largely reduced after correcting for patient characteristics and therefore overall admission rates seem to adequately reflect disease severity or a potential for a severe disease course. However, for certain patient groups variation remains high even after adjusting for patient characteristics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244810PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790386PMC
May 2021

Pitfalls of barcodes in the study of worldwide SARS-CoV-2 variation and phylodynamics.

Zool Res 2021 Jan;42(1):87-93

Unidade de Xenética, Instituto de Ciencias Forenses (INCIFOR), Facultade de Medicina, Universidade de Santiago de Compostela, and GenPoB Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario de Santiago (SERGAS), Galicia 15706, Spain.

Analysis of SARS-CoV-2 genome variation using a minimal number of selected informative sites conforming a genetic barcode presents several drawbacks. We show that purely mathematical procedures for site selection should be supervised by known phylogeny (i) to ensure that solid tree branches are represented instead of mutational hotspots with poor phylogeographic proprieties, and (ii) to avoid phylogenetic redundancy. We propose a procedure that prevents information redundancy in site selection by considering the cumulative informativeness of previously selected sites (as a proxy for phylogenetic-based criteria). This procedure demonstrates that, for short barcodes (e.g., 11 sites), there are thousands of informative site combinations that improve previous proposals. We also show that barcodes based on worldwide databases inevitably prioritize variants located at the basal nodes of the phylogeny, such that most representative genomes in these ancestral nodes are no longer in circulation. Consequently, coronavirus phylodynamics cannot be properly captured by universal genomic barcodes because most SARS-CoV-2 variation is generated in geographically restricted areas by the continuous introduction of domestic variants.
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http://dx.doi.org/10.24272/j.issn.2095-8137.2020.364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840454PMC
January 2021

Quantitative multiplex profiling of the complement system to diagnose complement-mediated diseases.

Clin Transl Immunology 2020 9;9(12):e1225. Epub 2020 Dec 9.

Laboratory of Medical Immunology Department of Laboratory Medicine Radboud Institute for Molecular Life Sciences Radboud University Medical Center Nijmegen The Netherlands.

Objectives: Complement deficiencies are difficult to diagnose because of the variability of symptoms and the complexity of the diagnostic process. Here, we applied a novel 'complementomics' approach to study the impact of various complement deficiencies on circulating complement levels.

Methods: Using a quantitative multiplex mass spectrometry assay, we analysed 44 peptides to profile 34 complement proteins simultaneously in 40 healthy controls and 83 individuals with a diagnosed deficiency or a potential pathogenic variant in 14 different complement proteins.

Results: Apart from confirming near or total absence of the respective protein in plasma of complement-deficient patients, this mass spectrometry-based profiling method led to the identification of additional deficiencies. In many cases, partial depletion of the pathway up- and/or downstream of the absent protein was measured. This was especially found in patients deficient for complement inhibitors, such as angioedema patients with a C1-inhibitor deficiency. The added value of complementomics was shown in three patients with poorly defined complement deficiencies.

Conclusion: Our study shows the potential clinical utility of profiling circulating complement proteins as a comprehensive read-out of various complement deficiencies. Particularly, our approach provides insight into the intricate interplay between complement proteins due to functional coupling, which contributes to the better understanding of the various disease phenotypes and improvement of care for patients with complement-mediated diseases.
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http://dx.doi.org/10.1002/cti2.1225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724921PMC
December 2020

Prevention of New Respiratory Episodes in Children with Recurrent Respiratory Infections: An Expert Consensus Statement.

Microorganisms 2020 Nov 17;8(11). Epub 2020 Nov 17.

Università degli Studi di Milano, 20122 Milan, Italy.

In healthy infants and young children, the development of respiratory tract infections (RTIs) is extremely common. In this paper, we present an international consensus of the available approaches for the prevention of recurrent RTIs in children, including the atopic/allergic ones as well as those with asthma. Few convincing measures for reducing the frequency and clinical relevance of recurrent respiratory episodes in RTI-prone children have been developed until now. Among the most recently suggested measures, immunotherapy is attractive, but only for OM-85 is there a sufficient number of well-conducted clinical trials confirming efficacy in RTIs prevention with an adequate safety profile. In the case of probiotics, it is not clear which bacteria can offer the best results and which dosage and schedule of administration are the most effective. The problems of dosage and the schedule of administration are not solved also for vitamin D, despite some promising efficacy results. While we wait for new knowledge, the elimination or reduction as much as possible of the environmental factors that favor RTIs, vaccination when available and/or indicated, and the systematic application of the traditional methods for infection prevention, such as hand washing, remain the best measures to prevent recurrent infections in RTI-prone children.
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http://dx.doi.org/10.3390/microorganisms8111810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698530PMC
November 2020

Development and validation of a prediction model for invasive bacterial infections in febrile children at European Emergency Departments: MOFICHE, a prospective observational study.

Arch Dis Child 2020 Nov 18. Epub 2020 Nov 18.

General Paediatrics, Erasmus MC Sophia Children's Hospital, Rotterdam, Zuid-Holland, The Netherlands

Objectives: To develop and cross-validate a multivariable clinical prediction model to identify invasive bacterial infections (IBI) and to identify patient groups who might benefit from new biomarkers.

Design: Prospective observational study.

Setting: 12 emergency departments (EDs) in 8 European countries.

Patients: Febrile children aged 0-18 years.

Main Outcome Measures: IBI, defined as bacteraemia, meningitis and bone/joint infection. We derived and cross-validated a model for IBI using variables from the Feverkidstool (clinical symptoms, C reactive protein), neurological signs, non-blanching rash and comorbidity. We assessed discrimination (area under the receiver operating curve) and diagnostic performance at different risk thresholds for IBI: sensitivity, specificity, negative and positive likelihood ratios (LRs).

Results: Of 16 268 patients, 135 (0.8%) had an IBI. The discriminative ability of the model was 0.84 (95% CI 0.81 to 0.88) and 0.78 (95% CI 0.74 to 0.82) in pooled cross-validations. The model performed well for the rule-out threshold of 0.1% (sensitivity 0.97 (95% CI 0.93 to 0.99), negative LR 0.1 (95% CI 0.0 to 0.2) and for the rule-in threshold of 2.0% (specificity 0.94 (95% CI 0.94 to 0.95), positive LR 8.4 (95% CI 6.9 to 10.0)). The intermediate thresholds of 0.1%-2.0% performed poorly (ranges: sensitivity 0.59-0.93, negative LR 0.14-0.57, specificity 0.52-0.88, positive LR 1.9-4.8) and comprised 9784 patients (60%).

Conclusions: The rule-out threshold of this model has potential to reduce antibiotic treatment while the rule-in threshold could be used to target treatment in febrile children at the ED. In more than half of patients at intermediate risk, sensitive biomarkers could improve identification of IBI and potentially reduce unnecessary antibiotic prescriptions.
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http://dx.doi.org/10.1136/archdischild-2020-319794DOI Listing
November 2020

Increased Serum Levels of sCD14 and sCD163 Indicate a Preponderant Role for Monocytes in COVID-19 Immunopathology.

Front Immunol 2020 23;11:560381. Epub 2020 Sep 23.

Grupo de Investigación en Genética, Vacunas, Infecciones y Pediatría, Instituto de Investigación Sanitaria de Santiago, Hospital Clinico Universitario and Universidade de Santiago de Compostela, Servizo Galego de Saúde, Galicia, Spain.

Background: Emerging evidence indicates a potential role for monocytes in COVID-19 immunopathology. We investigated two soluble markers of monocyte activation, sCD14 and sCD163, in COVID-19 patients, with the aim of characterizing their potential role in monocyte-macrophage disease immunopathology. To the best of our knowledge, this is the first study of its kind.

Methods: Fifty-nine SARS-Cov-2 positive hospitalized patients, classified according to ICU or non-ICU admission requirement, were prospectively recruited and analyzed by ELISA for levels of sCD14 and sCD163, along with other laboratory parameters, and compared to a healthy control group.

Results: sCD14 and sCD163 levels were significantly higher among COVID-19 patients, independently of ICU admission requirement, compared to the control group. We found a significant correlation between sCD14 levels and other inflammatory markers, particularly Interleukin-6, in the non-ICU patients group. sCD163 showed a moderate positive correlation with the time lapsed from admission to sampling, independently of severity group. Treatment with corticoids showed an interference with sCD14 levels, whereas hydroxychloroquine and tocilizumab did not.

Conclusions: Monocyte-macrophage activation markers are increased and correlate with other inflammatory markers in SARS-Cov-2 infection, in association to hospital admission. These data suggest a preponderant role for monocyte-macrophage activation in the development of immunopathology of COVID-19 patients.
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http://dx.doi.org/10.3389/fimmu.2020.560381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538662PMC
October 2020

Seroprevalence of SARS-CoV-2 Among Pediatric Healthcare Workers in Spain.

Front Pediatr 2020 11;8:547. Epub 2020 Sep 11.

Grupo de Investigación en Genética, Vacunas, Infecciones y Pediatría (GENVIP), Instituto de Investigación Sanitaria de Santiago (IDIS) and Hospital Clínico Universitario and Universidade de Santiago de Compostela (Servicio Gallego de Salud), Galicia, Spain.

Spain is one of the countries most severely affected by the SARS-CoV-2 pandemic, with almost 190,000 cases as of April 18, 2020. As healthcare workers (HCW) are one of the groups hardest hit by the infection, it is important to know the seroprevalence of antibodies against SARS-CoV-2 in pediatric departments. We performed 175 immunoglobulin (Ig)M and IgG immunochromatographic rapid tests in the personnel working at the Pediatric Department of the Hospital Clínico Universitario of Santiago de Compostela (Spain), including pediatricians, residents, nurses, and other staff, on days 31-33 since the lockdown started. Seven out of the 175 tests were positive, including four for IgM and three for IgG, leading to a seroprevalence of 4.0% (95% CI: 1.1-6.9%). Only one of them had symptoms at the time of testing (sore throat). All seropositive cases yielded negative RT-PCR of the upper and lower respiratory tract. This is the first SARS-CoV-2 serological survey among HCWs reported in Spain. Notwithstanding the test limitations, our results reveal that personal protection policy and lockdown measures have been effective to limit population exposure. The low seroprevalence rate poses a significant challenge for the next strategic steps of pandemic control.
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http://dx.doi.org/10.3389/fped.2020.00547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516980PMC
September 2020

Nebulised ALX-0171 for respiratory syncytial virus lower respiratory tract infection in hospitalised children: a double-blind, randomised, placebo-controlled, phase 2b trial.

Lancet Respir Med 2021 01 28;9(1):21-32. Epub 2020 Sep 28.

Ablynx, a Sanofi Company, Zwijnaarde, Belgium.

Background: Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory tract infection, with a high global health burden. There are no effective treatments available. ALX-0171 is a novel trivalent Nanobody with antiviral properties against RSV. We aimed to assess the safety and antiviral activity of nebulised ALX-0171 in children admitted to hospital with RSV lower respiratory tract infection.

Methods: This double-blind, randomised, placebo-controlled, phase 2b trial was done in 50 hospital paediatric departments across 16 countries. Previously healthy children aged between 28 days to younger than 24 months who were admitted to hospital with RSV acute severe lower respiratory tract infection were randomly assigned in three sequential safety cohorts (3:1) to receive nebulised ALX-0171 (cohort 1 received 3 mg/kg, cohort 2 received 6 mg/kg, and cohort 3 received 9 mg/kg) or placebo once daily for 3 days using web-based randomisation in the sequential safety part (first block size 12, subsequently four). In a parallel part of the study, participants (cohort 4) were randomly assigned (parallel 1:1:1:1) to receive nebulised ALX-0171 3 mg/kg, 6 mg/kg, 9 mg/kg, or placebo (blocks of eight by restricted randomisation). Study drug masking was by two consecutive nebulisations (each either ALX-0171 or placebo) depending on assigned treatment group. The primary outcome was to evaluate time for the RSV viral load to drop to below quantifiable limit, measured by plaque assay on mid-turbinate nasal swabs. Safety, clinical efficacy, pharmacokinetics, viral load by RT-qPCR, and immunogenicity were secondary outcomes. Analysis, including of the primary outcome, was by modified intention to treat (participants receiving at least one dose of study drug as assigned), and safety was assessed in all children who received at least one administration of study drug, as treated. This trial is registered with EudraCT, 2016-001651-49.

Findings: Between Jan 10, 2017, and April 26, 2018, 175 children (median age 4·8 months [IQR 2·0-10·8]), received at least one dose of study drug (45 received 3 mg/kg of ALX-0171, 43 received 6 mg/kg of ALX-0171, 45 received 9 mg/kg of ALX-0171, and 42 received placebo; the modified intention-to-treat population) commencing at a mean 3·3 days (SD 1·1) from symptom onset. Median time for the viral load to drop to below quantifiable limit on plaque assay was significantly faster for the 3 mg/kg group (median 14·2 h [IQR 5·0-28·0]), 6 mg/kg group (5·1 h [4·7-28·5]), and 9 mg/kg group (5·1 h [4·6-5·9]) than the placebo group (46·1 h [25·2-116·7]; hazard ratio [HR] all ALX-0171 groups vs placebo 2·6 [1·7-3·9]; p<0·0001). Median time for the viral load to drop below quantification limit with RT-qPCR was 95·9 h (IQR 26·7 to not estimable) for the placebo group (n=35) versus 49·4 h (25·1 to 351·4) for all ALX-0171 groups (n=118). Clinical outcomes were not improved by ALX-0171 compared with placebo, with no difference in time to clinical response (oxygen saturation >92% for 4 h in room air and adequate oral feeding) in ALX-0171 groups and the placebo group (median 43·8 h [IQR 21·7-68·5] vs 47·9 h [22·5-76·4]; HR 1·1 [95% CI 0·8-1·6]) or change in the global severity score from baseline to 5 h post-dose on day 2 (-4 [IQR -6 to -2] vs -4 [-6 to -1]; difference in least-squares mean -0·45 [95% CI -1·39 to 0·49]). Serum concentrations of ALX-0171 on day 2 exceeded the concentration estimated to give full RSV neutralisation in the lung at 6 mg/kg and 9 mg/kg doses. Treatment-emergent antidrug antibodies were detected at day 14 in 46 (34%) of 135 patients who received ALX-0171 and ten (26%) of 39 patients who received placebo. Serious adverse events were reported in five (13%) of 40 children in the placebo group and ten (7%) of 135 children in all ALX-0171 groups, leading to study drug discontinuation in three children (two in the 3 mg/kg group and one in the 6 mg/kg group). 13 of 15 serious adverse events (three of four in the 3 mg/kg group, two of three in the 6 mg/kg group, three of three in the 9 mg/kg group, and five of five in the placebo group) were related to worsening respiratory status, and none were considered to be related to the study drug.

Interpretation: Antivirals against RSV might be unable to improve clinical course once RSV lower respiratory tract infection is established. Future studies of RSV antivirals should focus on earlier intervention and more precise measurement of objective outcomes before the onset of significant lower respiratory tract inflammation.

Funding: Ablynx, a Sanofi Company.
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http://dx.doi.org/10.1016/S2213-2600(20)30320-9DOI Listing
January 2021

Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study.

Lancet Neurol 2020 10 16;19(10):840-848. Epub 2020 Sep 16.

Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands; Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Background: Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms.

Methods: We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country.

Findings: Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17-1·30], p=2·68 × 10; heterozygous model p=1·01 × 10), STX6 (rs3747957; OR 1·16 [1·10-1·22], p=9·74 × 10), and GAL3ST1 (rs2267161; OR 1·18 [1·12-1·25], p=8·60 × 10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions.

Interpretation: We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders.

Funding: Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust.
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http://dx.doi.org/10.1016/S1474-4422(20)30273-8DOI Listing
October 2020

Phylogeography of SARS-CoV-2 pandemic in Spain: a story of multiple introductions, micro-geographic stratification, founder effects, and super-spreaders.

Zool Res 2020 Nov;41(6):605-620

Unidade de Xenética, Instituto de Ciencias Forenses (INCIFOR), Facultade de Medicina, Universidade de Santiago de Compostela, and GenPoB Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario de Santiago (SERGAS), Galicia 15706, Spain.

Spain has been one of the main global pandemic epicenters for coronavirus disease 2019 (COVID-19). Here, we analyzed >41 000 genomes (including >26 000 high-quality (HQ) genomes) downloaded from the GISAID repository, including 1 245 (922 HQ) sampled in Spain. The aim of this study was to investigate genome variation of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and reconstruct phylogeographic and transmission patterns in Spain. Phylogeographic analysis suggested at least 34 independent introductions of SARS-CoV-2 to Spain at the beginning of the outbreak. Six lineages spread very successfully in the country, probably favored by super-spreaders, namely, A2a4 (7.8%), A2a5 (38.4%), A2a10 (2.8%), B3a (30.1%), and B9 (8.7%), which accounted for 87.9% of all genomes in the Spanish database. One distinct feature of the Spanish SARS-CoV-2 genomes was the higher frequency of B lineages (39.3%, mainly B3a+B9) than found in any other European country. While B3a, B9, (and an important sub-lineage of A2a5, namely, A2a5c) most likely originated in Spain, the other three haplogroups were imported from other European locations. The B3a strain may have originated in the Basque Country from a B3 ancestor of uncertain geographic origin, whereas B9 likely emerged in Madrid. The time of the most recent common ancestor (TMRCA) of SARS-CoV-2 suggested that the first coronavirus entered the country around 11 February 2020, as estimated from the TMRCA of B3a, the first lineage detected in the country. Moreover, earlier claims that the D614G mutation is associated to higher transmissibility is not consistent with the very high prevalence of COVID-19 in Spain when compared to other countries with lower disease incidence but much higher frequency of this mutation (56.4% in Spain vs. 82.4% in rest of Europe). Instead, the data support a major role of genetic drift in modeling the micro-geographic stratification of virus strains across the country as well as the role of SARS-CoV-2 super-spreaders.
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http://dx.doi.org/10.24272/j.issn.2095-8137.2020.217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671907PMC
November 2020

Reply to "Diagnostic criteria sets sensitivity".

J Allergy Clin Immunol Pract 2020 09;8(8):2840-2841.e1

Genetics, Vaccines, Infectious Diseases and Pediatric research group (GENVIP), Institute of Healthcare Research (IDIS), Hospital Clinico Universitario de Santiago de Compostela, Santiago de Compostela, Spain.

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http://dx.doi.org/10.1016/j.jaip.2020.05.038DOI Listing
September 2020

Mapping genome variation of SARS-CoV-2 worldwide highlights the impact of COVID-19 super-spreaders.

Genome Res 2020 10 2;30(10):1434-1448. Epub 2020 Sep 2.

Unidade de Xenética, Instituto de Ciencias Forenses (INCIFOR), Facultade de Medicina, Universidade de Santiago de Compostela, and GenPoB Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario de Santiago (SERGAS), 15706, Galicia, Spain.

The human pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the major pandemic of the twenty-first century. We analyzed more than 4700 SARS-CoV-2 genomes and associated metadata retrieved from public repositories. SARS-CoV-2 sequences have a high sequence identity (>99.9%), which drops to >96% when compared to bat coronavirus genome. We built a mutation-annotated reference SARS-CoV-2 phylogeny with two main macro-haplogroups, A and B, both of Asian origin, and more than 160 sub-branches representing virus strains of variable geographical origins worldwide, revealing a rather uniform mutation occurrence along branches that could have implications for diagnostics and the design of future vaccines. Identification of the root of SARS-CoV-2 genomes is not without problems, owing to conflicting interpretations derived from either using the bat coronavirus genomes as an outgroup or relying on the sampling chronology of the SARS-CoV-2 genomes and TMRCA estimates; however, the overall scenario favors haplogroup A as the ancestral node. Phylogenetic analysis indicates a TMRCA for SARS-CoV-2 genomes dating to November 12, 2019, thus matching epidemiological records. Sub-haplogroup A2 most likely originated in Europe from an Asian ancestor and gave rise to subclade A2a, which represents the major non-Asian outbreak, especially in Africa and Europe. Multiple founder effect episodes, most likely associated with super-spreader hosts, might explain COVID-19 pandemic to a large extent.
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http://dx.doi.org/10.1101/gr.266221.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605265PMC
October 2020

Variation in antibiotic prescription rates in febrile children presenting to emergency departments across Europe (MOFICHE): A multicentre observational study.

PLoS Med 2020 08 19;17(8):e1003208. Epub 2020 Aug 19.

Department of General Paediatrics, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.

Background: The prescription rate of antibiotics is high for febrile children visiting the emergency department (ED), contributing to antimicrobial resistance. Large studies at European EDs covering diversity in antibiotic and broad-spectrum prescriptions in all febrile children are lacking. A better understanding of variability in antibiotic prescriptions in EDs and its relation with viral or bacterial disease is essential for the development and implementation of interventions to optimise antibiotic use. As part of the PERFORM (Personalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union) project, the MOFICHE (Management and Outcome of Fever in Children in Europe) study aims to investigate variation and appropriateness of antibiotic prescription in febrile children visiting EDs in Europe.

Methods And Findings: Between January 2017 and April 2018, data were prospectively collected on febrile children aged 0-18 years presenting to 12 EDs in 8 European countries (Austria, Germany, Greece, Latvia, the Netherlands [n = 3], Spain, Slovenia, United Kingdom [n = 3]). These EDs were based in university hospitals (n = 9) or large teaching hospitals (n = 3). Main outcomes were (1) antibiotic prescription rate; (2) the proportion of antibiotics that were broad-spectrum antibiotics; (3) the proportion of antibiotics of appropriate indication (presumed bacterial), inappropriate indication (presumed viral), or inconclusive indication (unknown bacterial/viral or other); (4) the proportion of oral antibiotics of inappropriate duration; and (5) the proportion of antibiotics that were guideline-concordant in uncomplicated urinary and upper and lower respiratory tract infections (RTIs). We determined variation of antibiotic prescription and broad-spectrum prescription by calculating standardised prescription rates using multilevel logistic regression and adjusted for general characteristics (e.g., age, sex, comorbidity, referral), disease severity (e.g., triage level, fever duration, presence of alarming signs), use and result of diagnostics, and focus and cause of infection. In this analysis of 35,650 children (median age 2.8 years, 55% male), overall antibiotic prescription rate was 31.9% (range across EDs: 22.4%-41.6%), and among those prescriptions, the broad-spectrum antibiotic prescription rate was 52.1% (range across EDs: 33.0%-90.3%). After standardisation, differences in antibiotic prescriptions ranged from 0.8 to 1.4, and the ratio between broad-spectrum and narrow-spectrum prescriptions ranged from 0.7 to 1.8 across EDs. Standardised antibiotic prescription rates varied for presumed bacterial infections (0.9 to 1.1), presumed viral infections (0.1 to 3.3), and infections of unknown cause (0.1 to 1.8). In all febrile children, antibiotic prescriptions were appropriate in 65.0% of prescriptions, inappropriate in 12.5% (range across EDs: 0.6%-29.3%), and inconclusive in 22.5% (range across EDs: 0.4%-60.8%). Prescriptions were of inappropriate duration in 20% of oral prescriptions (range across EDs: 4.4%-59.0%). Oral prescriptions were not concordant with the local guideline in 22.3% (range across EDs: 11.8%-47.3%) of prescriptions in uncomplicated RTIs and in 45.1% (range across EDs: 11.1%-100%) of prescriptions in uncomplicated urinary tract infections. A limitation of our study is that the included EDs are not representative of all febrile children attending EDs in that country.

Conclusions: In this study, we observed wide variation between European EDs in prescriptions of antibiotics and broad-spectrum antibiotics in febrile children. Overall, one-third of prescriptions were inappropriate or inconclusive, with marked variation between EDs. Until better diagnostics are available to accurately differentiate between bacterial and viral aetiologies, implementation of antimicrobial stewardship guidelines across Europe is necessary to limit antimicrobial resistance.
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http://dx.doi.org/10.1371/journal.pmed.1003208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444592PMC
August 2020

Role of Monocytes/Macrophages in Covid-19 Pathogenesis: Implications for Therapy.

Infect Drug Resist 2020 22;13:2485-2493. Epub 2020 Jul 22.

Genetics, Vaccines, Infectious Diseases Research Group (GENVIP), Health Research Institute Santiago (IDIS), Hospital Clínico Universitario Santiago de Compostela (SERGAS), Galicia 15706, Spain.

Emerging studies from SARS-CoV-2-infected patients indicate a preponderant role of monocytes/macrophages in the pathogenesis of this viral infection, in a similar way to that previously observed in other coronavirus outbreaks (SARS and MERS). The clinical presentation of severe patients resembles viral-associated hemophagocytic syndrome, a rare condition previously seen during lethal influenza pandemics and during previous SARS and MERS coronavirus outbreaks. SARS-CoV-2 infection triggers an over-exuberant inflammatory response due to the development of a cytokine storm and the depletion of the adaptative immune compartment, which may prelude sepsis in many cases. The present review summarizes past evidence on the role of monocytes/macrophages in previous coronavirus outbreaks and the emerging knowledge on their role in COVID-19 pathogenesis. Treatment strategies incorporating the blockade of migration and differentiation of monocyte-macrophage, such as granulocyte macrophage-colony stimulating factor inhibitors, might enhance the promising results seen so far with selective cytokine blockade.
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http://dx.doi.org/10.2147/IDR.S258639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383015PMC
July 2020

Respiratory Syncytial Virus Consortium in Europe (RESCEU) Birth Cohort Study: Defining the Burden of Infant Respiratory Syncytial Virus Disease in Europe.

J Infect Dis 2020 10;222(Suppl 7):S606-S612

Department of Paediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital/University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants worldwide. Although prematurity and cardiopulmonary disease are risk factors for severe disease, the majority of infants hospitalized with RSV are previously healthy. Various vaccines and therapeutics are under development and expected to be available in the near future. To inform the use of these new vaccines and therapeutics, it is necessary to determine the burden of RSV disease in Europe. We will prospectively follow-up a birth cohort to obtain incidence data on RSV acute respiratory tract infection (ARTI).

Methods: Multicenter prospective study of a birth cohort consisting of 10 000 healthy infants, recruited during 3 consecutive years. RSV associated hospitalization in the first year of life will be determined by questionnaires and hospital chart reviews. A nested cohort of 1000 infants will be actively followed. In case of ARTI, a respiratory sample will be collected for RSV molecular diagnosis.

Results: The primary outcome is the incidence rate of RSV-associated hospitalization in the first year of life. In the active cohort the primary outcome is RSV associated ARTI and MA-ARTI.

Conclusions: We will provide key information to fill the gaps in knowledge about the burden of RSV disease in healthy infants.

Clinical Trials Registration: NCT03627572.
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http://dx.doi.org/10.1093/infdis/jiaa310DOI Listing
October 2020

Presumed Risk Factors and Biomarkers for Severe Respiratory Syncytial Virus Disease and Related Sequelae: Protocol for an Observational Multicenter, Case-Control Study From the Respiratory Syncytial Virus Consortium in Europe (RESCEU).

J Infect Dis 2020 10;222(Suppl 7):S658-S665

Department of Paediatrics, Oxford Vaccine Group, Oxford, United Kingdom.

Respiratory syncytial virus (RSV) is the leading viral pathogen associated with acute lower respiratory tract infection and hospitalization in children < 5 years of age worldwide. While there are known clinical risk factors for severe RSV infection, the majority of those hospitalized are previously healthy infants. There is consequently an unmet need to identify biomarkers that predict host response, disease severity, and sequelae. The primary objective is to identify biomarkers of severe RSV acute respiratory tract infection (ARTI) in infants. Secondary objectives include establishing biomarkers associated with respiratory sequelae following RSV infection and characterizing the viral load, RSV whole-genome sequencing, host immune response, and transcriptomic, proteomic, metabolomic and epigenetic signatures associated with RSV disease severity. Six hundred thirty infants will be recruited across 3 European countries: the Netherlands, Spain, and the United Kingdom. Participants will be recruited into 2 groups: (1) infants with confirmed RSV ARTI (includes upper and lower respiratory tract infections), 500 without and 50 with comorbidities; and (2) 80 healthy controls. At baseline, participants will have nasopharyngeal, blood, buccal, stool, and urine samples collected, plus complete a questionnaire and 14-day symptom diary. At convalescence (7 weeks ± 1 week post-ARTI), specimen collection will be repeated. Laboratory measures will be correlated with symptom severity scores to identify corresponding biomarkers of disease severity.

Clinical Trials Registration: NCT03756766.
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http://dx.doi.org/10.1093/infdis/jiaa239DOI Listing
October 2020

Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood.

Front Pediatr 2020 22;8:355. Epub 2020 Jul 22.

Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.

Kawasaki disease (KD) is a vasculitis of early childhood mimicking several infectious diseases. Differentiation between KD and infectious diseases is essential as KD's most important complication-the development of coronary artery aneurysms (CAA)-can be largely avoided by timely treatment with intravenous immunoglobulins (IVIG). Currently, KD diagnosis is only based on clinical criteria. The aim of this study was to evaluate whether routine C-reactive protein (CRP) and additional inflammatory parameters myeloid-related protein 8/14 (MRP8/14 or S100A8/9) and human neutrophil-derived elastase (HNE) could distinguish KD from infectious diseases. The cross-sectional study included KD patients and children with proven infections as well as febrile controls. Patients were recruited between July 2006 and December 2018 in Europe and USA. MRP8/14, CRP, and HNE were assessed for their discriminatory ability by multiple logistic regression analysis with backward selection and receiver operator characteristic (ROC) curves. In the discovery cohort, the combination of MRP8/14+CRP discriminated KD patients ( = 48) from patients with infection ( = 105), with area under the ROC curve (AUC) of 0.88. The HNE values did not improve discrimination. The first validation cohort confirmed the predictive value of MRP8/14+CRP to discriminate acute KD patients ( = 26) from those with infections ( = 150), with an AUC of 0.78. The second validation cohort of acute KD patients ( = 25) and febrile controls ( = 50) showed an AUC of 0.72, which improved to 0.84 when HNE was included. When used in combination, the plasma markers MRP8/14, CRP, and HNE may assist in the discrimination of KD from both proven and suspected infection.
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http://dx.doi.org/10.3389/fped.2020.00355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388698PMC
July 2020

TIPICO X: report of the 10th interactive infectious disease workshop on infectious diseases and vaccines.

Hum Vaccin Immunother 2021 Mar 5;17(3):759-772. Epub 2020 Aug 5.

Translational Paediatrics and Infectious Diseases, Department of Paediatrics, Hospital Clínico Universitario De Santiago De Compostela, Santiago De Compostela, Spain.

TIPICO is an expert meeting and workshop that aims to provide the most recent evidence in the field of infectious diseases and vaccination. The 10th Interactive Infectious Disease TIPICO workshop took place in Santiago de Compostela, Spain, on November 21-22, 2019. Cutting-edge advances in vaccination against respiratory syncytial virus, , rotavirus, human papillomavirus, , influenza virus, and Typhi were discussed. Furthermore, heterologous vaccine effects were updated, including the use of Bacillus Calmette-Guérin (BCG) vaccine as potential treatment for type 1 diabetes. Finally, the workshop also included presentations and discussion on emergent virus and zoonoses, vaccine resilience, building and sustaining confidence in vaccination, approaches to vaccine decision-making, pros and cons of compulsory vaccination, the latest advances in decoding infectious diseases by RNA gene signatures, and the application of big data approaches.
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http://dx.doi.org/10.1080/21645515.2020.1788301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996078PMC
March 2021

Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants.

N Engl J Med 2020 07;383(5):426-439

From the Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, and the Department of Science and Technology-National Research Foundation, Vaccine Preventable Diseases, University of the Witwatersrand (S.A.M., C.L.C.), and Shandukani Research Centre, Wits Reproductive Health and HIV Institute (M.S.M.), Johannesburg, Setshaba Research Centre, Soshanguve (K.A., A.O.), and the Family Centre for Research with Ubuntu, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg Hospital (M.F.C.), and the Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, South African Medical Research Council Unit on Child and Adolescent Health, University of Cape Town (H.J.Z.), Cape Town - all in South Africa; Fundación INFANT (F.P.P., R.L.), Hospital Militar Central Dr. Cosme Argerich (G.P.M.), and the National Scientific and Technical Research Council (R.L.), Buenos Aires, and the Department of Pediatric Pulmonology, Hospital del Niño Jesús, Tucumán (C.J.L.) - both in Argentina; the Departments of Pediatrics and Molecular Virology and Microbiology, Baylor College of Medicine, Houston (P.A.P., F.M.M.); the University of Auckland, Middlemore Hospital, Auckland, New Zealand (A.A.T.); the Department of Pediatrics, University of Colorado School of Medicine, and the Children's Hospital Colorado, Center for Global Health, Colorado School of Public Health, Aurora (E.A.F.S.); the Department of Obstetrics and Gynecology, Duke University, Durham, NC (G.K.S.); Novavax (S.A., A.A., J.C., I.C., A.F., J.S.P., V.S., D.N.T., J.W., G.M.G., L.F.F.), Gaithersburg, and the Department of International Health, International Center for Maternal and Newborn Health (A.H.B.), and the Center for American Indian Health, Department of International Health (L.H.), Johns Hopkins Bloomberg School of Public Health, Baltimore - all in Maryland; the Vaccine Institute (A.C., P.T.H.) and the Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute (A.K.), St. George's, University of London, London, Paediatric Infectious Diseases, Clinical and Experimental Sciences, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton (C.E.J.), and the Oxford Vaccine Group, Department of Paediatrics, University of Oxford and National Institute for Health Research Oxford Biomedical Research Centre (M.D.S.), and the Nuffield Department of Women's and Reproductive Health, University of Oxford (M.V.), Oxford - all in the United Kingdom; the Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle (J.A.E.);the Department of Obstetrics and Gynecology, Wayne State University, Detroit (B.G.); the Research Institute for Tropical Medicine, Muntinlupa, Philippines (J.N.J., M.L.); the Department of Pediatrics (D.W.K.) and the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology and Center for Women's Reproductive Health (A.T.T.), University of Alabama, Birmingham; the Women's and Children's Hospital and Robinson Research Institute, University of Adelaide, Adelaide, SA (H.S.M.), the Melbourne School of Population and Global Health, University of Melbourne, and Murdoch Children's Research Institute, Parkville, VIC (T.M.N., K.P.P.), and Wesfarmers Center of Vaccines and Infectious Diseases, Telethon Kids Institute, Division of Paediatrics, School of Medicine, University of Western Australia, Perth Children's Hospital, Perth (P.C.R., T.S.) - all in Australia; Marshfield Clinic Research Institute, Marshfield, WI (J.K.M.); Pediatría Clínica, Infectología y Traslacional Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain (F.M.-T.); the Division of General Pediatrics, Department of Pediatrics, School of Medicine (J.H.S.), and the Department of Obstetrics and Gynecology (M.W.V.), University of Utah Health Sciences Center, Salt Lake City; Meridian Clinical Research, Norfolk, NE (K.V.); and the International Center for Diarrhoeal Disease Research Bangladesh, Dhaka (K.Z.).

Background: Respiratory syncytial virus (RSV) is the dominant cause of severe lower respiratory tract infection in infants, with the most severe cases concentrated among younger infants.

Methods: Healthy pregnant women, at 28 weeks 0 days through 36 weeks 0 days of gestation, with an expected delivery date near the start of the RSV season, were randomly assigned in an overall ratio of approximately 2:1 to receive a single intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo. Infants were followed for 180 days to assess outcomes related to lower respiratory tract infection and for 364 days to assess safety. The primary end point was RSV-associated, medically significant lower respiratory tract infection up to 90 days of life, and the primary analysis of vaccine efficacy against the primary end point was performed in the per-protocol population of infants (prespecified criterion for success, lower bound of the 97.52% confidence interval [CI] of ≥30%).

Results: A total of 4636 women underwent randomization, and there were 4579 live births. During the first 90 days of life, the percentage of infants with RSV-associated, medically significant lower respiratory tract infection was 1.5% in the vaccine group and 2.4% in the placebo group (vaccine efficacy, 39.4%; 97.52% CI, -1.0 to 63.7; 95% CI, 5.3 to 61.2). The corresponding percentages for RSV-associated lower respiratory tract infection with severe hypoxemia were 0.5% and 1.0% (vaccine efficacy, 48.3%; 95% CI, -8.2 to 75.3), and the percentages for hospitalization for RSV-associated lower respiratory tract infection were 2.1% and 3.7% (vaccine efficacy, 44.4%; 95% CI, 19.6 to 61.5). Local injection-site reactions among the women were more common with vaccine than with placebo (40.7% vs. 9.9%), but the percentages of participants who had other adverse events were similar in the two groups.

Conclusions: RSV F protein nanoparticle vaccination in pregnant women did not meet the prespecified success criterion for efficacy against RSV-associated, medically significant lower respiratory tract infection in infants up to 90 days of life. The suggestion of a possible benefit with respect to other end-point events involving RSV-associated respiratory disease in infants warrants further study. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov NCT02624947.).
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http://dx.doi.org/10.1056/NEJMoa1908380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299433PMC
July 2020