Publications by authors named "Saul N Faust"

140 Publications

Mycotic aneurysm presenting as hip pain and severe anaemia.

Arch Dis Child 2021 Apr 14. Epub 2021 Apr 14.

Paediatric Immunology and Infectious diseases, Southampton University NHS Foundation Trust, Southampton, UK.

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http://dx.doi.org/10.1136/archdischild-2021-321632DOI Listing
April 2021

Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial.

Lancet 2021 04 30;397(10282):1351-1362. Epub 2021 Mar 30.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.

Background: A new variant of SARS-CoV-2, B.1.1.7, emerged as the dominant cause of COVID-19 disease in the UK from November, 2020. We report a post-hoc analysis of the efficacy of the adenoviral vector vaccine, ChAdOx1 nCoV-19 (AZD1222), against this variant.

Methods: Volunteers (aged ≥18 years) who were enrolled in phase 2/3 vaccine efficacy studies in the UK, and who were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 or a meningococcal conjugate control (MenACWY) vaccine, provided upper airway swabs on a weekly basis and also if they developed symptoms of COVID-19 disease (a cough, a fever of 37·8°C or higher, shortness of breath, anosmia, or ageusia). Swabs were tested by nucleic acid amplification test (NAAT) for SARS-CoV-2 and positive samples were sequenced through the COVID-19 Genomics UK consortium. Neutralising antibody responses were measured using a live-virus microneutralisation assay against the B.1.1.7 lineage and a canonical non-B.1.1.7 lineage (Victoria). The efficacy analysis included symptomatic COVID-19 in seronegative participants with a NAAT positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to vaccine received. Vaccine efficacy was calculated as 1 - relative risk (ChAdOx1 nCoV-19 vs MenACWY groups) derived from a robust Poisson regression model. This study is continuing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137.

Findings: Participants in efficacy cohorts were recruited between May 31 and Nov 13, 2020, and received booster doses between Aug 3 and Dec 30, 2020. Of 8534 participants in the primary efficacy cohort, 6636 (78%) were aged 18-55 years and 5065 (59%) were female. Between Oct 1, 2020, and Jan 14, 2021, 520 participants developed SARS-CoV-2 infection. 1466 NAAT positive nose and throat swabs were collected from these participants during the trial. Of these, 401 swabs from 311 participants were successfully sequenced. Laboratory virus neutralisation activity by vaccine-induced antibodies was lower against the B.1.1.7 variant than against the Victoria lineage (geometric mean ratio 8·9, 95% CI 7·2-11·0). Clinical vaccine efficacy against symptomatic NAAT positive infection was 70·4% (95% CI 43·6-84·5) for B.1.1.7 and 81·5% (67·9-89·4) for non-B.1.1.7 lineages.

Interpretation: ChAdOx1 nCoV-19 showed reduced neutralisation activity against the B.1.1.7 variant compared with a non-B.1.1.7 variant in vitro, but the vaccine showed efficacy against the B.1.1.7 variant of SARS-CoV-2.

Funding: UK Research and Innovation, National Institute for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.
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http://dx.doi.org/10.1016/S0140-6736(21)00628-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009612PMC
April 2021

COVID-19 symptom surveillance in immunocompromised children and young people in the UK: a prospective observational cohort study.

BMJ Open 2021 03 17;11(3):e044899. Epub 2021 Mar 17.

NIHR Southampton Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton, UK

Objectives: To describe the frequency of symptoms compatible with SARS-CoV-2 infection in immunocompromised children and young people in the UK during the SARS-CoV-2 pandemic. To describe patient/parent anxiety regarding SARS-CoV-2 infection in this cohort.

Design: A prospective observational cohort study.

Setting: 46 centres across the UK between 16 March and 4 July 2020. A weekly online questionnaire based on the International Severe Acute Respiratory and emerging Infections Consortium-WHO Case Report Form was used to collect participant reported data on symptoms, test results, National Health Service attendance, hospital admission and impact on daily life.

Participants: 1490 immunocompromised children, defined as those requiring an annual influenza vaccination due to their underlying condition or medication.

Main Outcome Measures: Incidence of SARS-CoV-2-like symptoms and patient/parent anxiety score.

Results: Over 16 weeks during the first wave of the pandemic, no SARS-CoV-2 infection was diagnosed in this large immunocompromised paediatric cohort (median age 11 years, 54.4% female). 110 symptomatic participants underwent a test for SARS-CoV-2; all were negative. 922 (67.4%) participants reported at least one symptom consistent with suspected SARS-CoV-2 infection over the study period. 476 (34.8%) reported three or more symptoms. The most frequently reported symptoms included joint pain, fatigue, headache, nausea and muscle pain. SARS-CoV-2 testing during this period was performed on admitted patients only. 137 participants had their medication suspended or changed during the study period due to assumed COVID-19 disease risk. 62% reported high levels of anxiety (scores of 7-10 out of 10) at the start of the study, with anxiety levels remaining high throughout the study period.

Conclusions: Although symptoms related to SARS-CoV-2 infection in children were common, there were no positive tests in this large immunocompromised cohort. Symptom-based screening to facilitate early detection of SARS-CoV-2 infection may not be helpful in these individuals. Patient/parent anxiety about SARS-CoV-2 infection was high.

Trial Registration Number: NCT04382508.
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http://dx.doi.org/10.1136/bmjopen-2020-044899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977081PMC
March 2021

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

Lancet 2021 03 19;397(10277):881-891. Epub 2021 Feb 19.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. Electronic address:

Background: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered.

Methods: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 10 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 10 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005).

Findings: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]).

Interpretation: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose.

Funding: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
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http://dx.doi.org/10.1016/S0140-6736(21)00432-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894131PMC
March 2021

Research Evaluation Alongside Clinical Treatment in COVID-19 (REACT COVID-19): an observational and biobanking study.

BMJ Open 2021 01 22;11(1):e043012. Epub 2021 Jan 22.

Faculty of Medicine, University of Southampton, Southampton, UK.

Introduction: The COVID-19 pandemic caused by SARS-CoV-2 places immense worldwide demand on healthcare services. Earlier identification of patients at risk of severe disease may allow intervention with experimental targeted treatments, mitigating the course of their disease and reducing critical care service demand.

Methods And Analysis: This prospective observational study of patients tested or treated for SARS-CoV-2, who are under the care of the tertiary University Hospital Southampton NHS Foundation Trust (UHSFT), captured data from admission to discharge; data collection commenced on 7 March 2020. Core demographic and clinical information, as well as results of disease-defining characteristics, was captured and recorded electronically from hospital clinical record systems at the point of testing. Manual data were collected and recorded by the clinical research team for assessments which are not part of the structured electronic healthcare record, for example, symptom onset date. Thereafter, participant records were continuously updated during hospital stay and their follow-up period. Participants aged >16 years were given the opportunity to provide consent for excess clinical sample storage with optional further biological sampling. These anonymised samples were linked to the clinical data in the Real-time Analytics for Clinical Trials platform and were stored within a biorepository at UHSFT.

Ethics And Dissemination: Ethical approval was obtained from the HRA Specific Review Board (REC 20/HRA/2986) for waiver of informed consent for the database-only cohort; the procedures conform with the Declaration of Helsinki. The study design, protocol and patient-facing documentation for the biobanking arm of the study have been approved by North West Research Ethics Committee (REC 17/NW/0632) as an amendment to the National Institute for Health Research Southampton Clinical Research Facility-managed Southampton Research Biorepository. This study will be published as peer-reviewed articles and presented at conferences, presentations and workshops.
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http://dx.doi.org/10.1136/bmjopen-2020-043012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830323PMC
January 2021

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

Lancet 2021 01 8;397(10269):99-111. Epub 2020 Dec 8.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. Electronic address:

Background: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials.

Methods: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 10 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674.

Findings: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; p=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation.

Interpretation: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials.

Funding: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
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http://dx.doi.org/10.1016/S0140-6736(20)32661-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723445PMC
January 2021

Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial.

Lancet 2021 12 19;396(10267):1979-1993. Epub 2020 Nov 19.

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

Background: Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19 (AZD1222), in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older.

Methods: In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18-55 years, 56-69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 10 virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18-55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56-69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5-6·5 × 10 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18-55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137.

Findings: Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18-55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56-69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18-55 years group, 22 (73%) of 30 in the 56-69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18-55 years group, 23 (77%) in the 56-69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18-55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898-33 550], n=39; 56-69 years, 16 170 AU/mL [10 233-40 353], n=26; and ≥70 years 17 561 AU/mL [9705-37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA at day 42 in the standard-dose groups: 18-55 years, 193 [IQR 113-238], n=39; 56-69 years, 144 [119-347], n=20; and ≥70 years, 161 [73-323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18-55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841-2428], n=24; 56-69 years: 797 SFCs [383-1817], n=29; and ≥70 years: 977 SFCs [458-1914], n=48).

Interpretation: ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities.

Funding: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.
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http://dx.doi.org/10.1016/S0140-6736(20)32466-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674972PMC
December 2021

Evaluating Ceftriaxone 80 mg/kg Administration by Rapid Intravenous Infusion-A Clinical Service Evaluation.

Pediatr Infect Dis J 2021 Feb;40(2):128-129

NIHR Southampton Clinical Research Facility and NIHR Southampton Biomedical Research Centre.

In pediatric ambulatory care, the speed of medication infusion can have major impact on healthcare staff workload and the number of children able to be treated by services designed to reduce inpatient length of stay. In many regions of the world, local and supraregional guidelines allow ceftriaxone infusions of ≥50 mg/kg in infants and children up to 12 years of age to be given over 10 minutes. The generic European summary of product characteristics for ceftriaxone does not state a specific infusion time for this dose range, although 1 manufacturers' summary of product characteristics in the United Kingdom states a 30-minute minimum infusion time. We conducted a formal service evaluation of a change in practice at a large UK pediatric children's hospital and demonstrated the clinical feasibility, safety, and high parent satisfaction of 10-minute ceftriaxone infusions for prescribed doses ≥50 mg/kg. This approach can improve patient flow within hospital-based ambulatory services as well as by community nursing teams administering antibiotics at home.
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http://dx.doi.org/10.1097/INF.0000000000002923DOI Listing
February 2021

'Be on the TEAM' Study (Teenagers Against Meningitis): protocol for a controlled clinical trial evaluating the impact of 4CMenB or MenB-fHbp vaccination on the pharyngeal carriage of meningococci in adolescents.

BMJ Open 2020 10 22;10(10):e037358. Epub 2020 Oct 22.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.

Introduction: Capsular group B (MenB) is the most common cause of invasive meningococcal disease (IMD) in many parts of the world. A MenB vaccine directed against the polysaccharide capsule remains elusive due to poor immunogenicity and safety concerns. The vaccines licensed for the prevention of MenB disease, 4CMenB (Bexsero) and MenB-fHbp (Trumenba), are serogroup B 'substitute' vaccines, comprised of subcapsular proteins and are designed to provide protection against most MenB disease-causing strains. In many high-income countries, such as the UK, adolescents are at increased risk of IMD and have the highest rates of meningococcal carriage. Beginning in the late 1990s, immunisation of this age group with the meningococcal group C conjugate vaccine reduced asymptomatic carriage and disrupted transmission of this organism, resulting in lower group C IMD incidence across all age groups. Whether vaccinating teenagers with the novel 'MenB' protein-based vaccines will prevent acquisition or reduce duration of carriage and generate herd protection was unknown at the time of vaccine introduction and could not be inferred from the effects of the conjugate vaccines. 4CMenB and MenB-fHbp may also impact on non-MenB disease-causing capsular groups as well as commensal spp. This study will evaluate the impact of vaccination with 4CMenB or MenB-fHbp on oropharyngeal carriage of pathogenic meningococci in teenagers, and consequently the potential for these vaccines to provide broad community protection against MenB disease.

Methods And Analysis: The 'Be on the TEAM' (Teenagers Against Meningitis) Study is a pragmatic, partially randomised controlled trial of 24 000 students aged 16-19 years in their penultimate year of secondary school across the UK with regional allocation to a 0+6 month schedule of 4CMenB or MenB-fHbp or to a control group. Culture-confirmed oropharyngeal carriage will be assessed at baseline and at 12 months, following which the control group will be eligible for 4CMenB vaccination. The primary outcome is the carriage prevalence of potentially pathogenic meningococci (defined as those with genogroups B, C, W, Y or X), in each vaccine group compared separately to the control group at 12 months post-enrolment, that is, 12 months after the first vaccine dose and 6 months after the second vaccine dose. Secondary outcomes include impact on carriage of: genogroup B meningococci; hyperinvasive meningococci; all meningococci; those meningococci expressing vaccine antigens and; other spp. A sample size of 8000 in each arm will provide 80% power to detect a 30% reduction in meningococcal carriage, assuming genogroup B, C, W, Y or X meningococci carriage of 3.43%, a design effect of 1.5, a retention rate of 80% and a significance level of 0.05. Study results will be available in 2021 and will inform the UK and international immunisation policy and future vaccine development.

Ethics And Dissemination: This study is approved by the National Health Service South Central Research Ethics Committee (18/SC/0055); the UK Health Research Authority (IRAS ID 239091) and the UK Medicines and Healthcare products Regulatory Agency. Publications arising from this study will be submitted to peer-reviewed journals. Study results will be disseminated in public forums, online, presented at local and international conferences and made available to the participating schools.

Trial Registration Numbers: ISRCTN75858406; Pre-results, EudraCT 2017-004609-42.
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http://dx.doi.org/10.1136/bmjopen-2020-037358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583083PMC
October 2020

Problem-solving in clinical practice: Persisting respiratory distress in a premature infant.

Arch Dis Child Educ Pract Ed 2020 Oct 19. Epub 2020 Oct 19.

Paediatric Infectious Diseases and Immunology, University Hospital Southampton NHS Foundation Trust, Southampton, UK

The deterioration of a previously stable preterm infant is a common scenario on the neonatal unit. The the most common bacterial causes of deterioration are nosocomial infections, such as coagulase-negative and Non-infective conditions such as pulmonary haemorrhage, anaemia of prematurity and necrotising enterocolitis may also cause preterm infants to deteriorate. This case chronicles the unusual diagnostic journey of an infant born at 27+1 weeks who deteriorated at 26 days of life and did not respond to antimicrobial therapy as anticipated.
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http://dx.doi.org/10.1136/archdischild-2019-317757DOI Listing
October 2020

Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19.

N Engl J Med 2020 Nov 8;383(21):2030-2040. Epub 2020 Oct 8.

The affiliations of the members of the writing committee are as follows: the Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine (P.H., J.T., J.A.W., N.J.W.), Nuffield Department of Population Health (M.M., L.L., J.L.B., N.S., J.R.E., E.J., R.H., M.J.L.), the Medical Research Council (MRC) Population Health Research Unit (N.S., J.R.E., R.H., M.J.L.), University of Oxford, the Oxford University Hospitals NHS Foundation Trust (K.J., M.J.L.), and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (M.J.L.), Oxford, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester (M.W.), the Regional Infectious Diseases Unit, North Manchester General Hospital (A.U.), University of Manchester (A.U., T.F.), and Manchester University NHS Foundation Trust (T.F.), Manchester, the Research and Development Department, Northampton General Hospital, Northampton (E.E.), the Department of Respiratory Medicine, North Tees and Hartlepool NHS Foundation Trust, Stockton-on-Tees (B.P.), University Hospitals Birmingham NHS Foundation Trust and Institute of Microbiology and Infection, University of Birmingham, Birmingham (T.W.), James Cook University Hospital, Middlesbrough (J.W.), North West Anglia NHS Foundation Trust, Peterborough (J.F.), the Department of Infectious Diseases, Cardiff and Vale University Health Board, and the Division of Infection and Immunity, Cardiff University, Cardiff (J.U.), Roslin Institute, University of Edinburgh, Edinburgh (J.K.B.), the School of Life Course Sciences, King's College London (L.C.C.), and the Intensive Care National Audit and Research Centre (K.R.), London, the NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton (S.N.F.), the Department of Mathematics and Statistics, Lancaster University, Lancaster (T.J.), the MRC Biostatistics Unit, University of Cambridge, Cambridge (T.J.), and the Respiratory Medicine Department, Nottingham University Hospitals NHS Trust (W.S.L.), and the School of Medicine, University of Nottingham (A.M., E.J.), Nottingham - all in the United Kingdom; and the Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand (J.T., J.A.W., N.J.W.).

Background: Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (Covid-19) on the basis of in vitro activity and data from uncontrolled studies and small, randomized trials.

Methods: In this randomized, controlled, open-label platform trial comparing a range of possible treatments with usual care in patients hospitalized with Covid-19, we randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive usual care. The primary outcome was 28-day mortality.

Results: The enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, after an interim analysis determined that there was a lack of efficacy. Death within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P = 0.15). Consistent results were seen in all prespecified subgroups of patients. The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03 to 1.27). There was a small numerical excess of cardiac deaths (0.4 percentage points) but no difference in the incidence of new major cardiac arrhythmia among the patients who received hydroxychloroquine.

Conclusions: Among patients hospitalized with Covid-19, those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care. (Funded by UK Research and Innovation and National Institute for Health Research and others; RECOVERY ISRCTN number, ISRCTN50189673; ClinicalTrials.gov number, NCT04381936.).
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http://dx.doi.org/10.1056/NEJMoa2022926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556338PMC
November 2020

COVID-19 in children: current evidence and key questions.

Curr Opin Infect Dis 2020 12;33(6):540-547

NIHR Southampton Clinical Research Facility and NIHR Southampton Biomedical Research Unit, University Hospital Southampton NHS Foundation Trust.

Purpose Of Review: SARS-CoV-2 infection in children has been less well characterized than in adults, primarily due to a significantly milder clinical phenotype meaning many cases have gone undocumented by health professionals or researchers. This review outlines the current evidence of the epidemiology of infection in children, the clinical manifestations of disease, the role of children in transmission of the virus and the recently described hyperinflammatory syndrome observed later during the first phase of the pandemic.

Recent Findings: International seroprevalence studies have found younger children to have lower prevalence of antibodies to SARS-CoV-2, indicating they have not been infected as much as adults. This may be due to shielding by school closures, or by a reduced susceptibility to infection, as indicated by a significantly lower attack rate in children than adults in household contact tracing studies. The most well recognized symptoms in adults of cough, fever, anosmia and ageusia are less frequent in children, who may often present with mild and nonspecific symptoms, or with gastrointestinal symptoms alone. Risk factors for severe disease in children include chronic lung, cardiac or neurological disease, and malignancy. However, the absolute risk still appears very low for these cohorts. A new hyperinflammatory syndrome has emerged with an apparent immune cause.

Summary: Important questions remain unanswered regarding why children have mild disease compared with adults; how children of different ages contribute to asymptomatic community transmission of the virus; and the pathophysiology of and most appropriate investigation and treatment strategies for the novel hyperinflammatory syndrome.
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http://dx.doi.org/10.1097/QCO.0000000000000690DOI Listing
December 2020

It's Time to Put Children and Young People First During the Global COVID-19 Pandemic.

JAMA Pediatr 2021 02;175(2):127-128

National Institute of Health Research Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and the University of Southampton, Southampton, United Kingdom.

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http://dx.doi.org/10.1001/jamapediatrics.2020.4582DOI Listing
February 2021

A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process.

Lancet Child Adolesc Health 2021 02 18;5(2):133-141. Epub 2020 Sep 18.

Department of Paediatric Surgery, Alder Hey Children's Hospital, Liverpool, UK; School of Life Sciences, University of Liverpool, Liverpool, UK; NHS England/Improvement, Redditch, UK.

Paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS) is a novel condition that was first reported in April, 2020. We aimed to develop a national consensus management pathway for the UK to provide guidance for clinicians caring for children with PIMS-TS. A three-phase online Delphi process and virtual consensus meeting sought consensus over the investigation, management, and research priorities from multidisciplinary clinicians caring for children with PIMS-TS. We used 140 consensus statements to derive a consensus management pathway that describes the initial investigation of children with suspected PIMS-TS, including blood markers to help determine the severity of disease, an echocardiogram, and a viral and septic screen to exclude other infectious causes of illness. The importance of a multidisciplinary team in decision making for children with PIMS-TS is highlighted throughout the guidance, along with the recommended treatment options, including supportive care, intravenous immunoglobulin, methylprednisolone, and biological therapies. These include IL-1 antagonists (eg, anakinra), IL-6 receptor blockers (eg, tocilizumab), and anti-TNF agents (eg, infliximab) for children with Kawasaki disease-like phenotype and non-specific presentations. Use of a rapid online Delphi process has made it possible to generate a national consensus pathway in a timely and cost-efficient manner in the middle of a global pandemic. The consensus statements represent the views of UK clinicians and are applicable to children in the UK suspected of having PIMS-TS. Future evidence will inform updates to this guidance, which in the interim provides a solid framework to support clinicians caring for children with PIMS-TS. This process has directly informed new PIMS-TS specific treatment groups as part of the adaptive UK RECOVERY trial protocol, which is the first formal randomised controlled trial of therapies for PIMS-TS globally.
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http://dx.doi.org/10.1016/S2352-4642(20)30304-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500943PMC
February 2021

Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial.

Lancet 2020 08 20;396(10249):467-478. Epub 2020 Jul 20.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK. Electronic address:

Background: The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2.

Methods: We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18-55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 10 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT]; a microneutralisation assay [MNA, MNA, and MNA]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606.

Findings: Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493-1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96-317; n=127), and were boosted following a second dose (639 EU, 360-792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA and in 35 (100%) participants when measured in PRNT. After a booster dose, all participants had neutralising activity (nine of nine in MNA at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R=0·67 by Marburg VN; p<0·001).

Interpretation: ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme.

Funding: UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen.
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http://dx.doi.org/10.1016/S0140-6736(20)31604-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445431PMC
August 2020

Addendum to: Children are not COVID-19 super spreaders: time to go back to school.

Arch Dis Child 2021 02 20;106(2):e9. Epub 2020 Jul 20.

Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, Hampshire, UK.

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http://dx.doi.org/10.1136/archdischild-2020-319908DOI Listing
February 2021

Dexamethasone in Hospitalized Patients with Covid-19.

N Engl J Med 2021 Feb 17;384(8):693-704. Epub 2020 Jul 17.

From the Nuffield Department of Medicine (P.H.), Nuffield Department of Population Health (J.R.E., M.M., J.L.B., L.L., N.S., E.J., R.H., M.J.L.), and MRC Population Health Research Unit (J.R.E., N.S., R.H., M.J.L.), University of Oxford, the Oxford University Hospitals NHS Foundation Trust (K.J.), and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (M.J.L.), Oxford, the Respiratory Medicine Department, Nottingham University Hospitals NHS Trust (W.S.L.), and the School of Medicine, University of Nottingham (A.M.), Nottingham, the Institute for Lung Health, Leicester NIHR Biomedical Research Centre, University of Leicester, Leicester (C.B.), the Regional Infectious Diseases Unit, North Manchester General Hospital and University of Manchester (A.U.), and the University of Manchester and Manchester University NHS Foundation Trust (T.F.), Manchester, the Research and Development Department, Northampton General Hospital, Northampton (E.E.), the Department of Respiratory Medicine, North Tees and Hartlepool NHS Foundation Trust, Stockton-on-Tees (B.P.), University Hospitals Birmingham NHS Foundation Trust and Institute of Microbiology and Infection, University of Birmingham, Birmingham (C.G.), the Centre for Clinical Infection, James Cook University Hospital, Middlesbrough (D.C.), the North West Anglia NHS Foundation Trust, Peterborough (K. Rege), the Department of Research and Development, Cardiff and Vale University Health Board, Cardiff (C.F.), the School of Life Course Sciences, King's College London (L.C.C.), and the Intensive Care National Audit and Research Centre (K. Rowan), London, the NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton (S.N.F.), the Department of Mathematics and Statistics, Lancaster University, Lancaster (T.J.), the MRC Biostatistics Unit, University of Cambridge, Cambridge (T.J.), and Roslin Institute, University of Edinburgh, Edinburgh (J.K.B.) - all in the United Kingdom.

Background: Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.

Methods: In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment.

Results: A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55).

Conclusions: In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.).
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http://dx.doi.org/10.1056/NEJMoa2021436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383595PMC
February 2021

Randomized clinical trial of DTaP5-HB-IPV-Hib vaccine administered concomitantly with meningococcal serogroup C conjugate vaccines during the primary infant series.

Vaccine 2020 07 10;38(35):5718-5725. Epub 2020 Jul 10.

Bristol Children's Vaccine Centre, University of Bristol & University Hospitals Bristol NHS Foundation Trust, Bristol, UK. Electronic address:

Background: Concomitant administration of vaccines simplifies delivery. DTaP5-HB-IPV-Hib is a fully liquid, combination vaccine against 6 diseases. This study evaluated the compatibility of DTaP5-HB-IPV-Hib with 2 different meningococcus group C conjugate (MCC) vaccines in infants.

Methods: In a phase 3, open-label study, 284 healthy infants from 11 UK centres received DTaP5-HB-IPV-Hib at age 2, 3, and 4 months; 13-valent pneumococcal conjugate vaccine (PCV13) at 2 and 4 months; a Haemophilus influenzae type b (Hib)-MCC vaccine and a measles/mumps/rubella vaccine at 12 months. Participants were randomised 1:1 to receive either an MCC-detoxified tetanus toxin vaccine (MCC-TT; n = 141) or an MCC-Corynebacterium diphtheriae CRM protein vaccine (MCC-CRM; n = 143) at 3 and 4 months. The primary outcome was seroprotection rate (SPR) to MCC (percent with rabbit complement serum bactericidal antibody titer ≥8).

Results: Per protocol analysis, MCC SPRs were 100 and 96.4 one month after the first dose, 100 and 99.1 after the second dose, and 100 and 97.3 after the third (booster) dose of MCC in the MCC-TT and MCC-CRM groups, respectively. One month after all 3 doses of DTaP5-HB-IPV-Hib, immunoglobulin G anti-polyribosylribitol phosphate SPRs (% ≥0.15 µg/mL) were 97.8 in the MCC-TT group and 100 in the MCC-CRM group; anti-hepatitis B antigen SPRs (% ≥10 mIU/mL) were 96.8 and 96.3 in the MCC-TT and MCC-CRM groups, respectively. All participants were seroprotected against diphtheria and tetanus (≥0.01 IU/mL) and poliovirus types 1, 2, and 3 (≥8 dilution), and seroresponse rates to all pertussis antigens were ≥90.4%. Two vaccine-related serious adverse events (transient severe abdominal pain and crying) occurred concomitantly in 1 participant in the MCC-CRM group. Adverse event rates were similar to other studies of DTaP5-HB-IPV-Hib, with pyrexia ≥38 °C in 10.9% of participants following any dose.

Conclusions: DTaP5-HB-IPV-Hib can be effectively used in a 2-, 3-, and 4-month infant priming schedule when given with 2 doses of MCC.
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http://dx.doi.org/10.1016/j.vaccine.2020.06.015DOI Listing
July 2020

Non-alcoholic fatty liver disease and childhood obesity.

Arch Dis Child 2021 01 14;106(1):3-8. Epub 2020 May 14.

Department of Paediatric Endocrinology, University Hospital Southampton NHS Foundation Trust, Southampton, UK

Non-alcoholic fatty liver disease (NAFLD) in children and adolescents has an estimated prevalence of 36.1% in the context of obesity. This figure is anticipated to increase in conjunction with the global obesity epidemic. Worryingly, NAFLD in childhood persisting into adulthood is likely to be harmful, contributing to significant hepatic and extrahepatic morbidities. Early disease detection is required, although the optimum timing, frequency and mode of screening remains undetermined. While the efficacy of several medications, antioxidants, fatty acid supplements and probiotics has been investigated in children, healthy eating and physical activity remain the only prevention and treatment strategies for paediatric NAFLD. This short review discusses the epidemiology, diagnosis, pathogenesis and management of NAFLD in childhood obesity.
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http://dx.doi.org/10.1136/archdischild-2019-318063DOI Listing
January 2021

Children are not COVID-19 super spreaders: time to go back to school.

Arch Dis Child 2020 07 5;105(7):618-619. Epub 2020 May 5.

NIHR Southampton Clinical Research Facility and NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, Hampshire, UK.

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http://dx.doi.org/10.1136/archdischild-2020-319474DOI Listing
July 2020

Discovery of Cephalosporin-3'-Diazeniumdiolates That Show Dual Antibacterial and Antibiofilm Effects against Clinical Cystic Fibrosis Isolates and Efficacy in a Murine Respiratory Infection Model.

ACS Infect Dis 2020 06 5;6(6):1460-1479. Epub 2020 May 5.

Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, New South Wales 2522, Australia.

The formation of biofilms provides a formidable defense for many bacteria against antibiotics and host immune responses. As a consequence, biofilms are thought to be the root cause of most chronic infections, including those occurring on medical indwelling devices, endocarditis, urinary tract infections, diabetic and burn wounds, and bone and joint infections. In cystic fibrosis (CF), chronic () respiratory infections are the leading cause of morbidity and mortality in adults. Previous studies have shown that many bacteria can undergo a coordinated dispersal event in the presence of low concentrations of nitric oxide (NO), suggesting that NO could be used to initiate biofilm dispersal in chronic infections, enabling clearance of the more vulnerable planktonic cells. In this study, we describe efforts to create "all-in-one" cephalosporin-based NO donor prodrugs (cephalosporin-3'-diazeniumdiolates, C3Ds) that show both direct β-lactam mediated antibacterial activity and antibiofilm effects. Twelve novel C3Ds were synthesized and screened against a panel of CF clinical isolates and other human pathogens. The most active compound, AMINOPIP2 (()-1-(4-(2-aminoethyl)piperidin-1-yl)-2-(((6,7)-7-(()-2-(2-aminothiazol-4-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methoxy)diazene 1-oxide)-ceftazidime , showed higher antibacterial potency than its parent cephalosporin and front-line antipseudomonal antibiotic ceftazidime, good stability against β-lactamases, activity against ceftazidime-resistant biofilms, and efficacy equivalent to ceftazidime in a murine respiratory infection model. The results support further evaluation of AMINOPIP2-ceftazidime for lung infections in CF and a broader study of "all-in-one" C3Ds for other chronic infections.
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http://dx.doi.org/10.1021/acsinfecdis.0c00070DOI Listing
June 2020

Experts' opinion for improving global adolescent vaccination rates: a call to action.

Eur J Pediatr 2020 Apr 18;179(4):547-553. Epub 2020 Feb 18.

University of Paris 7 Denis Diderot, 28 rue Parmentier, 92200, Neuilly sur Seine, France.

Worldwide, lifestyle and resource disparities among adolescents contribute to unmet health needs, which have crucial present and future public health implications for both adolescents and broader communities. Risk of infection among adolescents is amplified by biological, behavioral, and environmental factors; however, infectious diseases to which adolescents are susceptible are often preventable with vaccines. Beyond these concerns, there is a lack of knowledge regarding adolescent vaccination and disease risk among parents and adolescents, which can contribute to low vaccine uptake. Promising efforts have been made to improve adolescent vaccination by programs with motivational drivers and comprehensive communication with the public. In May 2017, a multidisciplinary group of experts met in Amsterdam, Netherlands, to discuss adolescent vaccine uptake, as part of an educational initiative called the Advancing Adolescent Health Spring Forum. This article presents consensus opinions resulting from the meeting, which pertain to the burden of vaccine-preventable diseases among adolescents, reasons for low vaccine uptake, and common characteristics of successful strategies for improving adolescent vaccination.Conclusion: There is an urgent "call to action," particularly targeting healthcare providers and public health authorities, for the prioritization of adolescent vaccination as a necessary element of preventive healthcare in this age group.What is Known:• Despite increased risk of certain infectious diseases, adolescent vaccination uptake remains low.What is New:• Barriers to adolescent vaccine uptake include lack of information regarding vaccines and disease risk, health system inadequacies, and insufficient healthcare follow-up.• Successful efforts to improve adolescent vaccine uptake need cohesive leadership and involvement of multiple stakeholders, as well as youth-friendly messaging; healthcare providers and policymakers should prioritize adolescent vaccination and implement proven program strategies to improve adolescent health worldwide.
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http://dx.doi.org/10.1007/s00431-019-03511-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080665PMC
April 2020

High frequency of paediatric facial nerve palsy due to Lyme disease in a geographically endemic region.

Int J Pediatr Otorhinolaryngol 2020 May 25;132:109905. Epub 2020 Jan 25.

NIHR Southampton Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; Paediatric Medicine, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, United Kingdom.

Introduction: Idiopathic facial nerve palsy (FNP) is an uncommon but important presentation in children, with Lyme disease known to be a common cause. The UK county of Hampshire is a high incidence area of Lyme disease. We conducted a retrospective review of the investigation and management of paediatric FNP at a large University hospital, including serologic testing and treatment of Lyme disease.

Methods: We conducted a retrospective chart review of children under 18 presenting between January 1st 2010 and December 31st 2017 with a diagnosis of FNP. Patients with clear non-Lyme aetiology at presentation were excluded. Data was collected on demographics, initial presentation, investigations including Lyme serology, and management.

Results: A total of 93 children were identified, with an even proportion of male to female and median age 9.3 years (IQR 4.6-12 years). A history of rash was present in 5.4%, tick bite in 14% and recent travel to, or residence in the New Forest in 22.6%. Lyme serology was performed in 81.7% of patients, of which 29% were positive. Antibiotics were prescribed for 73.1% of patients, oral steroids for 44% and aciclovir for 17.2%.

Conclusion: Lyme disease is a significant cause of FNP in this endemic area of the UK, and there was a large degree of variability in management prior to national guideline publication. Areas with endemic Lyme disease should consider introducing local guidelines supporting routine investigation and management for FNP, including empiric treatment for Lyme disease in accordance with NICE guidelines to improve care and reduce variability.
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http://dx.doi.org/10.1016/j.ijporl.2020.109905DOI Listing
May 2020

Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children.

Pediatr Crit Care Med 2020 02;21(2):e52-e106

Paris South University Hospitals-Assistance Publique Hopitaux de Paris, Paris, France.

Objectives: To develop evidence-based recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with septic shock and other sepsis-associated organ dysfunction.

Design: A panel of 49 international experts, representing 12 international organizations, as well as three methodologists and three public members was convened. Panel members assembled at key international meetings (for those panel members attending the conference), and a stand-alone meeting was held for all panel members in November 2018. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and group heads, as well as within subgroups, served as an integral part of the guideline development process.

Methods: The panel consisted of six subgroups: recognition and management of infection, hemodynamics and resuscitation, ventilation, endocrine and metabolic therapies, adjunctive therapies, and research priorities. We conducted a systematic review for each Population, Intervention, Control, and Outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak, or as a best practice statement. In addition, "in our practice" statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate.

Results: The panel provided 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction. Overall, six were strong recommendations, 52 were weak recommendations, and nine were best-practice statements. For 13 questions, no recommendations could be made; but, for 10 of these, "in our practice" statements were provided. In addition, 49 research priorities were identified.

Conclusions: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations. Despite this challenge, these recommendations regarding the management of children with septic shock and other sepsis-associated organ dysfunction provide a foundation for consistent care to improve outcomes and inform future research.
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http://dx.doi.org/10.1097/PCC.0000000000002198DOI Listing
February 2020

Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.

Intensive Care Med 2020 02;46(Suppl 1):10-67

Paris South University Hospitals-Assistance Publique Hopitaux de Paris, Paris, France.

Objectives: To develop evidence-based recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with septic shock and other sepsis-associated organ dysfunction.

Design: A panel of 49 international experts, representing 12 international organizations, as well as three methodologists and three public members was convened. Panel members assembled at key international meetings (for those panel members attending the conference), and a stand-alone meeting was held for all panel members in November 2018. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and group heads, as well as within subgroups, served as an integral part of the guideline development process.

Methods: The panel consisted of six subgroups: recognition and management of infection, hemodynamics and resuscitation, ventilation, endocrine and metabolic therapies, adjunctive therapies, and research priorities. We conducted a systematic review for each Population, Intervention, Control, and Outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak, or as a best practice statement. In addition, "in our practice" statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate.

Results: The panel provided 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction. Overall, six were strong recommendations, 49 were weak recommendations, and nine were best-practice statements. For 13 questions, no recommendations could be made; but, for 10 of these, "in our practice" statements were provided. In addition, 52 research priorities were identified.

Conclusions: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations. Despite this challenge, these recommendations regarding the management of children with septic shock and other sepsis-associated organ dysfunction provide a foundation for consistent care to improve outcomes and inform future research.
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http://dx.doi.org/10.1007/s00134-019-05878-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095013PMC
February 2020

Quadrivalent Influenza Vaccine Prevents Illness and Reduces Healthcare Utilization Across Diverse Geographic Regions During Five Influenza Seasons: A Randomized Clinical Trial.

Pediatr Infect Dis J 2020 01;39(1):e1-e10

GSK, King of Prussia, Pennsylvania.

Background: We evaluated an inactivated quadrivalent influenza vaccine (IIV4) in children 6-35 months of age in a phase III, observer-blind trial.

Methods: The aim of this analysis was to estimate vaccine efficacy (VE) in preventing laboratory-confirmed influenza in each of 5 independent seasonal cohorts (2011-2014), as well as vaccine impact on healthcare utilization in 3 study regions (Europe/Mediterranean, Asia-Pacific and Central America). Healthy children were randomized 1:1 to IIV4 or control vaccines. VE was estimated against influenza confirmed by reverse transcription polymerase chain reaction on nasal swabs. Cultured isolates were characterized as antigenically matched/mismatched to vaccine strains.

Results: The total vaccinated cohort included 12,018 children (N = 1777, 2526, 1564, 1501 and 4650 in cohorts 1-5, respectively). For reverse transcription polymerase chain reaction confirmed influenza of any severity (all strains combined), VE in cohorts 1-5 was 57.8%, 52.9%, 73.4%, 30.3% and 41.4%, respectively, with the lower limit of the 95% confidence interval >0 for all estimates. The proportion of vaccine match for all strains combined in each cohort was 0.9%, 79.3%, 72.5%, 24.1% and 28.6%, respectively. Antibiotic use associated with influenza illness was reduced with IIV4 by 71% in Europe, 36% in Asia Pacific and 59% in Central America.

Conclusions: IIV4 prevented influenza in children 6-35 months of age in each of 5 separate influenza seasons in diverse geographical regions. A possible interaction between VE, degree of vaccine match and socioeconomic status was observed. The IIV4 attenuated the severity of breakthrough influenza illness and reduced healthcare utilization, particularly antibiotic use.
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http://dx.doi.org/10.1097/INF.0000000000002504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004464PMC
January 2020

Cephalosporin nitric oxide-donor prodrug DEA-C3D disperses biofilms formed by clinical cystic fibrosis isolates of Pseudomonas aeruginosa.

J Antimicrob Chemother 2020 01;75(1):117-125

National Biofilms Innovation Centre, University of Southampton, Southampton SO17 1BJ, UK.

Objectives: The cephalosporin nitric oxide (NO)-donor prodrug DEA-C3D ('DiEthylAmin-Cephalosporin-3'-Diazeniumdiolate') has been shown to initiate the dispersal of biofilms formed by the Pseudomonas aeruginosa laboratory strain PAO1. In this study, we investigated whether DEA-C3D disperses biofilms formed by clinical cystic fibrosis (CF) isolates of P. aeruginosa and its effect in combination with two antipseudomonal antibiotics, tobramycin and colistin, in vitro.

Methods: β-Lactamase-triggered release of NO from DEA-C3D was confirmed using a gas-phase chemiluminescence detector. MICs for P. aeruginosa clinical isolates were determined using the broth microdilution method. A crystal violet staining technique and confocal laser scanning microscopy were used to evaluate the effects of DEA-C3D on P. aeruginosa biofilms alone and in combination with tobramycin and colistin.

Results: DEA-C3D was confirmed to selectively release NO in response to contact with bacterial β-lactamase. Despite lacking direct, cephalosporin/β-lactam-based antibacterial activity, DEA-C3D was able to disperse biofilms formed by three P. aeruginosa clinical isolates. Confocal microscopy revealed that DEA-C3D in combination with tobramycin produces similar reductions in biofilm to DEA-C3D alone, whereas the combination with colistin causes near complete eradication of P. aeruginosa biofilms in vitro.

Conclusions: DEA-C3D is effective in dispersing biofilms formed by multiple clinical isolates of P. aeruginosa and could hold promise as a new adjunctive therapy to patients with CF.
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http://dx.doi.org/10.1093/jac/dkz378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910178PMC
January 2020

Thirteen-Valent Pneumococcal Conjugate Vaccine in Children With Acute Lymphoblastic Leukemia: Protective Immunity Can Be Achieved on Completion of Treatment.

Clin Infect Dis 2020 Aug;71(5):1271-1280

University Hospital Southampton National Health Service Foundation Trust, Southampton, England, United Kingdom.

Background: Children with acute lymphoblastic leukemia (ALL) are at increased risk of developing invasive pneumococcal disease. This study describes the immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV13) during and after chemotherapy.

Methods: Children with ALL were allocated to study groups and received a single dose of PCV13: group 1, maintenance chemotherapy; group 2, end of chemotherapy; group 3, 6 months after chemotherapy. A protective vaccine response was defined as at least 10 of 12 serotypes (or >83% of serotypes with data) achieving postvaccination serotype-specific immunoglobulin G ≥0.35 µg/mL and ≥4-fold rise, compared to prevaccination at 1 and 12 months.

Results: One hundred eighteen children were recruited. Only 12.8% (5/39; 95% confidence interval [CI], 4.3%-27.4%) of patients vaccinated during maintenance (group 1) achieved a protective response at 1 month postvaccination and none had a protective response at 12 months. For group 2 patients, 59.5% (22/37; 95% CI, 42.1%-75.3%) achieved a response at 1 month and 37.9% (11/29; 95% CI, 20.7%-57.7%) maintained immunity at 12 months. For group 3 patients, 56.8% (21/37; 95% CI, 39.5%-72.9%) achieved a protective response at 1 month and 43.3% (13/30; 95% CI, 25.5%-62.6%) maintained immunity at 12 months.

Conclusions: This study demonstrated that the earliest time point at which protective immunity can be achieved in children with ALL is on completion of chemotherapy. This is earlier than current recommendations and may improve protection during a period when children are most susceptible to infection.

Clinical Trials Registration: EudraCT 2009-011587-11.
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http://dx.doi.org/10.1093/cid/ciz965DOI Listing
August 2020