Paediatric acute hepatitis of unknown aetiology: a national investigation and adenoviraemia case-control study in the UK.

BACKGROUND: An increase in acute severe hepatitis of unknown aetiology in previously healthy children in the UK in March, 2022, triggered global case-finding. We aimed to describe UK epidemiological investigations of cases and their possible causes. METHODS: We actively surveilled unexplained paediatric acute hepatitis (transaminase >500 international units per litre) in children younger than 16 years presenting since Jan 1, 2022, through notifications from paediatricians, microbiologists, and paediatric liver units; we collected demographic, clinical, and exposure information. Then, we did a case-control study to investigate the association between adenoviraemia and other viruses and case-status using multivariable Firth penalised logistic regression. Cases aged 1-10 years and tested for adenovirus were included and compared with controls (ie, children admitted to hospital with an acute non-hepatitis illness who had residual blood samples collected between Jan 1 and May 28, 2022, and without known laboratory-confirmed diagnosis or previous adenovirus testing). Controls were frequency-matched on sex, age band, sample months, and nation or supra-region with randomised selection. We explored temporal associations between frequency of circulating viruses identified through routine laboratory pathogen surveillance and occurrence of cases by linear regression. SARS-CoV-2 seropositivity of cases was examined against residual serum from age-matched clinical comparison groups. FINDINGS: Between Jan 1 and July 4, 2022, 274 cases were identified (median age 3 years [IQR 2-5]). 131 (48%) participants were male, 142 (52%) were female, and one (<1%) participant had sex data unknown. Jaundice (195 [83%] of 235) and gastrointestinal symptoms (202 [91%] of 222) were common. 15 (5%) children required liver transplantation and none died. Adenovirus was detected in 172 (68%) of 252 participants tested, regardless of sample type; 137 (63%) of 218 samples were positive for adenovirus in the blood. For cases that were successfully genotyped, 58 (81%) of 72 had Ad41F, and 57 were identified as positive via blood samples (six of these were among participants who had undergone a transplant). In the case-control analysis, adenoviraemia was associated with hepatitis case-status (adjusted OR 37·4 [95% CI 15·5-90·3]). Increases in the detection of adenovirus from faecal samples, but not other infectious agents, in routine laboratory pathogen surveillance correlated with hepatitis cases 4 weeks later, which independently suggested an association (ß 0·06 [95% CI 0·02-0·11]). No association was identified for SARS-CoV-2 antibody seropositivity. INTERPRETATION: We observed an association between adenovirus 41F viraemia and paediatric acute hepatitis. These results can inform diagnostic testing recommendations, clinical management, and exploratory in vitro or clinical studies of paediatric acute hepatitis of unknown aetiology. The role of potential co-factors, including other viruses and host susceptibility, requires further investigation. FUNDING: None.

mRNA or ChAd0x1 COVID-19 Vaccination of Adolescents Induces Robust Antibody and Cellular Responses With Continued Recognition of Omicron Following mRNA-1273.

Children and adolescents generally experience mild COVID-19. However, those with underlying physical health conditions are at a significantly increased risk of severe disease. Here, we present a comprehensive analysis of antibody and cellular responses in adolescents with severe neuro-disabilities who received COVID-19 vaccination with either ChAdOx1 (n=6) or an mRNA vaccine (mRNA-1273, n=8, BNT162b2, n=1). Strong immune responses were observed after vaccination and antibody levels and neutralisation titres were both higher after two doses. Both measures were also higher after mRNA vaccination and were further enhanced by prior natural infection where one vaccine dose was sufficient to generate peak antibody response. Robust T-cell responses were generated after dual vaccination and were also higher following mRNA vaccination. Early T-cells were characterised by a dominant effector-memory CD4+ T-cell population with a type-1 cytokine signature with additional production of IL-10. Antibody levels were well-maintained for at least 3 months after vaccination and 3 of 4 donors showed measurable neutralisation titres against the Omicron variant. T-cell responses also remained robust, with generation of a central/stem cell memory pool and showed strong reactivity against Omicron spike. These data demonstrate that COVID-19 vaccines display strong immunogenicity in adolescents and that dual vaccination, or single vaccination following prior infection, generate higher immune responses than seen after natural infection and develop activity against Omicron. Initial evidence suggests that mRNA vaccination elicits stronger immune responses than adenoviral delivery, although the latter is also higher than seen in adult populations. COVID-19 vaccines are therefore highly immunogenic in high-risk adolescents and dual vaccination might be able to provide relative protection against the Omicron variant that is currently globally dominant.

Real-world data on immune responses following heterologous prime-boost COVID-19 vaccination schedule with Pfizer and AstraZeneca vaccines in England.

BACKGROUND: There are limited data on immune responses to heterologous COVID-19 immunisation schedules, especially following an extended ≥12-week interval between doses. METHODS: SARS-CoV-2 infection-naïve and previously-infected adults receiving ChAd-BNT (ChAdOx1 nCoV-19, AstraZeneca followed by BNT162b2, Pfizer-BioNTech) or BNT-ChAd as part of the UK national immunisation programme provided blood samples at 30 days and 12 weeks after their second dose. Geometric mean concentrations (GMC) of anti-SARS-CoV-2 spike (S-antibody) and nucleoprotein (N-antibody) IgG antibodies and geometric mean ratios (GMR) were compared with a contemporaneous cohort receiving homologous ChAd-ChAd or BNT-BNT. RESULTS: During March-October 2021, 75,827 individuals were identified as having received heterologous vaccination, 9,489 invited to participate, 1,836 responded (19.3%) and 656 were eligible. In previously-uninfected adults, S-antibody GMC at 30 days post-second dose were lowest for ChAd-ChAd (862 [95% CI, 694 - 1069]) and significantly higher for ChAd-BNT (6233 [5522-7035]; GMR 6.29; [5.04-7.85]; p<0.001), BNT-ChAd (4776 [4066-5610]; GMR 4.55 [3.56-5.81]; p<0.001) and BNT-BNT (5377 [4596-6289]; GMR 5.66 [4.49-7.15]; p<0.001). By 12 weeks after dose two, S-antibody GMC had declined in all groups and remained significantly lower for ChAd-ChAd compared to ChAd-BNT (GMR 5.12 [3.79-6.92]; p<0.001), BNT-ChAd (GMR 4.1 [2.96-5.69]; p<0.001) and BNT-BNT (GMR 6.06 [4.32-8.50]; p<0.001). Previously infected adults had higher S-antibody GMC compared to infection-naïve adults at all time-points and with all vaccine schedules. CONCLUSIONS: These real-world findings demonstrate heterologous schedules with adenoviral-vector and mRNA vaccines are highly immunogenic and may be recommended after a serious adverse reaction to one vaccine product, or to increase programmatic flexibility where vaccine supplies are constrained.

SARS Antibody Testing in Children: Development of Oral Fluid Assays for IgG Measurements.

Seroepidemiological studies to monitor antibody kinetics are important for assessing the extent and spread of SARS-CoV-2 in a population. Noninvasive sampling methods are advantageous for reducing the need for venipuncture, which may be a barrier to investigations, particularly in pediatric populations. Oral fluids are obtained by gingiva-crevicular sampling from children and adults and are very well accepted. Enzyme immunoassays (EIAs) based on these samples have acceptable sensitivity and specificity compared to conventional serum-based antibody EIAs and are suitable for population-based surveillance. We describe the development and evaluation of SARS-CoV-2 IgG EIAs using SARS-CoV-2 viral nucleoprotein (NP) and spike (S) proteins in IgG isotype capture format and an indirect receptor-binding-domain (RBD) IgG EIA, intended for use in children as a primary endpoint. All three assays were assessed using a panel of 1,999 paired serum and oral fluids from children and adults participating in school SARS-CoV-2 surveillance studies during and after the first and second pandemic wave in the United Kingdom. The anti-NP IgG capture assay was the best candidate, with an overall sensitivity of 75% (95% confidence interval [CI]: 71 to 79%) and specificity of 99% (95% CI: 78 to 99%) compared with paired serum antibodies. Sensitivity observed in children (80%, 95% CI: 71 to 88%) was higher than that in adults (67%, CI: 60% to 74%). Oral fluid assays (OF) using spike protein and RBD antigens were also 99% specific and achieved reasonable but lower sensitivity in the target population (78%, 95% CI [68% to 86%] and 53%, 95% CI [43% to 64%], respectively). IMPORTANCE We report on the first large-scale assessment of the suitability of oral fluids for detection of SARS-CoV-2 antibody obtained from healthy children attending school. The sample type (gingiva-crevicular fluid, which is a transudate of blood but is not saliva) can be self collected. Although detection of antibodies in oral fluids is less sensitive than that in blood, our study suggests an optimal format for operational use. The laboratory methods we have developed can reliably measure antibodies in children, who are able to take their own samples. Our findings are of immediate practical relevance for use in large-scale seroprevalence studies designed to measure exposure to infection, as they typically require venipuncture. Overall, our data indicate that OF assays based on the detection of SARS-CoV-2 antibodies are a tool suitable for population-based seroepidemiology studies in children and highly acceptable in children and adults, as venipuncture is no longer necessary.

TIPICO XI: report of the first series and podcast on infectious diseases and vaccines (aTIPICO).

TIPiCO is an annual expert meeting and workshop on infectious diseases and vaccination. The edition of 2020 changed its name and format to aTIPiCO, the first series and podcasts on infectious diseases and vaccines. A total of 13 prestigious experts from different countries participated in this edition launched on the 26 November 2020. The state of the art of coronavirus disease-2019 (COVID-19) and the responsible pathogen, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and the options to tackle the pandemic situation were discussed in light of the knowledge in November 2020. Despite COVID-19, the status of other infectious diseases, including influenza infections, respiratory syncytial virus disease, human papillomavirus infection, measles, pertussis, tuberculosis, meningococcal disease, and pneumococcal disease, were also addressed. The essential lessons that can be learned from these diseases and their vaccines to use in the COVID-19 pandemic were also commented with the experts.

Real-world data shows increased reactogenicity in adults after heterologous compared to homologous prime-boost COVID-19 vaccination, March-June 2021, England.

Adults receiving heterologous COVID-19 immunisation with mRNA (Comirnaty) or adenoviral-vector (Vaxzevria) vaccines had higher reactogenicity rates and sought medical attention more often after two doses than homologous schedules. Reactogenicity was higher among ≤ 50 than > 50 year-olds, women and those with prior symptomatic/confirmed COVID-19. Adults receiving heterologous schedules on clinical advice after severe first-dose reactions had lower reactogenicity after dose 2 following Vaxzevria/Comirnaty (93.4%; 95% confidence interval: 90.5-98.1 vs 48% (41.0-57.7) but not Comirnaty/Vaxzevria (91.7%; (77.5-98.2 vs 75.0% (57.8-87.9).

Meningococcal carriage in periods of high and low invasive meningococcal disease incidence in the UK: comparison of UKMenCar1-4 cross-sectional survey results.

BACKGROUND: The incidence of invasive meningococcal disease in the UK decreased by approximately four times from 1999 to 2014, with reductions in serogroup C and serogroup B disease. Lower serogroup C invasive meningococcal disease incidence was attributable to implementation of the meningococcal serogroup C conjugate vaccine in 1999, through direct and indirect protection, but no vaccine was implemented against serogroup B disease. UK Meningococcal Carriage surveys 1-3 (UKMenCar1-3), conducted in 1999, 2000, and 2001, were essential for understanding the impact of vaccination. To investigate the decline in invasive meningococcal disease incidence, we did a large oropharyngeal carriage survey in 2014-15, immediately before the changes to meningococcal vaccines in the UK national immunisation schedule. METHODS: UKMenCar4 was a cross-sectional survey in adolescents aged 15-19 years who were enrolled from schools and colleges geographically local to one of 11 UK sampling centres between Sept 1, 2014, and March 30, 2015. Participants provided an oropharyngeal swab sample and completed a questionnaire on risk factors for carriage, including social behaviours. Samples were cultured for putative Neisseria spp, which were characterised with serogrouping and whole-genome sequencing. Data from this study were compared with the results from the UKMenCar1-3 surveys (1999-2001). FINDINGS: From the 19 641 participants (11 332 female, 8242 male, 67 not stated) in UKMenCar4 with culturable swabs and completed risk-factor questionnaires, 1420 meningococci were isolated, with a carriage prevalence of 7·23% (95% CI 6·88-7·60). Carriage prevalence was substantially lower in UKMenCar4 than in the previous surveys: carriage prevalence was 16·6% (95% CI 15·89-17·22; 2306/13 901) in UKMenCar1 (1999), 17·6% (17·05-18·22; 2873/16 295) in UKMenCar2 (2000), and 18·7% (18·12-19·27; 3283/17 569) in UKMenCar3 (2001). Carriage prevalence was lower for all serogroups in UKMenCar4 than in UKMenCar1-3, except for serogroup Y, which was unchanged. The prevalence of carriage-promoting social behaviours decreased from 1999 to 2014-15, with individuals reporting regular cigarette smoking decreasing from 2932 (21·5%) of 13 650 to 2202 (11·2%) of 19 641, kissing in the past week from 6127 (44·8%) of 13 679 to 7320 (37·3%) of 19 641, and attendance at pubs and nightclubs in the past week from 8436 (62·1%) of 13 594 to 7662 (39·0%) of 19 641 (all p<0·0001). INTERPRETATION: We show that meningococcal carriage prevalence in adolescents sampled nationally during a low incidence period (2014-15) was less than half of that in an equivalent population during a high incidence period (1999-2001). Disease and carriage caused by serogroup C was well controlled by ongoing vaccination. The prevalence of behaviours associated with carriage declined, suggesting that public health policies aimed at influencing behaviour might have further reduced disease. FUNDING: Wellcome Trust, UK Department of Health, and National Institute for Health Research.

Invasive Pneumococcal Disease in People With Human Immunodeficiency Virus in England, 1999-2017.

BACKGROUND: The 7-valent and 13-valent pneumococcal conjugate vaccines (PCVs) were introduced into the UK childhood immunization program in 2006 and 2010, respectively, with high effectiveness and resulting in both direct and indirect protection. We describe the epidemiology of invasive pneumococcal disease (IPD) in adults with human immunodeficiency virus (HIV) in England following the introduction of both PCVs. METHODS: Data on a national cohort of people with HIV were linked to confirmed IPD cases in adults aged ≥ 15 years during 1999-2017. Date of HIV infection was estimated using a CD4 slope decline algorithm. RESULTS: Among 133 994 adults with HIV, 1453 developed IPD during 1999-2017, with 70% (1016/1453) developing IPD ≥ 3 months after their HIV diagnosis. IPD and HIV were codiagnosed within 90 days in 345 (24%) individuals. A missed opportunity for earlier HIV diagnosis was identified in 6% (89/1453), mostly in earlier years. IPD incidence in people with HIV increased from 147/100 000 in 1999 to 284/100 000 in 2007 before declining and stabilizing between 92 and 113/100 000 during 2014-2017. Mean annual IPD incidence was lower among those receiving antiretroviral therapy during 2014-17 (68 vs 720/100 000; incidence rate ratio [IRR] 9.3; 95% confidence interval [CI], 7.3-11.8; P < .001) and was markedly lower in those with a suppressed viral load (50 vs 523/100 000; IRR 10.4; 95% CI, 7.6-14.1; P < .001). The latter group still had 4.5-fold higher (95% CI, 3.8-5.3; P < .001) IPD incidence compared to the general population (11.2/100 000). CONCLUSIONS: IPD incidence among people with HIV reduced after PCV13 introduction and has remained stable. Adults presenting with IPD should continue to be tested for HIV infection.

Invasive meningococcal disease: Timing and cause of death in England, 2008-2015.

BACKGROUND: Neisseria meningitidis is a major cause of bacterial meningitis and septicaemia, with death often occurring rapidly after onset of the first symptoms. Later death can also occur, but may be due to other causes, such as underlying comorbidities. The study aimed to assess the timing and cause of death in patients with invasive meningococcal disease (IMD) prior to the introduction of two new meningococcal immunisation programmes in England. METHODS: Public Health England (PHE) conducts IMD surveillance in England through its national meningococcal reference unit. Laboratory-confirmed IMD cases diagnosed during 2008-2015 were linked to weekly and annual electronic death registration records as well as the Patient Demographic Service (PDS) database. RESULTS: Overall, 6734 of 6808 (99%) laboratory-confirmed IMD cases matched to PDS, including 668 fatalities. Of these, 667 linked to an annual death registration record compared to 405 reports linked to weekly death registrations. In total, 429/667 (64%) of all deaths and 428/502 (85%) of IMD-related deaths occurred within one day of diagnosis. In total, 498/667 (75%) deaths had occured by 30 days after IMD diagnosis and 98% (490/498) of these were IMD-related. Serogroup B contributed to 64% (323/502) of IMD-related deaths, followed by serogroup W (84/502, 17%) and serogroup Y (70/502, 14%). Deaths occurring after 30 days were less likely to be IMD-related, mainly amongst ≥65 year-olds, with malignancy, chronic respiratory and cardiac conditions predominating. CONCLUSIONS: Most IMD-related deaths occurred within a day of diagnosis and nearly all IMD-related deaths occurred within 30 days of diagnosis. The rapidity of death highlights the importance of prevention through vaccination.

Meningococcal B Vaccine and Meningococcal Carriage in Adolescents in Australia.

BACKGROUND: The meningococcal group B vaccine 4CMenB is a new, recombinant protein-based vaccine that is licensed to protect against invasive group B meningococcal disease. However, its role in preventing transmission and, therefore, inducing population (herd) protection is uncertain. METHODS: We used cluster randomization to assign, according to school, students in years 10 to 12 (age, 15 to 18 years) in South Australia to receive 4CMenB vaccination either at baseline (intervention) or at 12 months (control). The primary outcome was oropharyngeal carriage of disease-causing Neisseria meningitidis (group A, B, C, W, X, or Y) in students in years 10 and 11, as identified by polymerase-chain-reaction assays for PorA (encoding porin protein A) and N. meningitidis genogroups. Secondary outcomes included carriage prevalence and acquisition of all N. meningitidis and individual disease-causing genogroups. Risk factors for carriage were assessed at baseline. RESULTS: A total of 237 schools participated. During April through June 2017, a total of 24,269 students in years 10 and 11 and 10,220 students in year 12 were enrolled. At 12 months, there was no difference in the prevalence of carriage of disease-causing N. meningitidis between the vaccination group (2.55%; 326 of 12,746) and the control group (2.52%; 291 of 11,523) (adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.80 to 1.31; P = 0.85). There were no significant differences in the secondary carriage outcomes. At baseline, the risk factors for carriage of disease-causing N. meningitidis included later year of schooling (adjusted odds ratio for year 12 vs. year 10, 2.75; 95% CI, 2.03 to 3.73), current upper respiratory tract infection (adjusted odds ratio, 1.35; 95% CI, 1.12 to 1.63), cigarette smoking (adjusted odds ratio, 1.91; 95% CI, 1.29 to 2.83), water-pipe smoking (adjusted odds ratio, 1.82; 95% CI, 1.30 to 2.54), attending pubs or clubs (adjusted odds ratio, 1.54; 95% CI, 1.28 to 1.86), and intimate kissing (adjusted odds ratio, 1.65; 95% CI, 1.33 to 2.05). No vaccine safety concerns were identified. CONCLUSIONS: Among Australian adolescents, the 4CMenB vaccine had no discernible effect on the carriage of disease-causing meningococci, including group B. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT03089086.).

Invasive meningococcal disease in patients with complement deficiencies: a case series (2008-2017).

BACKGROUND: To describe patients with inherited and acquired complement deficiency who developed invasive meningococcal disease (IMD) in England over the last decade. METHODS: Public Health England conducts enhanced surveillance of IMD in England. We retrospectively identified patients with complement deficiency who developed IMD in England during 2008-2017 and retrieved information on their clinical presentation, vaccination status, medication history, recurrence of infection and outcomes, as well as characteristics of the infecting meningococcal strain. RESULTS: A total of 16 patients with 20 IMD episodes were identified, including four with two episodes. Six patients had inherited complement deficiencies, two had immune-mediated conditions associated with complement deficiency (glomerulonephritis and vasculitis), and eight others were on Eculizumab therapy, five for paroxysmal nocturnal haemoglobinuria and three for atypical haemolytic uraemic syndrome. Cultures were available for 7 of 11 episodes among those with inherited complement deficiencies/immune-mediated conditions and the predominant capsular group was Y (7/11), followed by B (3/11) and non-groupable (1/11) strains. Among patients receiving Eculizumab therapy, 3 of the 9 episodes were due to group B (3/9), three others were NG but genotypically group B, and one case each of groups E, W and Y. CONCLUSIONS: In England, complement deficiency is rare among IMD cases and includes inherited disorders of the late complement pathway, immune-mediated disorders associated with low complement levels and patients on Eculizumab therapy. IMD due to capsular group Y predominates in patient with inherited complement deficiency, whilst those on Eculizumab therapy develop IMD due to more diverse capsular groups including non-encapsulated strains.

B Part of It School Leaver protocol: an observational repeat cross-sectional study to assess the impact of a meningococcal serogroup B (4CMenB) vaccine programme on carriage of Neisseria meningitidis.

INTRODUCTION: Invasive meningococcal disease is uncommon but associated with a high-case fatality rate. Carriage prevalence of the causative bacteria, Neisseria meningitidis, is high in adolescents. A large (n=34 500) cluster randomised controlled trial (RCT) to assess the impact of a meningococcal B (MenB) vaccine on meningococcal carriage was implemented in the state of South Australia (SA) for year 10, 11 and 12 senior school students in 2017-2018. This study will assess the impact of MenB vaccine (4CMenB) on carriage prevalence in school leavers in SA, 1 and 2 years after implementation of the cluster RCT in adolescents. Measuring the impact of population programmes on carriage can assist in informing future meningococcal immunisation programmes such as targeted age groups and use of catch-up campaigns. METHODS AND ANALYSIS: This repeat cross-sectional study will assess carriage prevalence in 2018 and 2019. All school leavers who attended year 12 in any school in SA in 2018 or 2019 will be invited to participate in this study. An oropharyngeal swab will be taken from each participating student and a risk factor questionnaire completed by the student following informed consent. Students will attend clinics at SA universities, technical colleges, and metropolitan, rural and remote government council clinics. Confirmed vaccination history will allow a comparison in carriage prevalence between vaccinated and unvaccinated school leavers. A sample size of 4096 students per year will provide 80% power to detect a 20% difference in carriage prevalence of disease-causing meningococci (defined as genogroup A, B, C, W, X or Y) between years. ETHICS AND DISSEMINATION: The study was approved by the Women's and Children's Health Network Human Research Ethics Committee. Results will be published in international peer review journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: NCT03419533; Pre-results.

The introduction of the meningococcal B (MenB) vaccine (Bexsero®) into the national infant immunisation programme--New challenges for public health.

The United Kingdom is the first country to introduce Bexsero(®) (GSK Biologicals), a multicomponent, protein-based vaccine against meningococcal group B (MenB), into the national infant immunisation programme. This vaccine is like no other licensed vaccine and poses a number of implementation and surveillance challenges in England. From 01 September 2015, UK infants were offered a reduced two dose primary immunisation schedule at 2 and 4 months followed by a booster at 12 months. Because of high rates of fever post-vaccination, parents were advised to give their infants three doses of prophylactic paracetamol, with the first dose given as soon as possible after the primary MenB vaccination dose. Since the vaccine only protects against 73-88% of MenB strains causing invasive disease in England, clinical isolates and PCR-positive samples will require extensive characterisation by the Meningococcal Reference Unit (MRU) at Public Health England (PHE) in order to monitor vaccine effectiveness and identify potential vaccine failures. PHE is also conducting detailed clinical and epidemiological surveillance to assess the impact of the MenB immunisation programme on the morbidity and mortality associated with invasive meningococcal disease in infants and young children.

Targeted empiric antibiotic therapy for children with non-oncological comorbidities and community-onset invasive bacterial infections.

OBJECTIVES: To describe the aetiology, risk factors, treatment and outcome of children with community-onset invasive bacterial infections (IBI) and determine the appropriateness of the nationally recommended empiric antibiotic therapy in children with non-oncological comorbidities. METHOD: The CABIN network prospectively collected clinical information for all positive blood and cerebrospinal fluid cultures in children aged 1 month to 15 years in southwest London over three years. RESULTS: During 2009-11, 119 healthy children each had a single IBI episode and 61 children with non-oncological comorbidities had 83 IBI episodes. The pathogens causing IBI in children with comorbidities and no central venous catheter (CVC) were similar to those causing IBI in healthy children. However, those with a CVC had multiple IBI episodes, often with pathogens usually associated with nosocomial infection. In particular, gastro-intestinal commensals were frequently responsible for IBI in TPN-dependent children with gastro-intestinal disease (16/43 episodes) and those with liver disease (8/43). Nationally recommended antibiotics were commenced empirically in 93%, with additional or alternate antibiotics more likely to be prescribed in children with comorbidities or those requiring intensive care. Fifteen children died (11 healthy, 4 with comorbidity), including 12 who died before arrival or in the Emergency Department. CONCLUSION: Increasing care of children with comorbidities in the community has resulted in a significant proportion of community-onset IBI occurring in this group. Children with a CVC in situ - particularly those with gastro-intestinal and liver disease - were infected with a wider range of potentially more virulent pathogens. They might benefit from more broad-spectrum antimicrobial cover.

Interchangeability of meningococcal group C conjugate vaccines with different carrier proteins in the United Kingdom infant immunisation schedule.

An open, non-randomised study was undertaken in England during 2011-12 to evaluate vaccine antibody responses in infants after completion of the routine primary infant immunisation schedule, which included two doses of meningococcal group C (MenC) conjugate (MCC) vaccine at 3 and 4 months. Any of the three licensed MCC vaccines could be used for either dose, depending on local availability. Healthy term infants registered at participating general practices (GPs) in Hertfordshire and Gloucestershire, UK, were recruited prospectively to provide a single blood sample four weeks after primary immunisation, which was administered by the GP surgery. Vaccination history was obtained at blood sampling. MenC serum bactericidal antibody (SBA) and IgG antibodies against Haemophilus influenzae b (Hib), pertussis toxin (PT), diphtheria toxoid (DT), tetanus toxoid (TT) and thirteen pneumococcal serotypes were analysed according to MCC vaccines received. MenC SBA responses differed significantly (P<0.001) according to MCC vaccine schedule as follows: MenC SBA geometric mean titres (GMTs) were significantly lower in infants receiving a diphtheria cross-reacting material-conjugated MCC (MCC-CRM) vaccine followed by TT-conjugated MCC (MCC-TT) vaccine (82.0; 95% CI, 39-173; n=14) compared to those receiving two MCC-CRM (418; 95% CI, 325-537; n=82), two MCC-TT (277; 95% CI, 223-344; n=79) or MCC-TT followed by MCC-CRM (553; 95% CI, 322-949; n=18). The same group also had the lowest Hib geometric mean concentrations (0.60 µg/mL, 0.27-1.34) compared to 1.85 µg/mL (1.23-2.78), 2.86 µg/mL (2.02-4.05) and 4.26 µg/mL (1.94-9.36), respectively. Our results indicate that MCC vaccines with different carrier proteins are not interchangeable. When several MCC vaccines are available, children requiring more than one dose should receive MCC vaccines with the same carrier protein or, alternatively, receive MCC-TT first wherever possible.

Visceral Leishmaniasis in a UK Toddler following a Short Trip to a Popular Holiday Destination in Spain.

We herein present the case of a 15-month-old with visceral leishmaniasis diagnosed in the UK following a short trip to a popular holiday destination in Spain. Four months after the initial symptoms, the diagnosis was made incidentally on microscopy of a bone marrow biopsy taken for suspected haematological malignancy after the child developed hepatosplenomegaly, pancytopaenia, and Klebsiella pneumoniae septicaemia.

Invasive bacterial and fungal infections in paediatric patients with cancer: incidence, risk factors, aetiology and outcomes in a UK regional cohort 2009-2011.

BACKGROUND: Cancer is the second most common cause of childhood deaths in the United Kingdom and infection contributes to a quarter of all cancer-related deaths. This study aimed to estimate the risk, aetiology and outcome of bloodstream bacterial and fungal infections in children with cancer within a geographically defined region in South-West London over a 3-year period. METHODS: Web-based questionnaires were completed using case records of children with positive blood cultures admitted to five London hospitals during 2009-2011. RESULTS: A total of 112 children with a median age of 5.4 (IQR 3.6-11.2) years had 266 significant blood cultures during 149 infection episodes. Haematological malignancy affected 68 patients (60.7%) and solid tumours 44 (39.3%). The overall bloodstream infection rate was 1.5 episodes per 1,000 days-at-risk (95% CI, 1.2-1.8) and was similar for those with haematological malignancies and solid tumours. Most episodes were attributed to central venous catheter infection (120/149, 80.5%). Coagulase-negative staphylococci were isolated in almost half the bloodstream infections (127/266; 47.7%), while Gram-negative organisms accounted for a further quarter (64/266; 24.1%). Fungal isolates from blood were uncommon (8/112 children, 7.1%) but significantly associated with neutropenia (18/149 [12.1%] vs. 1/114 [0.9%], P = 0.0004). Six children (5.4%) died, including three (2.7%; 95% CI, 0.6-7.6%) whose deaths were infection-related. CONCLUSIONS: This study provides an updated risk estimate for bloodstream infections in children with cancer and adds to the framework for developing evidence-based guidance for management of suspected infections in this highly vulnerable group.

Epidemiology and clinical features of childhood chronic hepatitis B infection diagnosed in England.

BACKGROUND: This study aimed to estimate the prevalence of childhood chronic hepatitis B (CHB) infection diagnosed in England using capture-recapture analysis of 2 independent data sources and to describe the clinical and epidemiological characteristics, management, complications and outcome of children with CHB. METHODS: Pediatric specialists were contacted to report all CHB cases in children aged <16 years and complete a standardized questionnaire. Capture-recapture analysis of cases diagnosed during 2001-2009 using 2 independent data sources was performed to estimate the prevalence of childhood CHB. RESULTS: Capture-recapture analysis estimated 448 diagnosed CHB cases (prevalence, 4.6/100,000) in England, of whom only 44% had been referred for specialist follow up. Clinical information for 325 cases under specialist care revealed that half the cases (n = 164, 50%) had been born overseas, mainly Sub-Saharan Africa and Eastern Europe, whereas half the UK-born children were either Pakistani (25%) or Chinese (25%). Most children (n = 216, 66%) were asymptomatic, with only 60 (18.5%) ever receiving any antiviral therapy, although 2 developed cirrhosis in childhood and 1 hepatocellular carcinoma. Horizontal transmission among UK-born children was identified in only 3 children born since 2001, when universal antenatal hepatitis B virus screening was introduced. Most children born to antenatally diagnosed hepatitis B virus-positive mothers (49/51, 96%) had received at least 1 hepatitis B vaccine dose after birth. CONCLUSIONS: In England, the prevalence of diagnosed childhood CHB is low, although the potential number of undiagnosed cases is difficult to estimate. Further efforts are required to strengthen the current antenatal screening program and newly diagnosed cases should be referred for specialist follow up.

Invasive pneumococcal disease after routine pneumococcal conjugate vaccination in children, England and Wales.

We assessed known risk factors, clinical presentation, and outcome of invasive pneumococcal disease (IPD) in children 3-59 months of age after introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in England and Wales. During September 2006-March 2010, a total of 1,342 IPD episodes occurred in 1,332 children; 14.9% (198/1,332) had comorbidities. Compared with IPD caused by PCV7 serotypes (44/248; 17.7%), comorbidities were less common for the extra 3 serotypes in the 10-valent vaccine (15/299; 5.0%) but similar to the 3 additional PCV13 serotypes (45/336; 13.4%) and increased for the 11 extra serotypes in 23-valent polysaccharide vaccine (PPV23) (39/186; 21.0%) and non-PPV23 serotypes (38/138; 27.5%). Fifty-two (3.9%) cases resulted from PCV7 failure; 9 (0.7%) case-patients had recurrent IPD. Case-fatality rate was 4.4% (58/1,332) but higher for meningitis (11.0%) and children with comorbidities (9.1%). Thus, comorbidities were more prevalent in children with IPD caused by non-PCV13 serotypes and were associated with increased case fatality.