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.

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 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: 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.

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.

Continuing impact of infectious diseases on childhood deaths in England and Wales, 2003-2005.

BACKGROUND: Data on the contribution of specific infections to childhood deaths in developed countries are limited. METHODS: Infection-related deaths in children aged 28 days to 14 years who died in England and Wales between 2003 and 2005 were identified from routine anonymized death certificate dataset provided by the Office for National Statistics to the Health Protection Agency, using predefined International Classification of Diseases codes for infection. RESULTS: There were 1368 infection-related deaths documented, constituting 20% of all childhood deaths. An underlying medical condition was recorded in 50% (676 cases), the most common being prematurity in infants (322/660, 52%), cerebral palsy in 1 to 4 year olds (46/190, 24%), and malignancy (46/163, 28%) in 5 to 14 year olds. Of the 837 deaths where a pathogen was coded, 494 (59%) specified bacterial infection, 256 (31%) viral infection, and 69 (8%) fungal infection. Among deaths with recorded bacterial infections, a lower proportion of meningococcal and pneumococcal infections (14% [22/155] vs. 60% [205/339], P < 0.0001) and a higher proportion of Gram-negative enteric bacilli (78/155 cases [50%] vs. 17/339 cases [5%], P < 0.0001) were reported in children with and without documented underlying medical conditions, respectively. CONCLUSIONS: Infections continue to make a major contribution to deaths in children, particularly among those with underlying conditions. Identification of the pathogens associated with childhood deaths should help prioritize the development of intervention strategies for reducing pediatric mortality. Linkage of death registrations to national infectious disease surveillance systems should be undertaken to strengthen monitoring of infectious deaths and evaluate the effect of interventions.

Invasive Haemophilus influenzae Disease, Europe, 1996-2006.

An international collaboration was established in 1996 to monitor the impact of routine Haemophilus influenzae type b (Hib) vaccination on invasive H. influenzae disease; 14 countries routinely serotype all clinical isolates. Of the 10,081 invasive H. influenzae infections reported during 1996-2006, 4,466 (44%, incidence 0.28 infections/100,000 population) were due to noncapsulated H. influenzae (ncHi); 2,836 (28%, 0.15/100,000), to Hib; and 690 (7%, 0.036/100,000), to non-b encapsulated H. influenzae. Invasive ncHi infections occurred in older persons more often than Hib (median age 58 years vs. 5 years, p<0.0001) and were associated with higher case-fatality ratios (12% vs. 4%, p<0.0001), particularly in infants (17% vs. 3%, p<0.0001). Among non-b encapsulated H. influenzae, types f (72%) and e (21%) were responsible for almost all cases; the overall case-fatality rate was 9%. Thus, the incidence of invasive non-type b H. influenzae is now higher than that of Hib and is associated with higher case fatality.

Estimated progression rates in three United Kingdom hepatitis C cohorts differed according to method of recruitment.

OBJECTIVES: To estimate hepatitis C virus (HCV) progression rates between disease stages prior to cirrhosis, using data from liver biopsies in three observational cohorts. To demonstrate how the method of cohort recruitment can influence the estimation of HCV-progression rates. STUDY DESIGN AND SETTING: Data came from three United Kingdom observational cohorts, assembled from different referral sources. In total, 987 HCV-infected patients with an estimated (or known) date of infection and at least one histologically scored liver biopsy were eligible for inclusion in the analysis. Liver biopsy scores were used to determine the stage of HCV-related liver disease. A three-state continuous time Markov model was used to estimate covariate-specific average probabilities of progression of disease. RESULTS: After adjusting for confounders, considerably different rates of disease progression were estimated in the three cohorts. For a group of patients with the same demographics, the estimated 20-year probability of progression to cirrhosis was 12% (95% confidence interval CI = 6-22) in a hospital-based cohort, 6% (95% CI = 3-13) in a posttransfusion cohort, and 23% (95% CI = 14-37) in a cohort recruited from a tertiary referral center. CONCLUSION: Researchers using estimates of disease progression should be aware that the method of cohort recruitment has considerable influence on the progression rates that are derived.

Clinical course of hepatitis C virus during the first decade of infection: cohort study.

OBJECTIVE: To determine the clinical course of hepatitis C virus in the first decade of infection in a group of patients who acquired their infections on a known date. DESIGN: Cohort study. SETTING: Clinical centres throughout the United Kingdom. PARTICIPANTS: 924 transfusion recipients infected with the hepatitis C virus (HCV) traced during the HCV lookback programme and 475 transfusion recipients who tested negative for antibodies to HCV (controls). MAIN OUTCOME MEASURES: Clinical evidence of liver disease and survival after 10 years of infection. RESULTS: All cause mortality was not significantly different between patients and controls (Cox's hazards ratio 1.41, 95% confidence interval 0.95 to 2.08). Patients were more likely to be certified with a death related to liver disease than were controls (12.84, 1.73 to 95.44), but although the risk of death directly from liver disease was higher in patients than controls this difference was not significant (5.78, 0.72 to 46.70). Forty per cent of the patients who died directly from liver disease were known to have consumed excess alcohol. Clinical follow up of 826 patients showed that liver function was abnormal in 307 (37.2%), and 115 (13.9%) reported physical signs or symptoms of liver disease. Factors associated with developing liver disease were testing positive for HCV ribonucleic acid (odds ratio 6.44, 2.67 to 15.48), having acquired infection when older (at age > or = 40 years; 1.80, 1.14 to 2.85), and years since transfusion (odds ratio 1.096 per year, 1.00 to 1.20). For patients with severe disease, sex was also significant (odds ratio for women 0.38, 0.17 to 0.88). Of the 362 patients who had undergone liver biopsy, 328 (91%) had abnormal histological results and 35 (10%) of these were cirrhotic. CONCLUSIONS: Hepatitis C virus infection did not have a great impact on all cause mortality in the first decade of infection. Infected patients were at increased risk of dying directly from liver disease, particularly if they consumed excess alcohol, but this difference was not statistically significant.