Inflammation and cytomegalovirus viremia during pregnancy drive sex-differentiated differences in mortality and immune development in HIV-exposed infants.

Children who are HIV-exposed but uninfected have increased infectious mortality compared to HIV-unexposed children, raising the possibility of immune abnormalities following exposure to maternal viraemia, immune dysfunction, and co-infections during pregnancy. In a secondary analysis of the SHINE trial in rural Zimbabwe we explored biological pathways underlying infant mortality, and maternal factors shaping immune development in HIV-exposed uninfected infants. Maternal inflammation and cytomegalovirus viraemia were independently associated with infant deaths: mortality doubled for each log10 rise in maternal C-reactive protein (adjusted hazard ratio (aHR) 2.09; 95% CI 1.33-3.27), and increased 1.6-fold for each log10 rise in maternal cytomegalovirus viral load (aHR 1.62; 95% CI 1.11-2.36). In girls, mortality was more strongly associated with maternal C-reactive protein than cytomegalovirus; in boys, mortality was more strongly associated with cytomegalovirus than C-reactive protein. At age one month, HIV-exposed uninfected infants had a distinct immune milieu, characterised by raised soluble CD14 and an altered CD8 + T-cell compartment. Alterations in immunophenotype and systemic inflammation were generally greater in boys than girls. Collectively, these findings show how the pregnancy immune environment in women with HIV underlies mortality and immune development in their offspring in a sex-differentiated manner, and highlights potential new intervention strategies to transform outcomes of HIV-exposed children. ClinicalTrials.gov/NCT01824940.

Vaccine value profile for Klebsiella pneumoniae.

Klebsiella pneumoniae causes community- and healthcare-associated infections in children and adults. Globally in 2019, an estimated 1.27 million (95% Uncertainty Interval [UI]: 0.91-1.71) and 4.95 million (95% UI: 3.62-6.57) deaths were attributed to and associated with bacterial antimicrobial resistance (AMR), respectively. K. pneumoniae was the second leading pathogen in deaths attributed to AMR resistant bacteria. Furthermore, the rise of antimicrobial resistance in both community- and hospital-acquired infections is a concern for neonates and infants who are at high risk for invasive bacterial disease. There is a limited antibiotic pipeline for new antibiotics to treat multidrug resistant infections, and vaccines targeted against K. pneumoniae are considered to be of priority by the World Health Organization. Vaccination of pregnant women against K. pneumoniae could reduce the risk of invasive K.pneumoniae disease in their young offspring. In addition, vulnerable children, adolescents and adult populations at risk of K. pneumoniae disease with underlying diseases such as immunosuppression from underlying hematologic malignancy, chemotherapy, patients undergoing abdominal and/or urinary surgical procedures, or prolonged intensive care management are also potential target groups for a K. pneumoniae vaccine. A 'Vaccine Value Profile' (VVP) for K.pneumoniae, which contemplates vaccination of pregnant women to protect their babies from birth through to at least three months of age and other high-risk populations, provides a high-level, holistic assessment of the available information to inform the potential public health, economic and societal value of a pipeline of K. pneumoniae vaccines and other preventatives and therapeutics. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public-private partnerships, and multi-lateral organizations, and in collaboration with stakeholders from the WHO. All contributors have extensive expertise on various elements of the K.pneumoniae VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Effect of second booster vaccinations and prior infection against SARS-CoV-2 in the UK SIREN healthcare worker cohort.

Background: The protection of fourth dose mRNA vaccination against SARS-CoV-2 is relevant to current global policy decisions regarding ongoing booster roll-out. We aimed to estimate the effect of fourth dose vaccination, prior infection, and duration of PCR positivity in a highly-vaccinated and largely prior-COVID-19 infected cohort of UK healthcare workers. Methods: Participants underwent fortnightly PCR and regular antibody testing for SARS-CoV-2 and completed symptoms questionnaires. A multi-state model was used to estimate vaccine effectiveness (VE) against infection from a fourth dose compared to a waned third dose, with protection from prior infection and duration of PCR positivity jointly estimated. Findings: 1298 infections were detected among 9560 individuals under active follow-up between September 2022 and March 2023. Compared to a waned third dose, fourth dose VE was 13.1% (95% CI 0.9 to 23.8) overall; 24.0% (95% CI 8.5 to 36.8) in the first 2 months post-vaccination, reducing to 10.3% (95% CI -11.4 to 27.8) and 1.7% (95% CI -17.0 to 17.4) at 2-4 and 4-6 months, respectively. Relative to an infection >2 years ago and controlling for vaccination, 63.6% (95% CI 46.9 to 75.0) and 29.1% (95% CI 3.8 to 43.1) greater protection against infection was estimated for an infection within the past 0-6, and 6-12 months, respectively. A fourth dose was associated with greater protection against asymptomatic infection than symptomatic infection, whilst prior infection independently provided more protection against symptomatic infection, particularly if the infection had occurred within the previous 6 months. Duration of PCR positivity was significantly lower for asymptomatic compared to symptomatic infection. Interpretation: Despite rapid waning of protection, vaccine boosters remain an important tool in responding to the dynamic COVID-19 landscape; boosting population immunity in advance of periods of anticipated pressure, such as surging infection rates or emerging variants of concern. Funding: UK Health Security Agency, Medical Research Council, NIHR HPRU Oxford, Bristol, and others.

Post-COVID-19 paediatric inflammatory multisystem syndrome: association of ethnicity, key worker and socioeconomic status with risk and severity.

OBJECTIVES: Patients from ethnic minority groups and key workers are over-represented among adults hospitalised or dying from COVID-19. In this population-based retrospective cohort, we describe the association of ethnicity, socioeconomic and family key worker status with incidence and severity of Paediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-CoV-2 (PIMS-TS). SETTING: Evelina London Children's Hospital (ELCH), the tertiary paediatric hospital for the South Thames Retrieval Service (STRS) region. PARTICIPANTS: 70 children with PIMS-TS admitted 14 February 2020-2 June 2020. OUTCOME MEASURES: Incidence and crude ORs are presented, comparing ethnicity and socioeconomic status of our cohort and the catchment population, using census data and Index of Multiple Deprivation (IMD). Regression is used to estimate the association of ethnicity and IMD with admission duration and requirement for intensive care, inotropes and ventilation. RESULTS: Incidence was significantly higher in children from black (25.0 cases per 100 000 population), Asian (6.4/100 000) and other (17.8/100 000) ethnic groups, compared with 1.6/100 000 in white ethnic groups (ORs 15.7, 4.0 and 11.2, respectively). Incidence was higher in the three most deprived quintiles compared with the least deprived quintile (eg, 8.1/100 000 in quintile 1 vs 1.6/100 000 in quintile 5, OR 5.2). Proportions of families with key workers (50%) exceeded catchment proportions. Admission length of stay was 38% longer in children from black ethnic groups than white (95% CI 4% to 82%; median 8 days vs 6 days). 9/10 children requiring ventilation were from black ethnic groups. CONCLUSIONS: Children in ethnic minority groups, living in more deprived areas and in key worker families are over-represented. Children in black ethnic groups had longer admissions; ethnicity may be associated with ventilation requirement.This project was registered with the ELCH audit and service evaluation team, ref. no 11186.

The current state of immunization against Gram-negative bacteria in children: a review of the literature.

PURPOSE OF REVIEW: Gram-negative bacteria (GNB) are a major cause of infection worldwide and multidrug resistance in infants and children. The major pathogens include Klebsiella pneumoniae, Escherichia coli, Enterobacter spp., Pseudomonas aeruginosa and Acinetobacter baumannii. With new antibiotic options limited, immunization is likely to play a critical role in prevention. This review discusses their epidemiology, the current state of vaccine research and potential immunization strategies to protect children. A comprehensive review of the literature, conference abstracts along with web searches was performed to identify current and investigational vaccines against the major GNB in children. RECENT FINDINGS: Phase I--III vaccine trials have been undertaken for the major Gram-negative bacteria but not in infants or children. E. coli is a common infection in immune-competent children, including neonatal sepsis. Several vaccines are in late-phase clinical trials, with some already licensed for recurrent urinary tract infections in women. Klebsiella spp. causes community-acquired and hospital-acquired infections, including sepsis in neonates and immunocompromised children although no vaccine trials have extended beyond early phase 2 trials. P. aeruginosa is a common pathogen in patients with cystic fibrosis. Phase 1--3 vaccine and monoclonal antibody trials are in progress, although candidates provide limited coverage against pathogenic strains. Enterobacter spp. and A. baumannii largely cause hospital-acquired infections with experimental vaccines limited to phase 1 research. SUMMARY: The current immunization pipelines for the most prevalent GNB are years away from licensure. Similar to incentives for new antibiotics, global efforts are warranted to expedite the development of effective vaccines.

Biomarkers for Disease Severity in Children Infected With Respiratory Syncytial Virus: A Systematic Literature Review.

BACKGROUND: Clinical manifestations of respiratory syncytial virus (RSV) infection vary widely from mild, self-limiting illness to severe life-threatening disease. There are gaps in knowledge of biomarkers to objectively define severe disease and predict clinical outcomes. METHODS: A systematic search was performed, 1945-March 2019 in databases Ovid Medline, Embase, Global health, Scopus, and Web of Science. Risk of bias was assessed using the Cochrane tool. RESULTS: A total of 25 132 abstracts were screened and studies were assessed for quality, risk of bias, and extracted data; 111 studies met the inclusion criteria. RSV severity was correlated with antibody titers, reduced T and B cells, dysregulated innate immunity, neutrophil mobilization to the lungs and blood, decreased Th1 response, and Th2 weighted shift. Microbial exposures in respiratory tract may contribute to neutrophil mobilization to the lungs of the infants with severe RSV compared with mild RSV disease. CONCLUSIONS: Although a wide range of biomarkers have been associated with RSV disease severity, robust validated biomarkers are lacking. This review illustrates the broad heterogeneity of study designs and high variability in the definition of severe RSV disease. Prospective studies are required to validate biomarkers. Additional research investigating epigenetics, metabolomics, and microbiome holds promise for novel biomarkers.

Healthcare access for children and families on the move and migrants.

BACKGROUND: The United Kingdom (UK) National Health Service (NHS) charging regulations have increasingly restricted migrants' healthcare access, in the context of a wider national policy shift over the past few years intending to create a 'hostile environment' for migrants. With an estimated 144 000 undocumented children living in the UK and increasing public concern that these regulations are negatively impacting migrant health and well-being, as well as contravening international child rights agreements, it has become imperative to understand their implications. METHODS: A mixed methods digital survey, covering attitudes towards and understanding of UK healthcare charging, and giving space for relevant case submission, was disseminated through communications channels of the Royal College of Paediatrics and Child Health (RCPCH) to their members. Quantitative data were analysed on Stata, and basic proportions were calculated for each response proportion. Qualitative data were analysed using a framework analysis approach. RESULTS: There were 200 responses, from a range of healthcare professional backgrounds. The majority were not confident in interpreting and applying the charging regulations. One-third (34%) reported examples of the charging regulations impacting patient care, analysis of which elicited seven key themes. Our survey gathered 18 cases of migrants being deterred from accessing healthcare, 11 cases of healthcare being delayed or denied outright, and 12 cases of delay in accessing care leading to worse health outcomes, including two intrauterine deaths. DISCUSSION: Our results describe a range of harms arising from the current NHS charging regulations contributing to delays in or denials of healthcare, due to patients' fear of charging or immigration enforcement, including potential deportation, and confusion around entitlements. This harm affects individual patients, the migrant community and the NHS - often in multiple simultaneous ways. Many patients eligible for NHS care, such as trafficking victims, are not being identified as such. We found the current charging regulations to be unworkable, and that harm could not be eliminated simply through improved awareness or implementation.

Outcomes beyond hospital discharge in infants and children with viral meningitis: A systematic review.

Viruses are the commonest cause of childhood meningitis, but outcomes beyond hospital discharge are poorly described. We undertook a systematic literature review of long-term outcomes following paediatric viral meningitis. A search was carried out using MEDLINE, Embase, and Cochrane Review for studies from 1 January 1990 to 31 December 2018. Studies were included where specific outcome measures were available beyond hospital discharge for children <16 years old with viral meningitis. In total, 3588 papers were identified of which 14 were eligible for inclusion. Four studies reported outcomes in children with nonenterovirus 71 meningitis. A US study of 16 cases demonstrated subtle language difficulties at 3-year follow-up in infants in contrast to an Australian study, which revealed no impairment in language. A Fijian study showed that two out of eight cases had sensorineural hearing loss compared with none in a UK cohort of 668 infants. Three studies evaluated outcomes of enterovirus 71 meningitis in China and Taiwan, two showed cases recovered without sequelae, while one demonstrated an increased risk of attention deficit hyperactivity disorder. Two studies including 141 cases of human parechovirus revealed no evidence of neurodevelopmental sequelae. Conversely, an Australian study demonstrated neurodevelopmental sequelae in 11 out of 77 infants with parechovirus meningitis. Most studies identified in this review demonstrated a high proportion of good clinical outcomes following viral meningitis. However, the data are limited, so robustly conducted neurodevelopmental studies are warranted to inform the evidence-based management of viral meningitis beyond hospital discharge.

Nutrition and public health in medical education in the UK: reflections and next steps.

OBJECTIVE: Doctors play an important role in the identification of nutritional disorders and as advocates for a healthy diet, and although the key tenets of good nutrition education for medical students have been discussed, reports on implementation are sparse. The present commentary responds to a gap in UK medical students' understanding of nutrition and public health and suggests ways to improve it. DESIGN: We review literature about nutrition education in medical schools and discuss a 6-week elective in public health nutrition for medical students. We discuss suggested competencies in nutrition and compare means of students' confidence and knowledge before and after. SETTING: A nutrition and public health elective in a UK medical school, discussing advocacy, motivational interviewing, supplements, nutritional deficits, parenteral nutrition, obesity services. We utilised multidisciplinary teaching approaches including dietitians, managers and pharmacists, and students implemented a public health activity in a local school. SUBJECTS: Fifteen final-year medical students were enrolled; sixty school pupils participated in the public health activity. RESULTS: The students were not confident in nutrition competencies before and were taught less than European counterparts. Students enjoyed the course, had improved knowledge, and felt more confident in interviewing and prescribing supplements. Feedback from the local school was positive. CONCLUSIONS: Students in our UK medical school were not confident in their required competencies within the confines of the current educational programme. An elective course can improve medical students' knowledge. Similar courses could be implemented in other medical schools to improve nutrition and public health knowledge and practice in future doctors.

Discrimination, harassment and non-reporting in UK medical education.

CONTEXT: Discrimination and harassment create a hostile environment with deleterious effects on student well-being and education. In this study, we aimed to: (i) measure prevalences and types of discrimination and harassment in one UK medical school, and (ii) understand how and why students report them. METHODS: The study used a mixed-methods design. A medical school population survey of 1318 students was carried out in March 2014. Students were asked whether they had experienced, witnessed or reported discrimination or harassment and were given space for free-text comments. Two focus group sessions were conducted to elicit information on types of harassment and the factors that influenced reporting. Proportions were analysed using the Wilson score method and associations tested using chi-squared and regression analyses. Qualitative data were subjected to framework analysis. Degrees of convergence between data were analysed. RESULTS: A total of 259 (19.7%) students responded to the survey. Most participants had experienced (63.3%, 95% confidence interval [CI]: 57.3-69.0) or witnessed (56.4%, 95% CI: 50.3-62.3) at least one type of discrimination or harassment. Stereotyping was the form most commonly witnessed (43.2%, 95% CI: 37.4-49.3). In the qualitative data, reports of inappropriate joking and invasion of personal space were common. Black and minority ethnic students had witnessed and religious students had experienced a greater lack of provision (χ2  = 4.73, p = 0.03 and χ2  = 4.38, p = 0.04, respectively). Non-heterosexual students had experienced greater joking (χ2  = 3.99, p = 0.04). Students with disabilities had experienced more stereotyping (χ2  = 13.5, p < 0.01). Female students and students in clinical years had 2.6 (95% CI: 1.3-5.3) and 3.6 (95% CI: 1.9-7.0) greater odds, respectively, of experiencing or witnessing any type of discrimination or harassment. Seven of 140 survey respondents had reported incidents (5.0%, 95% CI: 2.4-10.0). Reporting was perceived as ineffective and as potentially victimising of the reporter. CONCLUSIONS: Harassment and discrimination are prevalent in this sample and associated with gender, ethnicity, sexuality, disability and year group. Reporting is rare and perceived as ineffective. These findings have informed local developments, future strategies and the development of a national prevention policy.

Infectious causes of microcephaly: epidemiology, pathogenesis, diagnosis, and management.

Microcephaly is an important sign of neurological malformation and a predictor of future disability. The 2015-16 outbreak of Zika virus and congenital Zika infection brought the world's attention to links between Zika infection and microcephaly. However, Zika virus is only one of the infectious causes of microcephaly and, although the contexts in which they occur vary greatly, all are of concern. In this Review, we summarise important aspects of major congenital infections that can cause microcephaly, and describe the epidemiology, transmission, clinical features, pathogenesis, management, and long-term consequences of these infections. We include infections that cause substantial impairment: cytomegalovirus, herpes simplex virus, rubella virus, Toxoplasma gondii, and Zika virus. We highlight potential issues with classification of microcephaly and show how some infants affected by congenital infection might be missed or incorrectly diagnosed. Although Zika virus has brought the attention of the world to the problem of microcephaly, prevention of all infectious causes of microcephaly and appropriately managing its consequences remain important global public health priorities.

Respiratory syncytial virus seasonality and its implications on prevention strategies.

With maternal and infant vaccines against respiratory syncytial virus (RSV) in development, it is timely to consider how the deployment of these vaccines might vary according to local RSV disease seasonality. In temperate regions RSV infection is predictably limited to a period of 3 to 5 months, while in tropical regions disease seasonality is often both more variable and more prolonged. Accordingly, in tropical regions a year-round immunisation schedule for both maternal and infant immunisation might be appropriate. In contrast, in temperate regions the benefit of year-round maternal immunisation would be heavily dependent on the duration of protection this provided, potentially necessitating a strategy directed at children due to be born in the months immediately prior to the RSV season. This review will consider the impact of seasonality on maternal and infant immunisation strategies against RSV, and the potential of an alternative approach of passive immunisation for all infants immediately prior to the RSV season.

Interventions to Improve the Response of Professionals to Children Exposed to Domestic Violence and Abuse: A Systematic Review.

Exposure of children to domestic violence and abuse (DVA) is a form of child maltreatment with short- and long-term behavioural and mental health impact. Health care professionals are generally uncertain about how to respond to domestic violence and are particularly unclear about best practice with regards to children's exposure and their role in a multiagency response. In this systematic review, we report educational and structural or whole-system interventions that aim to improve professionals' understanding of, and response to, DVA survivors and their children. We searched 22 bibliographic databases and contacted topic experts for studies reporting quantitative outcomes for any type of intervention aiming to improve professional responses to disclosure of DVA with child involvement. We included interventions for physicians, nurses, social workers and teachers. Twenty-one studies met the inclusion criteria: three randomised controlled trials (RCTs), 18 pre-post intervention surveys. There were 18 training and three system-level interventions. Training interventions generally had positive effects on participants' knowledge, attitudes towards DVA and clinical competence. The results from the RCTs were consistent with the before-after surveys. Results from system-level interventions aimed to change organisational practice and inter-organisational collaboration demonstrates the benefit of coordinating system change in child welfare agencies with primary health care and other organisations. Implications for policy and research are discussed. © 2015 The Authors. Child Abuse Review published by John Wiley & Sons Ltd. 'We searched 22 bibliographic databases and contacted topic experts'. KEY PRACTITIONER MESSAGES: We reviewed published evidence on interventions aimed at improving professionals' practice with domestic violence survivors and their children.Training programmes were found to improve participants' knowledge, attitudes and clinical competence up to a year after delivery.Key elements of successful training include interactive discussion, booster sessions and involving specialist domestic violence practitioners.Whole-system approaches aiming to promote coordination and collaboration across agencies appear promising but require funding and high levels of commitment from partners. 'Training programmes were found to improve participants' knowledge, attitudes and clinical competence up to a year after delivery'.