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Background Most studies assessing pathophysiological heterogeneity in asthma have been conducted in high-income countries (HICs), with little known about the prevalence and characteristics of different asthma inflammatory phenotypes in low-and middle-income countries (LMICs). This study assessed sputum inflammatory phenotypes in five centres, in Brazil, Ecuador, Uganda, New Zealand (NZ) and the United Kingdom (UK). Methods We conducted a cross-sectional study of 998 asthmatics and 356 non-asthmatics in 2016–20. All centres studied children and adolescents (age range 8–20 years), except the UK centre which involved 26–27 year-olds. Information was collected using questionnaires, clinical characterization, blood and induced sputum. Results Of 623 asthmatics with sputum results, 39% (243) were classified as eosinophilic or mixed granulocytic, i.e. eosinophilic asthma (EA). Adjusted for age and sex, with NZ as baseline, the UK showed similar odds of EA (odds ratio 1.04, 95% confidence interval 0.37–2.94) with lower odds in the LMICs: Brazil (0.73, 0.42–1.27), Ecuador (0.40, 0.24–0.66) and Uganda (0.62, 0.37–1.04). Despite the low prevalence of neutrophilic asthma in most centres, sputum neutrophilia was increased in asthmatics and non-asthmatics in Uganda. Conclusions This is the first time that sputum induction has been used to compare asthma inflammatory phenotypes in HICs and LMICs. Most cases were non-eosinophilic, including in settings where corticosteroid use was low. A lower prevalence of EA was observed in the LMICs than in the HICs. This has major implications for asthma prevention and management, and suggests that novel prevention strategies and therapies specifically targeting non-eosinophilic asthma are required globally.

Objectives Food processing facilities represent critical infrastructure that have stayed open during much of the COVID-19 pandemic. Understanding the burden of COVID-19 in this sector is thus important to help reduce the potential for workplace infection in future outbreaks. Methods We undertook a workplace survey in the UK food and drink processing sector and collected information on workplace size, characteristics (e.g. temperature, ventilation), and experience with COVID-19 (e.g. numbers of positive cases). For each site, we calculated COVID-19 case rates per month per 1000 workers. We performed an ecological analysis using negative binomial regression to assess the association between COVID-19 rates and workplace and local risk factors. Results Respondents from 33 companies including 66 individual sites completed the survey. COVID-19 cases were reported from the start of the pandemic up to June 2021. Respondents represented a range of industry subgroups, including grain milling/storage (n = 16), manufacture of malt (n = 14), manufacture of prepared meals (n = 12), manufacture of beverages (n = 8), distilling (n = 5), manufacture of baked goods (n = 5), and other (n = 6), with a total of 15 563 workers across all sites. Average monthly case rates per 1000 workers ranged from 0.9 in distilling to 6.1 in grain milling/storage. Incidence rate ratios were partially attenuated after adjusting for several local and workplace factors, though risks for one subgroup (grain milling/storage) remained elevated. Certain local and workplace characteristics were related to higher infection rates, such as higher deprivation (5 km only), a lower proportion of remote workers, lower proportion of workers in close proximity, and higher numbers of workers overall. Conclusions Our analysis suggests some heterogeneity in the rates of COVID-19 across sectors of the UK food and drink processing industry. Infection rates were associated with deprivation, the proportions of remote workers and workers in close proximity, and the number of workers.

Background It is widely accepted that the risk of hepatitis C virus (HCV) vertical transmission (VT) is 5%–6% in monoinfected women, and that 25%–40% of HCV infection clears spontaneously within 5 years. However, there is no consensus on how VT rates should be estimated, and there is a lack of information on VT rates “net” of clearance. Methods We reanalyzed data on 1749 children in 3 prospective cohorts to obtain coherent estimates of overall VT rate and VT rates net of clearance at different ages. Clearance rates were used to impute the proportion of uninfected children who had been infected and then cleared before testing negative. The proportion of transmission early in utero, late in utero, and at delivery was estimated from data on the proportion of HCV RNA positive within 3 days of birth, and differences between elective cesarean and nonelective cesarean deliveries. Results Overall VT rates were 7.2% (95% credible interval [CrI], 5.6%–8.9%) in mothers who were human immunodeficiency virus (HIV) negative and 12.1% (95% CrI, 8.6%–16.8%) in HIV-coinfected women. The corresponding rates net of clearance at 5 years were 2.4% (95% CrI, 1.1%–4.1%), and 4.1% (95% CrI, 1.7%–7.3%). We estimated that 24.8% (95% CrI, 12.1%–40.8%) of infections occur early in utero, 66.0% (95% CrI, 42.5%–83.3%) later in utero, and 9.3% (95% CrI, 0.5%–30.6%) during delivery. Conclusions Overall VT rates are about 24% higher than previously assumed, but the risk of infection persisting beyond age 5 years is about 38% lower. The results can inform design of trials of interventions to prevent or treat pediatric HCV infection, and strategies to manage children exposed in utero.

This review aimed to provide an overview of the literature assessing the extent of COVID-19 transmission in the food processing sector along with the risk factors associated with COVID-19 infection/mortality rates in this setting, and the preventive measures used to reduce transmission. An electronic search was conducted using scientific databases, including Web of Science, OVID, PubMed and MedRxiv. The search strategy identified 26 papers that met the inclusion criteria. Six of these studies were based in the UK and the country with the most papers was the USA, with a total of nine papers. Findings showed some evidence of a high transmission level of SARS-CoV-2 within some areas of the food production sector. Risk factors associated with the spread included ethnicity, poor ventilation, lack of social distancing and lack of sick pay. The preventative measures included/recommended were social distancing, testing, adequate ventilation, cleaning regimes and access to PPE. Additional research focusing on the food production sector could show the potential variations in transmission and risk between each sub-sector. Future research focusing on the application of various preventative measures and their efficacy by sub-sector would be beneficial, while further qualitative research could help provide in-depth information regarding knowledge gaps.

BackgroundAntibiotic prescribing during childhood, most commonly for respiratory tract infections (RTIs), contributes to antimicrobial resistance, which is a major public health concern.AimTo identify factors associated with amoxicillin prescribing and RTI consultation attendance in young children in primary care.Design and settingCohort study in Bradford spanning pregnancy to age 24 months, collected 2007–2013, linked to electronic primary care and air pollution data.MethodAmoxicillin prescribing and RTI consultation rates/1000 child–years were calculated. Mixed-effects logistic regression models were fitted with general practice (GP) surgery as the random effect.ResultsThe amoxicillin prescribing rate among 2493 children was 710/1000 child–years during year 1 (95% confidence interval [CI] = 677 to 744) and 780/1000 (95% CI = 745 to 816) during year 2. During year 1, odds of amoxicillin prescribing were higher for boys (adjusted odds ratio [aOR] 1.36, 95% CI = 1.14 to 1.61), infants from socioeconomically deprived households (aOR 1.36, 95% CI = 1.00 to 1.86), and infants with a Pakistani ethnic background (with mothers born in the UK [aOR 1.44, 95% CI = 1.06 to 1.94] and outside [aOR 1.42, 95% CI = 1.07 to 1.90]). During year 2, odds of amoxicillin prescribing were higher for infants with a Pakistani ethnic background (with mothers born in the UK [aOR 1.46, 95% CI = 1.10 to 1.94] and outside [aOR 1.56, 95% CI = 1.19 to 2.04]) and those born ConclusionSocioeconomic status and ethnic background were associated with amoxicillin prescribing during childhood. Efforts to reduce RTI spread in household and childcare settings may reduce antibiotic prescribing in primary care.

Objective: To estimate occupational differences in COVID-19 mortality, and test whether these are confounded by factors, such as regional differences, ethnicity and education or due to non-workplace factors, such as deprivation or pre-pandemic health. Design: Retrospective cohort study Setting: People living in private households England Participants: 14,295,900 people aged 40-64 years (mean age 52 years, 51% female) who were alive on 24 January 2020, living in private households in England in 2019, were employed in 2011, and completed the 2011 census. Main outcome measures: COVID-19 related death, assessed between 24 January 2020 and 28 December 2020. We estimated age-standardised mortality rates per 100,000 person-years at risk (ASMR) stratified by sex and occupations. To estimate the effect of occupation due to work-related exposures, we used Cox proportional hazard models to adjust for confounding (region, ethnicity, education), as well as non-workplace factors that are related to occupation. Results: There is wide variation between occupations in COVID-19 mortality. Several occupations, particularly those involving contact with patients or the public, show three-fold or four-fold risks. These elevated risks were greatly attenuated after adjustment for confounding and mediating non-workplace factors. For example, the hazard ratio (HR) for men working as taxi and cab drivers or chauffeurs changed from 4.60 [95%CI 3.62-5.84] to 1.47 [1.14-1.89] after adjustment. More generally, the overall HR for men working in essential occupations compared with men in nonessential occupations changed from 1.45 [1.34 - 1.56] to 1.22 [1.13 - 1.32] after adjustment. For most occupations, confounding and other mediating factors explained about 70% to 80% of the age-adjusted hazard ratios. Conclusions Working conditions are likely to play a role in COVID-19 mortality, particularly in occupations involving contact with COVID-19 patients or the public. However, there is also a substantial contribution from non-workplace factors, including regional factors, socio-demographic factors, and pre-pandemic health.

IntroductionThe coronavirus pandemic has been particularly severe in the UK, with high infection and death rates, including among working age population.ObjectiveTo estimate occupational differences in COVID-19 mortality, taking into account confounding factors, such as regional differences, ethnicity, education, deprivation and pre-pandemic health.MethodsWe used data on 14,295,900 individuals who completed the UK Census in 2011, who were alive on 24 January 2020, were employed and aged 31–55 years in 2011. Data were linked to death and other health records. We examined differences between occupational groups in the risk of COVID-19 death from 24 January to 28 December 2020. We estimated age-standardised mortality rates per 100,000 person-years at risk stratified by sex and occupations. To estimate the effect of occupation due to work-related exposures, we used Cox proportional hazard models to adjust for confounding factors.ResultsThere is wide variation between occupations in COVID-19 mortality. Several occupations, particularly those involving contact with patients or the public, show three- or four-fold risks. These elevated risks were greatly attenuated after adjustment for confounding and mediating factors. For example, the hazard ratio (HR) for men working as taxi and cab drivers or chauffeurs changed from 4.60 [95%CI 3.62–5.84] to 1.47 [1.14–1.89] after adjustment. The overall HR for men working in essential occupations compared with men in non-essential occupations changed from 1.45 [1.34 - 1.56] to 1.22 [1.13 - 1.32] after adjustment. For most occupations, confounding and other mediating factors explained about 70% to 80% of the age-adjusted hazard ratios.ConclusionsWorking conditions are likely to play a role in COVID-19 mortality, particularly in occupations involving contact with COVID-19 patients or the public. However, there is also a substantial contribution from non-workplace factors, including regional factors, socio-demographic factors, and pre-pandemic health.

BackgroundCurrent guidelines recommend that infants born to women with hepatitis C (HCV) viremia are screened for HCV antibody at age 18 months, and if positive, referred for RNA testing at 3 years to confirm chronic infection. This policy is based in part on analyses suggesting 25%-40% of vertically acquired HCV infections clear spontaneously within 4-5 years.MethodsData on 179 infants with RNA and/or anti-HCV evidence of vertically acquired viraemia (single PCR+) or confirmed infection (2 PCR+ or anti-HCV beyond 18 months) in three prospective European cohorts were investigated. Ages at clearance of viremia and confirmed infection were estimated taking account of interval censoring and delayed entry. We also investigated clearance in infants in whom RNA was not detectable until after 6 weeks.ResultsClearance rates decline rapidly over the first 6 months. An estimated 90.6% (95%CrI: 83.5-95.9) of viremia cleared by 5 years, most within 3 months, and 65.9% (50.1-81.6) of confirmed infection cleared by 5 years, at a median 12.4 (7.1-18.9) months. If treatment began at age 6 months, 18 months or 3 years, at least 59.0% (42.0-76.9), 39.7 (17.9-65.9), and 20.9 (4.6-44.8) of those treated would clear without treatment. In seven (6.6%) confirmed infections, RNA was not detectable until after 6 weeks, and in 2 (1.9%) not until after 6 months. However, all such cases subsequently cleared.ConclusionsMost viraemia clears within 3 months, and most confirmed infection by 3 years. Delaying treatment avoids but does not eliminate over-treatment and should be balanced against loss to follow-up.Key pointsBased on a re-analysis of the largest purely prospective dataset assembled so far, 66% (50-82) of confirmed vertically acquired HCV clears spontaneously by age 5 years, rather than the 25-40% assumed in guidelines.

BackgroundIt is widely accepted that the risk of HCV vertical transmission (VT) is 5-6% in mono-infected women, and that 25-40% of HCV infection clears spontaneously within 5 years. However, VT and clearance rates have not been estimated from the same datasets, and there is a lack of information on VT rates “net” of clearance.MethodsWe re-analysed data on 1749 children in 3 prospective cohorts to obtain coherent estimates of overall VT rate and VT rates “net” of clearance at different ages. Clearance rates were used to impute the proportion of uninfected children who had been infected and then cleared before testing negative. The proportion of transmission early in utero, late in utero and at delivery was estimated from data on the proportion of RNA positives in samples tested within three days of birth, and differences between elective caesarean and non-elective caesarean deliveries.FindingsOverall VT rates were 7.2% (95% credible interval 5.6-8.9) in mothers who were HIV negative and 12.1% (8.6-16.8) in HIV-co-infected women. The corresponding rates net of clearance at 5 years were 2.4% (1.1-4.1) and 4.1% (1.7-7.3). We estimated that 24.8% (12.1-40.8) of infections occur early in utero, 66.0% (42.5-83.3) later in utero, and 9.3% (0.5-30.6) during delivery.ConclusionOverall VT rates are about 24% higher than previously assumed, but the risk of infection persisting beyond age 5 years is about 38% lower. The results can inform design of trials of to prevent or treat pediatric HCV infection, and strategies to manage children exposed in utero.Key pointsTaking account of infections that would have cleared spontaneously before detection, the rate of HCV vertical transmission is 7.2% (95%CrI 5.6-8.9) in mono-infected women, but transmission “net” of clearance is 3.1% (1.8-4.4) at 3 years, and 2.4% (1.1-4.1) at 5.

Background Globally, it is becoming more common for pregnant women to deliver by caesarean section (CS). In 2020, 31% of births in England were CS, surpassing the recommended prevalence of CS. Concerns have been raised regarding potential unknown consequences of this mode of delivery. Childhood adiposity is also an increasing concern. Previous research provides inconsistent conclusions on the association between CS and childhood adiposity. More studies are needed to investigate the consequences of CS in different populations and ethnicities. Therefore, this study investigates the association between mode of delivery and BMI, in children of 4–5 years and if this differs between White British (WB) and Pakistani ethnicities, in Bradford UK. Methods Data were obtained from the Born in Bradford (BiB) cohort, which recruited pregnant women at the Bradford Royal Infirmary, between 2007 and 2010. For these analyses, a sub-sample (n = 6410) of the BiB cohort (n = 13,858) was used. Linear regression models determined the association between mode of delivery (vaginal or CS) and BMI z-scores at 4–5 years. Children were categorised as underweight/healthy weight, overweight and obese, and logistic regression models determined the odds of adiposity. Effect modification by ethnicity was also explored. Results Multivariable analysis found no evidence for a difference in BMI z-score between children of CS and vaginal delivery (0.005 kg/m2, 95% CI = − 0.062–0.072, p = 0.88). Neither was there evidence of CS affecting the odds of being overweight (OR = 1.05, 95% CI = 0.86–1.28, p = 0.65), or obese (OR = 0.98, 95% CI = 0.74–1.29, p = 0.87). There was no evidence that ethnicity was an effect modifier of these associations (p = 0.97). Conclusion Having CS, compared to a vaginal delivery, was not associated with greater adiposity in children of 4–5 years in this population. Concerns over CS increasing adiposity in children are not supported by the findings reported here using the BiB study population, of both WB and Pakistani families.

ObjectiveTo estimate occupational differences in COVID-19 mortality, and test whether these are confounded by factors, such as regional differences, ethnicity and education or due to non-workplace factors, such as deprivation or pre-pandemic health.DesignRetrospective cohort studySettingPeople living in private households EnglandParticipants14,295,900 people aged 40-64 years (mean age 52 years, 51% female) who were alive on 24 January 2020, living in private households in England in 2019, were employed in 2011, and completed the 2011 census.Main outcome measuresCOVID-19 related death, assessed between 24 January 2020 and 28 December 2020. We estimated age-standardised mortality rates per 100,000 person-years at risk (ASMR) stratified by sex and occupations. To estimate the effect of occupation due to work-related exposures, we used Cox proportional hazard models to adjust for confounding (region, ethnicity, education), as well as non-workplace factors that are related to occupation.ResultsThere is wide variation between occupations in COVID-19 mortality. Several occupations, particularly those involving contact with patients or the public, show three-fold or four-fold risks. These elevated risks were greatly attenuated after adjustment for confounding and mediating non-workplace factors. For example, the hazard ratio (HR) for men working as taxi and cab drivers or chauffeurs changed from 4.60 [95%CI 3.62-5.84] to 1.47 [1.14-1.89] after adjustment. More generally, the overall HR for men working in essential occupations compared with men in non-essential occupations changed from 1.45 [1.34 - 1.56] to 1.22 [1.13 - 1.32] after adjustment. For most occupations, confounding and other mediating factors explained about 70% to 80% of the age-adjusted hazard ratios.ConclusionsWorking conditions are likely to play a role in COVID-19 mortality, particularly in occupations involving contact with COVID-19 patients or the public. However, there is also a substantial contribution from non-workplace factors, including regional factors, socio-demographic factors, and pre-pandemic health.

Background Bronchiolitis caused by respiratory syncytial virus (RSV) is a major cause of mortality and morbidity in infants. Aim To describe RSV epidemiology in children in the community in a high-income setting. Methods We used stored blood samples from the United Kingdom Born in Bradford cohort study that had been collected at birth, age 1 and 2 years old, tested for IgG RSV postfusion F antibody and linked to questionnaires and primary and hospital care records. We used finite mixture models to classify children as RSV infected/not infected according to their antibody concentrations at age 1 and 2 years. We assessed risk factors for primary RSV infection at each age using Poisson regression models. Results The study cohort included 700 children with cord blood samples; 490 had additional blood samples taken at both ages 1 and 2 years old. Of these 490 children, 258 (53%; 95% confidence interval (CI): 48–57%) were first infected with RSV at age 1, 99 of whom (38%; 95% CI: 33–43%) had been in contact with healthcare during peak RSV season (November–January). Having older siblings, birth in October–June and attending formal childcare were associated with risk of RSV infection in infancy. By age 2, a further 164 of 490 children (33%; 95% CI: 29–38%) had been infected. Conclusion Over half of children experienced RSV infection in infancy, a further one third had evidence of primary RSV infection by age 2, and one in seven remained seronegative by their second birthday. These findings will inform future analyses to assess the cost-effectiveness of RSV vaccination programmes in high-income settings.

The World Asthma Phenotypes (WASP) study is being conducted in five centres in Brazil, Ecuador, Uganda, New Zealand and the United Kingdom, with a range of prevalence levels and exposures, and a likely range of phenotype distributions. Here we present the main findings with regards to asthma inflammatory phenotypes. We recruited 998 cases and 356 controls: 204/40 in Brazil, 176/67 in Ecuador, 207/50 in Uganda, 235/132 in New Zealand, and 176/67 in the United Kingdom. All centres studied children and adolescents (age-range 8–20 years), with the exception of the UK centre which involved 26–27 year olds. The proportion of participants who produced sputum samples was 87%, with a range from 74% (Brazil) to 91% (Ecuador), and of these 62% were countable with regards to the inflammatory cell types.The proportions of asthma cases who were classified as eosinophilic or mixed granulocytic asthma (the two inflammatory phenotypes which involve eosinophilia) was 39% overall: 35% in Brazil, 32% in Ecuador, 33% in Uganda, 50% in New Zealand, and 28% in the United Kingdom. The non-eosinophilic asthmatics (NEA) had similar chronic severity (e.g. in terms of attacks in the previous year) to the eosinophilic asthmatics (EA). Of the 61% of cases with NEA, 50% showed no signs of inflammation (paucigranulocytic), with 11% having neutrophilic inflammation. This is the first time that sputum induction has been used in a standardised manner to compare asthma inflammatory phenotypes in high income countries (HICs) and low-and-middle-income countries (LMICs). It confirms that most cases are non-eosinophilic, with the proportions ranging from 50% to 72%, across these varied environments; most of these non-eosinophilic cases were paucigranulocytic, with no sign of airways inflammation.

Metabolomics is the quantification of small molecules, commonly known as metabolites. Collectively, these metabolites and their interactions within a biological system are known as the metabolome. The metabolome is a unique area of study, capturing influences from both genotype and environment. The availability of high-throughput technologies for quantifying large numbers of metabolites, as well as lipids and lipoprotein particles, has enabled detailed investigation of human metabolism in large-scale epidemiological studies. The Born in Bradford (BiB) cohort includes 12,453 women who experienced 13,776 pregnancies recruited between 2007-2011, their partners and their offspring. In this data note, we describe the metabolomic data available in BiB, profiled during pregnancy, in cord blood and during early life in the offspring. These include two platforms of metabolomic profiling: nuclear magnetic resonance and mass spectrometry. The maternal measures, taken at 26-28 weeks� gestation, can provide insight into the metabolome during pregnancy and how it relates to maternal and offspring health. The offspring cord blood measurements provide information on the fetal metabolome. These measures, alongside maternal pregnancy measures, can be used to explore how they may influence outcomes. The infant measures (taken around ages 12 and 24 months) provide a snapshot of the early life metabolome during a key phase of nutrition, environmental exposures, growth, and development. These metabolomic data can be examined alongside the BiB cohorts� extensive phenotype data from questionnaires, medical, educational and social record linkage, and other �omics data.

Background The prevalence of allergic diseases has increased in recent decades, but the causes remain unclear. Changes in the epidemiology of childhood infections could have contributed, but the current evidence is inconclusive. This study aims to investigate whether age at cytomegalovirus (CMV), Epstein‐Barr virus (EBV) or varicella zoster virus (VZV) infection is associated with the development of atopy. Methods A total of 2559 children were enrolled in the Born in Bradford Allergy and Infection Study. Serum samples collected at 12 and 24 months were tested for CMV‐IgG, EBV‐IgG and VZV‐IgG for 1000 children to establish age at infection. Skin prick testing (SPT) was conducted at age 4 years. Results Serology and SPT results were available for 740 children. Of these, 135 (18%) were atopic. In girls, there was a strong association of CMV infection in the second year with increased odds of atopy (adjusted OR 4.38, 95% CI 1.87‐10.29) but this was not observed in boys. Age at EBV or VZV infection was not associated with risk of atopy in unadjusted analysis, but there was effect modification by sex; girls infected with VZV in the second year of life had increased odds of atopy (adjusted OR 2.85, 95% CI 1.29‐6.30). Conclusions Our results highlight potential sex‐specific effects of age at CMV infection and age at VZV infection on risk of atopy, which provide insight into the mechanisms involved in the development of atopy.

There are important differences in the risk of SARS-CoV-2 infection and death depending on occupation. Infections in healthcare workers have received the most attention, and there are clearly increased risks for intensive care unit workers who are caring for COVID-19 patients. However, a number of other occupations may also be at an increased risk, particularly those which involve social care or contact with the public. A large number of data sets are available with the potential to assess occupational risks of COVID-19 incidence, severity, or mortality. We are reviewing these data sets as part of the Partnership for Research in Occupational, Transport, Environmental COVID Transmission (PROTECT) initiative, which is part of the National COVID-19 Core Studies. In this report, we review the data sets available (including the key variables on occupation and potential confounders) for examining occupational differences in SARS-CoV-2 infection and COVID-19 incidence, severity and mortality. We also discuss the possible types of analyses of these data sets and the definitions of (occupational) exposure and outcomes. We conclude that none of these data sets are ideal, and all have various strengths and weaknesses. For example, mortality data suffer from problems of coding of COVID-19 deaths, and the deaths (in England and Wales) that have been referred to the coroner are unavailable. On the other hand, testing data is heavily biased in some periods (particularly the first wave) because some occupations (e.g. healthcare workers) were tested more often than the general population. Random population surveys are, in principle, ideal for estimating population prevalence and incidence, but are also affected by non-response. Thus, any analysis of the risks in a particular occupation or sector (e.g. transport), will require a careful analysis and triangulation of findings across the various available data sets.

Background Bronchiolitis caused by respiratory syncytial virus (RSV) is the most common reason for hospital admissions in infants. The community burden of RSV is less well understood. We used a unique dataset linking serial serological data, questionnaires, and routinely collected health records to undertake the first community-based serological survey of RSV in England. Methods We used stored blood samples, tested for immunoglobulin G RSV postfusion F antibody, linked to questionnaires and primary and secondary care records from the Born in Bradford cohort study, collected at birth, and ages 1 and 2 years. We used finite mixture models to classify children as RSV infected or not infected according to their antibody concentrations. We fitted multivariable Poisson regression models with robust error variances to identify factors associated with increased risk of primary RSV infection at ages younger than 1 year and 1–2 years. Findings The study included 490 children. By their first birthday, 258 children (53%, 95% CI 48–57%) had serological evidence of past RSV infection, 99 (38%) of whom contacted health-care services during peak RSV season (November–January) due to a respiratory tract infection. Having older siblings (adjusted risk ratio [aRR] 1·52, 95% CI 1·21–1·92, comparing one to no older siblings), Pakistani ethnicity (1·31, 1·04–1·65, compared with White British), blood sample taken outside October–December (1·74, 1·35–2·24 for January–March and 1·60, 1·23–2·08 for April–June, compared with October–December), and attending formal childcare (1·40, 1·12–1·75, compared with no formal childcare) were predictive of RSV infection in infancy. A further 164 children (33%, 95% CI 29–38%) were newly infected at ages 1–2 years, 58 (35%) of whom had contact with health-care services. 14% (95% CI 11–17%) had no evidence of RSV infection by age 2 years. Interpretation Around half of children are infected with RSV during the first year of life, and one in seven children remain unexposed after their second year. Our findings will inform future analyses to assess the cost-effectiveness of RSV vaccination programmes. Our novel approach reusing stored blood samples and linked data present a time-efficient and cheap method for future serological surveys of RSV. Funding Wellcome Trust Seed Award In Science (grant reference number 207673/Z/17/Z).

Background Cytomegalovirus (CMV), Epstein Barr virus (EBV) and varicella-zoster virus (VZV) are common herpesviruses frequently acquired in childhood, which establish persistent, latent infection and are likely to impact the developing immune system. Little is known about the epidemiology of CMV and EBV infections in contemporary UK paediatric populations, particularly whether age at infection differs by ethnic group. Methods Children enrolled in the Born in Bradford Allergy and Infection Study had a blood sample taken and a questionnaire completed at 12 and 24 months of age. Ordered logistic regression quantified associations between ethnicity and other risk factors and age at CMV/EBV/VZV infection (

HIV infection affects B cell function and is associated with increased immunoglobulin levels, including in HIV-infected pregnant women. It is unknown if maternal HIV infection affects immunoglobulins in their uninfected children. We investigated this using prospective longitudinal data from children born to HIV-infected women enrolled in the European Collaborative Study (ECS). Data from children enrolled in the European Paediatric Hepatitis C Virus Network (EPHN) were used as a comparison group. Associations between infant and maternal factors and child log(10) total IgG, IgM, and IgA levels were quantified in linear regression analyses. A total of 1751 HIV-uninfected (ECS) and 167 HCV-uninfected children (EPHN) were included. HIV-uninfected children had significantly higher IgG, IgM, and IgA levels than HCV-uninfected children up to at least 24 months. Among HIV-exposed uninfected children, IgG levels from birth until 5 years of age were correlated with increased maternal IgG levels. ART exposure in fetal and early neonatal life was associated with lower IgG. These findings indicate alterations in immunoglobulin levels in uninfected children born to HIV-infected women, suggesting that fetal exposure to a chronically activated maternal immune system is associated with an altered humoral response.

BACKGROUND: Serum alanine aminotransferase (ALT) levels are commonly used to indicate liver damage. Although elevated levels indicate possible liver injury, abnormalities, or disease, some patients with "normal" ALT levels have minimal to mild liver disease. Recently, ALT reference ranges for adults were queried and revised ranges proposed with lower upper limits of normality. The appropriateness of current paediatric ALT reference ranges is unclear. MATERIAL AND METHODS: Hepatitis C virus (HCV)-uninfected children from the European Paediatric HCV Network represent a large population of healthy children born to HCV-infected mothers, with ALT observations collected prospectively from birth. Linear regression identified factors associated with ALT levels while accounting for within-child repeated measurements. ALT centiles stratified by sex were calculated using maximum penalized likelihood methods and LMS software. RESULTS: A total of 1293 HCV-uninfected children had 5011 ALT measurements during follow-up. ALT levels significantly decreased with increasing age, whilst ALT levels were significantly lower in girls than boys. Reference cutoffs representing the 95th centiles before 18 months of age were 60 U/L for boys and 55 U/L for girls, decreasing to 40 U/L for boys and 35 U/L for girls after 18 months of age. CONCLUSIONS: These reference ranges represent a unique investigation of ALT levels in a healthy child population. We show lower and more detailed age-related cutoffs of normality than available. Additionally, we demonstrate a significant effect of sex on ALT reference ranges, which has not previously been described in children younger than 5 years of age.

To investigate whether it is appropriate to assume comparability of hepatitis virus C (HCV)-RNA results across laboratories in multi-centre studies, nine laboratories of the European Paediatric HCV Network participated in an international proficiency study of HCV-RNA assays. A panel of 12 samples of different dilutions and genotypes was sent to each laboratory and tested with qualitative and/or quantitative HCV-RNA assays according to local procedures. Commercial assays were used in seven laboratories and in-house assays in two. All six laboratories in which a commercial qualitative assay was used were proficient, as were four of six runs (in five laboratories) in which a commercial quantitative assay was used. The proficiency of the laboratories where in-house assays were used could not be assessed according to the VQC definition because of differences in the methods used. Overall, there were several false-negative results, but only one false-positive result with a quantitative assay and none with a qualitative assay. The false-negative results may have implications for the diagnosis of infection, and highlight the need for an antibody test to be performed at 18 months to confirm the absence of infection. The results of qualitative assays were generally consistent across laboratories but it was difficult to evaluate and compare the results of quantitative assays. Multivariate analysis of data collected in multi-centre studies should therefore allow for centre and/or assay used.

Objective To examine the putative protective effect of HIV-2 infection against subsequent HIV-1 infection. Design Retrospective analysis of data from two cross-sectional surveys in the same community. Methods Two surveys between 1989 and 1998 in a rural area in northwestern Guinea-Bissau provided data from residents aged 15-59 years. HIV testing was done in the first survey. In the second survey, tests were made for both HIV and syphilis, and data on sociodemographic factors and sexual behaviour, including commercial sex work, were gathered. Qualitative polymerase chain reaction amplification of HIV-1 and HIV-2 viral DNA was performed on serologically dually reactive samples. Results Of the 2276 eligible adult villagers initially tested, 60% (1360) provided a second sample. Of 110 HIV-2-infected subjects, 17 became additionally infected with HIV-1 [incidence rate (IR), 26.3/1000 person-years observation]. Of the 1250 HIV-seronegative subjects, 24 became infected with HIV-1 (IR, 2.8/1000 person-years observation). The incidence rate ratio (IRR), comparing the incidence rate in HIV-2-infected people with the rate in HIV-seronegative subjects, was > 1 in all three "risk groups": men, female commercial sex workers, and other women. The overall estimate of the IRR, adjusted for age group and risk group, was 3.24 (confidence interval, 1.5-7.1). Conclusions There was no protective effect of HIV-2 in this population. HIV-2 cannot be regarded as a vaccine, but, instead, may be a risk factor for HIV-1 infection.

Objectives To assess antenatal hepatitis B and syphilis screening policies in the UK. Design Postal questionnaire survey. Setting One hundred and ninety-two obstetric units and 116 Public Health directorates. Main outcome measures Antenatal screening policy and line of responsibility for ensuring vaccine uptake in hepatitis B virus exposed children. Results Replies were received from 140 (73%) obstetric centres and 99 (85%) Public Health directors. Forty per cent of obstetric centres now offer hepatitis B virus tests to all pregnant women, and nearly one-quarter (24.1 %) of all births in the UK in 1996 occurred in centres with a universal testing policy. The prevalence of chronic hepatitis B virus ranged from 0.3 to 17.5 per 1000 deliveries. Universal antenatal screening for serological evidence of syphilis was the norm, but five obstetric centres respondents and three Public Health directors were considering its discontinuation. In the nine London centres, syphilis prevalence was 2.06 per 1000 pregnant women, compared with 0.24 per 1000 elsewhere. Responses from Public Health directors indicated the nonspecific nature of the antenatal care contract. Responsibility for hepatitis B virus vaccination of the newly born infant rests with the hospital paediatrician, with transfer of responsibility to the community usually occurring through a discharge letter. Only two areas had a monitoring system to ensure full hepatitis B virus vaccination coverage of exposed infants. Conclusions If antenatal screening policies are to be equitable there is a need for a clear national policy, and systems need to be established to monitor local policy and practice.

Results To date we have received responses from clinicians from 16 centres, caring for a total of 35 HIV/HCV coinfected children. Four centres were not currently following any coinfected children. Only one centre had a written policy for the management and treatment of HIV/HCV coinfected children and in most other centres (8/11, 72%) decisions regarding the care of coinfected children were taken at the hospital or departmental level with only 3 out of 11 centres relying on regional or national decisionmaking. In addition to standard laboratory tests for monitoring HIV disease (HIV RNA quantification, CD4 counts etc), 6/12 centres also performed HCV RNA PCR tests at least annually and 6/12 centres carried out ALT and AST tests at least every 6 months in coinfected children. Liver biopsy was rarely performed but liver ultrasound was performed in 5 out of 12 centres at least annually. 91% of 11 centres performed HCV genotyping on all HIV/HCV coinfected children and 88% of 8 centres monitored for evidence of hepatotoxicity in coinfected children receiving antiretroviral treatment for HIV disease. Only one centre had ever treated coinfected children for HIV and HCV infections concurrently but 4/7 other centres stated they would consider treatment at the same time if necessary. In the situation of an HIV/HCV coinfection diagnosis later in childhood, 3/7 respondents stated that they would treat HCV infection before starting HIV therapy.

To identify the age at which HCV infection can be accurately excluded by serology in young children born to HCV-infected mothers and to determine an appropriate schedule of antibody testing, most informative to clinical practice.Children born to HCV-infected mothers were followed in centres of the European Paediatric HCV Network. Turnbull survival analysis techniques were used to estimate the age at which HCV-uninfected children will lose maternally acquired HCV antibodies. Factors associated with age at antibody loss were assessed in logistic regression.In 1104 children followed from birth and later confirmed to be HCV uninfected, an estimated 57% will have lost passively acquired HCV antibodies before 6 mo of age and an estimated 95% by 12 mo. Maternal HCV viraemia antenatally was associated with later, and maternal HIV-HCV co-infection with earlier loss of antibody. Actual antibody testing of uninfected children at 12 mo identified 82% of those tested to be anti-HCV negative.Serological confirmation of HCV uninfection remains necessary given the uncertainty in the specificity of virological tests. These results suggest that, in most children, HCV infection can be ruled out with serological testing at an earlier age than previously thought, and that nearly all children born to HCV-infected mothers will have lost passively acquired maternal antibodies by 1 y of age. Antibody loss was significantly later among children born to HCV viraemic mothers. The earlier loss of HCV antibodies in children born to HIV co-infected mothers may be due to HIV treatment.

BACKGROUND: Risk factors for mother-to-child transmission of hepatitis C virus (HCV) are poorly quantified. METHODS: We conducted a European multicenter prospective study of HCV-infected pregnant women and their infants. Children with > or =2 positive HCV RNA polymerase chain reaction test results and/or anti-HCV antibodies after 18 months of age were considered to be infected. RESULTS: The overall HCV vertical transmission rate was 6.2% (95% confidence interval [CI], 5.0%-7.5%; 91/1479). Girls were twice as likely to be infected as boys (adjusted odds ratio [OR], 2.07 [95% CI, 1.23-3.48]; P=.006). There was no protective effect of elective cesarean section (CS) delivery on HCV vertical transmission (adjusted OR, 1.46 [95% CI, 0.86-2.48]; P=.16). HCV/human immunodeficiency virus-coinfected women more frequently transmitted HCV than did women with HCV infection only, although the difference was not statistically significant (adjusted OR, 1.82 [95% CI, 0.94-3.52]; P=.08). Maternal history of injection drug use, prematurity, and breast-feeding were not significantly associated with transmission. Transmission occurred more frequently from viremic women, but it also occurred from a few nonviremic women. CONCLUSIONS: Our results strongly suggest that women should neither be offered an elective CS nor be discouraged from breast-feeding on the basis of HCV infection alone. The sex association is an intriguing finding that probably reflects biological differences in susceptibility or response to infection.

Based on research evidence the UK National Screening Committee recently recommended that routine antenatal screening for hepatitis C virus (HCV) infection should not be introduced into the UK antenatal screening programme. In this paper we review the evidence on which this decision was based, addressing the criteria that need to be considered before the introduction of a new screening programme.

To clarify policies regarding management of HIV-infected women, relating to pregnancy, in view of current European consensus guidelines.Postal questionnaire survey in 36 hospitals in 11 European countries.Responses were received from 22 (61%) centres, representing all 11 countries. In principle, antiretroviral therapy (ART) would be reviewed in treated women wanting to become pregnant in nearly all centres. Multidisciplinary management of infected pregnant women was routine in 17 (77%) centres, facilitating continuity of care. Approximately half the clinicians would use zidovudine monotherapy for pregnant women without indications for ART, while the remainder prescribed combination therapy. In 1998-2000, pre-eclampsia was the most prominent adverse event (22 centres) in women receiving ART, with congenital abnormalities (13 abnormalities in 6 centres) and stillbirth (5 centres) also reported.Policies varied, particularly regarding prophylactic ART for women without indications for treatment and did not always follow current European guidelines.

The prevalence of hepatitis C virus (HCV) infection among pregnant women in Europe is generally below 2%. Although women with a history of parenteral exposures or injecting drug use are at an increased risk of infection, a substantial proportion of infected women do not report any risk factors. Targeted screening is thus not recommended. The risk of mother-to-child, or vertical, transmission of HCV is about 5% overall but can be as high as 15%, depending on maternal HIV infection status and HCV RNA viral load. Larger studies are needed to confirm or refute the potential protective effect of elective cesarean section delivery. However, for HCV-positive women who are co-infected with HIV, elective cesarean section delivery is associated with a reduced risk of vertical transmission of HIV as well as HCV. The risk of postnatal transmission through breastfeeding cannot be excluded but is likely to be low for most HCV-infected women. The long-term natural history of vertically acquired HCV needs further elucidation and the efficacy of potential therapies for infected children need to be evaluated in randomized controlled trials.

BACKGROUND: Higher risks of asthma have been observed in children with prenatal exposure to antibiotics and during early life compared with those who have not. However, the causality of such associations is unclear. OBJECTIVE: To assess whether exposure to antibiotics in early life had a causal effect in increasing the risk of asthma in children diagnosed at 5-8 years of life, and the impact in the target population. METHODS: Data were from electronic health records and questionnaires for children and their mothers in the Born in Bradford birth cohort. Exposure variables were prescriptions of systemic antibiotics to the mother during pregnancy (prenatal) and to the children at 0-24 months of life (postnatal). We assessed the association in 12,476 children with several approaches to deal with different sources of bias (triangulation): the interactions with mother's ethnicity, mode of delivery, and between prenatal and postnatal exposures; dose-response; and estimated the population attributable risk. RESULTS: There was an association between prenatal exposure at 7-27 days before the child's birth and asthma (adjusted OR = 1.40; 1.05, 1.87), but no association with the negative control exposure (before pregnancy) (adjusted OR = 0.99 (0.88, 1.12)). For postnatal exposure, the adjusted OR was 2.00 (1.71, 2.34), and for sibling analysis, it was 1.99 (1.00, 3.93). For postnatal exposure, the risk of asthma increased with the number of prescriptions. The observed effect of both exposures was lower among children with mothers of Pakistani ethnicity, but inconclusive (p > .25). The interaction between prenatal and postnatal exposures was also inconclusive (p = .287). The population attributable risk of postnatal exposure for asthma was 4.6% (0.1% for prenatal). CONCLUSIONS: We conclude that the associations between both late-pregnancy prenatal exposure to antibiotics and postnatal exposure to antibiotics and an increased risk of asthma are plausible and consistent with a causal effect.

Background Immunoglobulin levels are known to be elevated in HIV infected children. However, little is known about the effect of maternal HIV infection and the maternal altered immune system on immunoglobulin levels in uninfected children. As few data are available on immunoglobulins from young healthy children, we used data from uninfected children born to hepatitis C virus (HCV) infected women as a comparison. Methods Prospective data on immunoglobulin levels were available from birth to 5 years for children enrolled in the European Collaborative Study (ECS) of children born to HIV-1 infected women and from birth to 24 months for children enrolled in the European Paediatric HCV Network (EPHN). Children born to HIV/HCV co-infected women were excluded. Smoothers (running means) illustrated patterns of immunoglobulins over age by infection status. Associations between infant and maternal factors and child log10 total IgG, IgM and IgA levels were quantified in linear regression analyses allowing for repeated measures within child. Further analyses were performed using only data of HIV exposed uninfected children to investigate associations between child immunoglobulins and maternal immunological and virological factors and anti-retroviral therapy exposure. Results 1751 HIV uninfected, 190 HIV infected children (ECS), 173 HCV uninfected and 30 HCV infected children (EPHN) were included. HIV infected children had higher levels of all immunoglobulins compared to uninfected children over all ages. HIV uninfected children had significantly higher IgG, IgM and IgA levels than HCV uninfected children upto at least 24 months, adjusting for gender, prematurity and race. Prematurity was associated with significantly lower levels of immunoglobulins upto 24 months. Children born to African women had higher IgG and IgA levels upto 24 months than those born to white women but lower IgM in the first 6 months. Among HIV uninfected children higher IgG levels were associated with elevated maternal IgG levels, as well for measurements from 18 months to 5 years of age. No significant effect of maternal CD4 count was observed. ART exposure was associated with significantly lower IgG levels at 6-24 months. Race was not associated with immunoglobulin levels in multivariable analyses in this sub-group. Conclusions These findings indicate significant alterations in immunoglobulin levels in uninfected children born to HIV infected women. This suggests that exposure to an activated maternal immune system is associated with an altered humoral response in children without antigen stimulation, and warrants further research.