Universal antenatal screening for group B streptococcus colonisation in the UK

Background: Group B Streptococcus (GBS) is the leading cause of neonatal sepsis and meningitis. Currently, the UK recommends against universal antenatal screening to prevent early-onset GBS disease (EOGBS, <7 days). Key gaps around GBS natural history, harms from screening and a lack of high-quality data to prove screening effectiveness make it difficult to ensure the benefits of GBS screening outweigh the harms. There is also a wider gap on policy-making processes for screening. The overall aim of this thesis is to address these gaps and examine whether the UK should introduce universal GBS screening as a result. Methods: In addition to a literature review, I used two approaches: systematic review/metaanalysis and ecological trend analysis. The systematic reviews synthesised evidence on the screening policy-making processes, mechanisms of EOGBS and adverse events from intrapartum antibiotic prophylaxis (IAP) to prevent EOGBS. In the absence of RCTs, I combined ecological data on the benefits and harms of GBS screening, then analysed their trends across time compared with other prevention strategies in regression analyses adjusting for context differences. Results: Evidence from 17 countries showed that most GBS screening recommendations were not developed by screening organisations and it is not known whether screening principles and the likely unseen harms of GBS screening were considered. Seventeen studies revealed that we do not fully understand the natural history of why some mothers, but not others, transmit GBS to their neonates, or which neonates will develop EOGBS. There was consistent evidence that heavy bacterial load was associated with transmission and progression to EOGBS. Neonates colonised with serotype III were also twice as likely to develop EOGBS compared with serotype Ia and II. However, the evidence was old and at high risk of bias. The selective culture test at 35 to 37 weeks gestation is not an accurate predictor of EOGBS and at least 99% of screen-positive and treated mothers (and their neonates) would be over-treated. Seventeen observational studies and 13 RCTs showed a wide range of potential harms from IAP, including cerebral palsy, functional impairment and antibiotic resistance. However, there was little high-quality and applicable evidence to quantify the frequency of adverse events. The three ecological trend analyses combining data from 59 geographical areas showed that EOGBS incidence decreased by approximately 0.02 per 1,000 livebirths per year in areas that most recently reported GBS screening, whereas it increased by approximately 0.01 to 0.02 per 1,000 livebirths in areas most recently reporting risk-based prevention. Areas that recently did not have GBS prevention displayed conflicting EOGBS trends. By contrast, there was no evidence that screening impacted annual early-onset sepsis trends compared with other, or no prevention strategies; however, this study did not have a sufficient sample size. The was no harmful impact of GBS screening on LOGBS trends compared with other, or no prevention. There was also no evidence that screening increased early-onset E. coli incidence and the percentage of GBS cases resistant to clindamycin and erythromycin, compared with risk-based or no prevention; again, these analyses did not have a sufficient sample size. The findings of these studies must be treated with caution as some results may be due to low statistical power and others were unstable across analyses. The findings also contain numerous limitations as covariates were poorly collected in most countries. Therefore, the evidence on the benefits and harms of universal GBS screening remains inconclusive. Conclusion: GBS infection is an important health condition and its persistence, poor screening tests and the IAP harms stress the need for a better understanding of the natural history of GBS and more effective prevention. Evidence on the harms and benefits of GBS screening is limited, therefore, screening should not be introduced in the UK. Ecological trend analysis was not an adequate method to inform GBS screening decisions, however, it may be useful for screening decisions on other conditions

Community-onset sepsis and its public health burden : a systematic review

Background: Sepsis is a life-threatening condition and major contributor to public health and economic burden in the industrialised world. The difficulties in accurate diagnosis lead to great variability in estimates of sepsis incidence. There has been even a greater uncertainty regarding the incidence of and risk factors for community-onset sepsis (COS). We systematically reviewed the recent evidence on the incidence and risk factors of COS in high income countries. Methods: Cohort and case-control studies were eligible for inclusion. Medline and Embase databases were searched from 2002 onwards. References of relevant publications were hand searched. Two reviewers screened titles/abstracts and full-texts independently. One reviewer extracted data and appraised studies which were cross-checked by independent reviewers. Disagreements were resolved via consensus. Odds ratios (ORs) and 95 percent confidence intervals (95% CIs) were ascertained by type of sepsis (non-severe, severe, and septic shock). Results: 10 cohort and 4 case-control studies were included. There was a wide variation in the incidence (# cases per 100,000 per year) of non-severe sepsis (range: 64 - 514), severe sepsis (range: 40 - 455), and septic shock (range: 9 - 31). Heterogeneity precluded statistical pooling. Two cohort and 4 case-control studies reported risk factors for sepsis. In one casecontrol and one cohort study, older age and diabetes were associated with increased risk of sepsis. The same case-control study showed an excess risk for sepsis in participants with clinical conditions (e.g., immunosuppression, lung disease, and peripheral artery disease). In one cohort study, higher risk of sepsis was associated with being a nursing home resident (OR=2.60, 95% CI: 1.20, 5.60) and in the other cohort study with being physically inactive (OR=1.33, 95% CI: 1.13, 1.56) and smoking tobacco (OR=1.85, 95% CI: 1.54, 2.22). The evidence on sex, ethnicity, statin use, and body mass index as risk factors was inconclusive. Conclusions: The lack of a valid standard approach for defining sepsis makes it difficult to determine the true incidence of COS. Differences in case ascertainment contribute to the variation in incidence of COS. The evidence on COS is limited in terms of the number and quality of studies. This review highlights the urgent need for an accurate and standard method for identifying sepsis. Future studies need to improve the methodological shortcomings of previous research in terms of case definition, identification, and surveillance practice

Targeted screening in the UK:A narrow concept with broad application

A recent report on screening in the UK proposed that the responsibility for recommendations on population and targeted screening programmes should be held by one new integrated advisory body. There is no wide international consensus on the definition of targeted screening. Our review identified and compared the defining components of screening terms: targeted, population, selective, and cascade screening, and case finding. Definitions of targeted screening and population screening were clearly demarcated by the eligible population; targeted and selective screening were found to be conceptually interchangeable; cascade screening, whilst conceptually similar to targeted screening across several components, was only used within the context of genetic diseases. There was little consensus between different definitions of case finding. These comparisons contributed to an updated definition of targeted screening. Considerable overlap between definition components across terms implies that a broad range of disease areas may fall into the remit of the new advisory body

Repeat screening for syphilis in pregnancy as an alternative screening strategy in the UK:a cost-effectiveness analysis

OBJECTIVES: To assess the cost-effectiveness of universal repeat screening for syphilis in late pregnancy, compared with the current strategy of single screening in early pregnancy with repeat screening offered only to high-risk women. DESIGN: A decision tree model was developed to assess the incremental costs and health benefits of the two screening strategies. The base case analysis considered short-term costs during the pregnancy and the initial weeks after delivery. Deterministic and probabilistic sensitivity analyses and scenario analyses were conducted to assess the robustness of the results. SETTING: UK antenatal screening programme. POPULATION: Hypothetical cohort of pregnant women who access antenatal care and receive a syphilis screen in 1 year. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the cost to avoid one case of congenital syphilis (CS). Secondary outcomes were the cost to avoid one case of intrauterine fetal demise (IUFD) or neonatal death and the number of women needing to be screened/treated to avoid one case of CS, IUFD or neonatal death. The cost per quality-adjusted life year gained was assessed in scenario analyses. RESULTS: Base case results indicated that for pregnant women in the UK (n=725 891), the repeat screening strategy would result in 5.5 fewer cases of CS (from 8.8 to 3.3), 0.1 fewer cases of neonatal death and 0.3 fewer cases of IUFD annually compared with the single screening strategy. This equates to an additional £1.8 million per case of CS prevented. When lifetime horizon was considered, the incremental cost-effectiveness ratio for the repeat screening strategy was £120 494. CONCLUSIONS: Universal repeat screening for syphilis in pregnancy is unlikely to be cost-effective in the current UK setting where syphilis prevalence is low. Repeat screening may be cost-effective in countries with a higher syphilis incidence in pregnancy, particularly if the cost per screen is low

Long-term healthcare utilisation, costs and quality of life after invasive group B Streptococcus disease: a cohort study in five low-income and middle-income countries

Introduction There are no published data on the long-term impact of invasive group B Streptococcus disease (iGBS) on economic costs or health-related quality of life (HRQoL) in low-income and middle-income countries. We assessed the impact of iGBS on healthcare utilisation, costs and HRQoL in Argentina, India, Kenya, Mozambique and South Africa. Methods Inpatient and outpatient visits, out-of-pocket (OOP) healthcare payments in the 12 months before study enrolment, and health-state utility of children and caregivers (using the EuroQol 5-Dimensions-3-Level) were collected from iGBS survivors and an unexposed cohort matched on site, age at recruitment and sex. We used logistic or Poisson regression for analysing healthcare utilisation and zero-inflated gamma regression models for family and health system costs. For HRQoL, we used a zero-inflated beta model of disutility pooled data. Results 161 iGBS-exposed and 439 unexposed children and young adults (age 1–20) were included in the analysis. Compared with unexposed participants, iGBS was associated with increased odds of any healthcare utilisation in India (adjusted OR 11.2, 95% CI 2.9 to 43.1) and Mozambique (6.8, 95% CI 2.2 to 21.1) and more frequent healthcare visits (adjusted incidence rate ratio (IRR) for India 1.7 (95% CI 1.4 to 2.2) and for Mozambique 6.0 (95% CI 3.2 to 11.2)). iGBS was also associated with more frequent days in inpatient care in India (adjusted IRR 4.0 (95% CI 2.3 to 6.8) and Kenya 6.4 (95% CI 2.9 to 14.3)). OOP payments were higher in the iGBS cohort in India (adjusted mean: Int$682.22 (95$364.28 to Int$1000.16) vs Int$133.95 (95% CI Int$72.83 to Int$195.06)) and Argentina (Int$244.86 (95$47.38 to Int$442.33) vs Int$52.38 (95% CI Int$−1.39 to Int$106.1)). For all remaining sites, differences were in the same direction but not statistically significant for almost all outcomes. Health-state disutility was higher in iGBS survivors (0.08, 0.04–0.13 vs 0.06, 0.02–0.10). Conclusion The iGBS health and economic burden may persist for years after acute disease. Larger studies are needed for more robust estimates to inform the cost-effectiveness of iGBS prevention

Group B streptococcus infection during pregnancy and infancy: estimates of regional and global burden

Background: Group B streptococcus (GBS) colonisation during pregnancy can lead to invasive GBS disease (iGBS) in infants, including meningitis or sepsis, with a high mortality risk. Other outcomes include stillbirths, maternal infections, and prematurity. There are data gaps, notably regarding neurodevelopmental impairment (NDI), especially after iGBS sepsis, which have limited previous global estimates. In this study, we aimed to address this gap using newly available multicountry datasets. Methods: We collated and meta-analysed summary data, primarily identified in a series of systematic reviews published in 2017 but also from recent studies on NDI and stillbirths, using Bayesian hierarchical models, and estimated the burden for 183 countries in 2020 regarding: maternal GBS colonisation, iGBS cases and deaths in infants younger than 3 months, children surviving iGBS affected by NDI, and maternal iGBS cases. We analysed the proportion of stillbirths with GBS and applied this to the UN-estimated stillbirth risk per country. Excess preterm births associated with maternal GBS colonisation were calculated using meta-analysis and national preterm birth rates. Findings: Data from the seven systematic reviews, published in 2017, that informed the previous burden estimation (a total of 515 data points) were combined with new data (17 data points) from large multicountry studies on neurodevelopmental impairment (two studies) and stillbirths (one study). A posterior median of 19·7 million (95% posterior interval 17·9–21·9) pregnant women were estimated to have rectovaginal colonisation with GBS in 2020. 231800 (114 100–455000) early-onset and 162 200 (70200–394 400) late-onset infant iGBS cases were estimated to have occurred. In an analysis assuming a higher case fatality rate in the absence of a skilled birth attendant, 91 900 (44800–187 800) iGBS infant deaths were estimated; in an analysis without this assumption, 58300 (26 500–125800) infant deaths from iGBS were estimated. 37100 children who recovered from iGBS (14600–96200) were predicted to develop moderate or severe NDI. 40500 (21500–66 200) maternal iGBS cases and 46200 (20 300–111300) GBS stillbirths were predicted in 2020. GBS colonisation was also estimated to be potentially associated with considerable numbers of preterm births. Interpretation: Our analysis provides a comprehensive assessment of the pregnancy-related GBS burden. The Bayesian approach enabled coherent propagation of uncertainty, which is considerable, notably regarding GBS-associated preterm births. Our findings on both the acute and long-term consequences of iGBS have public health implications for understanding the value of investment in maternal GBS immunisation and other preventive strategies

Tuberculosis incidence among migrants according to migrant status: a cohort study, Denmark, 1993 to 2015.

Background Migrants account for the majority of tuberculosis (TB) cases in low-incidence countries in western Europe. TB incidence among migrants might be influenced by patterns of migration, but this is not well understood.Aim To investigate differences in TB risk across migrant groups according to migrant status and region of origin. Methods This prospective cohort study included migrants ≥ 18 years of age who obtained residency in Denmark between 1 January 1993 and 31 December 2015, matched 1:6 to Danish-born individuals. Migrants were grouped according to legal status of residency and region of origin. Incidence rates (IR) and incidence rate ratios (IRR) were estimated by Poisson regression. Results The cohort included 142,314 migrants. Migrants had significantly higher TB incidence (IR: 120/100,000 person-years (PY); 95% confidence interval (CI): 115–126) than Danish-born individuals (IR: 4/100,000 PY; 95% CI: 3–4). The IRR was significantly higher in all migrant groups compared with Danish-born (p < 0.01). A particularly higher risk was seen among family-reunified to refugees (IRR: 61.8; 95% CI: 52.7–72.4), quota refugees (IRR: 46.0; 95% CI: 36.6–57.6) and former asylum seekers (IRR: 45.3; 95% CI: 40.2–51.1), whereas lower risk was seen among family-reunified to Danish/Nordic citizens (IRR 15.8; 95% CI: 13.6–18.4) and family-reunified to immigrants (IRR: 16.9; 95% CI: 13.5–21.3). Discussion All migrants had higher TB risk compared with the Danish-born population. While screening programmes focus mostly on asylum seekers, other migrant groups with high risk of TB are missed. Awareness of TB risk in all high-risk groups should be strengthened and screening programmes should be optimised

Modeling the population-level impact of treatment on COVID-19 disease and SARS-CoV-2 transmission

Different COVID-19 treatment candidates are under development, and some are becoming available including two promising drugs from Merck and Pfizer. This study provides conceptual frameworks for the effects of three types of treatments, both therapeutic and prophylactic, and to investigate their population-level impact, to inform drug development, licensure, decision-making, and implementation. Different drug efficacies were assessed using an age-structured mathematical model describing SARS-CoV-2 transmission and disease progression, with application to the United States as an illustrative example. Severe and critical infection treatment reduces progression to COVID-19 severe and critical disease and death with small number of treatments needed to avert one disease or death. Post-exposure prophylaxis treatment had a large impact on flattening the epidemic curve, with large reductions in infection, disease, and death, but the impact was strongly age dependent. Pre-exposure prophylaxis treatment had the best impact and effectiveness, with immense reductions in infection, disease, and death, driven by the robust control of infection transmission. Effectiveness of both pre-exposure and post-exposure prophylaxis treatments was disproportionally larger when a larger segment of the population was targeted than a specific age group. Additional downstream potential effects of treatment, beyond the primary outcome, enhance the population-level impact of both treatments. COVID-19 treatments are an important modality in controlling SARS-CoV-2 disease burden. Different types of treatment act synergistically for a larger impact, for these treatments and vaccination.The authors are grateful for support provided by the Biomedical Research Program and the Biostatistics, Epidemiology, and Biomathematics Research Core, both at Weill Cornell Medicine-Qatar. This publication was made possible by extension of models developed through the National Priorities Research Program (NPRP), Qatar, grant number 9–040-3–008 (Principal investigator: LJA) and NPRP grant number 12S-0216–190094 (Principal investigator: LJA) from the Qatar National Research Fund (a member of Qatar Foundation; https://www.qnrf.org). The statements made herein are solely the responsibility of the authors. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Screening for latent TB, HIV, and hepatitis B/C in new migrants in a high prevalence area of London, UK: a cross-sectional study.

BACKGROUND: Rising rates of infectious diseases in international migrants has reignited the debate around screening. There have been calls to strengthen primary-care-based programmes, focusing on latent TB. We did a cross-sectional study of new migrants to test an innovative one-stop blood test approach to detect multiple infections at one appointment (HIV, latent tuberculosis, and hepatitis B/C) on registration with a General Practitioner (GP) in primary care. METHODS: The study was done across two GP practices attached to hospital Accident and Emergency Departments (A&E) in a high migrant area of London for 6 months. Inclusion criteria were foreign-born individuals from a high TB prevalence country (>40 cases per 100,000) who have lived in the UK ≤ 10 years, and were over 18 years of age. All new migrants who attended a New Patient Health Check were screened for eligibility and offered the blood test. We followed routine care pathways for follow-up. RESULTS: There were 1235 new registrations in 6 months. 453 attended their New Patient Health Check, of which 47 (10.4%) were identified as new migrants (age 32.11 years [range 18-72]; 22 different nationalities; time in UK 2.28 years [0-10]). 36 (76.6%) participated in the study. The intervention only increased the prevalence of diagnosed latent TB (18.18% [95% CI 6.98-35.46]; 181.8 cases per 1000). Ultimately 0 (0%) of 6 patients with latent TB went on to complete treatment (3 did not attend referral). No cases of HIV or hepatitis B/C were found. Foreign-born patients were under-represented at these practices in relation to 2011 Census data (Chi-square test -0.111 [95% CI -0.125 to -0.097]; p < 0.001). CONCLUSION: The one-stop approach was feasible in this context and acceptability was high. However, the number of presenting migrants was surprisingly low, reflecting the barriers to care that this group face on arrival, and none ultimately received treatment. The ongoing UK debate around immigration checks and charging in primary care for new migrants can only have negative implications for the promotion of screening in this group. Until GP registration is more actively promoted in new migrants, a better place to test this one-stop approach could be in A&E departments where migrants may present in larger numbers

Analyzing inherent biases in SARS-CoV-2 PCR and serological epidemiologic metrics

Background: Prospective observational data show that infected persons with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain polymerase chain reaction (PCR) positive for a prolonged duration, and that detectable antibodies develop slowly with time. We aimed to analyze how these effects can bias key epidemiological metrics used to track and monitor SARS-CoV-2 epidemics. Methods: An age-structured mathematical model was constructed to simulate progression of SARS-CoV-2 epidemics in populations. PCR testing to diagnose infection and cross-sectional surveys to measure seroprevalence were also simulated. Analyses were conducted on simulated outcomes assuming a natural epidemic time course and an epidemic in presence of interventions. Results: The prolonged PCR positivity biased the epidemiological measures. There was a lag of 10 days between the true epidemic peak and the actually-observed peak. Prior to epidemic peak, PCR positivity rate was twofold higher than that based only on current active infection, and half of those tested positive by PCR were in the prolonged PCR positivity stage after infection clearance. Post epidemic peak, PCR positivity rate poorly predicted true trend in active infection. Meanwhile, the prolonged PCR positivity did not appreciably bias estimation of the basic reproduction number R0. The time delay in development of detectable antibodies biased measured seroprevalence. The actually-observed seroprevalence substantially underestimated true prevalence of ever infection, with the underestimation being most pronounced around epidemic peak. Conclusions: Caution is warranted in interpreting PCR and serological testing data, and any drawn inferences need to factor the effects of the investigated biases for an accurate assessment of epidemic dynamics