Mortality, neurodevelopmental impairments, and economic outcomes after invasive group B streptococcal disease in early infancy in Denmark and the Netherlands: a national matched cohort study.

BACKGROUND: Group B Streptococcus (GBS) disease is a leading cause of neonatal death, but its long-term effects have not been studied after early childhood. The aim of this study was to assess long-term mortality, neurodevelopmental impairments (NDIs), and economic outcomes after infant invasive GBS (iGBS) disease up to adolescence in Denmark and the Netherlands. METHODS: For this cohort study, children with iGBS disease were identified in Denmark and the Netherlands using national medical and administrative databases and culture results that confirmed their diagnoses. Exposed children were defined as having a history of iGBS disease (sepsis, meningitis, or pneumonia) by the age of 89 days. For each exposed child, ten unexposed children were randomly selected and matched by sex, year and month of birth, and gestational age. Mortality data were analysed with the use of Cox proportional hazards models. NDI data up to adolescence were captured from discharge diagnoses in the National Patient Registry (Denmark) and special educational support records (the Netherlands). Health care use and household income were also compared between the exposed and unexposed cohorts. FINDINGS: 2258 children-1561 in Denmark (born from Jan 1, 1997 to Dec 31, 2017) and 697 in the Netherlands (born from Jan 1, 2000 to Dec 31, 2017)-were identified to have iGBS disease and followed up for a median of 14 years (IQR 7-18) in Denmark and 9 years (6-11) in the Netherlands. 366 children had meningitis, 1763 had sepsis, and 129 had pneumonia (in Denmark only). These children were matched with 22 462 children with no history of iGBS disease. iGBS meningitis was associated with an increased mortality at age 5 years (adjusted hazard ratio 4·08 [95% CI 1·78-9·35] for Denmark and 6·73 [3·76-12·06] for the Netherlands). Any iGBS disease was associated with an increased risk of NDI at 10 years of age, both in Denmark (risk ratio 1·77 [95% CI 1·44-2·18]) and the Netherlands (2·28 [1·64-3·17]). A history of iGBS disease was associated with more frequent outpatient clinic visits (incidence rate ratio 1·93 [95% CI 1·79-2·09], p<0·0001) and hospital admissions (1·33 [1·27-1·38], p<0·0001) in children 5 years or younger. No differences in household income were observed between the exposed and unexposed cohorts. INTERPRETATION: iGBS disease, especially meningitis, was associated with increased mortality and a higher risk of NDIs in later childhood. This previously unquantified burden underlines the case for a maternal GBS vaccine, and the need to track and provide care for affected survivors of iGBS disease. FUNDING: The Bill & Melinda Gates Foundation. TRANSLATIONS: For the Dutch and Danish translations of the abstract see Supplementary Materials section.

Population-Based Assessment of Clinical Risk Factors for Legionnaires' Disease.

We used US population-based surveillance data to characterize clinical risk factors for Legionnaires' disease (LD). The LD incidence increased by age and the risk was elevated for 12 clinical conditions, when compared to healthy adults. This information can be used to guide testing, treatment, and public health prevention efforts.

The role of immune correlates of protection on the pathway to licensure, policy decision and use of group B Streptococcus vaccines for maternal immunization: considerations from World Health Organization consultations.

The development of a group B Streptococcus (GBS) vaccine for maternal immunization constitutes a global public health priority, to prevent GBS-associated early life invasive disease, stillbirth, premature birth, maternal sepsis, adverse neurodevelopmental consequences, and to reduce perinatal antibiotic use. Sample size requirements for the conduct of a randomized placebo-controlled trial to assess vaccine efficacy against the most relevant clinical endpoints, under conditions of appropriate ethical standards of care, constitute a significant obstacle on the pathway to vaccine availability. Alternatively, indirect evidence of protection based on immunologic data from vaccine and sero-epidemiological studies, complemented by data from opsonophagocytic in vitro assays and animal models, could be considered as pivotal data for licensure, with subsequent confirmation of effectiveness against disease outcomes in post-licensure evaluations. Based on discussions initiated by the World Health Organization we present key considerations about the potential role of correlates of protection towards an accelerated pathway for GBS vaccine licensure and wide scale use. Priority activities to support progress to regulatory and policy decision are outlined.

Group B Streptococcal Disease Worldwide for Pregnant Women, Stillbirths, and Children: Why, What, and How to Undertake Estimates?

Improving maternal, newborn, and child health is central to Sustainable Development Goal targets for 2030, requiring acceleration especially to prevent 5.6 million deaths around the time of birth. Infections contribute to this burden, but etiological data are limited. Group B Streptococcus (GBS) is an important perinatal pathogen, although previously focus has been primarily on liveborn children, especially early-onset disease. In this first of an 11-article supplement, we discuss the following: (1) Why estimate the worldwide burden of GBS disease? (2) What outcomes of GBS in pregnancy should be included? (3) What data and epidemiological parameters are required? (4) What methods and models can be used to transparently estimate this burden of GBS? (5) What are the challenges with available data? and (6) How can estimates address data gaps to better inform GBS interventions including maternal immunization? We review all available GBS data worldwide, including maternal GBS colonization, risk of neonatal disease (with/without intrapartum antibiotic prophylaxis), maternal GBS disease, neonatal/infant GBS disease, and subsequent impairment, plus GBS-associated stillbirth, preterm birth, and neonatal encephalopathy. We summarize our methods for searches, meta-analyses, and modeling including a compartmental model. Our approach is consistent with the World Health Organization (WHO) Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER), published in The Lancet and the Public Library of Science (PLoS). We aim to address priority epidemiological gaps highlighted by WHO to inform potential maternal vaccination.

Estimates of the Burden of Group B Streptococcal Disease Worldwide for Pregnant Women, Stillbirths, and Children.

BACKGROUND: We aimed to provide the first comprehensive estimates of the burden of group B Streptococcus (GBS), including invasive disease in pregnant and postpartum women, fetal infection/stillbirth, and infants. Intrapartum antibiotic prophylaxis is the current mainstay of prevention, reducing early-onset infant disease in high-income contexts. Maternal GBS vaccines are in development. METHODS: For 2015 live births, we used a compartmental model to estimate (1) exposure to maternal GBS colonization, (2) cases of infant invasive GBS disease, (3) deaths, and (4) disabilities. We applied incidence or prevalence data to estimate cases of maternal and fetal infection/stillbirth, and infants with invasive GBS disease presenting with neonatal encephalopathy. We applied risk ratios to estimate numbers of preterm births attributable to GBS. Uncertainty was also estimated. RESULTS: Worldwide in 2015, we estimated 205000 (uncertainty range [UR], 101000-327000) infants with early-onset disease and 114000 (UR, 44000-326000) with late-onset disease, of whom a minimum of 7000 (UR, 0-19000) presented with neonatal encephalopathy. There were 90000 (UR, 36000-169000) deaths in infants <3 months age, and, at least 10000 (UR, 3000-27000) children with disability each year. There were 33000 (UR, 13000-52000) cases of invasive GBS disease in pregnant or postpartum women, and 57000 (UR, 12000-104000) fetal infections/stillbirths. Up to 3.5 million preterm births may be attributable to GBS. Africa accounted for 54% of estimated cases and 65% of all fetal/infant deaths. A maternal vaccine with 80% efficacy and 90% coverage could prevent 107000 (UR, 20000-198000) stillbirths and infant deaths. CONCLUSIONS: Our conservative estimates suggest that GBS is a leading contributor to adverse maternal and newborn outcomes, with at least 409000 (UR, 144000-573000) maternal/fetal/infant cases and 147000 (UR, 47000-273000) stillbirths and infant deaths annually. An effective GBS vaccine could reduce disease in the mother, the fetus, and the infant.

Cost-effectiveness of maternal GBS immunization in low-income sub-Saharan Africa.

BACKGROUND: A maternal group B streptococcal (GBS) vaccine could prevent neonatal sepsis and meningitis. Its cost-effectiveness in low-income sub-Saharan Africa, a high burden region, is unknown. METHODS: We used a decision tree model, with Markov nodes to project infants' lifetimes, to compare maternal immunization delivered through routine antenatal care with no immunization. 37 countries were clustered on the basis of economic and health resources and past public health performance. Vaccine efficacy for covered serotypes was ranged from 50% to 90%. The model projected EOGBS (early-onset) and LOGBS (late-onset) cases and deaths, disability-adjusted life years (DALYs), healthcare costs (2014 US$), and cost-effectiveness for a representative country in each of the four clusters: Guinea-Bissau, Uganda, Nigeria, and Ghana. Maximum vaccination costs/dose were estimated to meet two cost-effectiveness benchmarks, 0.5 GDP and GDP per capita/DALY, for ranges of disease incidence (reported and adjusted for under-reporting) and vaccine efficacy. RESULTS: At coverage equal to the proportion of pregnant women with≥4 antenatal visits (ANC4) and serotype-specific vaccine efficacy of 70%, maternal GBS immunization would prevent one-third of GBS cases and deaths in Uganda and Nigeria, where ANC4 is 50%, 42-43% in Guinea-Bissau (ANC4=65%), and 55-57% in Ghana (ANC4=87%). At a vaccination cost of $7/dose, maternal immunization would cost $320-$350/DALY averted in Guinea-Bissau, Nigeria, and Ghana, less than half these countries' GDP per capita. In Uganda, which has the lowest case fatality ratios, the cost would be $573/DALY. If the vaccine prevents a small proportion of stillbirths, it would be even more cost-effective. Vaccination cost/dose, disease incidence, and case fatality were key drivers of cost/DALY in sensitivity analyses. CONCLUSION: Maternal GBS immunization could be a cost-effective intervention in low-income sub-Saharan Africa, with cost-effectiveness ratios similar to other recently introduced vaccines. The vaccination cost at which introduction is cost-effective depends on disease incidence and vaccine efficacy. Clinical Trial registry name and registration number: Not applicable.

Cost-effectiveness of a potential group B streptococcal vaccine for pregnant women in the United States.

BACKGROUND: In the U.S., intrapartum antibiotic prophylaxis (IAP) for pregnant women colonized with group B streptococcus (GBS) has reduced GBS disease in the first week of life (early-onset/EOGBS). Nonetheless, GBS remains a leading cause of neonatal sepsis, including 1000 late-onset (LOGBS) cases annually. A maternal vaccine under development could prevent EOGBS and LOGBS. METHODS: Using a decision-analytic model, we compared the public health impact, costs, and cost-effectiveness of five strategies to prevent GBS disease in infants: (1) no prevention; (2) currently recommended screening/IAP; (3) maternal GBS immunization; (4) maternal immunization with IAP when indicated for unimmunized women; (5) maternal immunization plus screening/IAP for all women. We modeled a pentavalent vaccine covering serotypes 1a, 1b, II, III, and V, which cause almost all GBS disease. RESULTS: In the base case, screening/IAP alone prevents 46% of EOGBS compared to no prevention, at a cost of $70,275 per quality-adjusted life-year (QALY) from a healthcare and $51,249/QALY from a societal perspective (2013 US$). At coverage rates typical of maternal vaccines in the U.S., a pentavalent vaccine alone would not prevent as much disease as screening/IAP until its efficacy approached 90%, but would cost less per QALY. At vaccine efficacy of ≥70%, maternal immunization together with IAP for unimmunized women would prevent more disease than screening/IAP, at a similar cost/QALY. CONCLUSIONS: GBS maternal immunization, with IAP as indicated for unvaccinated women, could be an attractive alternative to screening/IAP if a pentavalent vaccine is sufficiently effective. Coverage, typically low for maternal vaccines, is key to the vaccine's public health impact.

Cost-effectiveness of a potential group B streptococcal vaccine program for pregnant women in South Africa.

BACKGROUND: In low- and middle-income countries neonatal infections are important causes of infant mortality. Group B streptococcus (GBS) is a major pathogen. A GBS polysaccharide-protein conjugate vaccine, the only option that has the potential to prevent both early- and late-onset GBS disease, has completed Phase II trials. Screening-based intrapartum antibiotic prophylaxis (IAP) for pregnant women, an effective strategy in high-income countries, is often not practical in these settings. Risk factor-based IAP (RFB-IAP) for women with risk factors at delivery has had limited success in preventing neonatal infection. We evaluated the cost and health impacts of maternal GBS vaccination in South Africa. METHODS AND FINDINGS: We developed a decision-analytic model for an annual cohort of pregnant women that simulates the natural history of GBS disease in their infants. We compared four strategies: doing nothing, maternal GBS vaccination, RFB-IAP, and vaccination plus RFB-IAP. Assuming vaccine efficacy varies from 50% to 90% against covered serotypes and 75% of pregnant women are vaccinated, GBS vaccination alone prevents 30-54% of infant GBS cases compared to doing nothing. For vaccine prices between $10 and $30, and mid-range efficacy, its cost ranges from $676 to $2390 per disability-adjusted life-year (DALY) averted ($US 2010), compared to doing nothing. RFB-IAP alone, compared to doing nothing, prevents 10% of infant GBS cases at a cost of $240/DALY. Vaccine plus RFB-IAP prevents 48% of cases at a cost of $664-2128/DALY. CONCLUSIONS: Vaccination would substantially reduce the burden of infant GBS disease in South Africa and would be very cost-effective by WHO guidelines. RFB-IAP is also very cost-effective, but prevents only 10% of cases. Vaccination plus RFB-IAP is more effective and more costly than vaccination alone, and consistently very cost-effective.

The burden and severity of illness due to 2009 pandemic influenza A (H1N1) in a large US city during the late summer and early fall of 2009.

In estimates of illness severity from the spring wave of the 2009 influenza A (H1N1) pandemic, reported case fatality proportions were less than 0.05%. In prior pandemics, subsequent waves of illness were associated with higher mortality. The authors evaluated the burden of the pandemic H1N1 (pH1N1) outbreak in metropolitan Atlanta, Georgia, in the fall of 2009, when increased influenza activity heralded the second wave of the pandemic in the United States. Using data from a community survey, existing surveillance systems, public health laboratories, and local hospitals, they estimated numbers of pH1N1-associated illnesses, emergency department (ED) visits, hospitalizations, intensive care unit (ICU) admissions, and deaths occurring in metropolitan Atlanta during the period August 16, 2009-September 26, 2009. The authors estimated 132,140 pediatric and 132,110 adult symptomatic cases of pH1N1 in metropolitan Atlanta during the investigation time frame. Among children, these cases were associated with 4,560 ED visits, 190 hospitalizations, 51 ICU admissions, and 4 deaths. Among adults, they were associated with 1,130 ED visits, 590 hospitalizations, 140 ICU admissions, and 63 deaths. The combined symptomatic case hospitalization proportion, case ICU admission proportion, and case fatality proportion were 0.281%, 0.069%, and 0.024%, respectively. Influenza burden can be estimated using existing data and local surveys. The increased severity reported for subsequent waves in past pandemics was not evident in this investigation. Nevertheless, the second pH1N1 pandemic wave led to substantial numbers of ED visits, hospitalizations, and deaths in metropolitan Atlanta.

Opportunities to reduce overuse of antibiotics for perinatal group B streptococcal disease prevention and management of preterm premature rupture of membranes.

OBJECTIVE: To identify opportunities to reduce overuse of antibiotics for prevention of perinatal group B streptococcal (GBS) disease and management of preterm premature rupture of membranes (pPROM). METHODS: An anonymous written questionnaire was sent to each of 1031 Fellows of the American College of Obstetricians and Gynecologists, and the responses were subjected to statistical analysis. RESULTS: Among those of the 404 respondents who saw obstetric patients in 2001, most (84%) screened for GBS colonization, and 22% of these prescribed prenatal antibiotics to try to eradicate GBS colonization. Of the 382 respondents (95%) who prescribed antibiotics for pPROM, 36% continued antibiotics for more than 7 days despite negative results from GBS cultures collected before initiation of treatment. Having more years of clinical experience (adjusted odds ratio (OR) 3.0, 95% confidence interval (CI) 1.5 to 6.2), working in a non-academic setting (adjusted OR 2.7, 95% CI 1.0 to 6.9), and prescribing antibiotics prenatally for GBS colonization (adjusted OR 2.0, 95% CI 1.1 to 3.4) were associated with prescribing prolonged antibiotics for pPROM. CONCLUSION: Prenatal antibiotic treatment for GBS colonization and prolonged antibiotic treatment for pPROM contribute to overuse of antibiotics in obstetrics.

A population-based comparison of strategies to prevent early-onset group B streptococcal disease in neonates.

BACKGROUND: Guidelines issued in 1996 in the United States recommend either screening of pregnant women for group B streptococcal colonization by means of cultures (screening approach) or assessing clinical risk factors (risk-based approach) to identify candidates for intrapartum antibiotic prophylaxis. METHODS: In a multistate retrospective cohort study, we compared the effectiveness of the screening and risk-based approaches in preventing early-onset group B streptococcal disease (in infants less than seven days old). We studied a stratified random sample of the 629,912 live births in 1998 and 1999 in eight geographical areas where there was active surveillance for group B streptococcal infection, including all births in which the neonate had early-onset disease. Women with no documented culture for group B streptococcus were considered to have been cared for according to the risk-based approach. RESULTS: We studied 5144 births, including 312 in which the newborn had early-onset group B streptococcal disease. Antenatal screening was documented for 52 percent of the mothers. The risk of early-onset disease was significantly lower among the infants of screened women than among those in the risk-based group (adjusted relative risk, 0.46; 95 percent confidence interval, 0.36 to 0.60). Because women whose providers had no strategy for prophylaxis may have been misclassified in the risk-based group, we excluded all women with risk factors and adequate time for prophylaxis who did not receive antibiotics. The adjusted relative risk of early-onset disease associated with the screening approach in this secondary analysis was similar--0.48 (95 percent confidence interval, 0.37 to 0.63). CONCLUSIONS: Routine screening for group B streptococcus during pregnancy prevents more cases of early-onset disease than the risk-based approach. Recommendations that endorse both strategies as equivalent warrant reconsideration.