Paul T. Heath

Group B streptococcal disease in infants aged younger than 3 months: systematic review and meta-analysis

BACKGROUND Despite widespread use of intrapartum antibiotic prophylaxis, group B streptococcus remains a leading cause of morbidity and mortality in infants in Europe, the Americas, and Australia. However, estimates of disease burden in many countries outside of these regions is not available. We aimed to examine the current global burden of invasive disease and the serotype distribution of group B streptococcus isolates. METHODS We searched Medline, Embase, and Wholis databases for studies on invasive early-onset (day 0-6) and late-onset (day 7-89) group B streptococcal disease. Eligible studies were those that described incidence, deaths, or serotypes. We also reviewed reference lists and contacted experts to seek unpublished data and data missed by our search. Random effects meta-analysis was used to pool data. FINDINGS 74 studies met the inclusion criteria; 56 studies reported incidence, 29 case fatality, and 19 serotype distribution. An additional search for studies that reported serotype distribution from Jan 1, 1980, yielded a total of 38 articles. Only five low-income countries were represented in the review and contributed 5% weight to the meta-analysis. 47 (69%) studies reported use of any intrapartum antibiotic prophylaxis. Substantial heterogeneity existed between studies. Mean incidence of group B streptococcus in infants aged 0-89 days was 0·53 per 1000 livebirths (95% CI 0·44-0·62) and the mean case fatality ratio was 9·6% (95% CI 7·5-11·8). Incidence of early-onset group B streptococcus (0·43 per 1000 livebirths [95% CI 0·37-0·49]) and case fatality (12·1%, [6·2-18·3]) were two-times higher than late-onset disease. Serotype III (48·9%) was the most frequently identified serotype in all regions with available data followed by serotypes Ia (22·9%), Ib (7·0%), II (6·2%), and V (9·1%). Studies that reported use of any intrapartum antibiotic prophylaxis were associated with lower incidence of early-onset group B streptococcus (0·23 per 1000 livebirths [95% CI 0·13-0·59]) than studies in which patients did not use prophylaxis (0·75 per 1000 livebirths [0·58-0·89]). INTERPRETATION More high-quality studies are needed to accurately estimate the global burden of group B streptococcus, especially in low-income countries. A conjugate vaccine incorporating five serotypes (Ia, Ib, II, III, V) could prevent most global group B streptococcal disease. FUNDING Child Epidemiology Reference Group (CHERG), WHO.

Neonatal sepsis: an international perspective.

Neonatal infections currently cause about 1.6 million deaths annually in developing countries. Sepsis and meningitis are responsible for most of these deaths. Resistance to commonly used antibiotics is emerging and constitutes an important problem world wide. To reduce global neonatal mortality, strategies of proven efficacy, such as hand washing, barrier nursing, restriction of antibiotic use, and rationalisation of admission to neonatal units, need to be implemented. Different approaches require further research.

Neonatal infections in England: the NeonIN surveillance network.

Introduction Neonatal infection is an important cause of morbidity and mortality. Neonatal infection surveillance networks are necessary for defining the epidemiology of infections and monitoring changes over time. Design Prospective multicentre surveillance using a web-based database. Setting 12 English neonatal units. Participants Newborns admitted in 2006–2008, with positive blood, cerebrospinal fluid or urine culture and treated with antibiotics for at least 5 days. Outcome measure Incidence, age at infection, pathogens and antibiotic resistance profiles. Results With the inclusion of coagulase negative Staphylococci (CoNS), the incidence of all neonatal infection was 8/1000 live births and 71/1000 neonatal admissions (2007–2008). The majority of infections occurred in premature (<37 weeks) and low birthweight (<2500 g) infants (82% and 81%, respectively). The incidence of early onset sepsis (EOS; ≤48 h of age) was 0.9/1000 live births and 9/1000 neonatal admissions, and group B Streptococcus (58%) and Escherichia coli (18%) were the most common organisms. The incidence of late onset sepsis (LOS; >48 h of age) was 3/1000 live births and 29/1000 neonatal admissions (7/1000 live births and 61/1000 admissions including CoNS) and the most common organisms were CoNS (54%), Enterobacteriaceae (21%) and Staphylococcus aureus (18%, 11% of which were methicillin resistant S aureus). Fungi accounted for 9% of LOS (72% Candida albicans). The majority of pathogens causing EOS (95%) and LOS (84%) were susceptible to commonly used empiric first line antibiotic combinations of penicillin/gentamicin and flucloxacillin/gentamicin, respectively (excluding CoNS). Conclusions The authors have established NeonIN in England and defined the current epidemiology of neonatal infections. These data can be used for benchmarking among units, international comparisons and as a platform for interventional studies.

Severe and unrecognised: pertussis in UK infants

Aims: To diagnose pertussis using culture, polymerase chain reaction, and serology, in children admitted to intensive care units (PICUs) and some paediatric wards in London, and in their household contacts to determine the source of infection. Methods: Infants <5 months old admitted to London PICUs between 1998 and 2000 with respiratory failure, apnoea and/or bradycardia, or acute life threatening episodes (ALTE), and children <15 years admitted to paediatric wards at St Mary’s and St George’s Hospitals between 1999 and 2000 with lower respiratory tract infection, apnoea, or ALTE were studied. Results: Sixty seven per cent of eligible children (142/212) were recruited; 23% (33/142) had pertussis, 19.8% (25/126) on the PICU and 50% (8/16) on wards. Two died. Only 4% (6/142) were culture positive. Pertussis was clinically suspected on admission in 28% of infants (7/25) on the PICU and 75% (6/8) on the wards. Infants on PICU with pertussis coughed for longer, had apnoeas and whooped more often, and a higher lymphocyte count than infants without pertussis. Pertussis and respiratory syncytial virus (RSV) co-infection was frequent (11/33, 33%). Pertussis was confirmed in 22/33 (67%) of those who were first to become ill in the family. For 14/33 children the source of infection was a parent; for 9/33 the source of pertussis was an older fully vaccinated child in the household. Conclusions: Severe pertussis is under diagnosed. An RSV diagnosis does not exclude pertussis. Future changes to the UK vaccination programme should aim to reduce pertussis transmission to young infants by their parents and older siblings.

Group B streptococcal disease in UK and Irish infants younger than 90 days

The incidence, morbidity, and mortality of group B streptococcal disease in the UK and Republic of Ireland are largely unknown. Between Feb 1, 2000, and Feb 28, 2001, we identified cases of invasive group B streptococcal disease in infants younger than 90 days through surveillance involving paediatricians, microbiologists, and parents. 568 cases were identified, equivalent to a total incidence of 0.72 per 1000 live-births (95% CI 0.66-0.78); the incidence for early-onset disease (n=377) was 0.48 per 1000 (0.43-0.53), and for late-onset disease (n=191) was 0.24 per 1000 (0.21-0.28). Risk factors were identifiable for 218 (58%) cases of early-onset disease. 53 infants died (overall 9.7%). We have established the minimum current burden of group B streptococcal disease in UK and Irish infants. This information will assist in the formulation of guidelines for prevention of this disease.

X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease

X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression.

Safety and immunogenicity of AS03B adjuvanted split virion versus non-adjuvanted whole virion H1N1 influenza vaccine in UK children aged 6 months-12 years: open label, randomised, parallel group, multicentre study.

Objectives To compare the safety, reactogenicity, and immunogenicity of an adjuvanted split virion H1N1 vaccine and a non-adjuvanted whole virion vaccine used in the pandemic immunisation programme in the United Kingdom. Design Open label, randomised, parallel group, phase II study. Setting Five UK centres (Oxford, Southampton, Bristol, Exeter, and London). Participants Children aged 6 months to less than 13 years for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures were eligible. Those with laboratory confirmed pandemic H1N1 influenza or clinically diagnosed disease meriting antiviral treatment, allergy to egg or any other vaccine components, or coagulation defects, or who were severely immunocompromised or had recently received blood products were excluded. Children were grouped by age: 6 months-<3 years (younger group) and 3-<13 years (older group). Recruitment was by media advertising and direct mailing. Recruitment visits were attended by 949 participants, of whom 943 were enrolled and 937 included in the per protocol analysis. Interventions Participants were randomised 1:1 to receive AS03B (tocopherol based oil in water emulsion) adjuvanted split virion vaccine derived from egg culture or non-adjuvanted whole virion vaccine derived from cell culture. Both were given as two doses 21 days apart. Reactogenicity data were collected for one week after immunisation by diary card. Serum samples were collected at baseline and after the second dose. Main outcome measures Primary reactogenicity end points were frequency and severity of fever, tenderness, swelling, and erythema after vaccination. Immunogenicity was measured by microneutralisation and haemagglutination inhibition assays. The primary immunogenicity objective was a comparison between vaccines of the percentage of participants showing seroconversion by the microneutralisation assay (fourfold rise to a titre of ≥1:40 from before vaccination to three weeks after the second dose). Results Seroconversion rates were higher after the adjuvanted split virion vaccine than after the whole virion vaccine, most notably in the youngest children (163 of 166 participants with paired serum samples (98.2%, 95% confidence interval 94.8% to 99.6%) v 157 of 196 (80.1%, 73.8% to 85.5%), P<0.001) in children under 3 years and 226 of 228 (99.1%, 96.9% to 99.9%) v 95.9%, 92.4% to 98.1%, P=0.03) in those over 3 years). The adjuvanted split virion vaccine was more reactogenic than the whole virion vaccine, with more frequent systemic reactions and severe local reactions in children aged over 5 years after dose one (13 (7.2%, 3.9% to 12%) v 2 (1.1%, 0.1% to 3.9%), P<0.001) and dose two (15 (8.5%, 4.8% to 13.7%) v 2 (1.1%, 0.1% to 4.1%), P<0.002) and after dose two in those under 5 years (15 (5.9%, 3.3% to 9.6%) v 0 (0.0%, 0% to 1.4%), P<0.001). Dose two of the adjuvanted split virion vaccine was more reactogenic than dose one, especially for fever ≥38ºC in those aged under 5 (24 (8.9%, 5.8% to 12.9%) v 57 (22.4%, 17.5% to 28.1%), P<0.001). Conclusions In this first direct comparison of an AS03B adjuvanted split virion versus whole virion non-adjuvanted H1N1 vaccine, the adjuvanted vaccine, while more reactogenic, was more immunogenic and, importantly, achieved high seroconversion rates in children aged less than 3 years. This indicates the potential for improved immunogenicity of influenza vaccines in this age group. Trial registration Clinical trials.gov NCT00980850; ISRCTN89141709.

Invasive Haemophilus influenzae Disease, Europe, 1996-2006

Incidence and case-fatality ratios are higher for non–type b than for type b infection.

Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial

BACKGROUND Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. We assessed the effects of meningococcal quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in 18-24-year-olds. METHODS In this phase 3, observer-blind, randomised controlled trial, university students aged 18-24 years from ten sites in England were randomly assigned (1:1:1, block size of three) to receive two doses 1 month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. Participants were randomised with a validated computer-generated random allocation list. Participants and outcome-assessors were masked to the treatment group. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over 1 year. Primary outcomes were cross-sectional carriage 1 month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination. Reactogenicity and adverse events were monitored throughout the study. Analysis was done on the modified intention-to-treat population, which included all enrolled participants who received a study vaccination and provided at least one assessable swab after baseline. This trial is registered with ClinicalTrials.gov, registration number NCT01214850. FINDINGS Between Sept 21 and Dec 21, 2010, 2954 participants were randomly assigned (987 assigned to control [984 analysed], 979 assigned to 4CMenB [974 analysed], 988 assigned to MenACWY-CRM [983 analysed]); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1·2, 95% CI 0·8-1·7) or MenACWY-CRM (0·9, [0·6-1·3]) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18·2% [95% CI 3·4-30·8] carriage reduction), capsular groups BCWY (26·6% [10·5-39·9] carriage reduction), capsular groups CWY (29·6% [8·1-46·0] carriage reduction), and serogroups CWY (28·5% [2·8-47·5] carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39·0% (95% CI 17·3-55·0) carriage reduction for serogroup Y and 36·2% (15·6-51·7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified. INTERPRETATION Although we detected no significant difference between groups at 1 month after vaccine course, MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates during 12 months after vaccination and therefore might affect transmission when widely implemented. FUNDING Novartis Vaccines.

An overview of global GBS epidemiology

Streptococcus agalactiae (group B streptococcus (GBS)), remains the leading cause of neonatal sepsis and meningitis in many countries and an important cause of disease in pregnant women, immunocompromised adults and the elderly. Intrapartum antibiotic strategies have reduced the incidence of early-onset neonatal GBS where applied, but have had no impact on late onset GBS infection and only a limited impact on disease in pregnant women. In low/middle income settings, the disease burden remains uncertain although in several countries of Southern Africa appears comparable to that of high-income countries. Disease may be rapidly fulminating and cases therefore missed before appropriate samples are obtained. This may lead to significant underestimation of the true burden and be a particular issue in many African and Asian countries; comprehensive epidemiological data from such countries are urgently required. The available data suggest that the serotype distribution of GBS isolates is similar in Africa, Western Pacific, Europe, the Americas and the Eastern Mediterranean regions and has not changed over the past 30 years. Five serotypes (Ia, Ib, II, III, V) account for the majority of disease; conjugate vaccines including some or all of these serotypes therefore hold great promise for preventing this important disease.