Margie Danchin

Rapid Diagnostic Tests for Group A Streptococcal Pharyngitis: A Meta-analysis

BACKGROUND AND OBJECTIVE: Effective management of group A streptococcal (GAS) pharyngitis is hindered by impracticality of the gold standard diagnostic test: throat culture. Rapid antigen diagnostic tests (RADTs) are a promising alternative, although concerns about their sensitivity and specificity, and variation between test methodologies, have limited their clinical use. The objective of this study was to perform a systematic review with meta-analysis of the diagnostic accuracy of RADTs for GAS pharyngitis. METHODS: Medline and Embase from 1996 to 2013 were used as data sources. Of 159 identified studies, 48 studies of diagnostic accuracy of GAS RADTs using throat culture on blood agar as a reference standard were selected. Bivariate random-effects regression was used to estimate sensitivity and specificity with 95% confidence intervals (CIs). Additional meta-analyses were performed for pediatric data. RESULTS: A total of 60 pairs of sensitivity and specificity from 48 studies were included. Overall summary estimates for sensitivity and specificity of RADTs were 0.86 (95% CI 0.83 to 0.88) and 0.96 (95% CI 0.94 to 0.97), respectively, and estimates for pediatric data were similar. Molecular-based RADTs had the best diagnostic accuracy. Considerable variability exists in methodology between studies. There were insufficient studies to allow meta-regression/subgroup analysis within each test type. CONCLUSIONS: RADTs can be used for accurate diagnosis of GAS pharyngitis to streamline management of sore throat in primary care. RADTs may not require culture backup for negative tests in most low-incidence rheumatic fever settings. Newer molecular tests have the highest sensitivity, but are not true point-of-care tests.

Superantigen genes in group A streptococcal isolates and their relationship with emm types

Superantigens are important virulence factors in the pathogenesis of invasive disease caused by group A streptococcus (GAS). There has been a recent re-emergence of this disease worldwide. A number of novel superantigens have been described recently. This study investigated 107 isolates of GAS for possession of each of the 11 currently known superantigen genes to determine the prevalence, co-occurrence and genetic restriction amongst different emm types of GAS. The results were compared with those in previously published studies. Superantigen genes were not randomly distributed amongst GAS isolates. Certain combinations of superantigen genes were more common and the majority of emm types showed restricted superantigen profiles. This is the first prevalence study of GAS isolates to include the complete range of known superantigen genes and their restriction amongst emm types. This study contributes to the understanding of the relationship between superantigen genes and emm types, and highlights the importance of comprehensive studies in different populations.

New normal ranges of antistreptolysin O and antideoxyribonuclease B titres for Australian children.

Objective: To determine age‐specific upper limit of normal (ULN) values of the ASO and ADB titres in children aged 4–14 years in urban Melbourne. Serology is often used to diagnose a preceding Streptococcus pyogenes infection, particularly in potential cases of rheumatic fever and post‐streptococcal glomerulonephritis. The most commonly used antigens are antistreptolysin O (ASO) and antideoxyribonuclease B (ADB). Reference ranges used in Australia for these serological markers are usually based on data in adults from other countries. There are no age‐specific reference values for Australian children.

Phase I trial of RV3-BB rotavirus vaccine: a human neonatal rotavirus vaccine.

INTRODUCTION RV3 is a human neonatal rotavirus strain (G3P[6]) that has been associated with asymptomatic neonatal infection and replicates well in the infant gut. RV3-BB rotavirus vaccine has been developed as a rotavirus vaccine candidate for administration at birth. METHODS A single-centre, double-blind, randomised placebo-controlled Phase I study evaluated the safety and tolerability of a single oral dose of the second generation RV3-BB rotavirus vaccine (8.3×10(6)FFU/mL) in 20 adults, 20 children and 20 infants (10 vaccine and 10 placebo per age cohort). Vaccine take was defined as seroconversion (a 3-fold increase in serum anti-rotavirus IgA or serum neutralising antibody (SNA) from baseline at day 28 post-dose) or evidence of RV3-BB viral replication in the faeces by RT-PCR analysis 3-6 days post-vaccination. RV3-BB presence was confirmed by sequence analysis. RESULTS The RV3-BB vaccine was well tolerated in all participants, with no pattern of adverse events shown to be associated with the study vaccine. In the infant cohort, vaccine take was demonstrated in 8/9 infants following a single dose of vaccine compared with 2/7 placebo recipients. In the infant vaccine group, 5/9 infants exhibited either IgA or SNA seroconversion and 7/9 infants had evidence of RV3-BB replication on days 3-6, compared with 2/7 infants who seroconverted and 0/10 infants with evidence of replication in the placebo group. Two infants in the placebo group had serological evidence of a rotavirus infection within the 28-day study period: one demonstrated an IgA and the other an SNA response, with wild-type virus replication detected in another infant. CONCLUSION A single dose of RV3-BB rotavirus vaccine was well tolerated in adults, children and infants. Most infants (8/9) who received RV3-BB demonstrated vaccine take following a single dose. These data support progression of RV3-BB to Phase II immunogenicity and efficacy trials.

Trends in paediatric practice in Australia: 2008 and 2013 national audits from the Australian Paediatric Research Network

In adult medicine, rates of investigation and prescribing appear to be increasing. Such information is lacking for paediatrics. We audited Australian paediatricians’ practices in 2013 to determine changes since 2008 in: (i) conditions seen; (ii) consultation duration; (iii) imaging and pathology ordered; and (iv) prescribing.

Imposing penalties for vaccine rejection requires strong scrutiny

At a time when vaccine-preventable diseases (VPDs) are better controlled than ever, vaccine rejection presents a persistent challenge for clinicians and policy-makers. Efforts to address vaccine rejection often fail because its underpinning is complex and the traditional top-down models that enable efficient delivery of vaccines to children are not as effective with hesitant or rejecting parents. While there is evidence to support strategies to improve vaccination coverage more broadly, there is a very limited evidence base to address vaccine rejection. Rejection of vaccines is only one contributor to under-vaccination, with inadvertent lateness or missed opportunities due to access issues being the larger contributor to under-vaccination in Australia. However, the mainstream media tend to frame the cause as solely resting with ‘anti-vaxxers’, leaving the public to assume that the solution should focus on any policy that predominantly targets vaccine rejection. Australia and other countries have considered or implemented policies that ramp up the penalties for rejection of vaccination. In USA, California recently passed legislation, joining Mississippi and West Virginia, in eliminating all but medical exemptions for school entry. The American Academy of Pediatrics released a policy statement in August to support the elimination of all nonmedical exemptions and have given more explicit support to paediatricians who wish to dismiss vaccine-rejecting parents from their practice. By contrast, the Royal Australasian College of Physicians do not support the removal of non-medical exemptions and explicitly discourage dismissing unvaccinated children from paediatric practices. However, the Australian government has removed nonmedical exemptions, previously in place for parents who actively declined vaccination for their children. On 23 November 2015, the federal government passed The Social Services Legislation Amendment (No Jab, No Pay) Bill 2015. The amendment’s centrepiece was the removal of the vaccination ‘conscientious objection’ exemption to immunisation requirements, which had been linked to receipt of Family Assistance Payments since 1999. By 2015, these payments included Family Tax Benefit (FTB) part A (supplement), the Child Care Rebate and Child Care Benefit, which together could amount to approximately

Pediatric anaphylactic adverse events following immunization in Victoria, Australia from 2007 to 2013

15 000 each year for those on the lowest incomes. As of 2016, the only exemptions to the requirements include: a medical contraindication, natural immunity to a disease, being in a vaccine study, temporary unavailability of vaccine, child vaccinated overseas or a decision at the discretion of the Secretary. Meanwhile, three state governments have introduced ‘No Jab, No Play’ legislation, introducing or tightening requirements for enrolment into child care and pre-school. The most stringent legislation is in Victoria, which completely excludes children from early childhood services when they are not fully vaccinated and are without a medical exemption. Queensland has given child care providers discretionary power to exclude such children. New South Wales has not instituted a full removal of conscientious objection exemptions for enrolment in child care, but instead have tightened existing documentation requirements. The policies were explained as intending to increase vaccination rates and mitigate the risk of VPDs to the Australian community. Hence, understanding the evidence base and effectiveness of penalties to address vaccine rejection is vital, as Australia evaluates ‘No Jab, No Pay’ and as other countries consider implementing similar measures. Below we outline the issues for consideration through the Seven Ethical Principles for public health immunisation programmes outlined by Verweij and Dawson and elaborated by Isaacs. We relate them to the ‘No Jab, No Pay’ policy specifically where the penalty for vaccine rejection is financial, but a downstream effect can result in child care becoming unaffordable for those affected by the removal of the Child Care Benefit and Rebate. The article does not focus on impacts from state-based ‘No Jab, No Play’ policies that relate to refusing enrolment in child care or pre-school facilities for children not up-to-date with their vaccinations. However, there is a significant overlap to the extent that the end result is reduced access to child care.

Vaccine decision-making begins in pregnancy: Correlation between vaccine concerns, intentions and maternal vaccination with subsequent childhood vaccine uptake

BACKGROUND Anaphylaxis is a rare life-threatening adverse event following immunization (AEFI). Variability in presentation can make differentiation between anaphylaxis and other AEFI difficult. This study summarizes pediatric anaphylaxis AEFI reported to an Australian state-based passive surveillance system. METHODS All suspected and reported pediatric (<18 years) anaphylaxis AEFI notified to SAEFVIC (Surveillance of Adverse Events Following Vaccination In the Community) Melbourne, Australia, between May 2007 to May 2013 were analyzed. Clinical descriptions of the AEFI, using the internationally recognized Brighton Collaboration case definition (BCCD) and final outcome were documented. RESULTS 93% (25/27) of AEFI classified as anaphylaxis met BCCD criteria, with 36% (9/25), assessed as the highest level of diagnostic certainty (Level 1). Median age was 4.7 years (range 0.3-16.2); 48% of cases were male. The vaccine antigens administered included: diphtheria, tetanus, acellular pertussis (DTaP) alone or in combination vaccines containing other antigens in 11 of 25 cases (44%); and live attenuated measles mumps rubella (MMR) vaccine for six (five also had other vaccines concomitantly administered). The estimated incidence rate of anaphylaxis for DTaP vaccines was 0.36 cases per 100,000 doses, and 1.25 per 100,000 doses for MMR vaccines. The majority of cases had rapid onset, but in 24% (6/25) of cases, first symptoms of anaphylaxis developed ≥30 min after immunization. In 60% (15/25) of cases, symptoms resolved ≤60 min of presentation. Intramuscular adrenaline was administered in 90% (18/25) of cases. All cases made a full recovery with no sequelae identified. CONCLUSION This comprehensive case series of pediatric anaphylaxis as an AEFI identified that diagnostic criteria are useful when applied to a passive vaccine surveillance system when adequate clinical information is available. Anaphylaxis as an AEFI is rare and usually begins within 30 min of vaccination. However, healthcare professionals and vaccinees/parents should be aware that onset of anaphylaxis can be delayed beyond 30 min following immunization and that medical attention should be sought promptly if anaphylaxis is suspected.

Recurrent apnoea post immunisation: Informing re-immunisation policy.

INTRODUCTION Maternal and childhood vaccine decision-making begins prenatally. Amongst pregnant Australian women we aimed to ascertain vaccine information received, maternal immunisation uptake and attitudes and concerns regarding childhood vaccination. We also aimed to determine any correlation between a) intentions and concerns regarding childhood vaccination, (b) concerns about pregnancy vaccination, (c) socioeconomic status (SES) and (d) uptake of influenza and pertussis vaccines during pregnancy and routine vaccines during childhood. METHODS Women attending public antenatal clinics were recruited in three Australian states. Surveys were completed on iPads. Follow-up phone surveys were done three to six months post delivery, and infant vaccination status obtained via the Australian Childhood Immunisation Register (ACIR). RESULTS Between October 2015 and March 2016, 975 (82%) of 1184 mothers consented and 406 (42%) agreed to a follow up survey, post delivery. First-time mothers (445; 49%) had significantly more vaccine concerns in pregnancy and only 73% had made a decision about childhood vaccination compared to 89% of mothers with existing children (p-value<0.001). 66% of mothers reported receiving enough information during pregnancy on childhood vaccination. In the post delivery survey, 46% and 82% of mothers reported receiving pregnancy influenza and pertussis vaccines respectively. The mothers degree of vaccine hesitancy and two attitudinal factors were correlated with vaccine uptake post delivery. There was no association between reported maternal vaccine uptake or SES and childhood vaccine uptake. CONCLUSION First time mothers are more vaccine hesitant and undecided about childhood vaccination, and only two thirds of all mothers believed they received enough information during pregnancy. New interventions to improve both education and communication on childhood and maternal vaccines, delivered by midwives and obstetricians in the Australian public hospital system, may reduce vaccine hesitancy for all mothers in pregnancy and post delivery, particularly first-time mothers.

KHA‐CARI guideline: Diagnosis and treatment of urinary tract infection in children

BACKGROUND Preterm infants should receive immunisations according to their chronological, rather than gestational, age however concern about possible adverse events following immunisation (AEFI) in this group often means routine immunisations are delayed. A small number of infants may have apnoea with or without bradycardia temporally associated with immunisation. The risk factors for, and recurrence rate of apnoea with subsequent immunisations are unknown, which makes planning for subsequent immunisations for these highly vulnerable infants difficult. AIM To determine recurrence rates for apnoea temporally associated with immunisation in preterm and term infants and to explore potential risk factors associated with recurrent apnoea in preterm infants. METHOD A retrospective analysis of all apnoea +/-bradycardia AEFIs in preterm and term infants, reported to the Surveillance of Adverse Events Following Vaccination In the Community (SAEFVIC), Victoria, Australia over a 3-year period from May 2007 to April 2010. Apnoea +/-bradycardia was defined as temporally associated with immunisation if it occurred up to 48h after immunisation. RESULTS 7 out of 38 [18%, 95% confidence interval 6-31%] preterm infants with apnoea +/-bradycardia post initial immunisation had recurrent apnoea with subsequent immunisations. Possible risk factors for recurrence included: lower birth weight (p=0.04) and ongoing hospitalisation for complications relating to prematurity (p=0.01). No preterm infant with recurrent apnoea had a third episode of apnoea with subsequent immunisation. None of the 8 term infants with a reported apnoea AEFI had recurrence of apnoea with subsequent immunisation. CONCLUSION There is a risk of recurrence of apnoea associated with immunisation in preterm infants. We recommend that preterm infants with apnoea post immunisation should receive reliable cardio-respiratory monitoring for a minimum of 24h following the next scheduled immunisation.