Associations between gender and health-related quality of life in people with IgE-mediated food allergy and their caregivers: A systematic review.

OBJECTIVE: Understanding factors that impact health-related quality of life (HRQL) is essential to inform personalised food allergy management. However, there are inconsistencies about the impact of gender on HRQL in food allergy. This review aimed to collate all investigations of the association between gender and total or subdomain HRQL scores of individuals with food allergy and their caregivers. DESIGN: This is a narrative systematic review. We descriptively synthesised and compared HRQL outcomes by participant and parent genders according to statistical and clinical significance. Study quality was assessed using the ROBINS-I, inclusive of all domains. Sensitivity analysis of non-interventional studies was conducted using the ROBINS-E. DATA SOURCES: A systematic search of Medline and Embase databases was conducted on 4 April 2022 and updated on 5 December 2023. ELIGIBILITY CRITERIA: Studies were eligible for inclusion if they reported original data on the association between any sex and/or gender and HRQL, as measured with any validated instrument, in populations with IgE-mediated food allergy. Interventional and non-interventional studies were eligible. RESULTS: A comparison of 34 eligible studies (10 interventional and 24 non-interventional) indicated females with food allergy (62.5% of studies of children, 83.3% of studies of adults) and mothers of children with food allergy (50% of studies of caregivers) experienced poorer self-reported baseline HRQL than their counterparts, notably in domains of physical, emotional or food anxiety-related well-being. Gender differences in child HRQL after food allergen immunotherapy were observed. However, selective reporting in included interventional studies meant the direction of this association could not be determined. The proxy-reported total HRQL of participants was not affected by caregiver gender, nor was caregiver HRQL likely impacted by child gender. CONCLUSIONS: Gender should be considered an important modifier of participant HRQL outcomes in food allergy studies. Purposeful exploration of HRQL in all genders is needed to fully understand the implications of this construct on the lived experience of food allergy. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (CRD42022329901).

Longitudinal peanut and Ara h 2 specific-IgE, -IgG4, and -IgG4/-IgE ratios are associated with the natural resolution of peanut allergy in childhood.

BACKGROUND: There are no studies of longitudinal immunoglobulin measurements in a population-based cohort alongside challenge-confirmed peanut allergy outcomes. Little is known about biomarkers for identifying naturally resolving peanut allergy during childhood. OBJECTIVES: To measure longitudinal trends in whole peanut and component Ara h 2 sIgE and sIgG4 in the first 10 years of life, in a population cohort of children with challenge-confirmed peanut allergy, and to determine whether peanut-specific immunoglobulin levels or trends are associated with peanut allergy persistence or resolution by 10 years of age. METHODS: One-year-old infants with challenge-confirmed peanut allergy (n = 156) from the HealthNuts study (n = 5276) were prospectively followed at ages 4, 6, and 10 years with questionnaires, skin prick tests, oral food challenges, and plasma total-IgE, sIgE and sIgG4 to peanut and Ara h 2. RESULTS: Peanut allergy resolved in 33.9% (95% CI = 25.3%, 43.3%) of children by 10 years old with most resolving (97.4%, 95% CI = 86.5%, 99.9%) by 6 years old. Decreasing Ara h 2 sIgE (p = .01) and increasing peanut sIgG4 (p < .001), Ara h 2 sIgG4 (p = .01), peanut sIgG4/sIgE (p < .001) and Ara h 2 sIgG4/sIgE (p < .001) from 1 to 10 years of age were associated with peanut allergy resolution. Peanut sIgE measured at 1 year old had the greatest prognostic value (AUC = 0.75 [95% CI = 0.66, 0.82]); however, no single threshold produced both high sensitivity and specificity. CONCLUSION: One third of infant peanut allergy resolved by 10 years of age. Decreasing sIgE and sIgG4 to peanut and Ara h 2 over time were associated with natural resolution of peanut allergy. However, biomarker levels at diagnosis were not strongly associated with the natural history of peanut allergy.

TreEAT trial: Protocol for a randomized controlled trial investigating the efficacy and safety of early introduction of tree nuts for the prevention of tree nut allergy in infants with peanut allergy.

INTRODUCTION: Children with peanut allergy are at increased risk of developing tree nut allergies, which can be severe and for most lifelong. Introduction of peanut in the first year of life can reduce the risk of peanut allergy; however, prevention strategies for tree nut allergies have not been established. We aimed to test the efficacy and safety of a novel strategy, a supervised multi-nut oral food challenge (OFC) compared with standard care for tree nut allergy prevention in infants at high risk of developing tree nut allergy, TreEAT. METHODS AND ANALYSIS: TreEAT is a 2-armed, open-label, randomized, controlled trial (RCT). Infants (n = 212) aged 4-11 months with peanut allergy will be randomized 1:1 at peanut allergy diagnosis to either a hospital-based multi-tree nut (almond, cashew, hazelnut, and walnut) OFC using multi-nut butter or standard care (home introduction of individual tree nuts). All infants will be assessed at age 18 months, with questionnaires and SPT to peanut and tree nuts. Peanut and tree nut OFCs will be performed as required to determine the allergy status for each nut. The primary outcome is tree nut allergy at age 18 months. Secondary outcomes include peanut allergy resolution, proportion, and severity of adverse events related to tree nut ingestion, number and frequency of tree nuts ingested, quality of life and parental anxiety, and allergy-related healthcare visits from randomization to 18 months of age. Analyses will be performed on an intention-to-treat basis. ETHICS AND DISSEMINATION: TreEAT was approved by the Royal Children's Hospital Human Research Ethics Committee (#70489). Outcomes will be presented at scientific conferences and disseminated through publication. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov ID: NCT04801823.

Statewide prevalence of school children at risk of anaphylaxis and rate of adrenaline autoinjector activation in Victorian government schools, Australia.

BACKGROUND: The prevalence of school students at risk of anaphylaxis in Victoria is unknown and has not been previously studied. Similarly, rates of adrenaline autoinjector usage in the school environment have yet to be determined given increasing prescription rates. OBJECTIVES: We sought to determine time trends in prevalence of school children at risk of anaphylaxis across all year levels and the annual usage rate of adrenaline autoinjectors in the school setting relative to the number of students at risk of anaphylaxis. METHODS: Statewide surveys from more than 1,500 government schools including more than 550,000 students were used and prevalence rates (%) with 95% CIs were calculated. RESULTS: The overall prevalence of students at risk of anaphylaxis has increased 41% from 0.98% (95% CI, 0.95-1.01) in 2009 to 1.38% (95% CI, 1.35-1.41) in 2014. There was a significant drop in reporting of anaphylaxis risk with transition from the final year of primary school to the first year of secondary school, suggesting a change in parental reporting of anaphylaxis risk among secondary school students. The number of adrenaline autoinjectors activated per 1000 students at risk of anaphylaxis ranged from 6 to 8 per year, with consistently higher activation use in secondary school students than in primary school students. CONCLUSIONS: Statewide prevalence of anaphylaxis risk has increased in children attending Victorian government schools. However, adrenaline autoinjector activation has remained fairly stable despite known increase in the rates of prescription.

Interaction Between Baseline Participant Factors and Treatment Effects Following Peanut Oral Immunotherapy.

BACKGROUND: The Probiotic Peanut Oral Immunotherapy-003 multicenter randomized trial found that both probiotic peanut oral immunotherapy (PPOIT) and peanut OIT alone (OIT) were effective compared with placebo in inducing clinical remission after 18 months of treatment, and improving health-related quality of life (HRQL) at 12 months after treatment. Understanding treatment effect modifiers can optimize outcomes through precision care. OBJECTIVES: This post hoc study examined baseline clinical and demographic participant factors that modified treatment effects. METHODS: The study sample included 201 children (aged 1-10 years) with challenge-confirmed peanut allergy. Exposure variables were baseline clinical and demographic factors. Outcomes were remission (double-blind, placebo-controlled food challenge, cumulative 4,950-mg peanut protein at 8 weeks after treatment) and HRQL (change in Food Allergy Quality of Life Questionnaire-Parent Form score). Interactions between baseline factors and treatment effects on remission and HRQL were explored with regression models. RESULTS: A higher degree of peanut sensitivity (large peanut skin prick test, high peanut specific IgE, and low reaction-eliciting dose at study entry challenge) and other concurrent allergic conditions (multiple food allergies, asthma, or wheeze) were associated with the decreased likelihood of attaining remission after both PPOIT and OIT treatment. History of anaphylaxis was associated with the reduced likelihood of remission after PPOIT compared with OIT. For the HRQL outcome, there was evidence that sex, history of anaphylaxis, and age modified treatment effects. CONCLUSIONS: Baseline participant factors modify PPOIT and OIT effects on remission and HRQL. Considering modifiers of treatment effect during participant selection may optimize treatment success and clinical trial design toward specific outcomes, such as the achievement of remission.

The Prevalence of IgE-Mediated Food Allergy and Other Allergic Diseases in the First 10 Years: The Population-Based, Longitudinal HealthNuts Study.

BACKGROUND: There are limited longitudinal data on the population prevalence of allergic conditions during childhood, and few studies have incorporated the reference standard oral food challenge to confirm food allergy. OBJECTIVE: To describe the population prevalence of IgE-mediated food allergy, eczema, asthma, and rhinitis at ages 6 and 10 years in Melbourne, Australia. METHODS: The HealthNuts study recruited 5,276 1-year-old infants in Melbourne, Australia, with repeat assessments at ages 6 and 10 years. At ages 6 and 10 years, carers completed a questionnaire on symptoms and doctor diagnosis of allergic conditions (International Study of Asthma and Allergies in Children). Children were invited to attend a clinic assessment including skin prick test, lung function tests, and oral food challenges when indicated. To minimize the impact of attrition bias, prevalence estimates among participants at ages 6 and 10 years were weighted to reflect characteristics of the whole cohort at recruitment. RESULTS: In total, 4,455 and 4,065 families participated at ages 6 and 10 years, respectively (84% and 77% of the original cohort). Of those, 73% and 55% of participants ages 6 and 10 years, respectively, completed clinical assessments. Overall, 36.5% (95% CI, 34.8-38.2) and 38.2% (95% CI, 36.5-40.1%) of 6- and 10-year-olds had at least one current allergic disease, and around one third of those had two or more allergic diseases. Food allergy occurred in 6.4% (95% CI, 5.6-7.2) of 6-year olds and 6.3% (95% CI, 5.5-7.2) of 10-year-olds. Among infants with challenge-confirmed food allergy in infancy, 45% had persistent disease at age 10 years. The prevalence of current diagnosed asthma at ages 6 and 10 years were 12.1% (95% CI, 10.9-13.3) and 13.1% (95% CI, 11.9-14.4), respectively, current eczema decreased slightly from 15.3% (95% CI, 14.1-19.7) at age 6 years to 12.9% (95% CI, 11.7-14.2) at age 10 years, and current rhinitis increased from 15.1% (95% CI, 13.9-16.5) at age 6 years to 25.0% (95% CI, 23.4-26.7) at age 10 years. CONCLUSIONS: Allergic diseases affect 40% of primary school-age children; one third have multiple allergic diagnoses. Challenge-confirmed food allergy prevalence remains high, and 45% of infants with food allergy have persistent disease to age 10 years.

Food Allergen Immunotherapy in Preschool Children: Do We Have the Evidence?

Standard care for the management of food allergies previously centered on allergen avoidance and the treatment of adverse reactions after allergen exposure. An increase in the development of immunotherapy treatments for food allergy has occurred over the past 2 decades, with many centers now offering immunotherapy. Previous studies mainly focused on school-age children in whom food allergies are likely to be persistent. However, there is increasing evidence that delivering immunotherapy for food allergy to preschool-age children may deliver higher rates of success, and that peanut allergen immunotherapy leads the way. Conversely, the natural resolution of food allergies occurs primarily in these younger age groups, resulting in challenges to selecting patients who will ultimately benefit from these treatments. Both immunotherapy and natural history studies reveal the inherent plasticity of the immune system in early life, which may be more amenable to intervention, but this raises a delicate yet unknown balance between the optimal timing of intervention versus waiting for natural resolution of the food allergy. Here we review the evidence for early food allergen immunotherapy in preschoolers, and present the pros and cons of this approach while acknowledging important research gaps in this age group.

Cost-effectiveness analysis of probiotic peanut oral immunotherapy (PPOIT) versus placebo in Australian children with peanut allergy alongside a randomised trial.

OBJECTIVE: To compared the cost-effectiveness of coadministration of a probiotic adjuvant with peanut oral immunotherapy (PPOIT) with placebo (no treatment) in children with peanut allergy. DESIGN: Prospectively planned cost-effectiveness analysis alongside a randomised control trial. SETTING: The Royal Children's Hospital, Melbourne, Australia. PARTICIPANTS: 56 children with peanut allergy aged 1-10 years at recruitment. INTERVENTION: A daily dose of probiotic Lactobacillus rhamnosus CGMCC 1.3724 (NCC4007) and peanut oral immunotherapy administered for 1.5 years. MAIN OUTCOMES MEASURES: Costs were considered from a healthcare system perspective and included costs of treatment delivery and adverse events. Effectiveness outcomes included rate of sustained unresponsiveness (SU) and quality-adjusted life years (QALYs). The cost-effectiveness of PPOIT versus placebo was analysed using patient-level data. Time horizon was 10 years from commencement of PPOIT treatment, comprising 1.5 years of treatment (actual data), 4 years of post-treatment follow-up (actual data), and 4.5 years of extrapolation thereafter (modelling). RESULTS: Healthcare cost per patient over 10 years was higher for PPOIT compared with placebo ($A9355 vs $A1031, p<0.001). Over half of the per patient healthcare cost (53%) in the PPOIT group was attributable to treatment delivery, while the remaining cost was attributable to adverse events. Both measures of effectiveness were superior in the PPOIT group: the average SU rate over 10 years was 54% for PPOIT versus 6% for placebo (p<0.001); QALYs over 10 years were 9.05 for PPOIT versus 8.63 for placebo (p<0.001). Overall, cost per year of SU achieved was $A1694 (range $A1678, $A1709) for PPOIT compared with placebo, and cost per additional QALY gained was $A19 386 (range $A19 024, $A19 774). CONCLUSIONS: Cost per QALY gained using PPOIT compared with no treatment is approximately $A20 000 (£10 000) and is well below the conventional value judgement threshold of $A50 000 (£25 000) per QALY gained, thus deemed good value for money ($A1= £0.5 approximately). TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry ACTRN12608000594325; Post-results.

Association of Reaction Symptoms and Eliciting Dose With Health-Related Quality of Life in Children With Peanut Allergy.

BACKGROUND: Food allergy adversely affects the health-related quality of life (HRQoL) of patients. It is unclear whether factors such as the reaction eliciting dose (ED) and the nature of allergic reaction symptoms affect HRQoL. OBJECTIVE: To explore associations between reaction ED or the nature of allergic symptoms and HRQoL among children with peanut allergy. METHODS: This study was a secondary analysis of baseline data from the PPOIT-003 randomized trial in 212 children aged 1 to 10 years with challenge-confirmed peanut allergy. Children's past reaction symptoms were collected by clinicians during screening. Associations between variables of interest and parent-reported child-proxy HRQoL were examined by univariable and multivariable linear regression. RESULTS: Mean age of study participants was 5.9 years; 63.2% were male. Children with a low reaction ED of 80 mg peanut protein had significantly poorer HRQoL (ß = -0.81; 95% CI, -1.61 to -0.00; P = .049) compared with children with a high ED of 2,500 mg peanut protein. Gastrointestinal symptoms (ß = 0.45; 95% CI, 0.03-0.87; P = .037), lower airway symptoms (ß = 0.46; 95% CI, 0.05-0.87; P = .030), multisystem involvement (ß = 0.71; 95% CI, 0.25-1.16; P = .003), or anaphylaxis (ß = 0.46; 95% CI, 0.04-0.87; P = .031) during a previous reaction were associated with worse HRQoL. CONCLUSIONS: Peanut-allergic children with a lower allergen reaction threshold experienced a greater negative HRQoL impact compared with children with higher reaction thresholds. In addition, specific past allergic reaction symptoms were associated with comparatively worse HRQoL. Children experiencing these symptoms and those with lower reaction ED require increased clinical support to manage the food allergy and are likely to benefit from interventions that can improve HRQoL.

Varying Approaches to Management of IgE-Mediated Food Allergy in Children Around the World.

Food allergy is a chronic disease that affects individuals of all ages and is a significant public health problem globally. This narrative overview examines clinical management strategies for IgE-mediated food allergy in children around the world to understand variations in practice. Information was drawn from clinical practice guidelines, recent research, the websites of professional and governmental bodies with expertise in food allergy, and clinical experts from a broad cross-section of geographical regions. The structure and delivery of clinical services, allergen avoidance and food labeling, and resources to support the management of allergic reactions in the community are discussed in detail. The adoption of emerging food immunotherapies is also explored. Wide variations in clinical management of food allergy were apparent across the different countries. Common themes were continuing issues with access to specialist care and recognition of the need to balance risk reduction with dietary and social restrictions to avoid unnecessary detrimental impacts on the quality of life of food allergy sufferers. Findings highlight the need for standardized presentation of practice and priorities, and may assist clinicians and researchers when engaging with government and funding agencies to address gaps.

Inborn Errors of Immunity in Children With Invasive Pneumococcal Disease: A Multicenter Prospective Study.

BACKGROUND: In settings with universal conjugate pneumococcal vaccination, invasive pneumococcal disease (IPD) can be a marker of an underlying inborn error of immunity. The aim of this study was to determine the prevalence and characterize the types of immunodeficiencies in children presenting with IPD. METHODS: Multicenter prospective audit following the introduction of routinely recommended immunological screening in children presenting with IPD. The minimum immunological evaluation comprised a full blood examination and film, serum immunoglobulins (IgG, IgA and IgM), complement levels and function. Included participants were children in whom Streptococcus pneumoniae was isolated from a normally sterile site (cerebrospinal fluid, pleura, peritoneum and synovium). If isolated from blood, features of sepsis needed to be present. Children with predisposing factors for IPD (nephrotic syndrome, anatomical defect or malignancy) were excluded. RESULTS: Overall, there were 379 episodes of IPD of which 313 (83%) were eligible for inclusion and 143/313 (46%) had an immunologic evaluation. Of these, 17/143 (12%) were diagnosed with a clinically significant abnormality: hypogammaglobulinemia (n = 4), IgA deficiency (n = 3), common variable immunodeficiency (n = 2), asplenia (n = 2), specific antibody deficiency (n = 2), incontinentia pigmenti with immunologic dysfunction (n = 1), alternative complement deficiency (n = 1), complement factor H deficiency (n = 1) and congenital disorder of glycosylation (n = 1). The number needed to investigate to identify 1 child presenting with IPD with an immunologic abnormality was 7 for children under 2 years and 9 for those 2 years old and over. CONCLUSIONS: This study supports the routine immune evaluation of children presenting with IPD of any age, with consideration of referral to a pediatric immunologist.

Probiotic peanut oral immunotherapy versus oral immunotherapy and placebo in children with peanut allergy in Australia (PPOIT-003): a multicentre, randomised, phase 2b trial.

BACKGROUND: Oral immunotherapy is effective at inducing desensitisation to allergens and induces sustained unresponsiveness (ie, clinical remission) in a subset of patients, but causes frequent reactions. We aimed to investigate whether addition of a probiotic adjuvant improved the efficacy or safety of peanut oral immunotherapy. METHODS: PPOIT-003, a multicentre, randomised, phase 2b trial, was conducted in three tertiary hospitals in Australia (Adelaide [SA], Melbourne [VIC], and Perth [WA]) in children aged 1-10 years, weighing more than 7 kg, with peanut allergy confirmed by a double-blind placebo-controlled food challenge (cumulative 4950 mg dose of peanut protein) and positive peanut skin prick test (≥3 mm) or peanut-specific IgE (≥0·35 kU/L). Children were randomly assigned (2:2:1) to receive probiotic and peanut oral immunotherapy (PPOIT), placebo probiotic and peanut oral immunotherapy (OIT), or placebo probiotic and placebo OIT (placebo) for 18 months, and were followed up until 12 months after completion of treatment. Oral immunotherapy consisted of increasing doses of peanut protein (commercially available food-grade 12% defatted peanut flour [50% peanut protein]) until a 2000 mg daily maintenance dose was reached. The probiotic adjuvant was a daily dose of 2 × 1010 colony-forming units of the probiotic Lactobacillus rhamnosus ATCC 53103. Placebo immunotherapy comprised maltodextrin, brown food colouring, and peanut essence, and placebo probiotic was maltodextrin. Dual primary outcomes were 8-week sustained unresponsiveness, defined as no reaction to a cumulative dose of 4950 mg peanut protein at treatment completion and 8 weeks after treatment completion, in the PPOIT versus placebo groups and the PPOIT versus OIT groups, analysed by intention to treat. Safety endpoints were adverse events during the treatment phase, and peanut ingestion and reactions in the 12-month post-treatment period. This study is registered with the Australian New Zealand Clinical Trials Registry, 12616000322437. FINDINGS: Between July 4, 2016, and Sept 21, 2020, 201 participants were enrolled and included in the intention-to-treat analysis. 36 (46%) of 79 children in the PPOIT group and 42 (51%) of 83 children in the OIT group achieved sustained unresponsiveness compared with two (5%) of 39 children in the placebo group (risk difference 40·44% [95% CI 27·46 to 53·42] for PPOIT vs placebo, p<0·0001), with no difference between PPOIT and OIT (-5·03% [-20·40 to 10·34], p=0·52). Treatment-related adverse events were reported in 72 (91%) of 79 children in the PPOIT group, 73 (88%) of 83 children in the OIT group, and 28 (72%) of 39 children in the placebo group. Exposure-adjusted incidence of adverse events was 10·58 in the PPOIT group, 11·36 in the OIT, and 2·09 in the placebo group (ratio 0·92 [95% CI 0·85 to 0·99] for PPOIT vs OIT, p=0·042; 4·98 [4·11-6·03] for PPOIT vs placebo, p<0·0001; 5·42 [4·48-6·56] for OIT vs placebo, p<0·0001), with differences seen primarily in gastrointestinal symptoms and in children aged 1-5 years. During the 12-month post-treatment period, 60 (85%) of 71 participants in the PPOIT group, 60 (86%) of 70 participants in the OIT group, and six (18%) of 34 participants in the placebo group were eating peanut; rescue epinephrine use was infrequent (two [3%] of 71 in the PPOIT group, four [6%] of 70 in the OIT group, and none in the placebo group). INTERPRETATION: Both PPOIT and OIT were effective at inducing sustained unresponsiveness. Addition of a probiotic did not improve efficacy of OIT, but might offer a safety benefit compared with OIT alone, particularly in preschool children. FUNDING: National Health and Medical Research Council Australia and Prota Therapeutics.

Study protocol of a phase 2, dual-centre, randomised, controlled trial evaluating the effectiveness of probiotic and egg oral immunotherapy at inducing desensitisation or sustained unresponsiveness (remission) in participants with egg allergy compared with placebo (Probiotic Egg Allergen Oral Immunotherapy for Treatment of Egg Allergy: PEAT study).

INTRODUCTION: Egg allergy is the most common food allergy in children but recent studies have shown persistence or delayed resolution into adolescence. As there is currently no effective long-term treatment, definitive treatments that improve quality of life and prevent fatalities for food allergies are required. We have previously shown that a novel treatment comprising a combination of the probiotic Lactobacillus rhamnosus CGMCC 1.3724 with peanut oral immunotherapy (OIT) is highly effective at inducing sustained unresponsiveness, with benefit persisting to 4 years after treatment cessation in the majority of initial treatment responders. In this study, we plan to extend the probiotic food OIT platform to another allergen, namely egg. We describe the protocol for a phase 2, dual-centre, randomised, controlled trial evaluating the effectiveness of probiotic and egg OIT at inducing desensitisation or sustained unresponsiveness (remission) in participants with egg allergy compared with placebo. METHODS AND ANALYSIS: 80 participants aged 5-30 years of age with current egg allergy confirmed by double-blind placebo-controlled food challenge at study screening will be recruited from Australia and Singapore. There are two intervention arms-probiotic and egg OIT (active) or placebo. Interventions are administered once daily for 18 months. The primary outcome is the proportion of participants who attain 8-week sustained unresponsiveness in the active group versus placebo group. ETHICS AND DISSEMINATION: This study has been approved by the Human Research Ethics Committees at the Royal Children's Hospital (HREC 2019.082) and the National Healthcare Group Domain Specific Review Board (2019/00029). Results will be published in peer-reviewed journals and disseminated via presentations at international conferences. TRIAL REGISTRATION NUMBER: ACTRN12619000480189.

Peanut Oral Immunotherapy: State of the Art.

Cumulative evidence shows that peanut oral immunotherapy (OIT) is effective at inducing desensitization through downregulation of effector pathways in the allergic reaction cascade; however, only a subset of patients achieve sustained unresponsiveness (remission), which requires redirection of the underlying allergic response toward tolerance. A recent meta-analysis of peanut OIT randomized trials found that OIT is associated with a threefold greater risk of anaphylaxis and twofold greater risk of epinephrine use than allergen avoidance. Strategies to reduce adverse events associated with OIT and improve the ability for OIT to induce sustained unresponsiveness are required to improve the benefit-risk of peanut OIT.

Study protocol of a multicentre, randomised, controlled trial evaluating the effectiveness of probiotic and peanut oral immunotherapy (PPOIT) in inducing desensitisation or tolerance in children with peanut allergy compared with oral immunotherapy (OIT) alone and with placebo (the PPOIT-003 study).

INTRODUCTION: Peanut allergy is the the most common cause of life-threatening food-induced anaphylaxis. There is currently no effective long-term treatment. There is a pressing need for definitive treatments that improve the quality of life and prevent fatalities. Allergen oral immunotherapy (OIT) is a promising approach, which is effective at inducing desensitisation; however, OIT has a limited ability to induce sustained unresponsiveness (SU). We have previously shown that a novel treatment comprising a combination of the probiotic Lactobacillus rhamnosus CGMCC 1.3724 with peanut OIT (Probiotic Peanut Oral ImmunoTherapy (PPOIT)) is highly effective at inducing SU, with benefit persisting to 4 years after treatment cessation in the majority of initial treatment responders. Here we describe the protocol for a Phase IIb multicentre, double-blind, randomised, controlled trial (PPOIT-003) with dual primary objectives to evaluate the effectiveness of PPOIT at inducing SU (assessed at 8 weeks after treatment cessation) compared with placebo treatment and peanut OIT alone, in children with peanut allergy. METHODS AND ANALYSIS: 200 children 1 to 10 years of age with current peanut allergy confirmed by failed double-blind placebo-controlled food challenge (DBPCFC) at study screening will be recruited from three tertiary paediatric hospitals in Australia. There are three intervention arms-PPOIT, peanut OIT alone or placebo. Interventions are administered once daily for 18 months. The dual primary outcomes are: (1) the proportion of children who attain 8-week SU in the PPOIT group versus placebo group and (2) the proportion of children who attain 8-week SU in the PPOIT group versus OIT group. ETHICS AND DISSEMINATION: This study has been approved by the Human Research Ethics Committees at the Royal Children's Hospital (HREC 35246) and the Child and Adolescent Health Service (RGS 2543). Results will be published in peer-reviewed journals and disseminated via presentations at international conferences. TRIAL REGISTRATION NUMBER: ACTRN12616000322437.

Molecular cloning and functional characterisation of VanX, a D-alanyl-D-alanine dipeptidase from Streptomyces coelicolor A3(2).

The vanX gene which encodes a D-alanyl-D-alanine dipeptidase is critical for vancomycin resistance in enterococci. A putative vanX gene from Streptomyces coelicolor A3(2), which is not known for vancomycin production, was identified by homology-based analysis and cloned by polymerase chain reaction. The S. coelicolor vanX gene was heterologously expressed in Escherichia coli BL21(DE3) and enzymatic assays of soluble protein fractions of VanX revealed a 93-fold increase in dipeptidase activity as compared to the nonrecombinant control, thus confirming its functionality. Interestingly, S. coelicolor was also found to be of intermediate resistance to vancomycin although it does not produce vancomycin, thus suggesting the role of VanX in defence or immunity. As such, the prevalence of vanX genes in the environment may be more common than previously thought.

Accuracy of inter-hospital paediatric appendicitis referrals.

OBJECTIVE: Appendicitis is the most common paediatric surgical emergency. In our institution, the majority of inter-hospital transfers are for suspected appendicitis. We undertook an audit to assess the accuracy of the provisional diagnosis of the transferred cases. METHODS: Retrospective electronic data of a tertiary referral centre and a single referring regional hospital were collected between January 2009 and December 2010. Primary outcome of surgery, inpatient observation or discharge was assessed. The final appendix pathology results were examined. RESULTS: There were 187 paediatric surgical transfers (49% by ambulance) that were provisionally diagnosed as appendicitis. Of the 187 patients (M : F = 102 : 85, a median age of 11), 70% were admitted, 43% underwent appendicectomy, and only 40% had pathologically proven appendicitis. CONCLUSIONS: Of the surgical referrals for appendicectomy, 60% did not have appendicitis. An improved assessment protocol is required to reduce the margin of diagnostic error and transfer cost, while maintaining clinical safety.