Preparing Patients for Oral Immunotherapy (PPOINT): International Delphi consensus for procedural preparation and consent.

BACKGROUND: Despite the promise of oral immunotherapy (OIT) to treat food allergies, this procedure is associated with potential risk. There is no current agreement about what elements should be included in the preparatory or consent process. OBJECTIVE: We developed consensus recommendations about the OIT process considerations and patient-specific factors that should be addressed before initiating OIT and developed a consensus OIT consent process and information form. METHODS: We convened a 36-member Preparing Patients for Oral Immunotherapy (PPOINT) panel of allergy experts to develop a consensus OIT patient preparation, informed consent process, and framework form. Consensus for themes and statements was reached using Delphi methodology, and the consent information form was developed. RESULTS: The expert panel reached consensus for 4 themes and 103 statements specific to OIT preparatory procedures, of which 76 statements reached consensus for inclusion specific to the following themes: general considerations for counseling patients about OIT; patient- and family-specific factors that should be addressed before initiating OIT and during OIT; indications for initiating OIT; and potential contraindications and precautions for OIT. The panel reached consensus on 9 OIT consent form themes: benefits, risks, outcomes, alternatives, risk mitigation, difficulties/challenges, discontinuation, office policies, and long-term management. From these themes, 219 statements were proposed, of which 189 reached consensus, and 71 were included on the consent information form. CONCLUSION: We developed consensus recommendations to prepare and counsel patients for safe and effective OIT in clinical practice with evidence-based risk mitigation. Adoption of these recommendations may help standardize clinical care and improve patient outcomes and quality of life.

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.

Transcriptomic changes associated with oral immunotherapy for food allergy.

This review summarizes recent advances in characterizing the transcriptional pathways associated with outcomes following Oral Immunotherapy. Recent technological advances including single-cell sequencing are transforming the ways in which the transcriptional landscape is understood. The application of these technologies is still in its infancy in food allergy but here we summarize current understanding of gene expression changes following oral immunotherapy for food allergy and specific signatures underpinning the different clinical outcomes of desensitization and remission (sustained unresponsiveness). T helper 2A cells have been identified as a cell type which correlates with disease activity and is modified by treatment. Molecular features at study entry may differentiate individuals who achieve more positive outcomes during OIT. Recent findings point to T cell anergy and Type 1 interferon pathways as potential mechanisms supporting redirection of the allergen-specific immune response away from allergy towards remission. Despite these developments in our understanding of immune mechanisms following OIT, there are still significant gaps. Additional studies examining immune signatures associated with long term and well-defined clinical outcomes are required to gain a more complete understanding of the pathways leading to remission of allergy, in order to optimize treatments and gain improved outcomes for patients.

Physical activity and circulating inflammatory markers and cytokines during pregnancy: A population-based cohort study.

INTRODUCTION: Physical activity (PA) during pregnancy has numerous benefits, which may be mediated via effects on the immune system. However, supportive evidence is inconsistent and is mainly from studies in high-risk groups. We estimated the effect of PA during pregnancy on systemic inflammatory markers and cytokines in mothers recruited in the Barwon infant study. MATERIAL AND METHODS: The Barwon infant study is a prebirth cohort of 1064 mothers recruited in the Barwon Region of Victoria, Australia. Participants reported their previous week's PA at their 28-week antenatal appointment using the International PA Questionnaire. Women were grouped into low, moderate, and high PA categories based on daily duration and weekly frequency of walking, moderate- or vigorous-intensity PA. Women reporting moderate levels of PA, consistent with current recommendations, served as the comparison group. Markers of systemic inflammation, high-sensitivity C-reactive protein (hsCRP), glycoprotein acetyls (GlycA), and 17 cytokines were measured at 28 weeks gestation and log transformed as appropriate. Regression analyses adjusted for maternal smoking, gestational diabetes mellitus, prepregnancy BMI, and household size were performed. RESULTS: Compared to women in the moderate group (n = 371, 42%), women reporting low PA (n = 436, 50%) had 10.1% higher hsCRP (95% CI (3.7% to 16.6%), p < 0.01) while women in high PA (n = 76, 9%) had a 14% higher hsCRP (95% CI (3.1% to 24.8%), p = 0.01). Women in the high PA category had higher interleukin (IL)-4 (q = 0.03) and IL-9 (q = 0.03) levels compared to those in moderate category. Each vigorous MET minute/week was associated with lower GlycA (ß = -0.004, 95% CI (-0.044 to 0.035); p = 0.03). CONCLUSIONS: Low and high PA are each associated with higher hsCRP than moderate PA, suggesting that undertaking the recommended moderate PA during pregnancy decreases systemic inflammation. High PA affects T cell-associated cytokines during pregnancy. Evidence from our study suggests that PA can modulate the immune responses during pregnancy. Studies are now required to assess whether PA during pregnancy impacts maternal and infant clinical outcomes by modifying inflammatory responses.

Gut microbiota maturity mediates the protective effect of siblings on food allergy.

BACKGROUND: The mechanisms underlying the protective effect of older siblings on allergic disease remain unclear but may relate to the infant gut microbiota. OBJECTIVE: We sought to investigate whether having older siblings decreases the risk of IgE-mediated food allergy by accelerating the maturation of the infant gut microbiota. METHODS: In a birth cohort assembled using an unselected antenatal sampling frame (n = 1074), fecal samples were collected at 1 month, 6 months, and 1 year, and food allergy status at 1 year was determined by skin prick test and in-hospital food challenge. We used 16S rRNA gene amplicon sequencing to derive amplicon sequence variants. Among a random subcohort (n = 323), microbiota-by-age z scores at each time point were calculated using fecal amplicon sequence variants to represent the gut microbiota maturation over the first year of life. RESULTS: A greater number of siblings was associated with a higher microbiota-by-age z score at age 1 year (ß  = 0.15 per an additional sibling; 95% CI, 0.05-0.24; P = .003), which was in turn associated with decreased odds of food allergy (odds ratio, 0.45; 95% CI, 0.33-0.61; P < .001). Microbiota-by-age z scores mediated 63% of the protective effect of siblings. Analogous associations were not observed at younger ages. CONCLUSIONS: The protective effect of older siblings on the risk of developing IgE-mediated food allergy during infancy is substantially mediated by advanced maturation of the gut microbiota at age 1 year.

Understanding the pathways between prenatal and postnatal factors and overweight outcomes in early childhood: a pooled analysis of seven cohorts.

BACKGROUND/OBJECTIVES: Childhood overweight and obesity are influenced by a range of prenatal and postnatal factors. Few studies have explored the integrative pathways linking these factors and childhood overweight. This study aimed to elucidate the integrative pathways through which maternal pre-pregnancy body mass index (BMI), infant birth weight, breastfeeding duration, and rapid weight gain (RWG) during infancy are associated with overweight outcomes in early childhood from ages 3 to 5 years. SUBJECTS/METHODS: Pooled data from seven Australian and New Zealand cohorts were used (n = 3572). Generalized structural equation modelling was used to examine direct and indirect associations of maternal pre-pregnancy BMI, infant birth weight, breastfeeding duration, and RWG during infancy with child overweight outcomes (BMI z-score and overweight status). RESULTS: Maternal pre-pregnancy BMI was directly associated with infant birth weight (ß 0.01, 95%CI 0.01, 0.02), breastfeeding duration ≥6 months (OR 0.92, 95%CI 0.90, 0.93), child BMI z-score (ß 0.03, 95%CI 0.03, 0.04) and overweight status (OR 1.07, 95%CI 1.06, 1.09) at ages 3-5 years. The association between maternal pre-pregnancy BMI and child overweight outcomes was partially mediated by infant birth weight, but not RWG. RWG in infancy exhibited the strongest direct association with child overweight outcomes (BMI z-score: ß 0.72, 95%CI 0.65, 0.79; overweight status: OR 4.49, 95%CI 3.61, 5.59). Infant birth weight was implicated in the indirect pathways of maternal pre-pregnancy BMI with RWG in infancy, breastfeeding duration, and child overweight outcomes. The associations between breastfeeding duration (≥6 months) and lower child overweight outcomes were fully mediated by RWG in infancy. CONCLUSIONS: Maternal pre-pregnancy BMI, infant birth weight, breastfeeding duration and RWG in infancy act in concert to influence early childhood overweight. Future overweight prevention interventions should target RWG in infancy, which showed the strongest association with childhood overweight; and maternal pre-pregnancy BMI, which was implicated in several pathways leading to childhood overweight.

Childhood body mass index trajectories and asthma and allergies: A systematic review.

BACKGROUND: Previous systematic reviews have focused on associations between single time point measures of Body Mass Index (BMI) and asthma and allergic diseases. As BMI changes dynamically during childhood, examination of associations between longitudinal trajectories in BMI and allergic diseases is needed to fully understand the nature of these relationships. OBJECTIVE: To systematically synthesise the association between BMI trajectories in childhood (0-18 years) and allergic diseases (asthma, eczema, allergic rhinitis, or food allergies outcomes). DESIGN: We conducted a systematic review following the PRISMA guidelines, and two independent reviewers assessed the study quality using the ROBINS-E and GRADE tools. A narrative synthesis was performed as the statistical heterogeneity did not allow a meta-analysis. DATA SOURCES: A search was performed on PubMed and EMBASE databases on 4th January 2023. ELIGIBILITY CRITERIA: Longitudinal cohort studies assessing the associations between childhood BMI trajectories and allergic diseases were included. RESULTS: Eleven studies met the inclusion criteria with a total of 37,690 participants between 0 and 53 years of age. Ten studies examined asthma outcomes, three assessed association with allergic rhinitis, two assessed eczema, and one assessed food allergy. High heterogeneity and high risk of bias were observed. Overall, the quality of evidence was very low. Nevertheless, two consistent findings were identified: (1) a persistently high BMI between 6 and 10 years of age may be associated with an increased risk of asthma at 18 years and (2) a rapid increase in BMI in the first 2 years of life may be associated with subsequent asthma. CONCLUSIONS: Maintaining a normal BMI trajectory during childhood may reduce the risk of asthma. Future research that adequately addresses confounding and includes longer-term follow-up is needed. Moreover, additional studies examining potential associations with eczema, food allergies, and allergic rhinitis outcomes are needed.

Biomarkers of asthma relapse and lung function decline in adults with spontaneous asthma remission: A population-based cohort study.

BACKGROUND: The extent to which biomarkers of asthma activity persist in spontaneous asthma remission and whether such markers are associated with future respiratory outcomes remained unclear. We investigated the association between sub-clinical inflammation in adults with spontaneous asthma remission and future asthma relapse and lung function decline. METHODS: The Tasmanian Longitudinal Health Study is a population-based cohort (n = 8583). Biomarkers of systemic inflammation were measured on participants at age 45, and latent profile analysis was used to identify cytokine profiles. Bronchial hyperresponsiveness (BHR) and nitric oxide products in exhaled breath condensate (EBC NOx) were measured at age 50. Participants with spontaneous asthma remission at ages 45 (n = 466) and 50 (n = 318) were re-evaluated at age 53, and associations between baseline inflammatory biomarkers and subsequent asthma relapse and lung function decline were assessed. RESULTS: We identified three cytokine profiles in adults with spontaneous asthma remission: average (34%), Th2-high (42%) and Th2-low (24%). Compared to the average profile, a Th2-high profile was associated with accelerated decline in post-BD FEV1 /FVC (MD -0.18% predicted per-year; 95% CI -0.33, -0.02), while a Th2-low profile was associated with accelerated decline in both post-BD FEV1 (-0.41%; -0.75, -0.06) and post-BD FVC (-0.31%; -0.62, 0.01). BHR and high TNF-α during spontaneous remission were associated with an increased risk of asthma relapse. In contrast, we found no evidence of association between EBC NOx and either asthma relapse or lung function decline. CONCLUSION: BHR and serum inflammatory cytokines have prognostic value in adults with spontaneous asthma remission. At-risk individuals with BHR, Th2-high or Th2-low cytokine profiles may benefit from closer monitoring and on-going follow-up.

Maternal and Cord Blood 25-Hydroxyvitamin D3 Are Associated with Increased Cord Blood and Naive and Activated Regulatory T Cells: The Barwon Infant Study.

Vitamin D has shown immune-modulatory effects but mostly in in vitro and animal studies. Regulatory T cells (Treg) are important for a balanced immune system. The relationship between vitamin D on the number of circulating neonatal Treg is unclear. We sought to investigate the association between maternal and neonatal vitamin D metabolites and cord blood (CB) Treg subsets. In a cohort of Australian infants (n = 1074), recruited using an unselected antenatal sampling frame, 158 mother-infant pairs had data on the following: 1) 25-hydroxyvitamin D3 (25(OH)D3) measures in both maternal peripheral blood (28- to 32-wk gestation) and infant CB; 2) proportions (percentage of CD4+ T cells) of CB Treg subsets (CD4+CD45RA+ FOXP3low naive Treg, and CD4+CD45RA- FOXP3high activated Treg [aTreg]); and 3) possible confounders, including maternal personal UV radiation. Multiple regression analyses were used. The median 25(OH)D3 was 85.4 and 50.7 nmol/l for maternal and CB samples, respectively. Higher maternal 25(OH)D3 levels were associated with increased CB naive Treg (relative adjusted mean difference [AMD] per 25 nmol/l increase: 5%; 95% confidence interval [CI]: 1-9%), and aTreg (AMD per 25 nmol/l increase: 17%; 95% CI: 6-28%). Furthermore, a positive association between CB 25(OH)D3 levels and CB aTreg (AMD per 25 nmol/l increase: 29%; 95% CI: 13-48%) was also evident. These results persisted after adjustment for other factors such as maternal personal UV radiation and season of birth. 25(OH)D3, may play a role in the adaptive neonatal immune system via induction of FOXP3+ Tregs. Further studies of immune priming actions of antenatal 25(OH)D3 are warranted.

Sulforaphane prevents and reverses allergic airways disease in mice via anti-inflammatory, antioxidant, and epigenetic mechanisms.

Sulforaphane has been investigated in human pathologies and preclinical models of airway diseases. To provide further mechanistic insights, we explored L-sulforaphane (LSF) in the ovalbumin (OVA)-induced chronic allergic airways murine model, with key hallmarks of asthma. Histological analysis indicated that LSF prevented or reversed OVA-induced epithelial thickening, collagen deposition, goblet cell metaplasia, and inflammation. Well-known antioxidant and anti-inflammatory mechanisms contribute to the beneficial effects of LSF. Fourier transform infrared microspectroscopy revealed altered composition of macromolecules, following OVA sensitization, which were restored by LSF. RNA sequencing in human peripheral blood mononuclear cells highlighted the anti-inflammatory signature of LSF. Findings indicated that LSF may alter gene expression via an epigenetic mechanism which involves regulation of protein acetylation status. LSF resulted in histone and α-tubulin hyperacetylation in vivo, and cellular and enzymatic assays indicated decreased expression and modest histone deacetylase (HDAC) inhibition activity, in comparison with the well-known pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). Molecular modeling confirmed interaction of LSF and LSF metabolites with the catalytic domain of metal-dependent HDAC enzymes. More generally, this study confirmed known mechanisms and identified potential epigenetic pathways accounting for the protective effects and provide support for the potential clinical utility of LSF in allergic airways disease.

Epidemiology of eczema in South-Eastern Australia.

BACKGROUND/OBJECTIVES: Eczema is a common chronic debilitating skin condition in childhood. Data on the epidemiology and natural history of eczema across the life course are lacking. This analysis aimed to describe these epidemiological features in Australian children and adults. METHODS: Data collected on eczema from four Australian cohort studies were analysed: namely HealthNuts, Melbourne Atopic Cohort Study (MACS), Tasmanian Longitudinal Health Study (TAHS) and the Australian arm of the European Community Respiratory Health Survey (ECRHS). RESULTS: Among children aged under 6 years, 28.8%-35.6% have ever-had eczema, and 16.7%-26.6% had 'current eczema'. Among those aged 6-12 years, 14.6%-24.7% had 'current eczema' with 12.0%-18.5% of those at ages of 6 and 10 years classified as having moderate-to-severe eczema according to the Scoring of Atopic Dermatitis (SCORAD) index. In adults, the prevalence of 'eczema ever' ranged between 13.8% and 48.4%. The 12-month period prevalence of eczema was 15.1% at age 18, while current eczema was 8.5% at an average age of 51, and 8.8% at an average age 53 years. Eczema was more common among young boys, but this difference became non-significant for older children and early adolescents. In contrast, eczema was more common for adult women than men. CONCLUSIONS: Eczema is common both in children and adults. The proportion of severe eczema in children was substantial.

Changes in Australian food anaphylaxis admission rates following introduction of updated allergy prevention guidelines.

BACKGROUND: Food anaphylaxis admission rates have increased steadily in recent decades. Global food allergy prevention guidelines recommending early introduction of allergenic foods were introduced in 2015-2016. Australian guidelines to not delay the introduction of allergenic foods were introduced in 2007-2008. OBJECTIVE: Our aim was to examine whether introduction of Australian guidelines (2007-2008) and global allergy prevention guidelines (2015-2016) were associated with reductions in food anaphylaxis admission rates. METHODS: We compared food anaphylaxis admission rates across 3 periods: 1998-1999 to 2006-2007, 2007-2008 to 2014-2015, and 2015-2016 to 2018-2019. RESULTS: Annual food anaphylaxis admission rates increased 9-fold between 1998-1999 and 2018-2019, from 2.0 per 105 population to 18.2 per 105 population; the highest absolute rates were in those younger than 1 year. When year-on-year rates of change were examined across the 3 time periods, the annual rate of increase slowed after 2007-2008 in those aged 1 to 4 years (17.6%, 6.2%, and 3.9% per year, respectively) and those aged 5 to 9 years (22%, 13.9%, and -2.4%, respectively), and after 2015-2016, in those aged 10 to 14 years (17.5%, 18.0%, and 10.8%, respectively). By contrast, the year-on-year rate of increase accelerated in those younger than 1 year (5.2%, 8.0%, and 18.0%, respectively) and in all age groups older than 15 years. CONCLUSIONS: Although food anaphylaxis continues to increase overall, there is preliminary evidence indicating a slowing in the year-on-year rate of increase among those aged 1 to 4, 5 to 9, and 10 to 14 years, coinciding with introduction of updated infant feeding and allergy prevention guidelines in 2007-2008 and 2015-2016. Changes to the guidelines may have contributed to an attenuated rate of increase in food anaphylaxis in these age groups, as well as to increased rates in those younger than 1 year.

The natural history of peanut and egg allergy in children up to age 6 years in the HealthNuts population-based longitudinal study.

BACKGROUND: Prospectively collected data on the natural history of food allergy are lacking. OBJECTIVE: We examined the natural history of egg and peanut allergy in children from age 1 to 6 years and assessed whether a skin prick test (SPT) result or other clinical factors at diagnosis are associated with the persistence or resolution of food allergy in early childhood. METHODS: The HealthNuts cohort consists of 5276 children who were recruited at age 1 year and have been followed prospectively. Children with food allergy at age 1 year (peanut [n = 156] or raw egg [n = 471] allergy ) and children who developed new sensitizations or food reactions after age 1 year were assessed for food sensitization and allergy (confirmed by oral food challenge when indicated) at the 6-year follow-up. RESULTS: New-onset food allergy developed by age 6 years was more common for peanut (0.7% [95% CI = 0.5%-1.1%]) than egg (0.09% [95% CI = 0.03%-0.3%]). Egg allergy resolved more commonly (89% [95% CI = 85%-92%]) than peanut allergy (29% [95% CI = 22%-38%]) by age 6 years. The overall weighted prevalence of peanut allergy at age 6 years was 3.1% (95% CI = 2.6-3.7%) and that of egg allergy was 1.2% (95% = CI 0.9%-1.6%). The factors at age 1 year associated with persistence of peanut allergy were peanut SPT result of 8 mm or larger (odds ratio [OR] = 2.35 [95% CI 1.08-5.12]), sensitization to tree nuts (adjusted OR [aOR] = 2.51 [95% CI = 1.00-6.35]), and early-onset severe eczema (aOR = 3.23, [95% CI 1.17-8.88]). Factors at age 1 associated with persistence of egg allergy at age 6 were egg SPT result of 4 mm or larger (OR = 2.98 [95% CI 1.35-6.36]), other (peanut and/or sesame) food sensitizations (aOR = 2.80 [95% CI = 1.11-7.03]), baked egg allergy (aOR = 7.41 [95% CI = 2.16-25.3]), and early-onset severe eczema (aOR = 3.77 [95% CI = 1.35-10.52]). CONCLUSION: Most egg allergy and nearly one-third of peanut allergy resolves naturally by age 6 years. The prevalence of peanut allergy at age 6 years was similar to that observed at age 1 year, largely owing to new-onset food peanut allergy after age 1 year. Infants with early-onset eczema, larger SPT wheals, or multiple food sensitizations and/or allergies were less likely to acquire tolerance to either peanut or egg.

Longitudinal antibody responses to peanut following probiotic and peanut oral immunotherapy (PPOIT) in children with peanut allergy.

INTRODUCTION: Probiotic and Peanut Oral Immunotherapy (PPOIT) is effective at inducing sustained unresponsiveness (SU) at end-of-treatment and this effect persists up to four years post-treatment, referred to as persistent SU. We sought to evaluate (i) how PPOIT altered peanut-specific humoral immune indices, and (ii) how such longitudinal indices relate to persistent SU. METHODS: Longitudinal serum/plasma levels of whole peanut- and peanut component- (Ara-h1, -h2, -h3, -h8, -h9) specific-IgE (sIgE) and specific-IgG4 (sIgG4) antibodies were measured by ImmunoCAP and salivary peanut-specific-IgA (sIgA) by ELISA in children (n=62) enrolled in the PPOIT-001 randomised trial from baseline (T0) to 4-years post-treatment (T5). Multivariate regression analyses of log-transformed values were used for point-in-time between group comparisons. Generalised estimating equations (GEE) were used for longitudinal comparisons between groups. RESULTS: PPOIT was associated with changes in sIgE and sIgG4 over time. sIgE levels were significantly reduced post-treatment [T5, PPOIT v.s. Placebo ratio of geometric mean (GM): Ara-h1 0.07, p=0.008; Ara-h2 0.08, p=0.007; Ara-h3 0.15, p=0.021]. sIgG4 levels were significantly increased by end-of-treatment (T1, PPOIT v.s. Placebo ratio of GM: Ara-h1 3.77, p=0.011; Ara-h2 17.97, p<0.001; Ara-h3 10.42, p<0.001) but levels in PPOIT group decreased once treatment was stopped and returned to levels comparable with Placebo group by T5. Similarly, salivary peanut sIgA increased during treatment, as early as 4 months of treatment (PPOIT v.s. Placebo, ratio of GM: 2.04, p=0.014), then reduced post-treatment. CONCLUSION: PPOIT was associated with broad reduction in peanut specific humoral responses which may mediate the clinical effects of SU that persists to 4-years post-treatment.

Remission of peanut allergy is associated with rewiring of allergen-driven T helper 2-related gene networks.

BACKGROUND: The immunological changes underpinning acquisition of remission (also called sustained unresponsiveness) following food immunotherapy remain poorly defined. Limited access to effective therapies and biosamples from treatment responders has prevented progress. Probiotic peanut oral immunotherapy is highly effective at inducing remission, providing an opportunity to investigate immune changes. METHODS: Using a systems biology approach, we examined gene co-expression network patterns in peanut-specific CD4+ T cell responses before and after probiotic and peanut oral immunotherapy in subjects enrolled in the PPOIT-001 randomized trial: Responders who attained remission (n = 16), placebo-treated who remained allergic (n = 16). RESULTS: Acquisition of remission was associated with rewiring of gene network patterns, which was characterized by integration of T helper 2 and interferon signalling modules, markedly reduced T helper 2 gene connectivity, and shutdown in co-expression activity between T helper 2 effectors and cell cycle regulators. CONCLUSION: The immunological changes underlying remission following peanut oral immunotherapy are mediated by reprogramming of T helper 2-associated gene networks in the CD4+ T cell compartment. Findings provide insight into immune mechanisms driving the acquisition of remission following oral immunotherapy, paving the way for the development of improved approaches to induce remission/sustained unresponsiveness in patients with food allergy.

Infant inflammation predicts childhood emotional and behavioral problems and partially mediates socioeconomic disadvantage.

BACKGROUND: Emotional and behavioral problems (EBP) are common in children. Environmental factors like socioeconomic disadvantage influence EBP pathogenesis and can trigger inflammation. However, the link between early inflammation-EBP in children is unclear. We investigated the associations between i) infant inflammatory biomarkers and subsequent EBP and ii) early life environmental factors and EBP and assessed whether infant inflammation mediated these associations. METHODS: Inflammatory biomarkers glycoprotein acetyls (GlycA) and high-sensitivity C-reactive protein (hsCRP) were quantified at birth and 12 months in a population-derived birth cohort, the Barwon Infant Study. Early life factors including demographic, prenatal, and perinatal factors were collected from antenatal to the two-year period. Internalizing and externalizing problems at age two were measured by the Child Behavior Checklist. Prospective associations were examined by multivariable regression analyses adjusted for potential confounders. Indirect effects of early life factors on EBP through inflammation were identified using mediation analyses. RESULTS: Elevated GlycA levels at birth (GlycAbirth) were associated with greater internalizing problems at age two (ß = 1.32 per SD increase in GlycA; P = 0.001). Inflammation at birth had a stronger magnitude of effect with later EBP than at 12 months. GlycAbirth partially mediated the associations between lower household income (6%), multiparity (12%) and greater number of older siblings (13%) and EBP. Patterns were less evident for hsCRP or externalizing problems. CONCLUSIONS: GlycAbirth was positively associated with EBP at age two and partially mediated the association between several indicators of socioeconomic disadvantage and EBP. Prenatal and perinatal inflammation may be relevant to early neurodevelopment and emotional health.

Maternal inflammatory and omega-3 fatty acid pathways mediate the association between socioeconomic disadvantage and childhood cognition.

Poor cognitive outcomes in early childhood predict poor educational outcomes and diminished health over the life course. We sought to investigate (i) whether maternal metabolites predict child cognition, and (ii) if maternal metabolomic profile mediates the relationship between environmental exposures and child cognition. Metabolites were measured using nuclear magnetic resonance-based metabolomics in pregnant women from a population-derived birth cohort. Child cognition was measured at age 2 years. In 662 mother-child pairs, elevated inflammatory markers (ß = -2.62; 95% CI -4.10, -1.15; P = 0.0005) and lower omega-3 fatty acid-related metabolites (ß = 0.49; 95% CI 0.09, 0.88; P = 0.02) in the mother were associated with lower child cognition and partially mediated the association between lower child cognition and multiple risk factors common to socioeconomic disadvantage. Modifying maternal prenatal metabolic pathways related to inflammation and omega-3 fatty acids may offset the adverse associations between prenatal risk factors related to socioeconomic disadvantage and low child cognition.

The newborn metabolome: associations with gestational diabetes, sex, gestation, birth mode, and birth weight.

BACKGROUND: Pathways towards many adult-onset conditions begin early in life, even in utero. Maternal health in pregnancy influences this process, but little is known how it affects neonatal metabolism. We investigated associations between pregnancy and birth factors and cord blood metabolomic profile in a large, population-derived cohort. METHODS: Metabolites were measured using nuclear magnetic resonance in maternal (28 weeks gestation) and cord serum from 912 mother-child pairs in the Barwon Infant Study pre-birth cohort. Associations between maternal (metabolites, age, BMI, smoking), pregnancy (pre-eclampsia, gestational diabetes (GDM)), and birth characteristics (delivery mode, gestational age, weight, infant sex) with 72 cord blood metabolites were examined by linear regression. RESULTS: Delivery mode, sex, gestational age, and birth weight were associated with specific metabolite levels in cord blood, including amino acids, fatty acids, and cholesterols. GDM was associated with higher cord blood levels of acetoacetate and 3-hydroxybutyrate. CONCLUSIONS: Neonatal factors, particularly delivery mode, were associated with many cord blood metabolite differences, including those implicated in later risk of cardiometabolic disease. Associations between GDM and higher offspring ketone levels at birth are consistent with maternal ketosis in diabetic pregnancies. Further work is needed to determine whether these neonatal metabolome differences associate with later health outcomes. IMPACT: Variations in blood metabolomic profile have been linked to health status in adults and children, but corresponding data in neonates are scarce. We report evidence that pregnancy complications, mode of delivery, and offspring characteristics, including sex, are independently associated with a range of circulating metabolites at birth, including ketone bodies, amino acids, cholesterols, and inflammatory markers. Independent of birth weight, exposure to gestational diabetes is associated with higher cord blood ketone bodies and citrate. These findings suggest that pregnancy complications, mode of delivery, gestational age, and measures of growth influence metabolic pathways prior to birth, potentially impacting later health and development.

A pragmatic approach to infant feeding for food allergy prevention.

Early introduction of allergenic foods into an infant's diet is currently the most promising strategy to prevent food allergy, with infant guidelines around the world shifting from promoting avoidance to actively encourage the introduction of allergenic foods in the infant diet. Infant feeding guidelines vary according to regional public health priorities, and knowledge gaps remain, resulting in ongoing challenges for clinicians and families to translate guidelines into practical strategies for the introduction of complementary foods for food allergy prevention. Evidence from Australia demonstrates high community support and uptake of revised guidelines with most parents introducing allergenic foods in the first year of life, although this has not had the expected impact on substantially reducing food allergy prevalence. To uptake of guidelines from other countries is less clear, and several barriers have been noted in infant feeding RCTs, which may warrant intervention strategies. Further research is needed to understand additional strategies for food allergy prevention, particularly in infants who develop food allergy prior to when they are developmentally ready to commence solids. Several RCTs are underway investigating preventative strategies that target the window before allergen ingestion, such as vitamin D supplementation, emollient use, and immunizations that prime the immune response away from a Th2-driven allergic phenotype. Further research is also needed to understand the role of the environment and the host environment in the development of tolerance to foods.