Human milk oligosaccharide profiles and allergic disease up to 18 years.

BACKGROUND: Human milk oligosaccharides (HMO) are a diverse range of sugars secreted in breast milk that have direct and indirect effects on immunity. The profiles of HMOs produced differ between mothers. OBJECTIVE: We sought to determine the relationship between maternal HMO profiles and offspring allergic diseases up to age 18 years. METHODS: Colostrum and early lactation milk samples were collected from 285 mothers enrolled in a high-allergy-risk birth cohort, the Melbourne Atopy Cohort Study. Nineteen HMOs were measured. Profiles/patterns of maternal HMOs were determined using LCA. Details of allergic disease outcomes including sensitization, wheeze, asthma, and eczema were collected at multiple follow-ups up to age 18 years. Adjusted logistic regression analyses and generalized estimating equations were used to determine the relationship between HMO profiles and allergy. RESULTS: The levels of several HMOs were highly correlated with each other. LCA determined 7 distinct maternal milk profiles with memberships of 10% and 20%. Compared with offspring exposed to the neutral Lewis HMO profile, exposure to acidic Lewis HMOs was associated with a higher risk of allergic disease and asthma over childhood (odds ratio asthma at 18 years, 5.82; 95% CI, 1.59-21.23), whereas exposure to the acidic-predominant profile was associated with a reduced risk of food sensitization (OR at 12 years, 0.08; 95% CI, 0.01-0.67). CONCLUSIONS: In this high-allergy-risk birth cohort, some profiles of HMOs were associated with increased and some with decreased allergic disease risks over childhood. Further studies are needed to confirm these findings and realize the potential for intervention.

Early life acetaminophen exposure, glutathione S-transferase genes, and development of adolescent asthma in a high-risk birth cohort.

BACKGROUND: Although the impact of early life acetaminophen on asthma risk is still not clear, potential interactions with glutathione S-transferase (GST) genes due to reduced antioxidant function in particular polymorphisms, and possible impact on lung function, have never been investigated in adolescents. OBJECTIVE: We aimed to investigate associations between early life acetaminophen use and adolescent asthma and lung function and to assess potential interactions by GST polymorphisms. METHODS: Acetaminophen use was recorded 18 times up to age 2 years (n = 575 [92.7%]). Participants were genotyped for GST polymorphisms (GSTM1/T1/P1) (n = 429 [69.2%]). Asthma and lung function were measured at 12 (n = 365 [58.9%]) and 18 years (n = 413 [66.6%]). Regression models assessed associations and interactions. RESULTS: Doubling of days of acetaminophen use was associated with reduced prebronchodilator FEV1/forced vital capacity (ß coefficient, -0.10; 95% CI, -0.19 to -0.01) and midexpiratory flow (-0.09; 95% CI, -0.18 to 0) at 18 years, but this association was not found when restricted for nonrespiratory reasons, suggesting confounding by indication. However, in children with GSTM1 null and GSTT1 present, increasing acetaminophen use for nonrespiratory reasons was associated with reduced FEV1 and midexpiratory flow at 18 years (interaction between GSTM1/T1 and acetaminophen P < .05). Increased acetaminophen use was associated with asthma at 18 years for children with GSTP1 Ile/Ile (odds ratio, 1.66; 95% CI, 1.07 to 2.57), but not other GSTP1 genotypes. CONCLUSIONS: These novel findings need to be investigated for consistency in other studies but suggest that children carrying risk genotypes may be susceptible to respiratory consequences from acetaminophen use.

Postnatal probiotics and allergic disease in very preterm infants: Sub-study to the ProPrems randomized trial.

BACKGROUND: Probiotic supplementation to mothers and/or their term-born infants has been suggested to prevent allergic disease, in particular eczema; however, no studies have investigated probiotics for prevention of allergic diseases in very preterm infants. We evaluated the effect of a postnatal probiotic combination on development of allergic diseases in very preterm infants. METHODS: This sub-study was an a priori secondary outcome of the ProPrems multi-center, double-blind, placebo-controlled randomized trial (ANZCTR:12607000144415). ProPrems randomized 1099 very preterm infants to receive a probiotic combination or placebo from soon after birth until discharge from hospital or term corrected age (CA), whichever was earlier. Allergic disease (eczema, atopic eczema, food allergy, wheeze, atopic sensitization) was assessed in a subgroup of ProPrems infants (n = 281) as close to 12 months CA as possible by questionnaire, clinical examination, and skin prick tests to common allergens. RESULTS: There was no difference in eczema incidence between the probiotic and placebo groups (35[30%] of 118 infants vs 37[27%] of 137 infants, respectively, absolute difference 2.65%, 95% CI -8.45 to 13.75). Similarly, the incidence of atopic eczema (6[5%] of 118 vs 3[2%] of 137), food allergy (4[3%] of 124 vs 2[1%] of 154), wheeze (39[31%] of 127 vs 45[29%] of 154), and atopic sensitization (14[13%] of 106 vs 13[11%] of 123) were similar between the probiotic and placebo groups. CONCLUSION: This study found no effect of postnatal administration of a probiotic combination on the incidence of allergic diseases or atopic sensitization in the first 2 years of life in children born very preterm. Evidence that probiotics are effective for prevention of allergic disease in premature infants remains lacking; adequately powered randomized controlled trials evaluating probiotic supplementation for allergy prevention in very preterm infants are needed.

Age at onset and persistence of eczema are related to subsequent risk of asthma and hay fever from birth to 18 years of age.

BACKGROUND: Few studies have simultaneously addressed the importance of age of onset and persistence of eczema for the subsequent development of asthma and hay fever, particularly into early adulthood. METHODS: A high-risk birth cohort was recruited comprising 620 infants, who were then followed up frequently until 2 years of age, annually from age 3 to 7, then at 12 and 18 years, to document any episodes of eczema, current asthma, and hay fever. The generalized estimation equation technique was used to examine asthma and hay fever outcomes at 6 (n = 325), 12 (n = 248) and 18 (n = 240) years, when there was consistency of associations across the follow-ups. RESULTS: Very early-onset persistent (onset <6 months, still present from 2 to 5 years) eczema was related to current asthma (adjusted OR = 3.2 [95% CI = 1.7-6.1]), as was very early-onset remitting eczema (onset <6 months but not present from 2-5 years, OR = 2.7, 95% CI = 1.0-7.2) and early-onset persistent eczema (onset from 6-24 months, OR = 2.3, 95% CI = 1.2-4.7). Late-onset eczema (commenced from 2-5 years) was associated with increased risk of asthma at 12 years (OR = 3.0, 95% CI=1.1-8.2) but not at age 6 years. Only very early-onset persistent eczema was associated with increased risk of hay fever (aOR = 2.4, 95% CI = 1.4-4.1). CONCLUSION AND CLINICAL RELEVANCE: Eczema which commences in early infancy and persists into toddler years is strongly associated with asthma, and to a lesser extent hay fever, in high-risk children. If these associations are causal, prevention of early-life eczema might reduce the risk of respiratory allergy.

Sensitization to milk, egg and peanut from birth to 18 years: A longitudinal study of a cohort at risk of allergic disease.

BACKGROUND: Longitudinal data on the natural history of food sensitization beyond early childhood are scarce. We aimed to investigate the natural history of milk, egg and peanut sensitization from infancy to 18 years and assess whether early food sensitization predicted adolescent food allergy. METHODS: Sensitization to cow's milk, hen's egg and peanut was measured by skin prick testing at ages 6 months, 1, 2, 12 and 18 years in a high-risk allergy birth cohort (n = 620). Generalized additive models investigated interactions with sex, eczema and aeroallergen sensitization in infancy. Logistic regression assessed the relationships between early food sensitization and adolescent sensitization and probable food allergy up to 18 years. RESULTS: The prevalence of egg and peanut sensitization peaked at 12 months, while milk sensitization peaked at both 1 and 12 years. Boys with early eczema had the highest prevalences of milk and egg sensitization throughout follow-ups. However, neither sex nor eczema influenced the prevalence of peanut sensitization over time. New onset food sensitization beyond the age of 2 was observed in 7% of participants. Food sensitization at 12 months was associated with increased risk of adolescent food sensitization and adolescent probable food allergy, with sensitization to more than one food allergen had the strongest predictor. CONCLUSIONS: Food sensitization prevalence is highest in infancy and declines after 12 months of age. Boys with early-life eczema have the highest prevalence of milk and egg sensitization. Food sensitization at 12 months can predict children at greater risk of adolescent sensitization and probable food allergy at 12 and 18 years.

Childhood wheeze phenotypes show less than expected growth in FEV1 across adolescence.

RATIONALE: Better characterization of childhood wheeze phenotypes using newer statistical methods provides a basis for addressing the heterogeneity of childhood asthma. Outcomes of these phenotypes beyond childhood are unknown. OBJECTIVES: To determine if adolescent respiratory symptoms, lung function, and changes in lung function over adolescence differ by childhood wheeze phenotypes defined through latent class analysis. METHODS: A prospective birth cohort (Melbourne Atopy Cohort Study) followed 620 high allergy-risk children, recording respiratory symptoms and spirometry at 12 and 18 years. Regression analyses identified relationships between wheeze phenotypes (never/infrequent, early transient, early persistent, intermediate onset, and late onset) and lung function, change in lung function (12-18 yr), respiratory symptoms, and asthma. The baseline classification was never/infrequent wheeze. MEASUREMENTS AND MAIN RESULTS: Deficits in expected growth of lung function, measured by change in prebronchodilator FEV1 between 12 and 18 years, were found for early persistent (reduced 290 ml; 95% confidence interval [CI], 82-498), intermediate-onset (reduced 210 ml; 95% CI, 62-359), and late-onset wheeze (reduced 255 ml; 95% CI, 69-442). Intermediate-onset wheezers had persistent FEV1 deficit after bronchodilator at 18 years (reduced 198 ml; 46,350). Current asthma risk was increased for all phenotypes except early transient, which was also not associated with lung function deficits at 12 or 18 years. CONCLUSIONS: Persistent wheeze phenotypes in childhood were associated with reduced growth in prebronchodilator FEV1 over adolescence. Intermediate-onset wheezers showed irreversible airflow limitation by 18 years. Conversely, early transient wheeze was a benign condition with no sequelae for respiratory health by age 18.

Early-life risk factors for childhood wheeze phenotypes in a high-risk birth cohort.

OBJECTIVE: To define longitudinal childhood wheeze phenotypes and identify their early-life risk factors. STUDY DESIGN: Current wheeze was recorded 23 times up to age 7 years in a birth cohort at high risk for allergy (n = 620). Latent class analysis of wheeze responses identified 5 classes. Multinomial logistic regression estimated associations of probability-weighted wheezing classes with early-life factors. All phenotypes were compared with never/infrequent wheezers. RESULTS: Lower respiratory tract infection (LRTI) by 1 year (relative risk [RR], 3.00; 95% CI, 1.58-5.70), childcare by 1 year (RR, 1.51; 95% CI, 1.02-2.22), and higher body mass index (RR, 2.51; 95% CI, 1.09-5.81) were associated with increased risk of early transient wheeze, whereas breastfeeding was protective (RR, 0.54; 95% CI, 0.32-0.90). LRTI (RR, 6.54; 95% CI, 2.55-16.76) and aeroallergen sensitization (RR, 4.95; 95% CI, 1.74-14.02) increased the risk of early persistent wheeze. LRTI (RR, 5.31; 95% CI, 2.71-10.41), eczema (RR, 2.77; 95% CI, 1.78-4.31), aeroallergen sensitization (RR, 5.60; 95% CI, 2.86-10.9), and food sensitization (RR, 2.77; 95% CI, 1.56-4.94) increased the risk of intermediate-onset wheeze, whereas dog exposure at baseline (RR, 0.52; 95% CI, 0.32-0.84) and first-born status (RR, 0.49; 95% CI, 0.32-0.76) were protective. Heavy parental smoking at birth (RR, 3.18; 95% CI, 1.02-9.88) increased the risk of late-onset wheeze, whereas breastfeeding reduced it (RR, 0.34; 95% CI, 0.12-0.96). All wheeze classes except early transient had greater risk of wheeze at age 12 years compared with never/infrequent wheezers. CONCLUSION: We found distinct early-life risk factor profiles for each wheeze phenotype. These findings provide insight into possible wheeze mechanisms and have implications for identifying preventive strategies and addressing clinical management of early-life wheeze.

BNT162b2 COVID-19 vaccination in children alters cytokine responses to heterologous pathogens and Toll-like receptor agonists.

Background: Vaccines can have beneficial off-target (heterologous) effects that alter immune responses to, and protect against, unrelated infections. The heterologous effects of COVID-19 vaccines have not been investigated in children. Aim: To investigate heterologous and specific immunological effects of BNT162b2 COVID-19 vaccination in children. Methods: A whole blood stimulation assay was used to investigate in vitro cytokine responses to heterologous stimulants (killed pathogens, Toll-like receptor ligands) and SARS-CoV-2 antigens. Samples from 29 children, aged 5-11 years, before and 28 days after a second BNT162b2 vaccination were analysed (V2 + 28). Samples from eight children were analysed six months after BNT162b2 vaccination. Results: At V2 + 28, interferon-γ and monocyte chemoattractant protein-1 responses to S. aureus, E. coli, L. monocytogenes, BCG vaccine, H. influenzae, hepatitis B antigen, poly(I:C) and R848 stimulations were decreased compared to pre-vaccination. For most of these heterologous stimulants, IL-6, IL-15 and IL-17 responses were also decreased. There were sustained decreases in cytokine responses to viral, but not bacterial, stimulants six months after BNT162b2 vaccination. Cytokine responses to irradiated SARS-CoV-2, and spike glycoprotein subunits (S1 and S2) were increased at V2 + 28 for most cytokines and remained higher than pre-vaccination responses 6 months after BNT162b2 vaccination for irradiated SARS-CoV-2 and S1. There was no correlation between BNT162b2 vaccination-induced anti-SARS-CoV2-receptor binding domain IgG antibody titre at V2 + 28 and cytokine responses. Conclusions: BNT162b2 vaccination in children alters cytokine responses to heterologous stimulants, particularly one month after vaccination. This study is the first to report the immunological heterologous effects of COVID-19 vaccination in children.

Effect of a partially hydrolyzed whey infant formula at weaning on risk of allergic disease in high-risk children: a randomized controlled trial.

BACKGROUND: Partially hydrolyzed whey formula (pHWF) has been recommended for infants with a family history of allergic disease at the cessation of exclusive breast-feeding to promote oral tolerance and prevent allergic diseases. OBJECTIVE: To determine whether feeding infants pHWF reduces their risk of allergic disease. METHODS: A single-blind (participant) randomized controlled trial was conducted to compare allergic outcomes between infants fed a conventional cow's milk formula, a pHWF, or a soy formula. Before birth, 620 infants with a family history of allergic disease were recruited and randomized to receive the allocated formula at cessation of breast-feeding. Skin prick tests to 6 common allergens (milk, egg, peanut, dust mite, rye grass, and cat dander) were performed at 6, 12, and 24 months. The primary outcome was development of allergic manifestations (eczema and food reactions) measured 18 times in the first 2 years of life. RESULTS: Follow-up was complete for 93% (575/620) at 2 years and 80% (495/620) at 6 or 7 years of age. There was no evidence that infants allocated to the pHWF (odds ratio, 1.21; 95% CI, 0.81-1.80) or the soy formula (odds ratio, 1.26; 95% CI, 0.84-1.88) were at a lower risk of allergic manifestations in infancy compared with conventional formula. There was also no evidence of reduced risk of skin prick test reactivity or childhood allergic disease. CONCLUSION: Despite current dietary guidelines, we found no evidence to support recommending the use of pHWF at weaning for the prevention of allergic disease in high-risk infants.

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.

Long-term clinical and immunological effects of probiotic and peanut oral immunotherapy after treatment cessation: 4-year follow-up of a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Oral immunotherapy has attracted much interest as a potential treatment for food allergy, yet little is known about its long-term effects. We aimed to assess long-term outcomes in participants who completed a randomised, double-blind, placebo-controlled trial of combined probiotic and peanut oral immunotherapy (PPOIT), which was previously shown to induce desensitisation and 2-week sustained unresponsiveness. METHODS: All participants who completed the PPOIT randomised trial were eligible to participate in this follow-up study 4 years after treatment cessation. Peanut intake and adverse reactions to peanut in the 4 years after treatment cessation were systematically documented with a structured questionnaire administered by allergy nurses. Additionally, participants were invited to undergo peanut skin prick tests, measurement of peanut sIgE and sIgG4 concentrations, and double-blind placebo-controlled peanut challenge to assess 8-week sustained unresponsiveness. FINDINGS: 48 (86%) of 56 eligible participants were enrolled in the follow-up study. Mean time since stopping treatment was 4·2 years in both PPOIT (SD 0·6) and placebo (SD 0·7) participants. Participants from the PPOIT group were significantly more likely than those from the placebo group to have continued eating peanut (16 [67%] of 24 vs one [4%] of 24; absolute difference 63% [95% CI 42-83], p=0·001; number needed to treat 1·6 [95% CI 1·2-2·4]). Four PPOIT-treated participants and six placebo participants reported allergic reactions to peanut after intentional or accidental intake since stopping treatment, but none had anaphylaxis. PPOIT-treated participants had smaller wheals in peanut skin prick test (mean 8·1 mm [SD 7·7] vs 13·3 mm [7·6]; absolute difference -5·2 mm [95% CI -10·3 to 0·0]; age-adjusted and sex-adjusted p=0·035) and significantly higher peanut sIgG4:sIgE ratios than placebo participants (geometric mean 67·3 [95% CI 10·3-440·0] vs 5·2 [1·2-21·8]; p=0·031). Seven (58%) of 12 participants from the PPOIT group attained 8-week sustained unresponsiveness, compared with one (7%) of 15 participants from the placebo group (absolute difference 52% [95% CI 21-82), p=0·012; number needed to treat 1·9 [95% CI 1·2-4·8]). INTERPRETATION: PPOIT provides long-lasting clinical benefit and persistent suppression of the allergic immune response to peanut. FUNDING: Murdoch Childrens Research Institute and Australian Food Allergy Foundation.

Paracetamol use in early life and asthma: prospective birth cohort study.

OBJECTIVE: To determine if use of paracetamol in early life is an independent risk factor for childhood asthma. DESIGN: Prospective birth cohort study. SETTING: Melbourne Atopy Cohort Study. PARTICIPANTS: 620 children with a family history of allergic disease, with paracetamol use prospectively documented on 18 occasions from birth to 2 years of age, followed until age 7 years. MAIN OUTCOME MEASURES: The primary outcome was childhood asthma, ascertained by questionnaire at 6 and 7 years. Secondary outcomes were infantile wheeze, allergic rhinitis, eczema, and skin prick test positivity. RESULTS: Paracetamol had been used in 51% (295/575) of children by 12 weeks of age and in 97% (556/575) by 2 years. Between 6 and 7 years, 80% (495/620) were followed up; 30% (148) had current asthma. Increasing frequency of paracetamol use was weakly associated with increased risk of childhood asthma (crude odds ratio 1.18, 95% confidence interval 1.00 to 1.39, per doubling of days of use). However, after adjustment for frequency of respiratory infections, this association essentially disappeared (odds ratio 1.08, 0.91 to 1.29). Paracetamol use for non-respiratory causes was not associated with asthma (crude odds ratio 0.95, 0.81 to 1.12). CONCLUSIONS: In children with a family history of allergic diseases, no association was found between early paracetamol use and risk of subsequent allergic disease after adjustment for respiratory infections or when paracetamol use was restricted to non-respiratory tract infections. These findings suggest that early paracetamol use does not increase the risk of asthma.