High Degree of Desensitization After 1 Year of Early-Life Peanut Oral Immunotherapy: Small Children Oral Immunotherapy (SmaChO) Randomized Controlled Trial.

BACKGROUND: The prevalence of peanut allergy is about 2% and mostly lifelong. Studies of oral immunotherapy (OIT) with peanut (the daily oral intake of an initially low and then increasing dose of peanut) often show problematic side effects, but there are indications of better safety and effect in younger children compared with older children and adults. OBJECTIVE: To determine the safety and effectiveness of peanut OIT with a slow up-dosing strategy and low maintenance dose in children aged 1 to 3 years who were allergic to peanut, through a 1-year interim analysis. METHOD: In a randomized controlled trial (2:1 ratio), 75 children, median age 31 months (interquartile range [IQR], 23-40 months) were assigned to receive peanut OIT (n = 50) or peanut avoidance (n = 25). RESULTS: In the OIT and avoidance groups, 43 of 50 and 20 of 25 children, respectively, performed the 1-year open oral peanut challenge. A cumulative dose of 750 mg peanut protein after 1 year was tolerated by 72% (36 of 50 children) in the OIT group compared with 4% (1 of 25) in the avoidance group (P < .001). Median tolerated cumulative dose was 2,750 mg (IQR, 275-5,000 mg) peanut protein in the OIT group compared with 2.8 mg (IQR, 0.3-27.8 mg) in the avoidance group (P < .001). Of the doses administered at home during the first year of OIT, 1.4% resulted in adverse events and 79% were mild, and three doses of epinephrine were given at home to two individuals. CONCLUSION: In children aged 1 to 3 years, peanut OIT with the combination of slow up-dosing and low maintenance dose seems safe and effective after 1 year.

Rhinovirus-induced wheeze was associated with asthma development in predisposed children.

AIM: This study explored whether early-life factors, such as rhinovirus-induced wheeze and allergic sensitisation, were related to asthma at 11 years of age. METHODS: We focused on 107 children aged 6-48 months, who attended the paediatric emergency department at Astrid Lindgren's Children's Hospital in Stockholm, Sweden, with acute wheeze in 2008-2012. They also attended follow-up visits at 11 years of age and were compared with 46 age-matched healthy controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated with logistic regression. RESULTS: We found that 62.6% of the acute wheeze cases had asthma at 11 years of age. Rhinoviruses at inclusion were the only common airway viruses associated with an increased asthma risk (OR 2.4, 95% CI 1.02-5.6). Other increased risks were parental heredity for asthma and/or allergies (adjusted OR 3.4, 95% CI 1.1-9.9) and allergic sensitisation at 2 years of age (adjusted OR 3.0, 95% CI 1.02-8.7). The highest prevalence of asthma was when children had both rhinovirus-induced wheeze at inclusion and allergic sensitisation at 7 years of age. CONCLUSION: Our findings highlight the importance of hereditary factors and allergic sensitisation on the development of asthma and suggest that rhinoviruses are associated with asthma development in predisposed children.

Inflammatory related plasma proteins involved in acute preschool wheeze.

BACKGROUND: Preschool wheeze is a risk factor for asthma development. However, the molecular mechanism behind a wheezing episode is not well understood. OBJECTIVE: Our aims were to assess the association of plasma proteins with acute preschool wheeze and to study the proteins with differential expression at the acute phase at revisit after 3 months. Additionally, to investigate the relationship between protein expression and clinical parameters. METHOD: We measured 92 inflammatory proteins in plasma and clinical parameters from 145 children during an episode of preschool wheeze (PW) and at the revisit after 3 months (PW-R, n = 113/145) and 101 healthy controls (HC) aged 6-48 months in the GEWAC cohort using the antibody-mediated proximity extension-based assay (Olink Proteomics, Uppsala). RESULTS: Of the 74 analysed proteins, 52 were differentially expressed between PW and HC. The expression profiles of the top 10 proteins, Oncostatin M (OSM), IL-10, IL-6, Fibroblast growth factor 21 (FGF21), AXIN1, CXCL10, SIRT2, TNFSF11, Tumour necrosis factor ß (TNF-ß) and CASP8, could almost entirely separate PW from HC. Five out of 10 proteins were associated with intake of oral corticosteroids (OCS) 24 h preceding blood sampling (OSM, CASP8, IL-10, TNF-ß and CXCL10). No differences in protein expression were seen between PWs with or without OCS in comparison to HC. At the revisit after 3 months, differential protein expressions were still seen between PW-R and HC for three (IL-10, SIRT2 and FGF21) of the 10 proteins. CONCLUSION: Our results contribute to unravelling potential immunopathological pathways shared between preschool wheeze and asthma.

An update on the prevalence and diagnosis of cat and dog allergy - Emphasizing the role of molecular allergy diagnostics.

The clinical presentation of cat and dog allergy vary from discomfort caused by rhinoconjuncitivitis to severe asthma. Exposure to allergens from these animals is ubiquitous and allergic sensitization to cat or dog affect up to 25% of all children and adults, but allergic sensitization does not always cause symptoms. The introduction of molecular-based allergy diagnostics has improved the possibility to characterize the allergic patient in greater detail. However, the full clinical potential of using molecular allergology in the diagnosis, characterization and treatment of patients with allergy to cats and dogs has not yet been established, although significant progress has been made during the last decade, which will be reviewed in detail in this paper.

Development of sensitization to peanut and storage proteins and relation to markers of airway and systemic inflammation: A 24-year follow-up.

BACKGROUND: Long-time data of peanut allergy over time is sparse. We aimed to study the longitudinal development of sensitization to peanut extract and storage protein allergen molecules and associations with asthma status, airway and systemic inflammation markers. METHODS: The Swedish birth cohort BAMSE followed 4089 participants with questionnaires, clinical investigations and blood sampling between 0 and 24 years. Information on (i) background factors at 2 months, (ii) peanut allergy symptoms and IgE data (ImmunoCAP) at 4, 8, 16, and 24 years, and (iii) IgE to storage proteins, lung function data including exhaled nitric oxide (FENO) as well as systemic inflammatory markers at 24 years of age were collected. RESULTS: The prevalence of peanut extract sensitization, defined as IgE ≥ 0.35 kUA /L, was 5.4%, 8.0%, 7.5%, and 6.2% at 4, 8, 16, and 24 years of age, respectively. Between 8 and 24 years of age, (33/1565) participants developed IgE-ab to peanut extract (median 1,4, range 0.7-2.6 kUA /L), and among those 85% were also sensitized to birch. Only six individuals developed sensitization to Ara h 2 (≥0.1 kUA /L) between 8 and 24 years of age, of whom three had an IgE-ab level between 0.1-0.12 kUA /L. Storage protein sensitization was associated with elevated FENO, blood eosinophils and type 2 inflammation-related systemic proteins. CONCLUSION: Sensitization to peanut extract after 4 years of age is mainly induced by birch cross-sensitization and IgE to Ara h 2 rarely emerges after eight years of age. Storage protein sensitization is associated with respiratory and systemic inflammation.

Early food intervention and skin emollients to prevent food allergy in young children (PreventADALL): a factorial, multicentre, cluster-randomised trial.

BACKGROUND: Primary prevention of food allergy by early introduction of allergenic foods seems promising. We aimed to determine whether early food introduction or the application of regular skin emollients in infants from a general population reduced the risk of food allergy. METHODS: This 2 × 2 factorial, cluster-randomised trial was done at Oslo University Hospital and Østfold Hospital Trust, Oslo, Norway, and Karolinska University Hospital, Stockholm, Sweden. Infants of women recruited antenatally at the routine 18-week ultrasound examination were cluster-randomised at birth to the following groups: (1) no intervention group; (2) the skin intervention group (skin emollients; bath additives and facial cream; from age 2 weeks to <9 months, both at least four times per week); (3) the food intervention group (early complementary feeding of peanut, cow's milk, wheat, and egg from age 3 months); or (4) combined intervention group (skin and food interventions). Participants were randomly assigned (1:1:1:1) using computer-generated randomisation based on clusters of 92 geographical areas and eight 3-month time blocks. Study personnel performing clinical assessments were masked to group allocation. The primary outcome was allergy to any interventional food at 36 months of age. The primary efficacy analysis was done by intention-to-treat analysis, which included all participants who were randomly assigned, apart from three individuals who withdrew their consent. This was a study performed within ORAACLE (the Oslo Research Group of Asthma and Allergy in Childhood; the Lung and Environment). This study is registered as ClinicalTrials.gov, NCT02449850. FINDINGS: We recruited 2697 women with 2701 pregnancies, from whom 2397 newborn infants were enrolled between April 14, 2015, and April 11, 2017. Of these infants, 597 were randomly assigned to the no intervention group, 575 to the skin intervention group, 642 to the food intervention group, and 583 to the combined intervention group. One participant in each of the no intervention, food intervention, and skin intervention groups withdrew consent and were therefore not included in any analyses. Food allergy was diagnosed in 44 children; 14 (2·3%) of 596 infants in the non-intervention group, 17 (3·0%) of 574 infants in the skin intervention group, six (0·9%) of 641 infants in the food intervention group, and seven (1·2%) of 583 infants in the combined intervention group. Peanut allergy was diagnosed in 32 children, egg allergy in 12 children, and milk allergy in four children. None had allergy to wheat. Prevalence of food allergy was reduced in the food intervention group compared with the no food intervention group (risk difference -1·6% [95% CI -2·7 to -0·5]; odds ratio [OR] 0·4 [95% CI 0·2 to 0·8]), but not compared with the skin intervention group (0·4% [95% CI -0·6 to 1· 5%]; OR 1·3 [0·7 to 2·3]), with no significant interaction effect (p=1·0). Preventing food allergy in one child required early exposure to allergenic foods in 63 children. No serious adverse events were observed. INTERPRETATION: Exposure to allergenic foods from 3 months of age reduced food allergy at 36 months in a general population. Our results support that early introduction of common allergenic foods is a safe and effective strategy to prevent food allergy. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

Allergic sensitization to lipocalins reflects asthma morbidity in dog dander sensitized children.

Background: Sensitization to dog is an important risk factor for asthma in children, but the clinical relevance of IgE to available dog- and furry animal allergen molecules is uncertain. Methods: Spirometry, methacholine challenge, fraction of exhaled nitric oxide, nasal challenge with dog extract and questionnaires were performed in 59 dog-sensitized children (age 10-18 years). Serum IgE to dog-, cat-, horse extracts and the allergen molecules Can f 1-6, Fel d 1, Fel d 2, Fel d 4 and Equ c 1 were evaluated. Results: Median numbers of positive IgE results to furry animal allergen molecules among children without asthma was 3, with asthma 5.5 and with troublesome asthma 9 (asthma vs. no asthma; p = 0.039; troublesome asthma vs. no asthma; p = 0.009). The odds ratio for asthma if sensitized to any lipocalin was 7.2 (95% confidence Interval: 1.44-35.9). Children with troublesome asthma had higher IgE levels to the lipocalins Can f 2, Can f 4 and Can f 6 compared to the rest of the study population (44 vs. 4.1 kUA/L, p = 0.015; 5.8 vs. 0.9 kUA/L, p = 0.018 and 1.3 vs. 0.7 kUA/L, p = 0.03 respectively). Furthermore, a positive nasal challenge was more common among children with troublesome asthma (83% vs. 36%, p = 0.036). Conclusions: Polysensitization to furry animal allergens and lipocalins is associated with asthma in dog-sensitized children. Children with troublesome asthma have higher IgE levels to several dog lipocalins than other dog sensitized children. Key message: Polysensitization to furry animal allergens and high IgE levels to the dog lipocalins Can f 2, Can f 4 and Can f 6 is associated with asthma severity in dog dander sensitized children. Molecular allergy diagnostics may thus help the clinicians to evaluate the impact of allergic sensitization on asthma morbidity.

Development of Sensitization to Multiple Allergen Molecules from Preschool to School Age Is Related to Asthma.

INTRODUCTION: Allergic sensitization in early life has been identified as a strong risk factor for subsequent asthma in childhood. It is still unclear why only a part of sensitized children develop asthma, and the role of specific allergen molecules in asthma pathogenesis is ambiguous [Pharmacol Ther. 2009 Feb;121(2):174-84]. We assessed the sensitization to multiple allergen molecules longitudinally and explored its relation to persistent asthma at 7 years. METHODS: Seventy-two children included during an acute wheezing episode (cases) were followed prospectively from early preschool age (EPA) to age 7, and compared to 43 healthy controls at EPA. Allergen molecules were analyzed at EPA and age 7 using ImmunoCAP Solid-phase Allergen Chip (ISAC). Asthma diagnosis at 7 years was based on symptoms, medication, and spirometry. RESULTS: At EPA, cases compared to controls showed a tendency toward having a higher prevalence of allergic sensitization (23.6% vs. 9.3%, p = 0.055). The prevalence of sensitization increased in cases from EPA to 7 years (23.6% vs. 38.9%; p = 0.048) as well as the median number (range) of immunoglobulin E (IgE)-reactive molecules 3 (3-14) versus 6.5 (1-21); p = 0.024. Sensitization to each additional molecule from EPA to the age of 7 was significantly related to asthma at 7 (OR = 1.25, 95% confidence interval [1.01, 1.54]). CONCLUSION: Polysensitization, assessed by allergen molecules, had a significant impact on persistent asthma at school age. The extent of sensitization, illustrated by molecular spreading from preschool to school age, was related to asthma diagnosis at 7 years in children with a history of wheezing at early life.

Food allergy and hypersensitivity reactions in children and adults-A review.

Adverse reactions after food intake are commonly reported and a cause of concern and anxiety that can lead to a very strict diet. The severity of the reaction can vary depending on the type of food and mechanism, and it is not always easy to disentangle different hypersensitivity diagnoses, which sometimes can exist simultaneously. After a carefully taken medical history, hypersensitivity to food can often be ruled out or suspected. The most common type of allergic reaction is immunoglobulin E (IgE)-mediated food allergy (prevalence 5-10%). Symptoms vary from mild itching, stomach pain, and rash to severe anaphylaxis. The definition of IgE-mediated food allergy is allergic symptoms combined with specific IgE-antibodies, and therefore only IgE-antibodies to suspected allergens should be analyzed. Nowadays, methods of molecular allergology can help with the diagnostic process. The most common allergens are milk and egg in infants, peanut and tree nuts in children, and fish and shellfish in adults. In young children, milk/egg allergy has a good chance to remit, making it important to follow up and reintroduce the food when possible. Other diseases triggered by food are non-IgE-mediated food allergy, for example, eosinophilic esophagitis, celiac disease, food protein-induced enterocolitis syndrome, and hypersensitivity to milk and biogenic amines. Some of the food hypersensitivities dominate in childhood, others are more common in adults. Interesting studies are ongoing regarding the possibilities of treating food hypersensitivity, such as through oral immunotherapy. The purpose of this review was to provide an overview of the most common types of food hypersensitivity reactions.

Impaired skin barrier and allergic sensitization in early infancy.

BACKGROUND: Factors predicting allergic sensitization in the first 6 months of life are poorly understood. We aimed to determine whether eczema, dry skin, and high transepidermal water loss (TEWL) at 3 months were associated with allergic sensitization at 6 months of age and, secondarily, to establish whether these characteristics predicted sensitization from 3 to 6 months of age. METHODS: At 3 months of age, 1,994 infants from the population-based PreventADALL birth cohort in Norway and Sweden were assessed for eczema and dry skin on the cheeks and/or extensors; impaired skin barrier function, defined as TEWL in the upper quartile (>9.4 g/m2 /h), and allergen-specific IgE levels <0.1 kUA /L, available in 830. At 6 months, we assessed allergic sensitization to any food (egg, cow's milk, peanut, wheat, soy) or inhalant (birch, timothy grass, dog, and cat) allergen by a skin prick test wheal diameter ≥2 mm larger than negative control. RESULTS: Any sensitization was found in 198 of the 1,994 infants (9.9%), the majority to food allergens (n = 177, 8.9%). Eczema, dry skin, and high TEWL at 3 months increased the risk of sensitization at 6 months; adjusted odds ratios 4.20 (95% CI 2.93-6.04), 2.09 (95% CI 1.51-2.90) and 3.67 (95% CI 2.58-5.22), respectively. Eczema predicted sensitization with 55.6% sensitivity and 68.1% specificity; dry skin with 65.3% sensitivity and 57.3% specificity; and high TEWL with 61.7% sensitivity and 78.1% specificity. CONCLUSION: Eczema, dry skin, and high TEWL at 3 months predicted allergic sensitization at 6 months of age.

Prevalence and early-life risk factors for tree nut sensitization and allergy in young adults.

BACKGROUND: Tree nut allergy may cause anaphylaxis. There are limited population-based studies on prevalence and early-life risk factors. METHODS: We evaluated the prevalence of reported symptoms and allergic sensitization to tree nuts at age 24 years in the BAMSE population-based cohort study and assessed early-life factors associated with the development of tree nut allergy. We estimated tree nut allergy prevalence, by analysing questionnaire data on tree nut ingestion and symptoms at age 12, 16 and 24 years, and IgE sensitization at age 24 years to hazelnut, walnut, pecan, cashew, pistachio, Brazil nut, almond extracts and allergen molecules Cor a 1, 9, 14 (hazelnut), Jug r 1 (walnut) and Ana o 3 (cashew). We evaluated eczema, asthma, food allergies, inherited risk of allergy and gender as potential early-life risk factors. RESULTS: Data were available for 2215/4089 (54%) BAMSE study participants, for estimation of the prevalence of tree nut sensitization (21.2%), tree nut allergy symptoms (9.8%) and combined sensitization and symptoms (7.9%, 2.1% for storage protein sensitization and symptoms, 4.3% for any sensitization and non-mild symptoms). Sixty-three per cent of sensitized individuals (295/470) were asymptomatic, but only 76/470 (16%) storage protein sensitized individuals. Egg allergy (ORadj 8.50 95% CI 2.15-33.6), eczema (ORadj 2.53 95% CI 1.21-5.32) and asthma (ORadj 5.59 95% CI 2.35-13.3)) at pre-school age were associated with future development of tree nut symptoms and storage protein sensitization. At age 24 years, tree nut allergy was associated with current eczema and with markers of current asthma severity. Sensitization to storage proteins was more strongly associated with symptoms than sensitization to whole extract for all tree nuts evaluated. CONCLUSIONS: In this Swedish cohort, we found tree nut whole extract sensitization is common but usually asymptomatic. Storage protein sensitization is a more reliable indicator of tree nut symptoms. Tree nut allergy is associated with early onset, persistent and severe atopic disease.

Early Life Wheeze and Risk Factors for Asthma-A Revisit at Age 7 in the GEWAC-Cohort.

One third of all toddlers are in need of medical care because of acute wheeze and many of these children have persistent asthma at school age. Our aims were to assess risk factors for and the prevalence of asthma at age 7 in a cohort of children suffering from an acute wheezing episode as toddlers. A total of 113 children, included during an acute wheezing episode (cases), and 54 healthy controls were followed prospectively from early pre-school age to 7 years. The protocol included questionnaires, ACT, FeNO, nasopharyngeal virus samples, blood sampling for cell count, vitamin D levels, and IgE to food and airborne allergens. The prevalence of asthma at age 7 was 70.8% among cases and 1.9% among controls (p < 0.001). Acute wheeze caused by rhinovirus (RV) infection at inclusion was more common among cases with asthma at age 7 compared to cases without asthma (p = 0.011) and this association remained significant following adjustment for infection with other viruses (OR 3.8, 95% CI 1.4-10.5). Cases with asthma at age 7 had been admitted to hospital more often (p = 0.024) and spent more days admitted (p = 0.01) during the year following inclusion compared to cases without asthma. RV infection stands out as the main associated factor for wheeze evolving to persistent asthma. Cases who developed asthma also had an increased need of hospital time and care for wheeze during the year after inclusion.

Nasal upregulation of CST1 in dog-sensitised children with severe allergic airway disease.

BACKGROUND: The clinical presentation of children sensitised to dog dander varies from asymptomatic to severe allergic airway disease, but the genetic mechanisms underlying these differences are not clear. The objective of the present study was to investigate nasal transcriptomic profiles associated with dog dander sensitisation in school children and to reveal clinical symptoms related with these profiles. METHODS: RNA was extracted from nasal epithelial cell brushings of children sensitised to dog dander and healthy controls. Blood sample analyses included IgE against dog dander, dog allergen molecules, other airborne and food allergens, basophil activation and white blood cell counts. Clinical history of asthma and rhinitis was recorded, and lung function was assessed (spirometry, methacholine provocation and exhaled nitric oxide fraction). RESULTS: The most overexpressed gene in children sensitised to dog dander compared to healthy controls was CST1, coding for Cystatin 1. A cluster of these children with enhanced CST1 expression showed lower forced expiratory volume in 1 s, increased bronchial hyperreactivity, pronounced eosinophilia and higher basophil allergen threshold sensitivity compared with other children sensitised to dog dander. In addition, multi-sensitisation to lipocalins was more common in this group. CONCLUSIONS: Overexpression of CST1 is associated with more severe allergic airway disease in children sensitised to dog dander. CST1 is thus a possible biomarker of the severity of allergic airway disease and a possible therapeutic target for the future treatment of airborne allergy.

Extract and molecular-based early infant sensitization and associated factors-A PreventADALL study.

BACKGROUND: More knowledge about sensitization patterns in early infancy, including impact of molecular allergology, is needed to help predict future allergy development more accurately. OBJECTIVE: We aimed to determine the prevalence and patterns of allergic sensitization at 3 months of age, and explore possible associated factors. METHODS: From the Scandinavian antenatally recruited PreventADALL mother-child cohort, we included 1110 3-month infants with available serum. Sensitization was defined as s-IgE of ≥0.1 kUA /L by Phadiatop Infant® (ThermoFisher Scientific) including birch, cat, grass, dog, milk, egg, peanut and wheat. Further ImmunoCAP analyses to ovomucoid, casein, Ara h 1-3, omega-5-gliadin were performed in food extract s-IgE-positive children. Maternal sensitization was defined as s-IgE ≥ 0.35 kUA /L to Phadiatop® (inhalant allergen mix) and/or Fx5 (food allergen mix) at 18-week pregnancy. RESULTS: Overall 79 (7.3%) infants had specific sensitization, many with low s-IgE-levels (IQR 0.16-0.81 kUA /L), with 78 being sensitized to food extract allergens; 41 to egg, 27 to milk, 10 to peanut, and 25 to wheat. A total of 62/78 were further analysed, 18 (29%) had s-IgE to ovomucoid, casein, Ara h 1-3 and/or omega-5-gliadin. Eight infants (0.7%) were sensitized to inhalant allergens. Maternal sensitization to food allergens was associated with infant sensitization, odds ratio 3.64 (95% CI 1.53-8.68). CONCLUSION: Already at 3 months of age, 7% were sensitized to food, mostly without detectable s-IgE to food allergen molecules, and <1% to inhalant allergens. Maternal food sensitization was associated with infants' sensitization.

Male sex is strongly associated with IgE-sensitization to airborne but not food allergens: results up to age 24 years from the BAMSE birth cohort.

BACKGROUND: Up to half of the population in high-income countries has allergen-specific IgE antibodies. However, data regarding sex differences of IgE-sensitization from childhood to adulthood is limited. OBJECTIVE: To explore IgE-sensitization to common foods and airborne allergens in relation to sex over time in a population-based cohort followed up to young adulthood. METHODS: The Swedish population-based birth cohort BAMSE includes 4089 subjects who have been followed regularly with questionnaires and clinical investigations. A recent 24-year follow-up included 3069 participants (75%). Sera collected at 4, 8, 16 and 24 years were analyzed for IgE-antibodies to 14 common foods and airborne allergens. RESULTS: At 24 years sensitization to foods had decreased compared to previous follow-ups affecting 8.4%, while sensitization to airborne allergens was more common, affecting 42.2%. Male sex was associated with IgE-sensitization to airborne allergens at all ages (overall OR: 1.68, 95% CI 1.46-1.94) while there was no statistically significant association between sex and sensitization to food allergens (overall OR: 1.10, 95% CI 0.93-1.32). Levels of allergen-specific IgE did not differ significantly between males and females for any of the tested foods or airborne allergens at any age, following adjustment for multiple comparisons. CONCLUSION: IgE-sensitization to airborne allergens increases with age up to young adulthood, whereas sensitization to food allergens seems to level off. Male sex is strongly associated with IgE-sensitization to airborne allergens from early childhood up to young adulthood. In contrast, there is little evidence for associations between sex and IgE-sensitization to foods.

Skin emollient and early complementary feeding to prevent infant atopic dermatitis (PreventADALL): a factorial, multicentre, cluster-randomised trial.

BACKGROUND: Skin emollients applied during early infancy could prevent atopic dermatitis, and early complementary food introduction might reduce food allergy in high-risk infants. The study aimed to determine if either regular skin emollients applied from 2 weeks of age, or early complementary feeding introduced between 12 and 16 weeks of age, reduced development of atopic dermatitis by age 12 months in the general infant population. METHODS: This population-based 2×2 factorial, randomised clinical trial was done at Oslo University Hospital and Østfold Hospital Trust, Oslo, Norway; and Karolinska University Hospital, Stockholm, Sweden. Infants of women recruited antenatally at the routine ultrasound pregnancy screening at 18 weeks were cluster-randomised at birth from 2015 to 2017 to the following groups: (1) controls with no specific advice on skin care while advised to follow national guidelines on infant nutrition (no intervention group); (2) skin emollients (bath additives and facial cream; skin intervention group); (3) early complementary feeding of peanut, cow's milk, wheat, and egg (food intervention group); or (4) combined skin and food interventions (combined intervention group). Participants were randomly assigned (1:1:1:1) using computer- generated cluster randomisation based on 92 geographical living area blocks as well as eight 3-month time blocks. Carers were instructed to apply the interventions on at least 4 days per week. Atopic dermatitis by age 12 months was the primary outcome, based on clinical investigations at 3, 6 and 12 months by investigators masked to group allocation. Atopic dermatitis was assessed after completing the 12-month investigations and diagnosed if either of the UK Working Party and Hanifin and Rajka (12 months only) diagnostic criteria were fulfilled. The primary efficacy analyses was done by intention-to-treat analysis on all randomly assigned participants. Food allergy results will be reported once all investigations at age 3 years are completed in 2020. This was a study performed within ORAACLE (the Oslo Research Group of Asthma and Allergy in Childhood; the Lung and Environment). The study is registered at clinicaltrials.gov, NCT02449850. FINDINGS: 2697 women were recruited between Dec 9, 2014, and Oct 31, 2016, from whom 2397 newborn infants were enrolled from April 14, 2015, to April 11, 2017. Atopic dermatitis was observed in 48 (8%) of 596 infants in the no intervention group, 64 (11%) of 575 in the skin intervention group, 58 (9%) of 642 in the food intervention group, and 31 (5%) of 583 in the combined intervention group. Neither skin emollients nor early complementary feeding reduced development of atopic dermatitis, with a risk difference of 3·1% (95% CI -0·3 to 6·5) for skin intervention and 1·0% (-2·1 to 4·1) for food intervention, in favour of control. No safety concerns with the interventions were identified. Reported skin symptoms and signs (including itching, oedema, exanthema, dry skin, and urticaria) were no more frequent in the skin, food, and combined intervention groups than in the no intervention group. INTERPRETATION: Neither early skin emollients nor early complementary feeding reduced development of atopic dermatitis by age 12 months. Our study does not support the use of these interventions to prevent atopic dermatitis by 12 months of age in infants. FUNDING: The study was funded by several public and private funding bodies: The Regional Health Board South East, The Norwegian Research Council, Health and Rehabilitation Norway, The Foundation for Healthcare and Allergy Research in Sweden-Vårdalstiftelsen, Swedish Asthma and Allergy Association's Research Foundation, Swedish Research Council-the Initiative for Clinical Therapy Research, The Swedish Heart-Lung Foundation, SFO-V at the Karolinska Institute, Freemason Child House Foundation in Stockholm, Swedish Research Council for Health, Working Life and Welfare-FORTE, Oslo University Hospital, the University of Oslo, and Østfold Hospital Trust.