Louise Michaelis

Randomized controlled trial of primary prevention of atopy using house dust mite allergen oral immunotherapy in early childhood

BACKGROUND Children born to atopic parents are at increased risk of sensitization to environmental allergens. OBJECTIVE We sought to demonstrate proof of concept for oral immunotherapy to high-dose house dust mite (HDM) allergen in infancy in the prevention of allergen sensitization and allergic diseases. METHODS This was a prospective, randomized, double-blind, placebo-controlled, proof-of-concept study involving 111 infants less than 1 year of age at high risk of atopy (≥ 2 first-degree relatives with allergic disease) but with negative skin prick test responses to common allergens at randomization. HDM extract (active) and appropriate placebo solution were administered orally twice daily for 12 months, and children were assessed every 3 months. Coprimary outcomes were cumulative sensitization to HDM and sensitization to any common allergen during treatment, whereas development of eczema, wheeze, and food allergy were secondary outcomes. All adverse events were recorded. RESULTS There was a significant (P = .03) reduction in sensitization to any common allergen (16.0%; 95% CI, 1.7% to 30.4%) in the active (5 [9.4%]) compared with placebo (13 [25.5%]) treatment groups. There was no treatment effect on the coprimary outcome of HDM sensitization and the secondary outcomes of eczema, wheeze, and food allergy. The intervention was well tolerated, with no differences between active and placebo treatments in numbers or nature of adverse events. CONCLUSION Prophylactic HDM oral immunotherapy is well tolerated in children at high heredity risk. The results met the trials prespecified criteria for proof of concept in reducing sensitization to any allergen; however, no significant preventive effect was observed on HDM sensitization or allergy-related symptoms.

H1N1 Antibody Persistence 1 Year After Immunization With an Adjuvanted or Whole-Virion Pandemic Vaccine and Immunogenicity and Reactogenicity of Subsequent Seasonal Influenza Vaccine: A Multicenter Follow-on Study

Two doses of AS03B-adjuvanted pandemic influenza vaccine may be sufficient to maintain seroprotection across 2 influenza seasons. Administration of trivalent influenza vaccine to children who previously received 2 doses of pandemic influenza vaccine is safe and is immunogenic for the H1N1 strain.

Predictors of immune response and reactogenicity to AS03B-adjuvanted split virion and non-adjuvanted whole virion H1N1 (2009) pandemic influenza vaccines

In 2009, 943 children aged 6 months to 10 years were randomised to receive two doses of an oil-in water AS03B-adjuvanted split virion or a non-adjuvanted whole virion H1N1 (2009) vaccine. The large numbers allowed investigation of possible predictors of immune response and reactogenicity. We used regression analysis to examine the effect of variables including past receipt of seasonal vaccine, antipyretics post-vaccination, interval between doses and pre-existing antibodies to H1N1 (2009) on immunogenicity. We also examined the relationship between immunogenicity and reactogenicity and whether prior infection or underlying conditions affected reactogenicity. For both vaccines, haemagglutination-inhibition titres were 60% higher in children with fever ≥38 °C after vaccination and 29% lower in those previously given seasonal vaccine. Early use of antipyretics did not affect immunogenicity. Post-vaccination titres were higher with longer intervals between doses and in those with evidence of prior infection, but reactogenicity in the latter was unaffected. In the adjuvanted vaccine group, reactions were more common in children with atopy. Both vaccines were safe and immunogenic in those with prior infection. Reduction in the interval between doses for earlier protection would be at the cost of reduced immunogenicity. The effect of seasonal vaccine on immunogenicity merits further investigation.

Manifestations of food protein induced gastrointestinal allergies presenting to a single tertiary paediatric gastroenterology unit

BackgroundFood protein induced gastrointestinal allergies are difficult to characterise due to the delayed nature of this allergy and absence of simple diagnostic tests. Diagnosis is based on an allergy focused history which can be challenging and often yields ambiguous results. We therefore set out to describe a group of children with this delayed type allergy, to provide an overview on typical profile, symptoms and management strategies.MethodsThis retrospective analysis was performed at Great Ormond Street Children’s Hospital. Medical notes were included from 2002 – 2009 where a documented medical diagnosis of food protein induced gastrointestinal allergies was confirmed by an elimination diet with resolution of symptoms, followed by reintroduction with reoccurrence of symptoms. Age of onset of symptoms, diagnosis, current elimination diets and food elimination at time of diagnosis and co-morbidities were collected and parents were phoned again at the time of data collection to ascertain current allergy status.ResultsData from 437 children were analysis. The majority (67.7%) of children had an atopic family history and 41.5% had atopic dermatitis at an early age. The most common diagnosis included, non-IgE mediated gastrointestinal food allergy (n = 189) and allergic enterocolitis (n = 154) with symptoms of: vomiting (57.8%), back-arching and screaming (50%), constipation (44.6%), diarrhoea (81%), abdominal pain (89.9%), abdominal bloating (73.9%) and rectal bleeding (38.5%). The majority of patients were initially managed with a milk, soy, egg and wheat free diet (41.7%). At a median age of 8 years, 24.7% of children still required to eliminate some of the food allergens.ConclusionsThis large retrospective study on children with food induced gastrointestinal allergies highlights the variety of symptoms and treatment modalities used in these children. However, further prospective studies are required in this area of food allergy.

A synbiotic-containing amino acid-based formula improves gut microbiota in non-IgE-mediated allergic infants

BackgroundPrebiotics and probiotics (synbiotics) can modify gut microbiota and have potential in allergy management when combined with amino-acid-based formula (AAF) for infants with cow’s milk allergy (CMA).MethodsThis multicenter, double-blind, randomized controlled trial investigated the effects of an AAF-including synbiotic blend on percentages of bifidobacteria and Eubacterium rectale/Clostridium coccoides group (ER/CC) in feces from infants with suspected non-IgE-mediated CMA. Feces from age-matched healthy breastfed infants were used as reference (healthy breastfed reference (HBR)) for primary outcomes. The CMA subjects were randomized and received test or control formula for 8 weeks. Test formula was a hypoallergenic, nutritionally complete AAF including a prebiotic blend of fructo-oligosaccharides and the probiotic strain Bifidobacterium breve M-16V. Control formula was AAF without synbiotics.ResultsA total of 35 (test) and 36 (control) subjects were randomized; HBR included 51 infants. At week 8, the median percentage of bifidobacteria was higher in the test group than in the control group (35.4% vs. 9.7%, respectively; P<0.001), whereas ER/CC was lower (9.5% vs. 24.2%, respectively; P<0.001). HBR levels of bifidobacteria and ER/CC were 55% and 6.5%, respectively.ConclusionAAF including specific synbiotics, which results in levels of bifidobacteria and ER/CC approximating levels in the HBR group, improves the fecal microbiota of infants with suspected non-IgE-mediated CMA.

Phase II Study of a Three-Dose Primary Vaccination Course of DTPa-IPV/Hib-MenC-TT Followed by a 12-Month Hib-MenC-TT Booster in Healthy Infants

Aim: To test for immunologic noninferiority of antibody responses to Hib and MenC using a 6-in-1 combination vaccine (DTPa-IPV/Hib-MenC-TT) compared with DTPa-IPV-Hib plus MenC-CRM197, before and after a 12-month Hib-MenC-TT booster. Methods: Pragmatic open-label, randomized, multicenter, UK study. “6-in-1” group received DTPa-IPV/Hib-MenC-TT at 2, 3 and 4 months; control group received DTPa-IPV-Hib at 2, 3 and 4 months and MenC-CRM197 at 3 and 4 months. Both groups received Hib-MenC-TT at 12 months. Concomitant vaccines: pneumococcal conjugate vaccine at 2, 4 and 13 months, and measles, mumps and rubella vaccine at 13 months. Results: One hundred forty-two children were randomized to each group. One hundred children in the “6-in-1” group and 112 control group children completed the study according-to-protocol. One month postprimary immunizations: 100% of “6-in-1” group and 93.3% of control children had anti–polyribosylribitol phosphate (PRP) IgG ≥0.15 µg/mL; 96.2% and 100%, respectively, had rSBA-MenC titers ≥1:8. One month after booster all children met these thresholds, with anti-PRP geometric mean concentrations of 66.7 (53.3; 83.5) in “6-in-1” recipients and 26.9 (20.9; 34.6) in control children (4.4 [3.5; 5.4] and 3.0 [2.2–4.2] postprimary immunizations, respectively,). rSBA-MenC geometric mean titers were 3062.9 (2421.2; 3874.6) and 954.0 (761.3; 1195.5), respectively, postbooster and 393.2 (292.5; 528.7) and 3110.5 (2612; 3704.2) postprimary. Conclusion: Noninferiority of DTPa-IPV/Hib-MenC-TT compared with DTPa-IPV/Hib plus MenC-CRM197 was demonstrated. In the “6-in-1” group, lower postprimary and greater postbooster rSBA-MenC geometric mean titers suggest memory B-cell priming may be favored by this vaccine over plasma cell induction. Furthermore, greater immunogenicity of TT conjugates used in both primary and booster vaccines in this group may be important.

Dietary restriction causing iodine-deficient goitre

Iodine-deficient goitre was common in some parts of the UK prior to the introduction of salt iodisation. Many contemporary salt preparations do not contain much iodine, and there are renewed concerns about the iodine status of the population. We present a boy with severe allergy who developed goitre and significant thyroid dysfunction in association with an iodine-deficient ‘food-restricted’ diet. The case highlights the importance of a comprehensive nutritional assessment in all children on multiple food restrictions.

Dissociation of osmoregulation from plasma arginine vasopressin levels following thermal injury in childhood

Although the syndrome of inappropriate anti-diuretic hormone secretion has been recognised as a complication associated with burn and other trauma in adults, relatively little is known about its incidence in children. The objective of this study was to investigate whether it is a complication associated with burn injury in children. Plasma and urine levels of arginine vasopressin (anti-diuretic hormone), sodium and osmolality were measured in samples collected from 16 burn-injured children admitted to the burns unit of the regional childrens hospital. No significant correlations were found between plasma vasopressin and plasma sodium or osmolality levels, but there were significant correlations between plasma vasopressin and urine osmolality, 36 (r=0.74, p=0. 009), 60 (r=0.92, p=0.000) and 84 h (r=0.84, p=0.001) after admission, respectively. There were also significant correlations between plasma sodium and plasma osmolality, 24 (r=0.7, p=0.005), 36 (r=0.57, p=0.04) and 84 h (r=0.84, p=0.004) after admission. The data suggest dissociation between the osmolar control of vasopressin secretion and vasopressin levels after burn injury in children, but do not support the incidence of inappropriate secretion of antidiuretic hormone.

An amino acid-based formula with synbiotics affects faecal microbiota in Non-IgE mediated cow's milk allergic infants

Background: A body of evidence indicates that epigenetic modifications, including DNA methylation, play relevant roles in the differentiation and functions of immune cells. Therefore, these modifications have been increasingly implicated in the pathophysiology of allergic diseases. However, little is known about changes in DNA methylation during oral immunotherapy (OIT) in young children with food allergies. Here, we present genome-wide data of DNA methylation before and after OIT. Method: We gave rush OIT to two pediatric patients with egg allergy. Both the patients became tolerant and could consume eggs 1 year after the initiation of the therapy. CD14-positive monocytes and CD4-positive T cells were positively selected from peripheral blood mononuclear cells by magnetic bead-conjugated antibodies before and one year after starting OIT. Genomic DNA was purified from these cells and subjected to the Infinium Methylation Assay (Illumina). Results: A significant number of methylation-targeted CpG sites were found to be differentially methylated between the monocytes and T cells indicating that the cells represent different epigenetic profiles. DNA methylation profiles before and after starting OIT in the same type of cells were better correlated to each other than those between the two patients either before or after OIT. Gene ontology analysis of genes that displayed significant changes in methylation of promoter sequences in T cells showed that genes involved in the MAPK pathway were enriched the most. Conclusion: These results provide evidence that epigenetics plays a role in acquiring immune tolerance during OIT and can help further our understanding of the mechanisms involved in the immune tolerance of food allergy. 2 Grass pollen subcutaneous and sublingual immunotherapy inhibit allergen-induced nasal responses and local Th2 cytokines: a randomised controlled trial

Phase II study of a three-dose primary vaccination course of DTPa-IPV/Hib-MenC-TT followed by a 12-month Hib-MenC-TT booster in healthy infants

Aims Combining the licensed Haemophilus influenzae type b (Hib) and serogroup C meningococcal (MenC) conjugate vaccine (Hib-MenC-TT) and DTaP-IPV vaccine could reduce the number of injections needed to administer the United Kingdom routine infant immunisation schedule. We aimed to demonstrate immunologic non-inferiority for Hib and MenC using a 6-in-1 combination vaccine (DTPa-IPV/Hib-MenC-TT) compared to a schedule using DTPa-IPV-Hib-TT and MenC-CRM197 conjugate vaccines. Secondary objectives included demonstration of non-inferiority of diphtheria, tetanus and polio immunogenicity; persistence of immune response to all antigens at 12 months of age and the response to a 12 month Hib-MenC-TT booster. Methods Open-label, randomised, multi-centre, UK study. Combination group received DTPa-IPV/Hib-MenC-TT at 2, 3, 4 months. Control group received DTPa-IPV-Hib-TT at 2, 3, 4 months and MenC-CRM197 at 3, 4 months. Both groups received Hib-MenC-TT booster at 12 months. Concomitant vaccines: pneumococcal conjugate vaccine at 2, 4, 13 months; MMR at 13 months. Blood tests were performed at 4, 5, 12 and 13 months. Results 142 children were randomised in each group. 100 children were included in the according-to-protocol cohort for analysis of immunogenicity following the booster vaccine in the combination group; and 112 children in the control group. One month post-primary immunisations 100% of the combination group and 93.3 % of control children had anti-PRP IgG concentration ≥0.15 μg/mL. 96.2% and 100% respectively had rSBA-MenC titres ≥1:8. One month post-booster all children met these thresholds. At 13 months of age, anti-PRP geometric mean concentrations (with 95% confidence intervals) were 66.7 (53.3-83.5) in the combination group and 26.9 (20.9-34.6) in the control group (4.35 [3.51-5.39] and 3.04 [2.21-4.19] respectively at 5 months). rSBA-MenC geometric mean titres (GMTs) were 3062.9 (2421.2-3874.6) and 954.0 (761.3-1195.5) respectively (393.2 [292.5-528.7] and 3110.5 [2612-3704.2] respectively at 5 months). Conclusion Non-inferiority of DTPa-IPV/Hib-MenC-TT compared to DTPa-IPV-Hib-TT plus MenC-CRM197 was demonstrated. The lower rSBA-MenC GMTs after primary immunisations and greater booster responses in the combination group suggest that immune priming might be inversely related to post-primary antibody responses. Furthermore, greater immunogenicity of TT conjugates used in primary and booster MenC vaccines in this group may be important.