Ralf G. Heine

The importance of early complementary feeding in the development of oral tolerance: concerns and controversies.

Rising rates of food allergies in early childhood reflect increasing failure of early immune tolerance mechanisms. There is mounting concern that the current recommended practice of delaying complementary foods until 6 months of age may increase, rather than decrease, the risk of immune disorders. Tolerance to food allergens appears to be driven by regular, early exposure to these proteins during a ‘critical early window’ of development. Although the timing of this window is not clear in humans, current evidence suggests that this is most likely to be between 4 and 6 months of life and that delayed exposure beyond this period may increase the risk of food allergy, coeliac disease and islet cell autoimmunity. There is also evidence that other factors such as favourable colonization and continued breastfeeding promote tolerance and have protective effects during this period when complementary feeding is initiated. This discussion paper explores the basis for concern over the current recommendation to delay complementary foods as an approach to preventing allergic disease. It will also examine the growing case for introducing complementary foods from around 4 months of age and maintaining breastfeeding during this early feeding period, for at least 6 months if possible.

The diagnostic value of skin prick testing in children with food allergy

The diagnostic accuracy of the skin prick test (SPT) in food allergy is controversial. We have developed diagnostic cut‐off levels for SPT in children with allergy to cow milk, egg and peanut. Based on 555 open food challenges in 467 children (median age 3.0 yr) we defined food‐specific SPT weal diameters that were ‘100% diagnostic’ for allergy to cow milk (≥8 mm), egg (≥7 mm) and peanut (≥8 mm). In children <2 yr of age, the corresponding weal diameters were ≥6 mm, ≥5 mm and ≥4 mm, respectively. These SPT cut‐off levels were prospectively validated in 90 consecutive children ≤2 yr with challenge‐proven food allergy. In young infants under 6 months of age who have not previously been exposed to a particular food item, the SPT were often negative or below the diagnostic cut‐off but reached the diagnostic cut‐off at the time of challenge in the second year of life. We assessed the diagnostic agreement between food‐specific immunoglobulin E (IgE) antibody levels and SPT in a cohort of 820 infants and children under 2 yr of age (median age 13.1 months) with suspected allergy to cow milk, egg or peanut. When applying published 95%‐positive predictive CAP values, the diagnostic accuracy of SPT and IgE antibody levels was similar for cow milk, but SPT was more sensitive in diagnosing allergy to egg (p < 0.0001) and peanut (p < 0.0001). Further studies are required to define age‐specific diagnostic IgE antibody and SPT cut‐off levels use in infants under 2 yr of age with suspected food allergies.

Barriers to Adequate Nutrition in Critically Ill Children

OBJECTIVE The study assessed the adequacy of nutrition support in critically ill infants and children and identifies barriers impeding the delivery of estimated energy requirement (EER). METHODS Forty-two children (median age, 6.6 mo; range, 0-198) who were admitted to a tertiary-level pediatric intensive care unit (PICU) were studied prospectively over a 6-mo period. Patients staying in the PICU longer than a full 3 d and who received enteral or a combination of enteral and parenteral nutrition were eligible for inclusion. Patients were assigned to one of two groups: patients after cardiac surgery (n = 18) and all other diagnoses (n = 24). EERs were compared with actual energy intake, and clinical information was collected throughout the PICU admission. RESULTS Patients in the PICU received a median of 37.7% (range, 0.2-130.2%) of their EERs. The cardiac group achieved significantly lower energy intakes than did the non-cardiac group (P = 0.02). Only 22 of 42 patients (52%) achieved full EERs at any time during their admission, and this was more likely in non-cardiac patients (67% versus 33%, P = 0.03) Children undergoing cardiac surgery had a significant fall in weight-for-age Z scores (WAZ) from PICU admission to discharge (median WAZ, -1.44 versus -2.14; P < 0.001). In both groups, the major barrier to achieving EER was fluid volume restriction. Interruption of feeding for procedures and feeding intolerance reduced energy intake to a lesser degree. CONCLUSIONS This study highlights the inadequacy of nutrition support in critically ill children in the PICU. Restriction of fluid intake was the main barrier to the delivery of adequate nutrition, particularly in infants undergoing cardiac surgery.

World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines.

Alessandro Fiocchi, MD, Pediatric Division, Department of Child and Maternal Medicine, University of Milan Medical School at the Melloni Hospital, Milan 20129, Italy. Holger Schünemann, MD, Department of Clinical Epidemiology & Biostatistics, McMaster University Health Sciences Centre, 1200 Main Street West Hamilton, ON L8N 3Z5, Canada. Sami L. Bahna, MD, Pediatrics & Medicine, Allergy & Immunology, Louisiana State University Health Sciences Center, Shreveport, LA 71130. Andrea Von Berg, MD, Research Institute, Children s department , Marien-Hospital, Wesel, Germany. Kirsten Beyer, MD, Charité Klinik für Pädiatrie m.S. Pneumologie und Immunologie, Augustenburger Platz 1, D-13353 Berlin, Germany. Martin Bozzola, MD, Department of Pediatrics, British Hospital-Perdriel 74-CABA-Buenos Aires, Argentina. Julia Bradsher, PhD, Food Allergy & Anaphylaxis Network, 11781 Lee Jackson Highway, Suite 160, Fairfax, VA 22033. Jan Brozek, MD, Department of Clinical Epidemiology & Biostatistics, McMaster University Health Sciences Centre, 1200 Main Street West Hamilton, ON L8N 3Z5, Canada. Enrico Compalati, MD, Allergy & Respiratory Diseases Clinic, Department of Internal Medicine. University of Genoa, 16132, Genoa, Italy. Motohiro Ebisawa, MD, Department of Allergy, Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, Kanagawa 228-8522, Japan. Maria Antonieta Guzman, MD, Immunology and Allergy Division, Clinical Hospital University of Chile, Santiago, Chile. Santos Dumont 999. Haiqi Li, MD, Professor of Pediatric Division, Department of Primary Child Care, Children’s Hospital, Chongqing Medical University, China, 400014. Ralf G. Heine, MD, FRACP, Department of Allergy & Immunology, Royal Children’s Hospital, University of Melbourne, Murdoch Children’s Research Institute, Melbourne, Australia. Paul Keith, MD, Allergy and Clinical Immunology Division, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Gideon Lack, MD, King’s College London, Asthma-UK Centre in Allergic Mechanisms of Asthma, Department of Pediatric Allergy, St Thomas’ Hospital, London SE1 7EH, United Kingdom. Massimo Landi, MD, National Pediatric Healthcare System, Italian Federation of Pediatric Medicine, Territorial Pediatric Primary Care Group, Turin, Italy. Alberto Martelli, MD, Pediatric Division, Department of Child and Maternal Medicine, University of Milan Medical School at the Melloni Hospital, Milan 20129, Italy. Fabienne Rancé, MD, Allergologie, Hôpital des Enfants, Pôle Médicochirurgical de Pédiatrie, 330 av. de Grande Bretagne, TSA 70034, 31059 Toulouse CEDEX, France. Hugh Sampson, MD, Jaffe Food Allergy Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, NY 10029-6574. Airton Stein, MD, Conceicao Hospital, Porto Alegre, Brazil. Luigi Terracciano, MD, Pediatric Division, Department of Child and Maternal Medicine, University of Milan Medical School at the Melloni Hospital, Milan 20129, Italy. Stefan Vieths, MD, Division of Allergology, Paul-EhrlichInstitut, Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Str. 51-59, D-63225 Langen, Germany.

Treating infant colic with the probiotic Lactobacillus reuteri: double blind, placebo controlled randomised trial

Objective To determine whether the probiotic Lactobacillus reuteri DSM 17938 reduces crying or fussing in a broad community based sample of breastfed infants and formula fed infants with colic aged less than 3 months. Design Double blind, placebo controlled randomised trial. Setting Community based sample (primary and secondary level care centres) in Melbourne, Australia. Participants 167 breastfed infants or formula fed infants aged less than 3 months meeting Wessel’s criteria for crying or fussing: 85 were randomised to receive probiotic and 82 to receive placebo. Interventions Oral daily L reuteri (1×108 colony forming units) versus placebo for one month. Main outcomes measures The primary outcome was daily duration of cry or fuss at 1 month. Secondary outcomes were duration of cry or fuss; number of cry or fuss episodes; sleep duration of infant at 7, 14, and 21 days, and 1 and 6 months; maternal mental health (Edinburgh postnatal depression subscale); family functioning (paediatric quality of life inventory), parent quality adjusted life years (assessment of quality of life) at 1 and 6 months; infant functioning (paediatric quality of life inventory) at 6 months; infant faecal microbiota (microbial diversity, colonisation with Escherichia coli), and calprotectin levels at 1 month. In intention to treat analyses the two groups were compared using regression models adjusted for potential confounders. Results Of 167 infants randomised from August 2011 to August 2012, 127 (76%) were retained to primary outcome; of these, a subset was analysed for faecal microbial diversity, E coli colonisation, and calprotectin levels. Adherence was high. Mean daily cry or fuss time fell steadily in both groups. At 1 month, the probiotic group cried or fussed 49 minutes more than the placebo group (95% confidence interval 8 to 90 minutes, P=0.02); this mainly reflected more fussing, especially for formula fed infants. The groups were similar on all secondary outcomes. No study related adverse events occurred. ConclusionsL reuteri DSM 17938 did not benefit a community sample of breastfed infants and formula fed infants with colic. These findings differ from previous smaller trials of selected populations and do not support a general recommendation for the use of probiotics to treat colic in infants. Trial registration Current Controlled Trials ISRCTN95287767.

Clinical spectrum of food allergy in children in Australia and South-East Asia: identification and targets for treatment

The prevalence of atopic diseases is increasing worldwide for reasons that are not clear. Food allergies are the earliest manifestations of atopy. This review defines the foods most commonly involved in allergic reactions and identifies an emerging group of syndromes in which food allergy is involved. A study of the frequency of food allergies in Australia and South-East Asia has recently shown that egg, cows milk and peanut are the most common food allergens in Australia, but there were divergent results from different regions of South-East Asia. It is not clear whether the differences in reactivity to foods are due to genetic or cultural factors, but the findings raise the possibility that genetic susceptibility to food allergy may operate at the T-cell level modulated by the major histocompatibility complex. The Melbourne Milk Allergy Study defined a wide range of clinical symptoms and syndromes that could be reproduced by dietary challenge. A subsequent analysis of the infants with hypersensitivity to cows milk and other multiple food proteins identified a new syndrome, multiple food protein intolerance of infancy. Food challenges demonstrated reactions developing slowly days after commencement of low-allergen soy formula or extensively hydrolysed formula. Follow-up at the age of 3 years showed that most children with this disorder tolerated most foods apart from cows milk, egg and peanut. Atopic dermatitis affects about 18% of infants in the first 2 years of life. In a community-based study we have shown a very strong association (RR 3.5) between atopic dermatitis and infants with immunoglobulin E allergy to cows milk, egg or peanut. Family studies on these infants have shown a link between atopic dermatitis and the genomic region 5q31 adjacent to the interleukin-4 gene cluster. Infantile colic (distress) affects 15-40% of infants in the first 4 months of life. Many theories of causation have been proposed, but a study from our centre showed that dietary modification, particularly that of breastfeeding mothers whose infants present with colic before the age of 6 weeks, alleviated symptoms. Colic associated with vomiting has been attributed to gastro-oesophageal reflux (GOR). This has been considered primarily a motility disorder, but a secondary form resulting from food protein intolerance has been described recently. We have also recently identified a group of infants with distressed behaviour attributed to GOR who have failed to respond to H2-receptor antagonists, prokinetic agents and multiple formula changes. Symptoms resolved on commencement of an elemental amino acid-based formula. In two-thirds of the patients, symptoms relapsed when challenged with low-allergen soy formula or extensively hydrolysed formula. We propose that a period of food protein intolerance is a part of the normal development of the immune system as it encounters common dietary proteins in infancy and early childhood. Future targets for research are development of appropriate dietary and management strategies for these entities and identification of genetic markers for these disorders.

Changing incidence of acute pancreatitis: 10-year experience at the Royal Children's Hospital, Melbourne

Background and Aim:  The aim of this study was to assess the incidence and etiology of acute pancreatitis at a major pediatric referral center in Australia.

Early clinical predictors of remission of peanut allergy in children

BACKGROUND Understanding predictors of clinical remission would assist in clinical management of peanut allergy. OBJECTIVE We sought to determine the early clinical predictors of peanut allergy remission using a longitudinal cohort of young children with peanut allergy. METHODS Consecutive patients less than 2 years of age with peanut allergy were identified on the basis of skin prick test (SPT) wheal size of 95% positive predictive value or greater. Baseline SPT responses to peanuts, tree nuts, and sesame and serum peanut-specific IgE antibody levels were documented, and follow-up studies were conducted at 1- to 2-year intervals for up to 8 years. Peanut food challenges were performed when SPT responses decreased to less than the 95% positive predictive value for peanut allergy. RESULTS SPT wheal diameters to peanut extract of 6 mm or greater (hazard ratio, 2.16; 95% CI, 1.23-3.786; P = .008) and peanut-specific IgE antibody of 3 kUA/L or greater (hazard ratio, 2.74; 95% CI, 1.13-6.61; P = .025) before the age of 2 years were independent predictors of persistent peanut allergy. Mean SPT wheal diameters of nonremitters increased (r = 0.31, P < .001), whereas those of remitters decreased (r = -0.26, P = .002) between 1 and 4 years of age. Twenty-one percent of young children with peanut allergy became clinically tolerant by age 5 years. CONCLUSIONS Remission of peanut allergy can be predicted by low levels of IgE antibodies to peanut in the first 2 years of life or decreasing levels of IgE sensitization by the age of 3 years.

Clinical Use of Probiotics in Pediatric Allergy (cuppa): A World Allergy Organization Position Paper

BackgroundProbiotic administration has been proposed for the prevention and treatment of specific allergic manifestations such as eczema, rhinitis, gastrointestinal allergy, food allergy, and asthma. However, published statements and scientific opinions disagree about the clinical usefulness.ObjectiveA World Allergy Organization Special Committee on Food Allergy and Nutrition review of the evidence regarding the use of probiotics for the prevention and treatment of allergy.MethodsA qualitative and narrative review of the literature on probiotic treatment of allergic disease was carried out to address the diversity and variable quality of relevant studies. This variability precluded systematization, and an expert panel group discussion method was used to evaluate the literature. In the absence of systematic reviews of treatment, meta-analyses of prevention studies were used to provide data in support of probiotic applications.ResultsDespite the plethora of literature, probiotic research is still in its infancy. There is a need for basic microbiology research on the resident human microbiota. Mechanistic studies from biology, immunology, and genetics are needed before we can claim to harness the potential of immune modulatory effects of microbiota. Meanwhile, clinicians must take a step back and try to link disease state with alterations of the microbiota through well-controlled long-term studies to identify clinical indications.ConclusionsProbiotics do not have an established role in the prevention or treatment of allergy. No single probiotic supplement or class of supplements has been demonstrated to efficiently influence the course of any allergic manifestation or long-term disease or to be sufficient to do so. Further epidemiologic, immunologic, microbiologic, genetic, and clinical studies are necessary to determine whether probiotic supplements will be useful in preventing allergy. Until then, supplementation with probiotics remains empirical in allergy medicine. In the future, basic research should focus on homoeostatic studies, and clinical research should focus on preventive medicine applications, not only in allergy. Collaborations between allergo-immunologists and microbiologists in basic research and a multidisciplinary approach in clinical research are likely to be the most fruitful.

Postural drainage and gastro-oesophageal reflux in infants with cystic fibrosis

Gastro-oesophageal reflux is increased in cystic fibrosis and it is possible that postural drainage techniques may exacerbate reflux, potentially resulting in aspiration and further impairment of pulmonary function. AIM To evaluate the effects of physiotherapy with head down tilt (standard physiotherapy, SPT) on gastro-oesophageal reflux and to compare this with physiotherapy without head down tilt (modified physiotherapy, MPT). METHOD Twenty (mean age 2.1 months) infants with cystic fibrosis underwent 30 hour oesophageal pH monitoring during which SPT and MPT were carried out for two sessions each on consecutive days. RESULTS The number of reflux episodes per hour, but not their duration, was significantly increased during SPT compared with MPT (SPT 2.5 (0.4) v MPT 1.6 (0.3), p = 0.007) and to background (1.1 (0.)1, p = 0.0005). Fractional reflux time was also increased during SPT (11.7 (2.6)%) compared with background (6.9 (1.3)%, p = 0.03) but not compared with MPT (10.7 (2.7)%). There was no significant difference between MPT and background for number of reflux episodes, their duration, or fractional reflux time. CONCLUSION SPT, but not MPT, was associated with a significant increase in gastro-oesophageal reflux in infants with cystic fibrosis.