Jill A. Warner

Dietary prevention of allergic diseases in infants and small children.

Because of scientific fraud four trials have been excluded from the original Cochrane meta‐analysis on formulas containing hydrolyzed protein for prevention of allergy and food intolerance in infants. Unlike the conclusions of the revised Cochrane review the export group set up by the Section on Paediatrics, European Academy of Allergology and Clinical Immunology (SP‐EAACI) do not find that the exclusion of the four trials demands a change of the previous recommendations regarding primary dietary prevention of allergic diseases. Ideally, recommendations on primary dietary prevention should be based only on the results of randomized and quasi‐randomized trials (selection criteria in the Cochrane review). However, regarding breastfeeding randomization is unethical, Therefore, in the development of recommendations on dietary primary prevention, high‐quality systematic reviews of high‐quality cohort studies should be included in the evidence base. The study type combined with assessment of the methodological quality determines the level of evidence. In view of some methodological concerns in the Cochrane meta‐analysis, particularly regarding definitions and diagnostic criteria for outcome measures and inclusion of non peer‐reviewed studies/reports, a revision of the Cochrane analysis may seem warranted. Based on analysis of published peer‐reviewed observational and interventional studies the results still indicate that breastfeeding is highly recommended for all infants irrespective of atopic heredity. A dietary regimen is effective in the prevention of allergic diseases in high‐risk infants, particularly in early infancy regarding food allergy and eczema. The most effective dietary regimen is exclusively breastfeeding for at least 4–6 months or, in absence of breast milk, formulas with documented reduced allergenicity for at least the first 4 months, combined with avoidance of solid food and cows milk for the first 4 months.The role of primary prevention of allergic diseases has been a matter of debate for the last 40 years. In order to shed some light on this issue, a group of experts of the Section of Pediatrics EAACI reviewed critically the existing literature on the subject. An analysis of published peer-reviewed observational and interventional studies was performed following the statements of evidence as defined by WHO. The results of the analysis indicate that breastfeeding is highly recommended for all infants irrespective of atopic heredity. A dietary regimen is unequivocally effective in the prevention of allergic diseases in high-risk children. In these patients breastfeeding combined with avoidance of solid food and cows milk for at least 4-6 months is the most effective preventive regimen. In the absence of breast milk, formulas with documented reduced allergenicity for at least 4-6 months should be used.

Dietary prevention of allergic diseases in infants and small children. Part III: Critical review of published peer-reviewed observational and interventional studies and final recommendations

The role of primary prevention of allergic diseases has been a matter of debate for the last 40 years. In order to shed some light on this issue, a group of experts of the Section of Pediatrics EAACI reviewed critically the existing literature on the subject. An analysis of published peer‐reviewed observational and interventional studies was performed following the statements of evidence as defined by WHO. The results of the analysis indicate that breastfeeding is highly recommended for all infants irrespective of atopic heredity. A dietary regimen is unequivocally effective in the prevention of allergic diseases in high‐risk children. In these patients breastfeeding combined with avoidance of solid food and cows milk for at least 4–6 months is the most effective preventive regimen. In the absence of breast milk, formulas with documented reduced allergenicity for at least 4–6 months should be used.

Mechanical ventilation and high-efficiency vacuum cleaning: A combined strategy of mite and mite allergen reduction in the control of mite-sensitive asthma

BACKGROUND The relationship between exposure to house dust mite (HDM) allergens and prevalence of sensitization to these allergens in patients with asthma has been confirmed in many studies. Mite population growth is regulated by humidity. Reducing humidity and removing allergen by efficient vacuuming should control mite allergen and reduce symptoms. OBJECTIVE We sought to investigate the effect of mechanical ventilation and high-efficiency vacuuming on HDM numbers and Der p 1 concentrations in the homes of mite-sensitive asthmatic subjects and to evaluate the effect of any reductions on symptoms. METHODS The homes of 40 HDM-sensitive asthmatic subjects were randomized to receive (1) mechanical ventilation and a high-efficiency vacuum cleaner (HEVC); (2) mechanical ventilation alone; (3) an HEVC alone; and (4) no intervention. Homes and patients were monitored for 12 months. Change in absolute humidity, mite numbers, Der p 1 concentrations, lung function, bronchial hyperresponsiveness, and symptom scores were analyzed. RESULTS Homes with mechanical ventilation achieved significantly lower humidity levels than those without (P <.001), with an associated reduction of mite numbers (P <.05) and Der p 1 concentrations (P <.001 ¿in nanograms per gram, P =.006 ¿in milligrams per square meter) in bedroom carpets and some other mite sources in the ventilated areas of the homes. The addition of a vacuum cleaner enhanced this effect. There was a trend for an improvement in histamine PC(20) (P =.085) in the patients whose homes were ventilated. CONCLUSION The use of a mechanical ventilation system in suitable homes resulted in some reduction in numbers of HDM and Der p 1 concentrations. The addition of an HEVC slightly enhanced the effect but not sufficiently to see an improvement in symptoms.

Frequency of detection of picornaviruses and seven other respiratory pathogens in infants.

Background: Previous studies in which molecular-based techniques have been used to identify the causative pathogens of respiratory tract infection have investigated hospitalized children only. We report a prospective study designed to determine the frequency and clinical presentation of community-acquired respiratory illness in infancy associated with 8 common respiratory pathogens. Methods: Eighty-eight infants were monitored through their first winter. With each respiratory illness, infants were examined, and a nasal lavage specimen was collected. Individual reverse transcription-polymerase chain reactions were performed to detect infection with picornaviruses (rhinoviruses and enteroviruses), coronaviruses (serotypes OC43 and 229E), adenoviruses, parainfluenza viruses 1–3, influenza viruses (types A and B), respiratory syncytial virus (RSV), Chlamydia pneumoniae and Mycoplasma pneumoniae. Results: Picornaviruses were the most frequently detected pathogen identified in 46% (56 of 123) of episodes, followed by RSV (27%), parainfluenza viruses (13%) and coronaviruses (9%). Dual pathogen infections were identified in 20% of episodes, predominantly caused by picornaviruses together with either RSV or parainfluenza viruses. RSV infection was significantly associated with a diagnosis of bronchiolitis. No other associations were found between pathogen and clinical diagnosis. Dual infection did not predispose infants to a more severe clinical course. Conclusions: Picornaviruses are the predominant cause of community-acquired respiratory tract infection in the first year of life. Large prospective community-based studies will be needed to fully evaluate the contribution of picornaviruses, both in isolation and in combination with other respiratory pathogens, to the various clinical syndromes of respiratory infection observed during infancy.

Dietary prevention of allergic diseases in infants and small children. Part II : Evaluation of methods in allergy prevention studies and sensitization markers. Definitions and diagnostic criteria of allergic diseases

The role of primary prevention of allergic diseases has been a matter of debate for the last 40 years. In order to shed some light into this issue a group of experts of the Section of Pediatrics EAACI critically reviewed the existing literature on the subject. The design of observational and interventional studies was evaluated with relevance to the important factors influencing outcome of studies on allergy development/prevention. In this analysis the statements of evidence as defined by WHO were applied. Best evidence of recommendations are those fulfilling the criteria for statements category 1 and 2 and grade of recommendations A and B as proposed by WHO. This survey include target group for dietary prevention and methods and diagnostic criteria of atopic dermatitis, asthma and food allergy for prevention studies.

Early life events in allergic sensitisation

The timing of events leading to allergic sensitisation has become a very important area in the attempt to halt the dramatic increase in the prevalence of diseases such as asthma, eczema and hay fever. Recent research has demonstrated that events taking place during the gestational period may well play a role in determining whether or not a genetic susceptibility becomes translated into disease processes. Maternal atopy seems to have an important effect on the developing immune response of the infant and increases the chances of the child developing allergy in later life. Maternal IgE, IgG and amniotic fluid cytokines, combined with the presence of allergen in the feto-maternal environment are all possible factors involved in the ultimate outcome in terms of infant Th-1/Th-2 responses to common environmental antigens. Immune modulation at this stage of development may, in the future, be a way forward in the prevention of allergy.

Dietary prevention of allergic diseases in infants and small children. Part I: immunologic background and criteria for hypoallergenicity.

The role of primary prevention of allergic diseases has been a matter of debate for the last 40 years. In order to shed some light into this issue, a group of experts of the Section of Pediatrics EAACI critically reviewed the existing literature on the subject. In this paper, the immunology of the fetus and newborn is reviewed as well as the post‐natal development of the immune system. The influence of post‐natal environment and breastfeeding on tolerance induction and sensitization are examined. Allergic diseases result from a strong relationship between genetic and environmental factors. Sensitization to food allergens occurs in the first year of life and cows milk allergy is the first food allergy to appear in the susceptible infants. Hypoallergenicity of food formulas to be used is a critical issue both for treatment of cows milk‐allergic children and for prevention. Methods to document hypoallergenicity are discussed and evaluated in the preclinical and clinical steps.

Airway function correlates with circulating eosinophil, but not mast cell, markers of inflammation in childhood asthma

Background Lung function tests, including forced expiratory volume in one second (FEV1), forced expiratory flow at 25–75% of vital capacity (FEF25–75%) and provocation concentrations of histamine which reduce FEV] by 20% (PC20), are used as indicators of airway form and function in bronchial asthma. Recently, markers of eosinophil activation in bronchial lavage and serum have been suggested as a measure of eosinophil mediated inflammation in the airways. These include eosinophil cationic protein (ECP), eosinophil protein X (EPX) (also known as eosinophil derived neuro‐toxin) and eosinophil peroxidase (EPO). Similarly, serum tryptase has been used as a marker of mast cell activation in systemic anaphylaxis.

Fetal swallowing of IgE

Allergic disease is more frequently manifest by the offspring of atopic mothers than atopic fathers. Furthermore, newborn umbilical-cord blood mononuclear cells exhibit allergenspecific proliferation predicting subsequent allergic disease. Thus, intrauterine exposure to allergen and the development of immunological memory must occur in the fetus and be influenced by maternal health and environment. The key question is how does fetal-allergen exposure and sensitisation occur? Because increased IgE is a hallmark of allergy and can mediate allergen uptake via IgE receptor-mediated antigen focusing, we evaluated whether the fetus was exposed to IgE during life in utero. Matched samples of maternal blood and amniotic fluid were collected from women undergoing elective caesarean section at term ( 37 weeks of gestation), with maternal blood contamination of amniotic fluid determined by measuring IgA (in-house IgA-specific ELISA) and any sample containing above 2 g/mL IgA was excluded from the study; and also from women having amniocentesis at approximately 16 weeks of pregnancy with only samples from women who proceeded with the pregnancy included in this study. All samples were collected with the approval of the Joint Ethics Committee of Southampton University Hospitals and the consent of the mothers. Total IgE was measured in maternal plasma and in amniotic fluid with Magic Lite SQ Total IgE Extended Range and Total IgE High Sensitivity (ALK, Denmark) according to the manufacturer’s instructions. Non-parametric methods (Spearman’s correlation; SPSS 7.0) and linear regression (ANOVA; SPSS 7.0) were used for analysis. IgE was detectable in 23/23 of term amniotic fluid samples (median 0·547 IU/mL; range 0·155–2·862 IU/mL). A statistically significant correlation was found between maternal total IgE and that of amniotic fluid at both 16 weeks of pregnancy and at term (figure). Where does amniotic fluid IgE come from? Because the fetus is capable of producing IgE from 11 weeks of gestation, fetal production may account for at least some amniotic fluid IgE. However, the increasing amount of amniotic fluid IgE as maternal plasma concentrations increase, suggests that maternal IgE may pass into the amniotic fluid or that factors mediating increased maternal production of IgE similarly influence fetal production. We favour the former and, as IgE does not cross the human placenta, postulate that maternal IgE traverses the fetal membranes, a hypothesis currently under investigation. 70% of amniotic-fluid protein is turned over daily with most of this removal via fetal swallowing, since the fetus also aspirates amniotic fluid, the gastointestinal and respiratory tracts, in addition to the skin, are exposed to molecules in amniotic fluid. Whether allergen is also present and IgE receptors are expressed by cells within these tissues thereby allowing antigen focusing to occur is an ongoing study. We postulate that amnion transmission of IgE has evolved as a mechanism for sensitising and thereby protecting the fetus from parasites infesting the mother, as exposure of the newborn to these same parasites is inevitable. Filarial specific IgE was detected in the cord blood of 33/57 infants born in Madras, India, where there is a high prevalence of filariasis. Furthermore, a study in Thailand revealed that although infants at 6 months of age are infested with parasites they do not have the same parasite as their mother. This protective pathway may now be usurped for sensitisation to allergens and we hypothesise this pathway of allergen exposure as an alternative to transplacental transfer of allergen. Further elaboration of this mechanism will provide new therapeutic targets which we anticipate will reduce the current dramatically increasing prevalence of allergic diseases.

Altered T lymphocyte phenotype at birth in babies born to atopic parents.

Flow cytometry was used to analyse the cord blood T cells of 33 babies at high risk ‘HR’ for developing allergy (born to at least one atopic, asthmatic parent), and 10 low risk ‘LR’ babies (born to non‐atopic parents), following normal term deliveries. Significantly lower numbers of CD25+, (activated) T cells (p<0.005) were seen in the cord blood of the HR babies who had developed both allergic symptoms and positive skin prick tests by one year of age when compared with the LR group. CD45RO+ (memory) T cells were detected in both HR and LR babies with a trend for lower numbers of memory cells to be detected in HR infants who later developed allergic symptoms and/or positive skin prick tests. Significantly lower numbers of CD4+/CD45RO+ were seen in the cord blood of HR babies who developed allergic symptoms compared to HR babies who showed no sign of allergy by one year and to the LR babies (p<0.05 and p<0.005). The presence of activated and memory T cells at birth implies intra‐uterine priming. The significantly lower numbers of memory T cells in the HR babies suggests a suppression of T cell activation or lack of antigenic priming in this group. This prenatal influence on babies born to atopic parents may have important implications with regard to the mechanisms underlying atopic sensitisation.