Michael Mellon

Effect of combined maternal and infant food-allergen avoidance on development of atopy in early infancy: A randomized study

The effect of maternal and infant avoidance of allergenic foods on food allergy was examined in a prenatally randomized, controlled trial of infants of atopic parents. The diet of the prophylactic-treated group (N = 103) included (1) maternal avoidance of cows milk, egg, and peanut during the third trimester of pregnancy and lactation and (2) infant use of casein hydrolysate (Nutramigen) for supplementation or weaning, and avoidance of solid foods for 6 months; cows milk, corn, soy, citrus, and wheat, for 12 months; and egg, peanut, and fish, for 24 months. In the control group (N = 185), mothers had unrestricted diets, and infants followed American Academy of Pediatrics feeding guidelines. The cumulative prevalence of atopy was lower at 12 months in the prophylactic-treated (16.2%) compared to the control (27.1%) group (p = 0.039), resulting from reduced food-associated atopic dermatitis, urticaria and/or gastrointestinal disease by 12 months (5.1% versus 16.4%; p = 0.007), and any positive food skin test by 24 months (16.5% versus 29.4%; p = 0.019), caused primarily by fewer positive milk skin tests (1% versus 12.4%; p = 0.001). The prevalences of allergic rhinitis, asthma, and inhalant skin tests were unaffected. Serum IgE levels in the prophylactic-treated group were marginally lower only at 4 months. Thus, reduced exposure of infants to allergenic foods appeared to reduce food sensitization and allergy primarily during the first year of life.

Facilitated referral to asthma specialist reduces relapses in asthma emergency room visits

Facilitated asthma-specialist care delivered by allergists was compared to generalist care on the rate of relapse of asthma emergency room (ER) visits and hospitalizations and on asthma control in a prospective, controlled study of San Diego Kaiser Health Plan members with asthma. Subjects with asthma between the ages of 6 and 59 years presenting for acute ER care for asthma were systematically assigned by alternating, consecutively, the day of their ER visit to receive either (1) facilitated referral to an asthma specialist within the allergy department and concomitant comprehensive ongoing asthma care (intervention group, n = 149) or (2) continued outpatient management from generalist physicians (control group, n = 160). The course of their asthma was evaluated blindly during the subsequent 6 months by review of medical records, initial and follow-up questionnaires, and spirometry. Compared to the control group, the intervention group noted (1) a 75% reduction in the number of, and percent of, subjects with asthma awakenings per night (p less than or equal to 0.0001), (2) an almost 50% reduction in asthma ER relapses (p = 0.017) resulting from a reduction in the frequency of multiple relapse (p = 0.005), and (3) a greater use of inhaled corticosteroids (p less than 0.00001) and cromolyn (p = 0.002). Thus, facilitated referral of subjects with asthma to specialists in asthma therapy after acute ER therapy appears to reduce asthma ER relapses and to improve asthma outcome.

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.

Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing.

BACKGROUND Acute wheezing illnesses in preschoolers require better management strategies to reduce morbidity. OBJECTIVES We sought to examine the effectiveness of episodic use of an inhaled corticosteroid and a leukotriene receptor antagonist in preschoolers with intermittent wheezing. METHODS In a randomized, double-blind, placebo-controlled 12-month trial, 238 children aged 12 to 59 months with moderate-to-severe intermittent wheezing received 7 days of either budesonide inhalation suspension (1 mg twice daily), montelukast (4 mg daily), or placebo in addition to albuterol with each identified respiratory tract illness (RTI). Proportion of episode-free days (EFDs) during the 12-month trial was the primary outcome. RESULTS The 3 treatment groups did not differ in proportions of EFDs, with adjusted mean EFDs of 76% (95% CI, 70% to 81%) for budesonide, 73% (95% CI, 66% to 79%) for montelukast, and 74% (95% CI, 65% to 81%) for conventional therapy (P = .66). The 3 groups did not differ in oral corticosteroid use, health care use, quality of life, or linear growth. However, during RTIs, budesonide and montelukast therapy led to modest reductions in trouble breathing (38% [P = .003] and 37% [P = .003], respectively) and interference with activity scores (32% [P = .01] and 40% [P = .001], respectively) that were most evident in those with positive asthma predictive indices. CONCLUSIONS In preschool children with moderate-to-severe intermittent wheezing, episodic use of either budesonide or montelukast early in RTIs, when added to albuterol, did not increase the proportion of EFDs or decrease oral corticosteroid use over a 12-month period. However, indicators of severity of acute illnesses were reduced, particularly in children with positive asthma predictive indices.

Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial

BACKGROUND Daily inhaled corticosteroids are an effective treatment for mild persistent asthma, but some children have exacerbations even with good day-to-day control, and many discontinue treatment after becoming asymptomatic. We assessed the effectiveness of an inhaled corticosteroid (beclomethasone dipropionate) used as rescue treatment. METHODS In this 44-week, randomised, double-blind, placebo-controlled trial we enrolled children and adolescents with mild persistent asthma aged 5-18 years from five clinical centres in the USA. A computer-generated randomisation sequence, stratified by clinical centre and age group, was used to randomly assign participants to one of four treatment groups: twice daily beclomethasone with beclomethasone plus albuterol as rescue (combined group); twice daily beclomethasone with placebo plus albuterol as rescue (daily beclomethasone group); twice daily placebo with beclomethasone plus albuterol as rescue (rescue beclomethasone group); and twice daily placebo with placebo plus albuterol as rescue (placebo group). Twice daily beclomethasone treatment was one puff of beclomethasone (40 μg per puff) or placebo given in the morning and evening. Rescue beclomethasone treatment was two puffs of beclomethasone or placebo for each two puffs of albuterol (180 μg) needed for symptom relief. The primary outcome was time to first exacerbation that required oral corticosteroids. A secondary outcome measured linear growth. Analysis was by intention to treat. This study is registered with clinicaltrials.gov, number NCT00394329. RESULTS 843 children and adolescents were enrolled into this trial, of whom 288 were assigned to one of four treatment groups; combined (n=71), daily beclomethasone (n=72), rescue beclomethasone (n=71), and placebo (n=74)-555 individuals were excluded during the run-in, according to predefined criteria. Compared with the placebo group (49%, 95% CI 37-61), the frequency of exacerbations was lower in the daily (28%, 18-40, p=0·03), combined (31%, 21-43, p=0·07), and rescue (35%, 24-47, p=0·07) groups. Frequency of treatment failure was 23% (95% CI 14-43) in the placebo group, compared with 5·6% (1·6-14) in the combined (p=0·012), 2·8% (0-10) in the daily (p=0·009), and 8·5% (2-15) in the rescue (p=0·024) groups. Compared with the placebo group, linear growth was 1·1 cm (SD 0·3) less in the combined and daily arms (p<0·0001), but not the rescue group (p=0·26). Only two individuals had severe adverse events; one in the daily beclomethasone group had viral meningitis and one in the combined group had bronchitis. INTERPRETATION Children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids. Inhaled corticosteroids as rescue medication with albuterol might be an effective step-down strategy for children with well controlled, mild asthma because it is more effective at reducing exacerbations than is use of rescue albuterol alone. Use of daily inhaled corticosteroid treatment and related side-effects such as growth impairment can therefore be avoided. FUNDING National Heart, Lung and Blood Institute.

Genetic and environmental factors affecting the development of atopy through age 4 in children of atopic parents: a prospective randomized study of food allergen avoidance

The effect of food allergen avoidance, as well as other environmental and genetic factors, on the development of atopy were determined in this follow‐up report of a prospective randomized controlled study of 288 infants of atopic parents, in which 78% were available for evaluation at age 4 years. The prophylactictreated group consisted of mothers who avoided cow milk. egg. and peanut during the last trimester of pregnancy and lactation and of infants who avoided cow milk until 1 year (casein hydrolysate supplementation prior to 1 year) and egg, peanut, and fish until after 2 years. The control group consisted of maternal/infant pairs who followed standard feeding practices. The cumulative prevalence of food allergy and food sensitization remained lower in the prophylactic treated group from 1 to 4 years of age. However, the period (current) prevalence of food allergy in both study groups was similar (about 5%) at 3 and 4 years. Such findings suggest that period prevalence may represent the more appropriate measure to assess the impact of intervention measures on the development of atopic disease at older ages. Prophylactic‐treated children evidenced lower levels of IgG beta lacloglobulin (BLG) at 4 months and I and 2 years (p < 0.0001) and lower IgG ovalbumen/ovomucoid (OVA) levels only at 2 years (p < 0.001). Both groups evidenced similar prevalences of asthma, allergic rhinitis, and positive inhalant skin tests from birth to 4 years. Children with food allergy evidenced higher 4 year cumulative prevalences of allergic rhinitis and asthma (p < 0.05). Risk factors for atopic disease by age 4 years were shown by multivariate analysis (p < 0.05) to include (1) unrestricted diet and elevated cord blood IgE with food allergy, (2) male gender and lower paternal level of education with asthma, and (3) non‐caucasian ethnicity and spring/summer birth with atopic dermatitis and allergic rhinitis. Serum IgE levels were not significantly different between groups at 3 and 4 years, despite their being a trend towards lower serum IgE levels in the prophylactic‐treated group at 4 months (p < 0.07). In the control group, formula feeding prior to 4 months was associated with higher 4 month serum IgE levels (p < 0.05). Stepwise linear regression revealed that serum IgE variability from birth to 4 years was influenced by male gender, non‐caucasian ethnicity, maternal and paternal serum IgE levels, 4 month IgG BLG levels, positive food and inhalant skin tests, and the development of atopic dermatitis, food allergy, asthma, and allergic rhinitis. These findings demonstrate the strength of genetic factors and their modulation by dietary and envi‐ronmental influences in the development of atopy and reveal that the reduction in food allergy in infancy by maternal/infant food allergen avoidance fails to affect respiratory allergy development from birth to 4 years.

Daily or Intermittent Budesonide in Preschool Children with Recurrent Wheezing

BACKGROUND Daily inhaled glucocorticoids are recommended for young children at risk for asthma exacerbations, as indicated by a positive value on the modified asthma predictive index (API) and an exacerbation in the preceding year, but concern remains about daily adherence and effects on growth. We compared daily therapy with intermittent therapy. METHODS We studied 278 children between the ages of 12 and 53 months who had positive values on the modified API, recurrent wheezing episodes, and at least one exacerbation in the previous year but a low degree of impairment. Children were randomly assigned to receive a budesonide inhalation suspension for 1 year as either an intermittent high-dose regimen (1 mg twice daily for 7 days, starting early during a predefined respiratory tract illness) or a daily low-dose regimen (0.5 mg nightly) with corresponding placebos. The primary outcome was the frequency of exacerbations requiring oral glucocorticoid therapy. RESULTS The daily regimen of budesonide did not differ significantly from the intermittent regimen with respect to the frequency of exacerbations, with a rate per patient-year for the daily regimen of 0.97 (95% confidence interval [CI], 0.76 to 1.22) versus a rate of 0.95 (95% CI, 0.75 to 1.20) for the intermittent regimen (relative rate in the intermittent-regimen group, 0.99; 95% CI, 0.71 to 1.35; P=0.60). There were also no significant between-group differences in several other measures of asthma severity, including the time to the first exacerbation, or adverse events. The mean exposure to budesonide was 104 mg less with the intermittent regimen than with the daily regimen. CONCLUSIONS A daily low-dose regimen of budesonide was not superior to an intermittent high-dose regimen in reducing asthma exacerbations. Daily administration led to greater exposure to the drug at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; MIST ClinicalTrials.gov number, NCT00675584.).

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.

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.