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No reason to change the current guidelines on allergy prevention

Published:October 31, 2011DOI:https://doi.org/10.1016/j.jaci.2011.08.038
      To the Editor:
      Lowe et al
      • Lowe A.J.
      • Hosking C.S.
      • Bennett C.M.
      • Allen K.J.
      • Axelrad C.
      • Carlin J.B.
      • et al.
      Effect of a partially hydrolyzed whey infant formula at weaning on risk of allergic disease in high-risk children: a randomized controlled trial.
      report on a single-blind randomized trial on the effects of soy or partially hydrolyzed whey formula (pHWF) compared with cow's milk protein formula (CMF) on allergy risk in 620 infants with a family history of allergy and found no group difference at age 2 years for cumulative incidence of any allergic manifestation (CMF, 48.7%; soy, 54.5%; pHWF, 53.4%), eczema, or food allergy. In contrast to the authors, we conclude that this study should not lead to changing current recommendations on allergy prevention because of its severe methodological limitations, including addition of a third intervention arm after study start, high randomization losses, lack of double blinding and information on allocation concealment, changing definitions of outcome parameters compared with previous publications on this cohort, unsatisfactory assessment thereof, and limited statistical power.
      Lowe et al
      • Lowe A.J.
      • Hosking C.S.
      • Bennett C.M.
      • Allen K.J.
      • Axelrad C.
      • Carlin J.B.
      • et al.
      Effect of a partially hydrolyzed whey infant formula at weaning on risk of allergic disease in high-risk children: a randomized controlled trial.
      reported a far higher prevalence for allergic outcomes than other high-quality trials, such as the German Infant Nutritional Intervention study,
      • von Berg A.
      • Koletzko S.
      • Grubl A.
      • Filipiak-Pittroff B.
      • Wichmann H.E.
      • Bauer C.P.
      • et al.
      The effect of hydrolyzed cow's milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial.
      • von Berg A.
      • Koletzko S.
      • Filipiak-Pittroff B.
      • Laubereau B.
      • Gruebl A.
      • Wichmann H.E.
      • et al.
      Certain hydrolyzed formulas reduce the incidence of atopic dermatitis, but not of asthma: three year results of the GINI-Study.
      • von Berg A.
      • Filipiak-Pittroff B.
      • Kramer U.
      • Link E.
      • Bollrath C.
      • Brockow I.
      • et al.
      Preventive effect of hydrolyzed infant formulas persists until age 6: long-term results from the German Infant Nutritional Intervention Study GINI.
      which appears to be due to weak outcome assessment. Moreover, different case definitions of eczema were used in the present publication
      • Lowe A.J.
      • Hosking C.S.
      • Bennett C.M.
      • Allen K.J.
      • Axelrad C.
      • Carlin J.B.
      • et al.
      Effect of a partially hydrolyzed whey infant formula at weaning on risk of allergic disease in high-risk children: a randomized controlled trial.
      compared with previous publications on this study (see Table E1, the Methods section, and references in this article's Online Repository at www.jacionline.org).
      • Hill D.J.
      • Hosking C.S.
      Food allergy and atopic dermatitis in infancy: an epidemiologic study.
      • Hill D.J.
      • Sporik R.
      • Thorburn J.
      • Hosking C.S.
      The association of atopic dermatitis in infancy with immunoglobulin E food sensitization.
      Even the single blinding must be questioned. In earlier publications an intervention was not reported, but it was considered an “epidemiologic study.”
      • Hill D.J.
      • Hosking C.S.
      Food allergy and atopic dermatitis in infancy: an epidemiologic study.
      • Hill D.J.
      • Sporik R.
      • Thorburn J.
      • Hosking C.S.
      The association of atopic dermatitis in infancy with immunoglobulin E food sensitization.
      A later publication reported randomization but no masking
      • Koplin J.
      • Dharmage S.C.
      • Gurrin L.
      • Osborne N.
      • Tang M.L.
      • Lowe A.J.
      • et al.
      Soy consumption is not a risk factor for peanut sensitization.
      and stated that “parents of infants in any of the 3 randomly allocated formula groups could elect to give their child a non-randomly allocated soy formula or soy milk at any stage during the first 2 years of life.” Children allocated to soy formula were more likely to consume parent-selected soy formulas or soy milk (35.9% vs 22.8% and 23.3% in the other groups).
      • Koplin J.
      • Dharmage S.C.
      • Gurrin L.
      • Osborne N.
      • Tang M.L.
      • Lowe A.J.
      • et al.
      Soy consumption is not a risk factor for peanut sensitization.
      The preferential parental selection of soy milk in infants allocated to soy study formula questions whether the study's blinding was effective.
      The current publication does not report any data on nonadherence but only numbers of children who did not receive allocated formula. The results are uninterpretable without disclosing the number of infants exposed to a formula other than the allocated formula during the intervention. The authors do not reveal the number of study formula–fed infants compliant with the allocated feeding regimens in the first 4 months of life. The data suggest that 32% (61/193) of subjects receiving CMF and 23.6% (45/191) of subjects receiving pHWF were noncompliant. Only 80 to 82 children per group consumed the allocated formula for 2 or more weeks during the first 4 months. The calculated statistical power based on such a small group number is only 12% with the reported 6% difference in prevalence.
      It is unexplained why this report on primary study outcome assessed at age 2 years was only published some 17 years after the end of recruitment, whereas several publications on secondary questions have been previously published.
      • Koplin J.
      • Dharmage S.C.
      • Gurrin L.
      • Osborne N.
      • Tang M.L.
      • Lowe A.J.
      • et al.
      Soy consumption is not a risk factor for peanut sensitization.
      • Hill D.J.
      • Hosking C.S.
      Food allergy and atopic dermatitis in infancy: an epidemiologic study.
      • Hill D.J.
      • Sporik R.
      • Thorburn J.
      • Hosking C.S.
      The association of atopic dermatitis in infancy with immunoglobulin E food sensitization.
      • Lowe A.J.
      • Hosking C.S.
      • Bennett C.M.
      • Carlin J.B.
      • Abramson M.J.
      • Hill D.J.
      • et al.
      Skin prick test can identify eczematous infants at risk of asthma and allergic rhinitis.
      • Lowe A.J.
      • Carlin J.B.
      • Bennett C.M.
      • Abramson M.J.
      • Hosking C.S.
      • Hill D.J.
      • et al.
      Atopic disease and breast-feeding—cause or consequence?.
      • Lowe A.J.
      • Abramson M.J.
      • Hosking C.S.
      • Carlin J.B.
      • Bennett C.M.
      • Dharmage S.C.
      • et al.
      The temporal sequence of allergic sensitization and onset of infantile eczema.
      The authors postulate a publication bias of the Cochrane review supporting the preventive use of pHWF in infants with a family risk of allergy.
      • Osborn D.A.
      • Sinn J.
      Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants.
      They fail to cite 2 further meta-analyses on the subject
      • Szajewska H.
      • Horvath A.
      Meta-analysis of the evidence for a partially hydrolyzed 100% whey formula for the prevention of allergic diseases.
      • Alexander D.D.
      • Cabana M.D.
      Partially hydrolyzed 100% whey protein infant formula and reduced risk of atopic dermatitis: a meta-analysis.
      and that the Cochrane review excluded their study because of excessive randomization losses (38%), which are not reported in the present publication.
      The reported study results and the authors' conclusions do not provide a sufficient basis to change the evidence-based recommendations for infant feeding strategies to reduce allergy risk.

      Additional comments

      According to the retrospective trial registration of the Melbourne Allergy Cohort Study (ACTRN12609000734268, registered on 25.08.2009, http://www.anzctr.org.au), the primary outcome of the study (allergic manifestations, such as eczema, food reactions, and urticaria) was assessed by means of telephone interviews with parents. The present publication reported that a case definition was based on doctor-diagnosed eczema or any rash that was treated with a topical steroid preparation, excluding a rash that only affected the scalp or nappy region.
      • Lowe A.J.
      • Hosking C.S.
      • Bennett C.M.
      • Allen K.J.
      • Axelrad C.
      • Carlin J.B.
      • et al.
      Effect of a partially hydrolyzed whey infant formula at weaning on risk of allergic disease in high-risk children: a randomized controlled trial.
      In contrast, the authors reported using different case definitions for eczema in previous publications on this cohort, such as at least 8 days
      • Lowe A.J.
      • Hosking C.S.
      • Bennett C.M.
      • Allen K.J.
      • Axelrad C.
      • Carlin J.B.
      • et al.
      Effect of a partially hydrolyzed whey infant formula at weaning on risk of allergic disease in high-risk children: a randomized controlled trial.
      or at least 10 days
      • von Berg A.
      • Koletzko S.
      • Grubl A.
      • Filipiak-Pittroff B.
      • Wichmann H.E.
      • Bauer C.P.
      • et al.
      The effect of hydrolyzed cow's milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial.
      of steroid treatment. Many parents could not recall whether their doctor had mentioned the word “eczema.”
      • Lowe A.J.
      • Hosking C.S.
      • Bennett C.M.
      • Allen K.J.
      • Axelrad C.
      • Carlin J.B.
      • et al.
      Effect of a partially hydrolyzed whey infant formula at weaning on risk of allergic disease in high-risk children: a randomized controlled trial.
      Different numbers are reported in the different publications. For example, in the 2007 publication, it was stated that “50 had insufficient data to determine whether they had eczema during the first year of life,”
      • Lowe A.J.
      • Hosking C.S.
      • Bennett C.M.
      • Carlin J.B.
      • Abramson M.J.
      • Hill D.J.
      • et al.
      Skin prick test can identify eczematous infants at risk of asthma and allergic rhinitis.
      whereas the recent article states that 45 children (620-575 children) had insufficient data and therefore did not enter final analysis.
      • Lowe A.J.
      • Hosking C.S.
      • Bennett C.M.
      • Allen K.J.
      • Axelrad C.
      • Carlin J.B.
      • et al.
      Effect of a partially hydrolyzed whey infant formula at weaning on risk of allergic disease in high-risk children: a randomized controlled trial.
      Similarly, the definition on food reaction was based on parental reporting of development of a skin rash, a flare of pre-existing eczema, signs of anaphylaxis, or vomiting. It is well known that parental reporting leads to a marked overestimation of food allergy prevalence.
      • Rona R.J.
      • Keil T.
      • Summers C.
      • Gislason D.
      • Zuidmeer L.
      • Sodergren E.
      • et al.
      The prevalence of food allergy: a meta-analysis.
      In contrast, in the German Infant Nutritional Intervention study all outcome items were fixed in a study manual before recruitment. The children were seen 6 times within the first 2 years of life, with extra visits in case of suspected allergic manifestation.
      • von Berg A.
      • Koletzko S.
      • Grubl A.
      • Filipiak-Pittroff B.
      • Wichmann H.E.
      • Bauer C.P.
      • et al.
      The effect of hydrolyzed cow's milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial.
      • von Berg A.
      • Koletzko S.
      • Filipiak-Pittroff B.
      • Laubereau B.
      • Gruebl A.
      • Wichmann H.E.
      • et al.
      Certain hydrolyzed formulas reduce the incidence of atopic dermatitis, but not of asthma: three year results of the GINI-Study.
      If eczema was identified by the study physician, a specialist in allergy who was blinded to any information on that child assessed the morphology of the skin lesions and the location/spreading, severity, subjective symptoms, and duration with a SCORAD score.
      European Task Force on Atopic Dermatitis
      Severity scoring of atopic dermatitis.
      The persistence of skin lesions was documented in parental diaries on a weekly basis for the first 6 months of life and monthly thereafter. Diagnosis of atopic dermatitis was based on an algorithm with the requirement that 2 physicians confirmed skin lesions plus itching or use of steroid/antihistamines in addition to a documented persistence of dermatitis for more than 14 days or recurrent lesions. Case definitions for urticaria and food allergy were based on a meaningful allergen elimination and challenge procedure.
      • von Berg A.
      • Koletzko S.
      • Grubl A.
      • Filipiak-Pittroff B.
      • Wichmann H.E.
      • Bauer C.P.
      • et al.
      The effect of hydrolyzed cow's milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial.
      Table E1Comparison between the GINI study
      • von Berg A.
      • Koletzko S.
      • Grubl A.
      • Filipiak-Pittroff B.
      • Wichmann H.E.
      • Bauer C.P.
      • et al.
      The effect of hydrolyzed cow's milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial.
      and MACS
      • Lowe A.J.
      • Hosking C.S.
      • Bennett C.M.
      • Allen K.J.
      • Axelrad C.
      • Carlin J.B.
      • et al.
      Effect of a partially hydrolyzed whey infant formula at weaning on risk of allergic disease in high-risk children: a randomized controlled trial.
      regarding recruitment, study characteristics, and definitions of outcome parameters
      GINI (n = 2252)MACS (n = 620)
      Recruitment years1995-19981990-1994
      At-risk childrenYesYes
      Control formulaCMFCMF
      InterventionpHWF, eHWF, eHCFpHWF, soy formula
      Intervention period6 mo12 mo
      Randomization at birthYesYes but later addition of pHWF arm
      BlindingDouble blind, 4 letters for each of the 4 formulas, which were packed in identical tinsSingle blind, no information given whether size and shape of tins were identical
      Allocation concealmentYesNo
      Exclusive breast-feeding until 4 mo42% to 44%∼50%
      Assessment at follow-upWeekly diaries, 0-6 mo; monthly diaries, 7-12 mo; interviews at visits and per telephoneTelephone interview monthly until 64 wk and at 78 and 104 wk
      Physical examination≥6 times within 2 y
      Definition of outcome parametersDefined in study manual before recruitment, strict algorithm for case definitionCase definition changed over the years and between different publications on the same cohort
      EczemaSkin inspection by 2 independent study physicians and SCORAD score,
      • Alexander D.D.
      • Cabana M.D.
      Partially hydrolyzed 100% whey protein infant formula and reduced risk of atopic dermatitis: a meta-analysis.
      symptoms, and medication
      Parental reporting by telephone
      UrticariaTwo times by the same food, elimination/challenge procedureParental reporting by telephone
      Food allergyElimination/challenge procedureParental reporting by telephone
      Specific IgESpecific IgE in serum at 4, 12, and 36 moSkin prick tests at 6, 12, and 24 mo
      Eczema in ITT at 2 y in CMF16.2%43.0%
      Eczema in ITT at 2 y in pHWF14.9%48.7%
      Sensitization to milk at 12 mo4.4%5.8%
      The cumulative prevalence of eczema at 2 years of age was 2.7 to 3.3 times higher in MACS compared with that seen in the GINI study, with similar rates for milk sensitization.
      eHCF, Extensively hydrolyzed casein formula; eHWF, extensively hydrolyzed whey formula; GINI, German Infant Nutritional Intervention; ITT, intention-to-treat population; MACS, Melbourne Allergy Cohort Study.

      References

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        • et al.
        Effect of a partially hydrolyzed whey infant formula at weaning on risk of allergic disease in high-risk children: a randomized controlled trial.
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        Meta-analysis of the evidence for a partially hydrolyzed 100% whey formula for the prevention of allergic diseases.
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