Correspondence
References 1. Soares-Weiser K, Takwoingi Y, Panesar SS, Muraro A, Werfel T, Hoffmann-Sommergruber K et al. The diagnosis of food allergy: a systematic review and meta-analysis. Allergy 2014;69:76–86. 2. Soares-Weiser K, Panesar SS, Rader T, Takwoingi Y, Werfel T, Muraro A et al. The diagnosis of food allergy: protocol for a systematic review. Clin Transl. Allergy 2013;3:18. 3. Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107:891–896. 4. Sampson HA, Albergo R. Comparison of results of skin tests, RAST, and double-blind,
placebo-controlled food challanges in children with atopic dermatitis. J Allergy Clin Immunol 1984;74:26–33. 5. Sampson HA, Ho DG. Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents. J Allergy Clin Immunol 1997;100:444–451. 6. Ott H, Baron J, Heise R, Stanzel S, Merk H, Niggemann B et al. Clinical usefulness of microarray-based IgE detection in children with suspected food allergy. Allergy 2007;62:63–63. 7. Macaskill P, Gatsonis C, Deeks JJ, Harbord RM, Takwoingi Y. Chapter 10: Analysing
and Presenting Results. In: Deeks JJ, Bossuyt PM, Gatsonis C editors. Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy Version 1.0. The Cochrane Collaboration, 2010. Available from: srdta.cochrane. org/. 8. Leeflang MM, Deeks JJ, Gatsonis C, Bossuyt PMM; Cochrane Diagnostic Test Accuracy Working Group. Systematic reviews of diagnostic test accuracy. Ann Intern Med 2008;149:889–897.
Primary prevention of food allergy in children and adults DOI:10.1111/all.12417
de Silva et al. (1) summarized the literature on primary prevention of food allergy, concluding that: there was evidence to recommend avoiding cow’s milk and substituting with extensively or partially hydrolyzed whey or casein formulas for infants at high risk for the first 4 months
We believe this conclusion is premature and does not appropriately reflect the level of evidence currently available (2) for the following reasons. Firstly, the authors based these comments on studies that had imprecise measures of food allergy. These studies used either aggregate outcomes (including all atopic disease in one outcome variable) or heterogeneous outcomes varying from self-report (well known to overestimate food allergy) to the gold standard of challenge-proven food allergy. Of the six original RCTs included in this review which both had a food allergy outcome and compared either extensively or partially hydrolyzed formula with cow’s milk formula, five studies comprising 1145 children showed no significant difference and only one study comprising 58 children showed reduced cow’s milk sensitivity associated with hydrolyzed formula at 6 months of age. Furthermore, inclusion of studies using parent report and other non-gold standard measures severely limits the robustness of the findings when these studies are summarized in systematic reviews (3). Neither of the two systematic reviews (4, 5) cited in support of extensively hydrolyzed formula had a specific food allergy or food sensitization outcome; the outcomes instead were measured as ‘atopic disease’. Secondly, conclusions drawn from the two systematic reviews cited to support the use of partially hydrolyzed
formula for food allergy prevention are questionable. One of the systematic reviews does not advocate the use of partially hydrolyzed formulas for food allergy prevention. Rather, after noting the poor quality and heterogeneity of the studies within the review, the authors recommend that further trials of a larger and better quality are required before firm conclusions can be drawn (6). Although the second review (7) concluded that the use of partially hydrolyzed formula instead of standard formula was effective in allergy prevention, when the results were broken down by type of allergy, this was only true for atopic dermatitis/eczema. In this review, evidence to support the use of partially hydrolyzed formula for the prevention of food allergy came from a single RCT that included only 67 exclusively formula-fed infants. In this study, differences in atopic symptoms were found only for the first 6 months of a 5-year follow-up. In contrast, neither of the two largest RCTs investigating this question, the Melbourne Atopy Cohort Study and the German Infant Nutritional Intervention, have shown a reduction in food allergy associated with the use of hydrolyzed formulas. Finally, the majority of these studies are underpowered. The number of participants for individual studies varied from 58 to 2252; however, these were then divided into three or more groups for different formula arms, and positive outcomes within these groups were rare. To have 80% power to detect a reduction of at least 30% in food allergy between different formula groups, assuming a food allergy prevalence of 10%, you would require 1422 participants in each formula group. As any recommendation for the prevention of allergic disease, including food allergy, has the potential to affect
Allergy 69 (2014) 969–973 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
971
Correspondence
thousands, if not millions, of infants, care should be exercised in conclusions based on heterogeneous studies that are not adequately powered. Despite the summary presented by de Silva et al., there is still inadequate evidence from appropriately powered, well-conducted randomized controlled trials to advocate the widespread use of hydrolyzed formulas, whether partially or extensively hydrolyzed, for the prevention of food allergy.
C. J. Lodge1, A. J. Lowe1,2 and K. J. Allen2,3,4 School of Population and Global Health, University of Melbourne; 2 Murdoch Children’s Research Institute, Royal Children’s Hospital; 3 Department of Allergy and Clinical Immunology, Royal Children’s Hospital; 4 Department of Paediatrics, University of Melbourne, Parkville, Vic., Australia E-mail: [email protected]
1
Conflicts of interest Prof. Allen has received speaker honorarium from Abott, Pfizer, Nutricia and Alphapharm. AL and CL have no conflicts of interest. References 1. de Silva D, Geromi M, Halken S, Host A, Panesar SS, Muraro A et al. Primary prevention of food allergy in children and adults: systematic review. Allergy 2014;69:581–589. 2. Lodge CJ, Allen KJ, Lowe AJ, Dharmage SC. Overview of evidence in prevention and aetiology of food allergy: a review of systematic reviews. Int J Environ Res Public Health 2013;10:5781–5806. 3. Burks AW, Tang M, Sicherer S, Muraro A, Eigenmann PA, Ebisawa M et al. ICON:
food allergy. J Allergy Clin Immunol 2012;129:906–920. 4. Hays T, Wood RA. A systematic review of the role of hydrolyzed infant formulas in allergy prevention. Arch Pediatr Adolesc Med 2005;159:810–816. 5. van Odijk J, Kull I, Borres MP, Brandtzaeg P, Edberg U, Hanson LA et al. Breastfeeding and allergic disease: a multidisciplinary review of the literature (1966–2001) on the mode of early feeding in infancy and its impact on
later atopic manifestations. Allergy 2003;58:833–843. 6. Osborn DA, Sinn J. Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev 2006;CD003664. 7. Szajewska H, Horvath A. Meta-analysis of the evidence for a partially hydrolyzed 100% whey formula for the prevention of allergic diseases. Curr Med Res Opin 2010;26:423–437.
REPLY
We agree with the sentiments expressed by Lodge et al. that the data in relation to avoiding cow’s milk and substituting this with extensively or partially hydrolysed whey or casein formulas in high risk infants who are unable to breast-feed need to be interpreted with caution. It is for this reason that we emphasized the modest quantity and quality of the evidence, and the need for further research (1). Whilst we recognize the problems with drawing definitive conclusions from the current evidence base, given that food allergy now affects so many children (2), it is also important to take a practical approach to interpreting these data such that the evidence has the potential to help clinicians. Based on the totality of evidence uncovered, including data on parental-reported and other related atopic outcomes (e.g. atopic eczema/dermatitis) (3), and the absence of evidence of harms associated with this preventive approach, there is we believe limited evidence that some children may be helped by the suggested approach (1). Our interpretation of these data is in keeping with previous systematic reviews on this subject including, in particular, the Cochrane systematic review by Osbon and Sinn, which concluded that: ‘In high risk infants who are unable to be completely breast fed, there is limited evidence that prolonged feeding with a hydrolysed formula
972
compared to a cow’s milk formula reduces infant and childhood allergy and infant CMA’ (4). Overall, however, we agree that there is a need for larger, more definitive, randomized controlled trials investigating the effectiveness of this approach as a primary prevention strategy, which is judged by its impact on the full spectrum of relevant objective (e.g. oral food challenge), subjective (e.g. parentalreported), health economic and safety outcomes. Our article was bound by the word limit for journal articles, but these and other issues are more fully covered in the fuller version of this review, which will shortly be published on the EAACI website. Conflicts of interest Debra de Silva and Sukhmeet Panesar have no conflict of interests in relation to this document. Graham Roberts has provided scientific advice for Danone and ALK-Abell o; Thermo Fisher and ALK-Abell o have provided consumables for his research activities. Susanne Halken has provided scientific advice for ALK-Abell o. Arne Høst has provided scientific advice for ALK-Abell o and Danone. Kate Grimshaw has provided scientific advice for Nutricia Ltd. Carina Venter has produced educational material for
Allergy 69 (2014) 969–973 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Correspondence
Danone, Mead Johnson and Nestle and has received research funding from Thermo Fisher, Danone and Mead Johnson. Aziz Sheikh has provided scientific advice to ALK-Abell o, Meda, Lincoln Medical, Thermo Fisher, Pfizer, and Stallergenes; he is on the Anaphylaxis Campaign UK’s Scientific Committee, World Allergy Organization’s Anaphylaxis Special Committee, UK Resuscitation Council’s Anaphylaxis Committee, and the BSACI’s Standard of Care Committee. Antonella Muraro has provided scientific advice for Meda. D. de Silva1, G. Roberts2,3,4, S. Halken5, A. Høst6, K. Grimshaw7, C. Venter2, S. Panesar8, A. Sheikh8,9,10 and A. Muraro11 1 The Evidence Centre, London; 2 David Hide Asthma and Allergy Research Centre, St Mary’s Hospital, Newport, Isle of Wight; 3 NIHR Southampton Respiratory Biomedical Research Unit, University of Southampton and University Hospital Southampton NHS Foundation Trust;
4
Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, UK; 5 Odense University Hospital, Odense C; 6 Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark; 7 Clinical and Experimental Sciences Academic Unit, University of Southampton Faculty of Medicine, Southampton; 8 Allergy & Respiratory Research Group, Centre for Population Health Sciences, The University of Edinburgh, UK; 9 Division of General Internal Medicine and Primary Care, Brigham and Women’s Hospital; 10 Harvard Medical School, Boston, MA, USA; 11 Department of Mother and Child Health Referral Centre Food Allergy Diagnosis and Treatment, Veneto Region, University of Padua, Padua, Italy E-mail: [email protected]
References 1. de Silva D, Geromi M, Halken S, Host A, Panesar SS, Muraro A et al. Primary prevention of food allergy in children and adults: systematic review. Allergy 2014;69:581–589. 2. Nwaru BI, Hickstein L, Panesar SS, Muraro A, Werfel T, Cardona V et al. The epidemiology of food allergy in Europe: a systematic
review and meta-analysis. Allergy 2014;69: 62–75. 3. von Berg A, Filipiak-Pittroff B, Kr€amer U, Link E, Bollrath C, Brockow I et al. Preventive effect of hydrolyzed infant formulas persists until age 6 years: long-term results from the German Infant Nutritional Intervention
Allergy 69 (2014) 969–973 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Study (GINI). J Allergy Clin Immunol 2008;121:1442–1447. 4. Osborn DA, Sinn JKH. Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev 2006; CD003664.
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References 1. Soares-Weiser K, Takwoingi Y, Panesar SS, Muraro A, Werfel T, Hoffmann-Sommergruber K et al. The diagnosis of food allergy: a systematic review and meta-analysis. Allergy 2014;69:76–86. 2. Soares-Weiser K, Panesar SS, Rader T, Takwoingi Y, Werfel T, Muraro A et al. The diagnosis of food allergy: protocol for a systematic review. Clin Transl. Allergy 2013;3:18. 3. Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107:891–896. 4. Sampson HA, Albergo R. Comparison of results of skin tests, RAST, and double-blind,
placebo-controlled food challanges in children with atopic dermatitis. J Allergy Clin Immunol 1984;74:26–33. 5. Sampson HA, Ho DG. Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents. J Allergy Clin Immunol 1997;100:444–451. 6. Ott H, Baron J, Heise R, Stanzel S, Merk H, Niggemann B et al. Clinical usefulness of microarray-based IgE detection in children with suspected food allergy. Allergy 2007;62:63–63. 7. Macaskill P, Gatsonis C, Deeks JJ, Harbord RM, Takwoingi Y. Chapter 10: Analysing
and Presenting Results. In: Deeks JJ, Bossuyt PM, Gatsonis C editors. Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy Version 1.0. The Cochrane Collaboration, 2010. Available from: srdta.cochrane. org/. 8. Leeflang MM, Deeks JJ, Gatsonis C, Bossuyt PMM; Cochrane Diagnostic Test Accuracy Working Group. Systematic reviews of diagnostic test accuracy. Ann Intern Med 2008;149:889–897.
Primary prevention of food allergy in children and adults DOI:10.1111/all.12417
de Silva et al. (1) summarized the literature on primary prevention of food allergy, concluding that: there was evidence to recommend avoiding cow’s milk and substituting with extensively or partially hydrolyzed whey or casein formulas for infants at high risk for the first 4 months
We believe this conclusion is premature and does not appropriately reflect the level of evidence currently available (2) for the following reasons. Firstly, the authors based these comments on studies that had imprecise measures of food allergy. These studies used either aggregate outcomes (including all atopic disease in one outcome variable) or heterogeneous outcomes varying from self-report (well known to overestimate food allergy) to the gold standard of challenge-proven food allergy. Of the six original RCTs included in this review which both had a food allergy outcome and compared either extensively or partially hydrolyzed formula with cow’s milk formula, five studies comprising 1145 children showed no significant difference and only one study comprising 58 children showed reduced cow’s milk sensitivity associated with hydrolyzed formula at 6 months of age. Furthermore, inclusion of studies using parent report and other non-gold standard measures severely limits the robustness of the findings when these studies are summarized in systematic reviews (3). Neither of the two systematic reviews (4, 5) cited in support of extensively hydrolyzed formula had a specific food allergy or food sensitization outcome; the outcomes instead were measured as ‘atopic disease’. Secondly, conclusions drawn from the two systematic reviews cited to support the use of partially hydrolyzed
formula for food allergy prevention are questionable. One of the systematic reviews does not advocate the use of partially hydrolyzed formulas for food allergy prevention. Rather, after noting the poor quality and heterogeneity of the studies within the review, the authors recommend that further trials of a larger and better quality are required before firm conclusions can be drawn (6). Although the second review (7) concluded that the use of partially hydrolyzed formula instead of standard formula was effective in allergy prevention, when the results were broken down by type of allergy, this was only true for atopic dermatitis/eczema. In this review, evidence to support the use of partially hydrolyzed formula for the prevention of food allergy came from a single RCT that included only 67 exclusively formula-fed infants. In this study, differences in atopic symptoms were found only for the first 6 months of a 5-year follow-up. In contrast, neither of the two largest RCTs investigating this question, the Melbourne Atopy Cohort Study and the German Infant Nutritional Intervention, have shown a reduction in food allergy associated with the use of hydrolyzed formulas. Finally, the majority of these studies are underpowered. The number of participants for individual studies varied from 58 to 2252; however, these were then divided into three or more groups for different formula arms, and positive outcomes within these groups were rare. To have 80% power to detect a reduction of at least 30% in food allergy between different formula groups, assuming a food allergy prevalence of 10%, you would require 1422 participants in each formula group. As any recommendation for the prevention of allergic disease, including food allergy, has the potential to affect
Allergy 69 (2014) 969–973 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
971
Correspondence
thousands, if not millions, of infants, care should be exercised in conclusions based on heterogeneous studies that are not adequately powered. Despite the summary presented by de Silva et al., there is still inadequate evidence from appropriately powered, well-conducted randomized controlled trials to advocate the widespread use of hydrolyzed formulas, whether partially or extensively hydrolyzed, for the prevention of food allergy.
C. J. Lodge1, A. J. Lowe1,2 and K. J. Allen2,3,4 School of Population and Global Health, University of Melbourne; 2 Murdoch Children’s Research Institute, Royal Children’s Hospital; 3 Department of Allergy and Clinical Immunology, Royal Children’s Hospital; 4 Department of Paediatrics, University of Melbourne, Parkville, Vic., Australia E-mail: [email protected]
1
Conflicts of interest Prof. Allen has received speaker honorarium from Abott, Pfizer, Nutricia and Alphapharm. AL and CL have no conflicts of interest. References 1. de Silva D, Geromi M, Halken S, Host A, Panesar SS, Muraro A et al. Primary prevention of food allergy in children and adults: systematic review. Allergy 2014;69:581–589. 2. Lodge CJ, Allen KJ, Lowe AJ, Dharmage SC. Overview of evidence in prevention and aetiology of food allergy: a review of systematic reviews. Int J Environ Res Public Health 2013;10:5781–5806. 3. Burks AW, Tang M, Sicherer S, Muraro A, Eigenmann PA, Ebisawa M et al. ICON:
food allergy. J Allergy Clin Immunol 2012;129:906–920. 4. Hays T, Wood RA. A systematic review of the role of hydrolyzed infant formulas in allergy prevention. Arch Pediatr Adolesc Med 2005;159:810–816. 5. van Odijk J, Kull I, Borres MP, Brandtzaeg P, Edberg U, Hanson LA et al. Breastfeeding and allergic disease: a multidisciplinary review of the literature (1966–2001) on the mode of early feeding in infancy and its impact on
later atopic manifestations. Allergy 2003;58:833–843. 6. Osborn DA, Sinn J. Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev 2006;CD003664. 7. Szajewska H, Horvath A. Meta-analysis of the evidence for a partially hydrolyzed 100% whey formula for the prevention of allergic diseases. Curr Med Res Opin 2010;26:423–437.
REPLY
We agree with the sentiments expressed by Lodge et al. that the data in relation to avoiding cow’s milk and substituting this with extensively or partially hydrolysed whey or casein formulas in high risk infants who are unable to breast-feed need to be interpreted with caution. It is for this reason that we emphasized the modest quantity and quality of the evidence, and the need for further research (1). Whilst we recognize the problems with drawing definitive conclusions from the current evidence base, given that food allergy now affects so many children (2), it is also important to take a practical approach to interpreting these data such that the evidence has the potential to help clinicians. Based on the totality of evidence uncovered, including data on parental-reported and other related atopic outcomes (e.g. atopic eczema/dermatitis) (3), and the absence of evidence of harms associated with this preventive approach, there is we believe limited evidence that some children may be helped by the suggested approach (1). Our interpretation of these data is in keeping with previous systematic reviews on this subject including, in particular, the Cochrane systematic review by Osbon and Sinn, which concluded that: ‘In high risk infants who are unable to be completely breast fed, there is limited evidence that prolonged feeding with a hydrolysed formula
972
compared to a cow’s milk formula reduces infant and childhood allergy and infant CMA’ (4). Overall, however, we agree that there is a need for larger, more definitive, randomized controlled trials investigating the effectiveness of this approach as a primary prevention strategy, which is judged by its impact on the full spectrum of relevant objective (e.g. oral food challenge), subjective (e.g. parentalreported), health economic and safety outcomes. Our article was bound by the word limit for journal articles, but these and other issues are more fully covered in the fuller version of this review, which will shortly be published on the EAACI website. Conflicts of interest Debra de Silva and Sukhmeet Panesar have no conflict of interests in relation to this document. Graham Roberts has provided scientific advice for Danone and ALK-Abell o; Thermo Fisher and ALK-Abell o have provided consumables for his research activities. Susanne Halken has provided scientific advice for ALK-Abell o. Arne Høst has provided scientific advice for ALK-Abell o and Danone. Kate Grimshaw has provided scientific advice for Nutricia Ltd. Carina Venter has produced educational material for
Allergy 69 (2014) 969–973 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Correspondence
Danone, Mead Johnson and Nestle and has received research funding from Thermo Fisher, Danone and Mead Johnson. Aziz Sheikh has provided scientific advice to ALK-Abell o, Meda, Lincoln Medical, Thermo Fisher, Pfizer, and Stallergenes; he is on the Anaphylaxis Campaign UK’s Scientific Committee, World Allergy Organization’s Anaphylaxis Special Committee, UK Resuscitation Council’s Anaphylaxis Committee, and the BSACI’s Standard of Care Committee. Antonella Muraro has provided scientific advice for Meda. D. de Silva1, G. Roberts2,3,4, S. Halken5, A. Høst6, K. Grimshaw7, C. Venter2, S. Panesar8, A. Sheikh8,9,10 and A. Muraro11 1 The Evidence Centre, London; 2 David Hide Asthma and Allergy Research Centre, St Mary’s Hospital, Newport, Isle of Wight; 3 NIHR Southampton Respiratory Biomedical Research Unit, University of Southampton and University Hospital Southampton NHS Foundation Trust;
4
Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, UK; 5 Odense University Hospital, Odense C; 6 Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark; 7 Clinical and Experimental Sciences Academic Unit, University of Southampton Faculty of Medicine, Southampton; 8 Allergy & Respiratory Research Group, Centre for Population Health Sciences, The University of Edinburgh, UK; 9 Division of General Internal Medicine and Primary Care, Brigham and Women’s Hospital; 10 Harvard Medical School, Boston, MA, USA; 11 Department of Mother and Child Health Referral Centre Food Allergy Diagnosis and Treatment, Veneto Region, University of Padua, Padua, Italy E-mail: [email protected]
References 1. de Silva D, Geromi M, Halken S, Host A, Panesar SS, Muraro A et al. Primary prevention of food allergy in children and adults: systematic review. Allergy 2014;69:581–589. 2. Nwaru BI, Hickstein L, Panesar SS, Muraro A, Werfel T, Cardona V et al. The epidemiology of food allergy in Europe: a systematic
review and meta-analysis. Allergy 2014;69: 62–75. 3. von Berg A, Filipiak-Pittroff B, Kr€amer U, Link E, Bollrath C, Brockow I et al. Preventive effect of hydrolyzed infant formulas persists until age 6 years: long-term results from the German Infant Nutritional Intervention
Allergy 69 (2014) 969–973 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Study (GINI). J Allergy Clin Immunol 2008;121:1442–1447. 4. Osborn DA, Sinn JKH. Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev 2006; CD003664.
973
