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Reply To the Editor: We thank Szajewska et al1 for raising important issues in the discussion about the use of probiotics with the intent of prevention of development of allergies in children. Please allow us to begin by clarifying that in our systematic review we attempted only to summarize the currently available evidence about the health effects of probiotics in this setting and we deliberately refrained from making any recommendations for clinical practice. Specific recommendations were provided by the World Allergy Organization (WAO) guideline panel in a separate document.2 We believe that authors of systematic reviews should not make clinical recommendations. They typically review only the studies of health effects of interventions and do not seek information about other factors required to make a decision whether or not to use an intervention, for example, patients’ values and preferences, acceptability, resource requirements, and feasibility of implementation. This point of view is shared by Cochrane as expressed in the Cochrane Handbook for Systematic Reviews of Interventions (chapter 12: Interpreting results and drawing conclusions, 12.7.2 Implications for practice).3 Thus, allow us to discuss only the evidence synthesis and abstain from discussion of clinical recommendations and implications for practice. Szajewska et al1 pointed out that our review did not answer a few specific questions: which probiotics should be used, in what dose, and when should the probiotic supplementation be stopped. Our review was designed to summarize the evidence required to answer the questions determined by the WAO guideline panel. Both the WAO guidelines and our systematic review did not intend to be comprehensive and answer all questions in this area. As much as we agree with Szajewska et al1 that the answer to the above questions would be beneficial, it was either beyond the scope of our project or impossible to answer on the basis of currently available data, which we discuss in the next paragraph. Any clinical practice guidelines should be reviewed and updated once new evidence becomes available. We are confident that the WAO guideline panel will address these and similar questions in the update of the guidelines if they determine that clinicians seek advice in this area and the information to answer them is available. Szajewska et al1 suggest that we should have refrained from pooling data on different probiotics to avoid misleading consumers, parents, and health care professionals. Our choice to combine the results of all studies followed a standard approach in systematic reviews designed to summarize information for decision making by attempting a meta-analysis of all studies and investigating heterogeneity. We saw inconsistency not only in results among studies of different probiotics but also among studies that used the same strain (Fig 1). In our view, the magnitude of heterogeneity did not provide a compelling reason not to combine the results. We recognize that decisions concerning which results should or should not be combined are inevitably subjective and consensus may be difficult to reach in many cases. We agree with Szajewska et al1 that the conclusion that all probiotics are equal would be premature. However, on the basis of available data from randomized trials in humans, we also believe that it is too early for an opposite conclusion, that is, that probiotics differ in their effect on the development of eczema. The available evidence from randomized trials does
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not allow excluding the possibility that the effect of probiotics is a class effect or that, indeed, there are differences among the strains. We also emphasized in our review that because of the very inconsistency in study results and other limitations one might have only very low confidence that observed effects reflect the actual effect of each and all probiotics. Furthermore, we identified a study that directly compared the effects of 2 strains of probiotics: Lactobacillus rhamnosus HN001 with Bifidobacterium animalis subsp lactis HN019.4 This study found a reduced risk of developing eczema in those children who received HN001 (hazard ratio, 0.57; 95% CI, 0.39-0.83). The estimate of the effect of HN019 was not statistically significant; however, point estimate and the CI did not exclude an appreciable benefit (hazard ratio, 0.79; 95% CI, 0.56-1.11). Thus, on the basis of currently available data from experimental studies in humans, we believe that one cannot confidently determine whether the effects of various strains are similar or whether there are some strains whose effects are different (larger or smaller) from those of other strains. We share the view of Szajewska et al1 that data on the effects of individual probiotic strains are needed. Until they become available, clinicians, parents, and others will need to make decisions under uncertainty about the magnitude of benefits from different strains of probiotics. Carlos A. Cuello-Garcia, MDa,b Jan L. Brozek, _ MD, PhDa,c Alessandro Fiocchi, MDd Ruby Pawankar, MD, PhDe Juan Jos e Yepes-Nu~ nez, MD, MSca,f Luigi Terracciano, MDg Shreyas Gandhi, BHScc,h Arnav Agarwal, BHScc,h Yuan Zhang, MSca Holger J. Sch€ unemann, MD, MSc, PhDa,c From athe Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada; bthe Tecnologico de Monterrey School of Medicine, Monterrey, Mexico; cthe Department of Medicine, McMaster University, Hamilton, Ontario, Canada; dthe Pediatric Hospital Bambino Gesu, Vatican City; ethe Department of Pediatrics, Nippon Medical School, Tokyo, Japan; fthe School of Medicine, University of Antioquia, Medellın, Colombia; gthe Department of Child and Maternal Medicine, University of Milan Medical School at the Melloni Hospital, Milan, Italy; and hthe Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada E-mail:
[email protected]. The World Allergy Organization supported this study. Disclosure of potential conflict of interest: C. A. Cuello-Garcia has received consultancy fees and travel support, paid through McMaster University, from the World Allergy Organization (WAO). J. L. Bro_zek has received research support paid to McMaster University and travel support from the WAO. A. Fiocchi has received travel support from the WAO; has received consultancy fees from GlaxoSmithKline; and has received travel support and lecture fees from Danone. R. Pawankar is employed by Nippon Medical School in Tokyo; has received research support from the Ministry of Education of Japan; and receives royalties from Springer. J. J. Yepes-Nu~nez has received consultancy fees and fees for the creation of WAO clinical practice guidelines paid to McMaster University from the WAO and has received travel support from the WAO. L. Terracciano has received travel support from the WAO and has received consultancy fees from Heinz-Plada. S. Gandhi and Y. Zhang have received consultancy fees paid to McMaster University from the WAO and travel support from the WAO. H. J. Sch€unemann has received consultancy fees, travel support, and payment for systematic reviews from the WAO. A. Agarwal declares no relevant conflicts of interest.
REFERENCES 1. Szajewska H, Shamir R, Turck D, van Goudoever JB, Mihatsch WA, Fewtrell M. Recommendations on probiotics in allergy prevention should not be based on pooling data from different strains. J Allergy Clin Immunol 2015;136:1422.
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FIG 1. Forest plot of comparison probiotic vs placebo. Different probiotic strains portrayed as subgroups. CUL34 1 CUL20 1 CUL61 1 CUL08: Bifidobacterium animalis subsp lactis (CUL34) 1 Bifidobacterium bifidum (CUL20) 1 Lactobacillus salivarus (CUL61) 1 Lactobacillus paracasei (CUL08). LGG 1 Bb-12 1 La-5: Lactobacillus rhamnosus GG (LGG) 1 Bifidobacterium animalis subsp lactis Bb-12 (Bb-12) 1 Lactobacillus
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2. Fiocchi A, Pawankar R, Cuello-Garcia C, Ahn K, Al-Hammadi S, Agarwal A, et al. World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics. World Allergy Organ J 2015;8:4. 3. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration; 2011. Available at: www.cochrane-handbook.org. 4. Wickens K, Black PN, Stanley TV, Mitchell E, Fitzharris P, Tannock GW, et al. A differential effect of 2 probiotics in the prevention of eczema and atopy: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol 2008;122:788-94. Available online August 30, 2015. http://dx.doi.org/10.1016/j.jaci.2015.07.021
Impact of sex on anaphylaxis severity—data from the Anaphylaxis Registry
To the Editor: We read with great interest the article ‘‘Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production’’ by Hox et al.1 Therein, the authors provide experimental evidence that female mice exhibit more severe anaphylactic reactions than do their male counterparts and offer mechanistic insights by showing that estrogen promotes vascular leakage during an anaphylactic event via enhanced nitric oxide production. This animal study prompted us to analyze cases from the Anaphylaxis Registry2 in which data from anaphylactic patients are collected via an online questionnaire in a standardized manner. We focused on sex differences by designing an ordinal logistic regression model. A cohort of 5765 patients (2792 males and 2973 females) was stratified into different severity grades. The severity grades were according to Brown3 (3 levels) and Ring and Messmer4 (4 levels), respectively. To better compare our results with those of Hox et al,1 we divided patients into 3 age groups reflecting differences in sex hormone (especially estrogen) levels: prepubertal (aged 0-12 years), premenopausal (aged 13-56 years), and postmenopausal (aged 57 years and older). Our analysis indicated a slightly higher risk of more severe anaphylaxis for males aged 13 to 56 years when compared with age-matched females. Conversely, there were no significant
differences in anaphylaxis severity grades in children younger than 13 years and adults older than 56 years (see Table I). Several reports from the literature are in agreement with our data and suggest that even though the prevalence of anaphylaxis in adults is higher in women than in men,2,5 the opposite picture seems to evolve as far as the severity of anaphylaxis is concerned. Clinical severity of anaphylaxis in the mouse model was determined by a drop in core body temperature. In contrast, the grading systems by Ring and Messmer4 or Brown3 consider symptoms from different organ systems, which may differ in their susceptibility to hormonal influences. Moreover, the sensitivity of these scales might not be sufficient to unravel possible sex differences. In addition, in real life, patients are typically sensitized to different allergens exhibiting diverse sensitization patterns. Excluding the impact of possible confounding factors, which are relevant in real life (ie, chronic and acute disease or medication6) from our analysis, we still failed to detect sex differences mirroring those reported by Hox et al1 for mice. Wojciech Francuzik, MD* Maria Nassiri, PhD* Magda Babina, PhD Margitta Worm, MD From the Allergy Center Charite, CCM, Department of Dermatology and Allergy, Charite-Universit€atsmedizin Berlin, Berlin, Germany. E-mail: Margitta.Worm@ charite.de. *These authors contributed equally to this work. M.N. is supported by a grant to M.W. from the German Research Foundation Deutsche Forschungsgemeinschaft (grant no. WO 541/16-1). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. REFERENCES 1. Hox V, Desai A, Bandara G, Gilfillan AM, Metcalfe DD, Olivera A. Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production. J Allergy Clin Immunol 2015;135:729-36.e5. 2. Worm M, Edenharter G, Ru€eff F, Scherer K, Pf€ohler C, Mahler V, et al. Symptom profile and risk factors of anaphylaxis in Central Europe. Allergy 2012;67:691-8. 3. Brown SG. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol 2004;114:371-6. 4. Ring J, Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet 1977;1:466-9. 5. Webb LM, Lieberman P. Anaphylaxis: a review of 601 cases. Ann Allergy Asthma Immunol 2006;97:39-43.
TABLE I. Sex as ordinal logistic regression predictor for severity (according to Ring and Messmer4 and Brown3), ranked by OR with CIs Scale
Group
OR
2.5% CI
97.5% CI
P value
Total
Females (F)
Males (M)
F:M ratio
R&M R&M R&M Brown Brown Brown
Prepubertal Premenopausal Postmenopausal Prepubertal Premenopausal Postmenopausal
1.204 1.269 1.109 2.325 1.407 1.187
0.252 0.999 0.894 0.193 1.085 0.945
6.153 1.609 1.375 14.201 1.818 1.492
.407 .025 .173 .212 .005 .07
1072 3134 1308 1072 3133 1308
341 1794 708 341 1794 708
731 1340 600 731 1339 600
0.466 1.339 1.18 0.466 1.34 1.18
F:M ratio, Total observations (females) divided by total observations (males) of the respective age group; OR, odds ratio for male sex as a predictor of anaphylaxis; R&M, Ring and Messmer scale.
=
acidophilus La-5 (La- 5). LGG 1 Bb-12: Lactobacillus rhamnosus GG (LGG) 1 Bifidobacterium lactis Bb12 (Bb-12). BGN4 1 AD011 1 AD031: Bifidobacterium bifidum (BGN4) 1 Bifidobacterium lactis (AD011) 1 Lactobacillus acidophilus (AD031). LGG 1 DSM 7061 1 DSM 13692 1 DSM 7076: Lactobacillus rhamnosus GG (LGG) 1 Lactobacillus rhamnosus LC705 (DSM 7061) 1 Bifidobacterium breve Bb99 (DSM 13692) 1 Propionibacterium freudenreichii ssp. shermanii JS (DSM 7076). W23 1 W52 1 W58: Bifidobacterium bifidum (W23) 1 Bifidobacterium lactis (W52) [Bifidobacterium infantis] 1 Lactococcus lactis (W58). LPR 1 BL999: Lactobacillus rhamnosus (LPR) 1 Bifidobacterium longum (BL999).
