Dear Editor,
I have read the article titled, "Non-syndromic hyper-IgE in children: A practical approach", by Castagnoli et al with great interest.1 This exciting review article addresses elevated IgE levels not associated with syndromic disorders. While reading this interesting article,1 we observed some omissions in definitions and concepts that made certain points difficult to understand. Clarifying these issues would help readers better understand this review article.1
Hyper-IgE, as mentioned in the article,1 is generally defined as serum IgE levels exceeding 2.000 IU/mL. However, for non-syndromic hyper-IgE in children, should we consider values above 2.000, or values above the upper limit of the range, or values above +2SD? When searching PubMed for “non-syndromic hyper-IgE,” nothing comes up. This needs to be clearly established.
In this article,1 the distinction between elevated IgE and hyper-IgE terms should have been clearly made. Figure 1 and 2 in the article1 support my point. In the captions for Figure 1 and 2, the term “hyper-IgE” is used, while the text above the figure refers to “elevated total serum IgE.” In fact, the article's text also includes a heading titled “Non-syndromic condition associated with elevated serum IgE.” When the term “hyper-IgE” is used, it is generally understood to refer to well-known situations, as is the case with syndromic conditions, rather than nonsyndromic conditions. Ultimately, it would have been better if the article's title had been “Non-syndromic elevated IgE.”
In the article,1 while elevated IgE levels are defined as “mean ± 2SD,” the main text also mentions an age-specific range. It is unclear whether this range refers to values of -2SD and +2SD, or something like the 95% reference range/interval, or the minimum and maximum values.
Although various articles in the literature that investigate and describe this topic (non-syndromic hyper-IgE) provide data on the rates and frequencies of the causes, this review article1 lacks such information. This could be significant for the approach to this condition and the prioritization of evaluations. While a step-by-step approach is described here,1 providing the percentages would have been even more helpful. For example, in a study evaluating 70 patients with elevated IgE levels, the causes were identified as atopic diseases (77%), parasitic diseases (1.5%), malignancy (3%), and HIES (8%), among other causes.2
Although this article1 lists all viral and fungal infections and infestations as causes of elevated IgE levels in Figures 1 and 2, it makes no mention of the relationship between bacterial infections and elevated IgE levels.3
Similarly, the relationship between elevated IgE levels and eosinophilia, as well as the presence and/or absence of these findings, has not been discussed in terms of their role in diagnosing various non-syndromic causes. There are numerous articles in the literature on this topic, particularly regarding immune deficiency and immune dysregulation.4, 5, 6, 7, 8 Furthermore, do elevated eosinophil and IgE levels, once they exceed a certain threshold, suggest the presence of an atopic condition (such as atopic dermatitis, etc.), and is there a relationship between them? Discussing these points could also be beneficial for the reader.9,10
In conclusion, I would like to thank the authors for this high-quality research and its findings, which could contribute to the literature on a topic related to "Non-syndromic hyper-IgE in children" that is not well known and understood, and which could lead to a better understanding of the disorders.
Funding
none.
Author contributions
ÖÖ; has done everything.
Disclosure statement
No GenAI or other AI-assisted Technologies was used.
Declaration of competing interest
None.
Footnotes
Full list of author information is available at the end of the article
References
- 1.Castagnoli R., Pecoraro L., Mastrorilli C., et al. Non-syndromic hyper-IgE in children: a practical approach. World Allergy Organ J. 2026;19(3) doi: 10.1016/j.waojou.2026.101346. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Joshi A.Y., Iyer V.N., Boyce T.G., et al. Elevated serum immunoglobulin E (IgE): when to suspect hyper-IgE syndrome-A 10-year pediatric tertiary care center experience. Allergy Asthma Proc. 2009;30(1):23–27. doi: 10.2500/aap.2009.30.3193. [DOI] [PubMed] [Google Scholar]
- 3.Chiriaco M., Di Matteo G., Conti F., et al. First case of patient with two homozygous mutations in MYD88 and CARD9 genes presenting with pyogenic bacterial ınfections, elevated IgE, and persistent EBV viremia. Front Immunol. 2019 Feb 14;10:130. doi: 10.3389/fimmu.2019.00130. 00130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Oprițescu S., Nițescu G.V., Cîrnațu D., et al. Elevated immunoglobulin E serum levels: possible underlying factors that can cause an inborn error of immunity in the pediatric population with recurrent infections. Antibodies. 2024;13(2):47. doi: 10.3390/antib13020047. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Sutanto H., Adytia G.J., Fetarayani D. Hyper IgE Syndrome: bridging the gap between immunodeficiency, atopy, and allergic diseases. Curr Allergy Asthma Rep. 2025;25(1):17. doi: 10.1007/s11882-025-01196-8. [DOI] [PubMed] [Google Scholar]
- 6.Olbrich P., Ortiz Aljaro P., Freeman A.F. Eosinophilia associated with immune deficiency. J Allergy Clin Immunol Pract. 2022;10(5):1140–1153. doi: 10.1016/j.jaip.2022.02.016. [DOI] [PubMed] [Google Scholar]
- 7.Williams K.W., Milner J.D., Freeman A.F. Eosinophilia associated with disorders of immune deficiency or immune dysregulation. Immunol Allergy Clin North Am. 2015;35(3):523–544. doi: 10.1016/j.iac.2015.05.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Navabi B., Upton J.E. Primary immunodeficiencies associated with eosinophilia. Allergy Asthma Clin Immunol. 2016;12:27. doi: 10.1186/s13223-016-0130-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Sultan T., Skov F., Brustad N., et al. Levels of total IgE versus specific IgE during childhood for defining and predicting T2-high asthma. World Allergy Organ J. 2024;17(12) doi: 10.1016/j.waojou.2024.100994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Rael E.L., Marshall R.T., McClain J.J. The Hyper-IgE syndromes: lessons in Nature, from bench to bedside. World Allergy Organ J. 2012;5(7):79–87. doi: 10.1097/WOX.0b013e31825a73b2. [DOI] [PMC free article] [PubMed] [Google Scholar]