Making sense of total IgE: Narrow indications in clinical care

Authors

Melody Li MD (biography, no disclosures) and Siobhan Perkins MD (biography, no disclosures)

What care gaps or frequently asked questions we have noticed

Immunoglobulin E (IgE) is an antibody produced by plasma cells that is primarily involved in immediate hypersensitivity reactions and defence against parasitic infections.^1-3 IgE is present at the lowest serum concentration of all immunoglobulin classes because it is largely bound to mast cells and basophils and has a short half-life.³ Total serum IgE measures the sum of all IgE (bound and unbound) within the blood.

In the allergy clinic, we often see patients referred for elevated total IgE levels. Many of these patients had total IgE ordered as a screening test for a suspected allergy or as part of a nonspecific workup. In practice, the clinical utility of total IgE is limited and its indications are narrow, leading to the question:

When should total IgE be ordered?

Data that answers these questions or gaps

Case 1: Common Allergy Clinic Referral

The patient is a 25-year-old with a history of pruritic non-specific maculopapular lesions on her arms for two weeks. She is otherwise healthy with no history of constitutional symptoms, lymphadenopathy, atopy, asthma or risk factors for parasitic infection, and no history of recurrent or persistent infections. As part of her workup, an IgE test is performed and comes back at 800 microg/L (normal <515 microg/L). A referral is sent to her local allergist for further assessment.

A number of conditions can result in an elevation of IgE, underscoring why total IgE is not a reliable screening tool for specific allergies (see Table 1).

Table 1. Conditions associated with elevated IgE^3,4

Not all elevations in total IgE are clinically equivalent. Mild to moderate increases of IgE are commonly associated with atopic conditions (e.g., allergic rhinitis, asthma and eczema) with limited diagnostic utility. Additionally, management decisions for these conditions are primarily based on the severity of clinical symptoms rather than IgE measurements.⁵ When a patient’s total IgE is very elevated (>2,000 IU/mL), inborn errors of immunity should be considered if they have other clinical features like erythroderma, severe infantile atopic dermatitis, recurrent infections, syndromic features, autoimmunity or allergies.^4,6 However, IgE alone is not diagnostic of inborn errors of immunity and provides limited value in the absence of other clinical features.⁷

Interpretation of total IgE must also account for patient context. Levels vary depending on sex, age, diet and environmental exposures, which can make interpreting a single total IgE value difficult.⁸ Geographic location is also very important. IgE can be elevated in areas with endemic parasitic infections, although this is less relevant in Canadian practice.⁸ Even smoking can be associated with increased IgE, further illustrating the nonspecificity of the total IgE test.⁹

Case 2: Hyper-IgE Syndrome

A 7-year-old presents with recurrent Staphylococcus skin abscesses, severe eczema since infancy, recurrent fractures and a history of recurrent pneumonia. Physical examination reveals coarse facial features, scoliosis and retained primary teeth. Laboratory evaluation shows an IgE level of 5,831 IU/mL and eosinophilia. Subsequent genetic testing confirms a STAT3 mutation, consistent with autosomal dominant hyper-IgE syndrome (Job’s syndrome).

This case illustrates a situation where an extremely elevated IgE in combination with clinical features supported the diagnosis of a rare immunodeficiency. First described by Davis and Wedgwood in 1966, hyper-IgE syndromes are a group of syndromes that result from variable genetic factors, leading to variable phenotypes and endotypes.¹⁰

The diagnosis and management of these conditions are beyond the scope of this article. Although clinical features vary depending on the underlying genetic mutation, a high index of suspicion is warranted in patients with a family history of disease, extensive treatment-refractory dermatitis, recurrent skin and pulmonary infections, coarse facial features, failure or delayed shedding of primary teeth, recurrent fractures, hyperextensible joints or scoliosis.¹¹

It is important to note that, in addition to the classical hyper-IgE syndromes, there are several combined immunodeficiencies that present with elevated IgE and infections, such as Wiskott-Aldrich syndrome, DOCK8 deficiency, PGM3 deficiency and Omenn syndrome.¹¹

There are a few scenarios in which total IgE measurement is indicated. When considering omalizumab therapy for asthma, total IgE is measured because dosing is determined by the patient’s baseline total IgE level and body weight.¹² In suspected ABPA, total IgE is included in the diagnostic criteria and used to monitor disease activity and response to therapy. However, it is not sufficient alone for diagnosis; clinical, radiologic and immunologic features must also be present.¹³

What we recommend

There are very few clinical scenarios in which total IgE measurement is useful, and it is not a reliable marker of allergy status. Elevated levels may be associated with a number of conditions, while low or normal values do not exclude the presence of an IgE-mediated disease.¹⁴

For most patients in the primary care setting with suspected allergy, total IgE testing is unnecessary. The test neither confirms nor excludes allergy, and the results can often lead to unnecessary concerns and/or referrals. Total IgE should not be used as a screening tool for allergy, and raised total IgE in isolation is not an indication for specialist referral. Instead, if the clinical suspicion for allergy is high, consider ordering a specific IgE test or referring to an allergist for formal skin prick testing.

In everyday practice, total IgE should be reserved for these specific scenarios. There are circumstances where someone with elevated IgE without clinical relevance may require more workup, but this would be done in the allergy office. Unnecessary total IgE testing incurs superfluous costs on the already burdened health-care system.

Avoiding routine total IgE testing helps reduce unnecessary investigations, patient anxiety and referrals, supporting efficient, evidence-based care.

References

1. Greene D, Moore Fried J, Wang J. IgE in allergic diseases. Immunological Reviews. 2025;334(1):e70057. doi:10.1111/imr.70057 (View with UBC) 
2. Kelly BT, Grayson MH. Immunoglobulin E, what is it good for? Ann Allergy Asthma Immunol. 2016;116(3):183-187. doi:10.1016/j.anai.2015.10.026 (View) 
3. Adkinson NF Jr, Bochner BS, Burks AW, et al, eds. Middleton’s Allergy: Principles and Practice. 8th ed. Elsevier Saunders; 2014. (View with UBC) 
4. Khan YW, Williams KW. Inborn errors of immunity associated with elevated immunoglobulin E. Ann Allergy Asthma Immunol. 2022;129(5):552-561. doi:10.1016/j.anai.2022.07.013 (View) 
5. Tu YL, Chang SW, Tsai HJ, et al. Total serum IgE in a population-based study of Asian children in Taiwan: reference value and significance in the diagnosis of allergy. PloS One. 2013;8(11):e80996. Published 2013 Nov 20. doi:10.1371/journal.pone.0080996 (View) 
6. Ponsford MJ, Klocperk A, Pulvirenti F, et al. Hyper-IgE in the allergy clinic–when is it primary immunodeficiency?  Allergy. 2018;73(11):2122-2136. doi:10.1111/all.13578 (View) 
7. Joshi AY, Iyer VN, Boyce TG, Hagan JB, Park MA, Abraham RS. 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 (View with UBC) 
8. Martins TB, Bandhauer ME, Bunker AM, Roberts WL, Hill HR. New childhood and adult reference intervals for total IgE. J Allergy Clin Immunol. 2014;133(2):589-591. doi:10.1016/j.jaci.2013.08.037 (View) 
9. Kim YS, Kim HY, Ahn HS, et al. The Association between Tobacco Smoke and Serum Immunoglobulin E Levels in Korean Adults. Intern Med. 2017;56(19):2571-2577. doi:10.2169/internalmedicine.8737-16 (View) 
10. Davis, SD, Schaller J, Wedgwood R. Job’s Syndrome: Recurrent, “cold” staphylococcal abscesses. The Lancet. 1966; 1:1013-1015. doi:https://doi: 10.1016/s0140-6736(66)90119-x (View with UBC) 
11. Minegishi Y. Hyper-IgE syndrome, 2021 update. Allergol Int. 2021;70(4):407-414. doi:10.1016/j.alit.2021.07.007 (View) 
12. Brusselle GG, Koppelman GH. Biologic therapies for severe asthma. N Engl J Med. 2022;386(2):157-171. doi:10.1056/NEJMra2032506 (View with UBC) 
13. Thompson GR 3rd, Young JH. Aspergillus infections. N Engl J Med. 2021;385(16):1496-1509. doi:10.1056/NEJMra2027424 (View with UBC) 
14. Ansotegui IJ, Melioli G, Canonica GW, et al. IgE allergy diagnostics and other relevant tests in allergy, a World Allergy Organization position paper. World Allergy Organ J.   2020;13(2):100080. Published 2020 Feb 25. doi:10.1016/j.waojou.2019.100080 (View) 
15. Bernstein IL, Li JT, Bernstein DI, et al. Allergy diagnostic testing: an updated practice parameter.  Ann Allergy Asthma Immunol. 2008;100(3 Suppl 3):S1-S148. doi:10.1016/s1081-1206(10)60305-5 (View with UBC) 

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