1. Utility of Total Serum IgE in Allergy
Anne Barasa, MBChB, MMed (Path)
Lecturer, Immunology Unit
Department of Human Pathology
University of Nairobi
KPA 2019
University of Nairobi ISO 9001: Certified

2. Immunoglobulin E 5th Immunoglobulin class
Once produced, IgE binds to its receptors, through which it mediates its functions
High-affinity receptors (FcεRI) - mast cells, basophils, APCs
Low-affinity receptors (FcεRII/CD23) – B cells, monocytes, dendritic cells
Present in serum in small quantities (0.0005% of total immunoglobulin)
In equilibrium with that which is cell-bound

3. Role of IgE in Health and Disease
Physiological role – defense against parasites
Helminths
Protozoa
Pathological - Type I hypersensitivity reactions

4. Pathogenesis of Allergy
Re-exposure
Binding of allergen to IgE-FcεRI complexes cross-links the receptors, leading to cellular activation
Degranulation & mediator release (histamine)
Synthesis of lipid mediators (prostaglandins, leukotrienes)
Synthesis of cytokines (IL-4, -5)
Sensitization

5. Serum levels of Total IgE
Age-dependent
Progressive increase in healthy children, up to age 10 – 15 years
Increase in atopic children is earlier and steeper
Gradual decline from 2nd decade of life
Should always be evaluated to the reference intervals established from age-stratified healthy (non-atopic) populations

6. Serum levels of Total IgE
Serum levels also influenced by
Race
Gender
Geographic area
Season
Exposure to environmental pollutants
Non-allergic diseases
These make determination of reference ranges difficult
Clinical utility dependent on establishment of reliable reference values for the respective population

7. IgE Levels in Populations in the Tropics
High serum levels of tIgE in people living in helminth endemic areas of the tropics, despite being non-atopic
Helminths capable of inducing IgE synthesis markedly
Mostly non-specific IgE
Postulated that polyclonal IgE synthesis is a mechanism of the parasite to evade the host immune response against it

8. Causes of Elevated Serum tIgE
Allergic disease
Levels significantly higher in atopic disorders than age-adjusted healthy populations
Significantly increased in parasitic infections (helminths)

9. Causes of Elevated Serum tIgE
Non-parasitic infections (EBV, CMV, HIV, M.Tb)
Inflammatory diseases (Vasculitides)
PIDs (Hyper IgE, Wiskott-Aldrich syndrome)
Malignancies (Hodgkins lymphoma, IgE myeloma)

10. Diagnostic Performance
i.e.. Ability to detect aetiology
Expressed as clinical sensitivity and specificity
Based on a given cut-off value, below which the test is considered negative, and above which it is considered positive
Raising the cut-off makes the test more specific but less sensitive; and vice-versa

11. 6 – 7 yr
12 – 13 yr
tIgE cut-off
kU/L
258.8 kU/L
38.4 kU/L
63 kU/L
Sensitivity (%)
67.1
48.7
90.3
87.9
Specificity (%)
75.4
88.2
52.8
66.6
PPV (%)
65.4
74.2
70.0
75.0
NPV (%)
75.1
81.6
Limited diagnostic value of tIgE despite many patients with allergic disorders having elevated levels

12. tIgE cut-off
77 kU/L
164.3 kU/L
100 kU/L
Sensitivity (%)
82.3
61.2
74.4
Specificity (%)
87.1
95.0
90.8
PPV (%)
89.5
94.3
91.5
NPV (%)
78.6
64.6
72.5
Insufficient diagnostic accuracy of tIgE levels alone to detect allergic diseases, regardless of cut-off used
77.7 kU/L – optimal cut-off on ROC curve
164.3 kU/L – upper 95% CI in non-atopic children
100 kU/L – commonly used cut-off in clinical practice

13. Total IgE n
Any sIgE positive
< 10 kU/L 73 3
11 – 20 kU/L 74 13
21 – 40 kU/L 16
41 – 80 kU/L 81 22

14. Clinical Utility of tIgE for Allergy
Commonly requested test as first line test to clarify a state of sensitization, as a risk factor for allergic disease
Higher levels of tIgE in patients with allergic diseases compared with non-allergic patients
Does not prove existence of an allergic disease state
As many as 5% of healthy children may have serum tIgE concentrations above the age-specific reference range
10% children with clinical signs of hypersensitivity may have serum tIgE concentrations within the age-specific reference range
(Some studies report up to 33%)

15. Clinical Utility
Necessitated identification of cut-off levels to aid in diagnosis of allergy
Cut-off of >200 kU/L proposed to have high probability in predicting presence of sensitization/allergy

16. Positive sIgE findings found in 8% study subjects
Total IgE values below 10 kU/L do not exclude the presence of sensitization
Recommended that sIgE concentrations should be determined in children with low tIgE values in cases of clinically suspect allergic reactions

17. Clinical Utility - Limitations
Considerable overlap in serum tIgE levels between atopic and non-atopic populations reduces its utility in identifying atopy
Detects total amount of IgE present in blood, irrespective of what these IgE molecules bind to
Need to distinguish allergen-specific vs non-allergen-specific IgE

18. Clinical Utility in Allergy
Supplemental diagnostic measure for the diagnosis of allergic asthma
(Szefler SJ et al, Asthma outcomes: biomarkers; Journal of Allergy and Clinical Immunology; 2012)
Evaluation of candidates for anti-IgE therapy

19. Clinical Governance and Value-Based Care
Lab medicine practitioners take responsibility to ensure cost effective use of lab tests
In children in whom allergy might be suspected but no definite clues exist to explain vague symptoms, a battery of tests (tIgE and sIgE) not recommended
The practice of “over use” of blood screening tests not recommended
Sinclair D, Peters SA; J Clin Pathol 2004

20. Clinical Governance and Value-Based Care
Clinical justification of the test based on careful history and physical examination
Total IgE should not be used as a screen for subsequent testing
If the clinical history is of a convincing allergic reaction, a low total IgE does not preclude the presence of allergen sIgE
With a history of an acute reaction, proceed with clinically appropriate allergen sIgE tests
Sinclair D, Peters SA; J Clin Pathol 2004

21. Conclusions
Elevated serum IgE can be detected in subjects sensitized to allergens, as well as in non-allergic diseases
Measurement of total IgE (and then allergen sIgE if the level is above a certain cut-off) has relatively low levels of sensitivity and specificity
High total IgE levels do not indicate an allergy
Normal levels do not necessarily indicate absence of allergy

22. Conclusions
Serum tIgE testing for allergy is non-specific; does not give information on sensitizing allergens
Therefore of limited clinical utility as a screen or diagnostic test for allergic disorders
Replaced by more specific and sensitive markers (sIgE; component resolved diagnostics)

23. Recommendations Comprehensive atopic history of the patients
Proper selection and interpretation of specific IgE testing
Interpretation within clinical context