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 9001:2008 1 Certified http://www.uonbi.ac.ke

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

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

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

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

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

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

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

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)

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

6 – 7 yr 12 – 13 yr tIgE cut-off 127.7 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

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

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

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%)

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

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

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

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

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

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

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

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)

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