Utility of Total Serum Ig E in Allergy

Utility of Total Serum Ig. E in Allergy Anne Barasa, MBCh. B, 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 • 5 th Immunoglobulin class • Once produced, Ig. E binds to its receptors, through which it mediates its functions • High-affinity receptors (FcεRI) - mast cells, basophils, APCs • Low-affinity receptors (FcεRII/CD 23) – 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 Ig. E 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 Ig. E-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 Ig. E • Age-dependent • Progressive increase in healthy children, up to age 10 – 15 years • Increase in atopic children is earlier and steeper • Gradual decline from 2 nd decade of life • Should always be evaluated to the reference intervals established from age-stratified healthy (non-atopic) populations

Serum levels of Total Ig. E • 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

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

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

Causes of Elevated Serum t. Ig. E • Non-parasitic infections (EBV, CMV, HIV, M. Tb) • Inflammatory diseases (Vasculitides) • PIDs (Hyper Ig. E, Wiskott-Aldrich syndrome) • Malignancies (Hodgkins lymphoma, Ig. E 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 t. Ig. E cut-off 127. 7 k. U/L 12 – 13 yr 258. 8 k. U/L 38. 4 k. U/L 63 k. U/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 88. 2 81. 6 75. 1 Limited diagnostic value of t. Ig. E despite many patients with allergic disorders having elevated levels

t. Ig. E cut-off 77 k. U/L 164. 3 k. U/L 100 k. U/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 t. Ig. E levels alone to detect allergic diseases, regardless of cut-off used 77. 7 k. U/L – optimal cut-off on ROC curve 164. 3 k. U/L – upper 95% CI in non-atopic children 100 k. U/L – commonly used cut-off in clinical practice

Total Ig. E n Any s. Ig. E positive < 10 k. U/L 73 3 11 – 20 k. U/L 74 13 21 – 40 k. U/L 74 16 41 – 80 k. U/L 81 22

Clinical Utility of t. Ig. E 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 t. Ig. E 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 t. Ig. E concentrations above the age-specific reference range • 10% children with clinical signs of hypersensitivity may have serum t. Ig. E 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 k. U/L proposed to have high probability in predicting presence of sensitization/allergy

• Positive s. Ig. E findings found in 8% study subjects • Total Ig. E values below 10 k. U/L do not exclude the presence of sensitization • Recommended that s. Ig. E concentrations should be determined in children with low t. Ig. E values in cases of clinically suspect allergic reactions

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

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-Ig. E 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 (t. Ig. E and s. Ig. E) 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 Ig. E should not be used as a screen for subsequent testing • If the clinical history is of a convincing allergic reaction, a low total Ig. E does not preclude the presence of allergen s. Ig. E • With a history of an acute reaction, proceed with clinically appropriate allergen s. Ig. E tests Sinclair D, Peters SA; J Clin Pathol 2004

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

Conclusions • Serum t. Ig. E 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 (s. Ig. E; component resolved diagnostics)

Recommendations • Comprehensive atopic history of the patients • Proper selection and interpretation of specific Ig. E testing • Interpretation within clinical context