Anne Barasa MBChB MMed Path Lecturer Immunology Unit Department of Human Pathology University of Nairobi KPA 2019 University of Nairobi ID: 784712
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Slide1
Utility of Total Serum IgE in Allergy
Anne Barasa, MBChB, MMed (Path) Lecturer, Immunology UnitDepartment of Human PathologyUniversity of NairobiKPA 2019
University of Nairobi
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Slide2Immunoglobulin E
5th Immunoglobulin classOnce produced, IgE binds to its receptors, through which it mediates its functionsHigh-affinity receptors (FcεRI) - mast cells, basophils, APCsLow-affinity receptors (FcεRII/CD23) – B cells, monocytes, dendritic cellsPresent in serum in small quantities (0.0005% of total immunoglobulin)In equilibrium with that which is cell-bound
Slide3Role of IgE in Health and Disease
Physiological role – defense against parasites HelminthsProtozoaPathological - Type I hypersensitivity reactions
Slide4Pathogenesis of Allergy
SensitizationRe-exposureBinding of allergen to IgE-FcεRI complexes cross-links the receptors, leading to cellular activationDegranulation & mediator release (histamine)
Synthesis of lipid mediators (prostaglandins, leukotrienes)
Synthesis of cytokines (IL-4, -5)
Slide5Serum levels of Total IgE
Age-dependentProgressive increase in healthy children, up to age 10 – 15 yearsIncrease in atopic children is earlier and steeperGradual decline from 2nd decade of lifeShould always be evaluated to the reference intervals established from age-stratified healthy (non-atopic) populations
Slide6Serum levels of Total IgE
Serum levels also influenced byRaceGenderGeographic areaSeasonExposure to environmental pollutantsNon-allergic diseasesThese make determination of reference ranges difficultClinical utility dependent on establishment of reliable reference values for the respective population
Slide7IgE Levels in Populations in the Tropics
High serum levels of tIgE in people living in helminth endemic areas of the tropics, despite being non-atopicHelminths capable of inducing IgE synthesis markedlyMostly non-specific IgEPostulated that polyclonal IgE synthesis is a mechanism of the parasite to evade the host immune response against it
Slide8Causes of Elevated Serum tIgE
Allergic diseaseLevels significantly higher in atopic disorders than age-adjusted healthy populationsSignificantly increased in parasitic infections (helminths)
Slide9Causes 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)
Slide10Diagnostic Performance
i.e.. Ability to detect aetiologyExpressed as clinical sensitivity and specificityBased on a given cut-off value, below which the test is considered negative, and above which it is considered positiveRaising the cut-off makes the test more specific but less sensitive; and vice-versa
Slide116 – 7 yr
12 – 13 yrtIgE cut-off127.7 kU/L258.8 kU/L38.4 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
88.2
81.6
75.1
Limited diagnostic value of tIgE despite many patients with allergic disorders having elevated levels
Slide12tIgE
cut-off77 kU/L164.3 kU/L100 kU/LSensitivity (%)82.361.2
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
Slide13Total
IgEnAny sIgE positive< 10 kU/L733
11 – 20 kU/L
74
13
21 – 40 kU/L
74
16
41 – 80 kU/L
81
22
Slide14Clinical Utility of tIgE for Allergy
Commonly requested test as first line test to clarify a state of sensitization, as a risk factor for allergic diseaseHigher levels of tIgE in patients with allergic diseases compared with non-allergic patientsDoes not prove existence of an allergic disease stateAs many as 5% of healthy children may have serum tIgE concentrations above the age-specific reference range10% children with clinical signs of hypersensitivity may have serum tIgE concentrations within the age-specific reference range(Some studies report up to 33%)
Slide15Clinical Utility
Necessitated identification of cut-off levels to aid in diagnosis of allergyCut-off of >200 kU/L proposed to have high probability in predicting presence of sensitization/allergy
Slide16Positive sIgE findings found in 8% study subjects
Total IgE values below 10 kU/L do not exclude the presence of sensitizationRecommended that sIgE concentrations should be determined in children with low tIgE values in cases of clinically suspect allergic reactions
Slide17Clinical Utility - Limitations
Considerable overlap in serum tIgE levels between atopic and non-atopic populations reduces its utility in identifying atopyDetects total amount of IgE present in blood, irrespective of what these IgE molecules bind toNeed to distinguish allergen-specific vs non-allergen-specific IgE
Slide18Clinical 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
Slide19Clinical Governance and Value-Based Care
Lab medicine practitioners take responsibility to ensure cost effective use of lab testsIn children in whom allergy might be suspected but no definite clues exist to explain vague symptoms, a battery of tests (tIgE and sIgE) not recommendedThe practice of “over use” of blood screening tests not recommendedSinclair D, Peters SA; J Clin Pathol 2004
Slide20Clinical Governance and Value-Based Care
Clinical justification of the test based on careful history and physical examinationTotal IgE should not be used as a screen for subsequent testingIf the clinical history is of a convincing allergic reaction, a low total IgE does not preclude the presence of allergen sIgEWith a history of an acute reaction, proceed with clinically appropriate allergen sIgE testsSinclair D, Peters SA; J Clin Pathol 2004
Slide21Conclusions
Elevated serum IgE can be detected in subjects sensitized to allergens, as well as in non-allergic diseasesMeasurement of total IgE (and then allergen sIgE if the level is above a certain cut-off) has relatively low levels of sensitivity and specificityHigh total IgE levels do not indicate an allergyNormal levels do not necessarily indicate absence of allergy
Slide22Conclusions
Serum tIgE testing for allergy is non-specific; does not give information on sensitizing allergensTherefore of limited clinical utility as a screen or diagnostic test for allergic disordersReplaced by more specific and sensitive markers (sIgE; component resolved diagnostics)
Slide23Recommendations
Comprehensive atopic history of the patientsProper selection and interpretation of specific IgE testingInterpretation within clinical context