Transcript Document 7256037

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GLORIA MODULE 9:
The Diagnosis of Allergic Diseases
Diagnosis of IgE Sensitization
Authors
Michael A Kaliner, USA
Stephen R Durham, UK
Robert Hamilton, USA
S.G.O. Johansson, Sweden
Connie Katelaris, Australia
John Oppenheimer, USA
Reviewers:
Joaquin Sastre, Spain; Cassim Motala, South Africa
Nomenclature of allergy
Hypersensitivity
Allergic hypersensitivity
Non-allergic hypersensitivity
(immunological mechanism
defined or strongly suspected)
(immunological mechanism
excluded)
IgE-mediated
Not IgE-mediated
Johansson SGO et al. Allergy 2001 and JACI 2004
Atopy
Atopy is a personal and/or familial tendency, usually expressed
anytime in life from childhood and adolescence, into maturity,
to become sensitized and produce IgE antibodies in response to
ordinary exposures to allergens, usually proteins.
As a consequence, atopic persons can develop IgE-mediated
allergic diseases including asthma, rhinoconjunctivitis, or
eczema.
WAO Nomenclature Review Committee
Johansson et al. J Allergy Clin Immunol 2004;113:832-6
Allergic Disease Progression with Age
Saarinen UM et al. Lancet 1995
Pathophysiology of an Allergic Reaction
The Essential Components of Allergy
Diagnosis
Clinical History and Physical Examination
Symptoms versus Exposure
Diagnostic Confirmatory Test
Skin Test (Puncture, Intradermal)
Allergen-specific IgE antibody serology
Provocation Test
Oral, Nasal, Bronchial Challenge
Key Concepts in Allergy Diagnosis
•
•
•
•
•
•
A proper allergy history involves determining the symptom complex, any
relationship to allergen exposure and a careful physical examination, looking for
the specific signs of allergy.
Once allergic disease is suspected, a confirmatory test (skin test or IgE antibody
serology) is performed to verify sensitization by the presence of allergen specific
IgE antibody.1-3
Where it can be performed and interpreted, skin prick testing (SPT) remains the
primary confirmatory test because it is fast, safe, sensitive, minimally invasive and
results correlate with nasal and bronchial challenges.
Quantitative IgE antibody serology is an accepted alternative.
SPT and/or IgE serology are essential adjuncts to history and physical exam when
making the diagnosis of allergy.
Provocation tests are sometimes needed to confirm sensitization.
1. Oppenheimer Ann Allergy 2006;S1:6-12, 2. Bousquet Clin Allergy 17:529-36, 1987
3. Cockroft Am Rev Respir Dis 135:264-7., 1987
Allergy History
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Demographics (age)
Symptoms: frequency and severity
Pattern: intermittent, persistent or seasonal
Response to environmental factors:
– Temperature changes, odors, humidity, alcohol
Occupation and hobbies
Identification of allergens/irritants in the home, office or environment
Treatment, past and present: efficacy, compliance, side effects
Allergy Symptoms
Clinical History Drives the Diagnosis
• Hypersensitivity to an injected, ingested, or inhaled
antigen in response to a first exposure.
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–
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Skin: itch, rash, swelling, redness
Eyes: itchy, tears, watery, redness, crusting
Nose: runny, itchy, congestion, sneezing
Lung: wheezing, cough, tightness, shortness of breath
Stomach-Intestines: nausea, vomiting, bloating, diarrhea
Heart-Blood Vessels: anaphylaxis, syncope, faintness, death
Allergy Physical Examination:
The Everted Eyelid
Allergy Physical Examination: The
Swollen Nasal Mucosa
What is an Allergen?
An antigen causing an allergic disease is called an “allergen”.
Most allergens initiating an IgE-antibody mediated allergic reaction are
glycoproteins with a molecular weight of 5 to 100 kD, most around 20 kD.
Many pollen allergens are surface enzymes.
Some food allergens are remarkably stable and are stable even after cooking.
A genetically predisposed (atopic) person can become IgE-sensitized after
several years of inhaling <1 µg of grass pollen allergen per season.
Spectrum of Allergen Sources
Allergen Extracts
• An allergen extract used for diagnosis or treatment is prepared by incubating
the allergenic material in a physiological buffer (e.g., phosphate buffered
saline) followed by lipid extraction.
• The allergen content was commonly expressed in crude terms such as
protein nitrogen units (PNU) or weight:volume, but it may now be
expressed as micrograms of specific allergen per ml.
• Several commercial extracts used in skin testing are “standardized”
regarding allergen protein concentration, composition and lack of irritating
contaminants.
• In some countries such as the USA, grass, ragweed, dust mite and cat
allergens are currently standardized
Selection of Aeroallergens
• An evidence-based approach that minimizes irrelevant test antigens can
reduce patient discomfort and costs.
• An understanding of pollen aerobiology and knowledge of allergenic crossreactivity between regional pollinating plant families is necessary in
selecting appropriate aeroallergen test panels.
• Extensive allergenic cross-reactivity exists between northern pasture
grasses, permitting the use of a single northern grass pollen for testing in
most regions outside of southern regions of North America and Europe
Practice Parameters for Allergy Diagnostic Testing
Ann Allergy 1995; 75:543-625
Allergy Diagnosis - Definitions
• Sensitivity: proportion of subjects with allergy who test positive
• Specificity: proportion of subjects without allergy who test negative
• PPV: probability that a subject has allergy if they test positive
• NPV: probability that a subject does not have allergy if they test negative
• Efficiency: % of allergy patients correctly classified as diseased and
not diseased
Skin Testing and IgE Antibody Serology
Powerful adjuncts for confirming allergy in:
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•
•
•
•
•
•
•
Rhinitis and sinusitis
Asthma, cough, dyspnea
Eczema
Food allergy
Insect sting allergy
Drug allergy (some i.e. beta-lactams and local anesthetics)
Occupational (some)
Anaphylaxis
Confirmatory Skin Testing
Use of Skin Prick Tests (SPT)
• Diagnosis of allergy
• Confirmatory evidence (positive, negative) of IgE sensitization in
support of the clinical history
• Identifies the allergen against which IgE is specifically directed, which
is essential for allergen avoidance measures
• Educational value: visual reinforcement strengthens compliance of
verbal advice
General Rules for Successful SPT
• It is imperative that the technician performing the skin tests as well as the
clinician ordering/interpreting these tests understands the characteristics of
the specific tests they are administering.
• This includes:
– type of skin testing
– device used
– placement of tests (location and adjacent testing)
– the particular extracts (source, concentration) being used
– the potential confounder of medications that may suppress skin test
response.
Skin Prick Testing
• SPT is easy to perform and rarely causes generalized reactions.
• Patients may have positive SPT but no clinical disease. A positive SPT
indicates the presence of IgE antibodies against that allergen but does not
indicate clinical sensitivity. A correlation between the history and SPT is
essential
• The results can be unreliable if the patient takes certain drugs, such as antihistamines and tricyclic anti-depressants.
Skin Prick Testing Solutions
Skin Prick Testing
Not all Allergens are Available as a Skin
Test Extract: Fruit Prick-Prick Test
Prick-Prick Test Reactions
Skin Testing with Natural Foods in
Subjects Suspected of Having Food Allergy
• 22 patients with highly suspected food allergies but with negative
SPT to commercial extracts had positive prick-prick skin tests with
fresh natural foods:
- 7 fish and seafood
- 4 fruit and vegetable
- 9 peanut and tree nuts
- 1 milk
- 1 egg
Rosen. J Allergy Clin Immunol 1994;93:1068
Puncture Skin Testing Devices
• There are several different devices
available for skin prick testing.
GTK
QTS
• These devices result in varying
degrees of trauma to the skin with
differing levels of skin test reaction.
• Thus, the physician should be
familiar with the characteristics of
the device used in his/her practice,
as each require different criteria for
what constitutes a positive reaction.
MT
2
AS QT ST
QNT
GP
Intracutaneous Skin Testing (ICT)
• ICT should be interpreted cautiously. Many positive reactions (up to 70%
according to some published reports) are not clinically relevant.
• Because ICT uses larger volumes of injected allergen preparations, there
may be some irritant reactions not mediated by an allergic mechanism.
Many drugs may directly stimulate mast cells to release mediators.
• The incidence of severe systemic effects, while rare, are more likely to
occur with ICT than with SPT
Comparison of SPT and ICT
Advantages of SPT
• Safer
• More rapid
• Less discomfort to patient
• Technically less demanding
• More specific
• More allergens in one session
• Allergen more stable (50% glycerin)
• Positive and negative tests more easily
distinguished
• Steeper dose response curve
• Positive tests correlate better with
clinical disease
Advantages of ICT
More sensitive:
(300 to >1000 fold)
More reproducible
More positives
Recording Skin Test Responses
Results of both SPT and ICT skin tests should be reported in the most quantitative
terms possible.
•
•
Reports of minimal usefulness include:
– Positive or negative
– 0 to 4+ (unless accompanied by an indication of what these numbers represent).
Useful to report both wheal and flare measurements in mm:
– A superior method is to measure the reaction in mm across the cross-diameter
– Area (cross-diameter in mm) of the wheal and erythema is the most accurate
way to present results.
– Measurements of:
• the product of the orthogonal diameters
• the sum of the orthogonal diameters
• the longest diameters
– Correlate very well with area (r values greater than 0.9).
Ownby JACI 1982:69:536-8
Are Skin Tests Easy to Interpret?
Reproducibility of Skin Test Scoring and
Interpretation by Board-Certified/Eligible
Allergists
• Methods:
– Series of SPT were digitally photographed
• 22 tests with controls
– a questionnaire regarding interpretation was sent to 70 allergists to
assess
• positive, negative or intermediate
• positive or whether a ICT test was desired
McCann Ann Allergy Asthma Immun 2002;89:368-71
Reproducibility of Skin Test Scoring and
Interpretation by Board-Certified/Eligible Allergists
• Results:
– 33 interpretable responses
• 24 relied on a grading scale (0-4+);
• 2 measured in mm,
• 7 provided only interpretation with no grading
– Greatest agreement with median/mode score 4+
– Least agreement with median/mode score 1-2+
– Range of requested ICT test was 0-11 tests
• Conclusion:
– Significant variability in scoring and interpreting skin tests
– Reinforces the need to report skin test reactions by measuring and
recording reaction size in mm
McCann Ann All Asthma Immun 2002;89:368-71
Inter-Individual Variation in SPT
Test result
Nurse 1
Nurse 2
Nurse 3
Nurse 4
CV
Negative control
0.1 mm
0.4 mm
0.2 mm
0.2 mm
55.9%
Histamine
11.7 mm
9.7 mm
12.9 mm
14.5 mm
16.6%
Grass
2.1 mm
2.5 mm
4.7 mm
5.2 mm
42.8%
Mugwort
7.7 mm
4.8 mm
7.4 mm
9.1 mm
24.7%
Dog
1.5 mm
1.1 mm
3.0 mm
2.5 mm
House dust mite
1.7 mm
2.2 mm
1.6 mm
2.8 mm
43.3%
26.5%
CV = inter-individual coefficient of variation, Target < 25%; Vohlonen I et al. Allergy 1989; 44: 525-531
www.AAAAI.ORG
Suppression of Skin Tests by Medication
• Most antihistamines and anti-depressants suppress skin tests for 37 days. Astemizole suppresses for 1-3 months.
• H2 antagonists have no, or a very minor, effect.
• Bronchodilators do not affect skin tests.
• Short-term and low dose oral corticosteroids have no effect.
– Reports vary on long-term high-dose use.
Cook J Allergy Clin Immunol 1973;51:71-7
Rao KS J Allergy Clin Immunol 1988;82:752-7
Miller J J Allergy Clin Immunol 1989;84:895-99
Slott RIJ Allergy Clin Immunol 1974;554:229-34
Skin Test Safety
Review of surveys of fatal reactions to skin testing between
1959-2001
• 9 deaths associated with skin testing
• 1 death associated with SPT
– History of unstable asthma with FEV-1 36% 1 week prior
– Tested to 90 foods
Lockey JACI 1987;79:660-77
Reid JACI 1993;92:6-15
Bernstein JACI 2004;113:1129-36
In-Vivo Provocation Tests
• Provocation tests involve the challenge of the affected organ by serial
dilutions of an allergen extract or by the actual, suspected allergen source
material, e.g. food or drug.
• A provocation test is time-consuming. It can result in dangerous clinical
reactions and should only be performed by experienced persons with
access to lifesaving equipment.
Due to space limitations, details of nasal, lung and insect sting challenge tests
will not be discussed further in this presentation.
Food Allergy Diagnosis:
Oral Food challenges
Challenge types
Open
* useful when the history is vague and when the reaction is likely
to be negative (-ve specific IgE antibodies and unconvincing
history)
Single blind
* useful to confirm negative reactions
* useful to confirm non-subjective reactions
Double Blind Placebo Controlled (DBPCFC)
* gold standard - mandatory for research studies
* usually definitive; excellent for subjective reactions
* alternate placebo and active randomly
Confirmatory
Total and Allergen-Specific IgE
Antibody Serological Testing
Serological Tests Performed in
Diagnostic Allergy Laboratories
• Allergen-specific IgE (over 400 allergen specificities)
– Pollen (weeds, grasses, trees), Epidermals, Dust Mites, Molds, Foods,
Venoms, Drugs, Occupational allergens (Ispagula, Natural Rubber
Latex)
• Total Serum IgE (Xolair: anti-IgE; ABPA)
• Phadiatop (Multi-allergen screen) IgE (define atopy)
• Fx5e (Multi-allergen screening test for foods)
• Mast Cell Tryptase (indicator of anaphylaxis)
• Eosinophil Cationic Protein (eosinophil activation marker)
• Precipitin-IgG antibody (Hypersensitivity Pneumonitis, anaphylactic
reactions to dextran)
Total Serum IgE Levels in Allergy
Patients with allergic asthma may have increased total serum IgE
concentrations, but this is not an allergy-specific finding:
• 60% of “allergic” asthmatics have increased IgE
• 40% of “allergic” rhinitis patients have increased IgE
Measurement of total serum IgE may be of value in patients with:
• Gastrointestinal symptoms/eosinophilic esophagitis
• Suspected occupational allergy with unclear genesis
• Anaphylaxis
• Allergic Bronchopulmonary Aspergillosis (ABPA)
• Allergic Fungal Sinusitis
Total serum IgE may be measured to determine the dosage of omalizumab
Some Disorders
with Elevated Total Serum IgE Levels
• Helminth infestation, e.g. Ascaris, Schistosoma
• Infections with Staphylococcal strains containing enterotoxins, so called
“super-antigens”
• Virus infections, e.g. cytomegalovirus (CMV)
• ABPA and Allergic fungal sinusitis
• Graft Versus Host Disease (GVHD)
• Hyper-IgE Syndrome
Serological Testing for Allergen-IgE
Antibody is Recommended when In-Vivo
Tests Cannot be Used
•
•
•
•
When the patient is taking anti-histamines or other confounding
medications for skin tests
When the patient has eczema or dermographism
Immediately (up to 6 weeks) following an anaphylactic event
If the patient is morbidly afraid of skin testing
Allergen-Specific IgE
In-Vitro and In-Vivo Tests
In-vitro
IgE Antibody
Serology
Yes
Yes
Yes
Yes
Yes
Yes
In-vivo
SPT
Can be used independently
of pharmaceutical treatment
Yes
No
Can be used independently
of patient skin status
Time factor
Cost factor
Usefulness in motivating patients
Yes
No
1-7 days
more expensive
obscure
15-30 minutes
inexpensive
dramatic
High sensitivity
High specificity
High reproducibility
Quantitative results in kIU/L
WHO Standard calibrated
Quality assurance test program
Yes
Yes
Yes
No
No
No
Evolution in Specific IgE Antibody
Assay Technology
1st generation: manual chemistries
• RAST® =Radio Allergo Sorbent test, Phadia* 1974
• Hycor Hy-Tec (paper disc based)
• FAST = Allergenics/Biowhittaker, fluorescent allergosorbent test
• MAST = Hitachi: thread pipette
• EAST = Sanofi Dignostics Pasteur
• Magic Lite = ALK/Corning/Bayer
• Matrix = Abbott
2nd generation (semi-automated chemistries)
• Alastat, Diagnostic Products Corp. (DPC, biotin-allergen)
• Pharmacia CAP System® , ImmmunoCAPTM 3D Solid Phase, Phadia* 1989
3rd generation (autoanalyzers)
• Immulite 2000: Diagnostic Products Corporation
• ImmunoCAP 250TM, 1000): Phadia* 2001
*Phadia is the new name of Pharmacia Diagnostics (2006)
Evolution from Qualitative to
Quantitative IgE Antibody Results
• 1974-80: PRU/ml: Phadebas Relative Units
• 1980s-1990s: AU/ml: AU = allergen unit
Normalized Counts, ASM (adjusted counts)
sIgE/ml, IU/ml, FSU/ml, VRU/ml
EAU/ml; Classes
• 1997: Clinical and Laboratory Standards Institute: LA20A: Evaluation
Methods and Analytical Performance of Immunological assays for human
IgE Antibody: (www. CLSI.org)
• 1989-present: kIU/L or kIUa/L (interpolation from total serum IgE
heterologous dose response curve traceable to WHO 75/502 IgE Serum
Standard) [1U = 2.44 ng of IgE]
Design of Serological Assays for Allergen
Specific IgE Antibody
Step 1:
Separate allergen-specific
IgE from other antibodies
present with a solid phase
allergosorbent
Step 2:
A buffer wash separates
bound IgE from unbound
antibodies
Step 3:
Bound IgE is detected with
a labeled anti-human IgE
reagent
JACI 2003;111:S687-701
Solid Phase Allergosorbent
• As with skin testing, the allergen used in the solid phase is critical to the
validity of the test:
– Characterization of allergen
– Ensure that critical antigen epitopes are on the solid phase
– Antigen epitopes should be present in excess to maximize binding of
IgE antibody
– If not in excess, can have competitive binding from antibody of other
isotypes (IgG)
– Antigen excess binds IgE in an affinity-independent fashion
Illustration of a Widely
Used Assay
(ImmunoCAP® System)
for Allergen Specific IgE
Quantification
Patient IgE
Allergen coupled to
ImmunoCAP
Conjugate;
Enzyme Anti-IgE
Patient IgE ab bound to
ImmunoCAP allergen
Fluorogenic substrate
Conjugate bound to
patient IgE
Conjugate enzyme reacts with
substrate forming a
fluorescent product
The Clinical Validity of IgE Antibody
Serology Testing
Sensitivity
Specificity
Physician’s conclusion
Positive
89%
91%
UniCAP® Specific IgE
Positive
Negative
Total
1121
144
1265
Negative
360
3545
3905
Total
1481
3689
5170
The clinical performance of UniCAP® Specific IgE was documented in clinical trials in six
countries: Italy, Spain, Germany, The Netherlands, Sweden and Great Britain,
on 894 patients with suspected allergy.
Clinical sensitivity and sensitivity were calculated as agreement between the test result and a
specialist diagnosis based on the established diagnostic routines of the clinic.
Paganelli R et al., Allergy 1998; 53: 763-8
Proficiency and Quality Control
• Clinical and Laboratory Standards Institute Guideline:
Evaluation of Methods and Analytical Performance Characteristics of
Immunological Assays for Human Immunoglobulin E Antibodies of
Defined Allergy Specificities
• Recommends quality control for daily performance of testing with minimal
performance targets for IgE antibody assays:
– Intra-assay and Inter-assay coefficient of variation in IgE antibody assays
should not exceed 10% and 15%, respectively.
– Laboratories encouraged to participate in an inter-laboratory external
proficiency testing program: 3 cycles per year, 5 or 6 sera per cycle, measure
total IgE, multi-allergen screen, specific IgE to 5 allergen specificities in each
cycle
– Laboratories should be credentialed (licensed) by appropriate government
agencies
– Document available from CLSI (www.CLSI.org I/LA20 guideline)
Interpretation of Allergen-Specific IgE
Antibody Results
• Presence of allergen-specific IgE antibodies in serum indicates
sensitization. It does not equal clinical symptoms.
• Serum IgE antibody is an absolute prerequisite for the development of
IgE-mediated symptoms.
• With precise, quantitative assays, IgE antibody production can be
detected at an early stage, even before clinical symptoms have fully
developed.
Controversial: Unproven In-Vitro Allergy Tests
1.
Tests with no diagnostic value for any disease under any circumstance
(not based on sound scientific principles):
* Cytotoxic test,
* Antigen leukocyte cellular antibody test (ALCAT)
2.
Tests intrinsically capable of valid measurements; effective/appropriate
for diagnosing certain diseases but not for allergy:
* Serum IgG antibodies
* Total serum immunoglobulin (IgG/IgA/IgM)
* Cytokine/cytokine receptor assays
* Lymphocyte subset counts, lymphocyte function assays
* Chemical analysis of body fluids/tissues
* Food immune complex assays
Practice Parameters for Allergy Diagnostic Testing. Ann. Allergy 1995; 75: 616
Cytotoxic Test: Unproven Diagnostic Utility
Method:
Buffy coat from centrifuged whole blood is placed on
Siliconized microscope slide previously coated with dried extracts of up
to 150 to 200 foods.
Interpretation:
Unstained cells are viewed microscopically at varying
intervals up to 2 hours for changes in shape and appearance of
leukocytes. Swelling, vacuolation, crenation, lack of movement =
evidence of allergy to food.
Concerns:
Incubation time, pH, osmolarity not standardized.
Controlled studies show results are non-reproducible and do not
correlate with clinical evidence of food allergy.
Practice Parameters for Allergy Diagnostic Testing. Ann. Allergy 1995; 75: 616
Performance Characteristics
and
Clinical Utility of Diagnostic
(Skin and Serology) Confirmatory Tests
Prick Skin Tests Correlate with Nasal
Challenge
Nasal Challenge (Pollen Grains)
1215
Relationship between nasal challenges
with pollen grains and skin prick test
Endpoints in patients allergic to
Dactylis glomerata
405
135
Bousquet Clin Allergy 1987;17:529-38
45
15
0
0
1
2
3
4
5
6
7
8
Prick Test Endpoint (Log3 Allergen Dose)
Rs= 0.54
p< 0.005
Even SPT May Result in “False Positives”
in Respiratory Allergy
• Skin prick tests are positive in many patients who have no respiratory
symptoms:
- 42% with a positive family history for asthma or rhinitis may have +SPT
and no disease.
- 29% of those with a negative family history for asthma or rhinitis may
have +SPT.
• SPT results need to be interpreted carefully. There MUST be a
correlation with the history
• Skin tests are a diagnostic tool, an adjunct to the history, and do not
make the diagnosis
Adinoff & Nelson. JACI 1990;86:766
SPT vs ICT Skin Tests in
Diagnosis of Allergic Diseases
In patients who had history of spring allergy-like symptoms but a negative
SPT to timothy grass, there was no difference in nasal challenge or
correlations between symptoms and pollen counts during the grass season
in those with positive or negative ICT to grass.
Nelson. JACI 1996;97:1193-1201.
Evidence Based Medicine
• Likelihood ratio:
– the ratio of post-test odds after a test result to the pre-test odds indicates
how much the odds change after a test
• Likelihood ratios (positive – negative)
– >5.0 or < 0.2 generate moderate to large shifts in disease probability
– 1.0 to 2.0 and 0.5 to 1.0 generate very small and often clinically
insignificant changes in disease probability
Jaeschke JAMA 1994;271:703-7
SPT vs ICT
Comparison Using Evidenced Based Medicine
Test
Allergen
+ Likelihood - Likelihood
SPT
Cat
4.93
0.08
IDT
Cat
0.89
1.24
SPT
Grass
6.82
0.28
IDT
Grass
1.05
0.98
Conclusion:
SPT relate closely to disease, while ICT do not (there are presently no
available data in children or in allergens other than cat and grass).
Gendo Ann Int Med 2004;140:278-89
Allergy Skin Testing (SPT vs ICT)
Conclusions
Skin Prick Tests:
- Diagnostically sensitive, safest, easy to perform and may even detect
asymptomatic sensitivity
- Correlate well with clinical rhinitis & asthma
- Correlate well with challenge tests and IgE antibody serology
measurements
Intradermal Skin Tests:
- Do not differentiate clinically allergic from non-allergic subjects in
epidemiologic studies or in studies of cat and grass sensitivity in
adults.
IgE Antibody Determination Allows
Evaluation of Disease Prognosis
Early sensitization can be predictive of future allergies:
•
•
•
IgE antibodies to food early in life may be associated with a high
risk of developing IgE antibodies to inhalants later in life.
IgE antibodies to inhalants prior to symptoms also predict evolving
allergic disease.
Even low levels of IgE antibodies to an allergen are of importance,
since they can predict a later development of symptoms caused by
this allergen.
IgE Antibodies to Food Early in Life
Predict Later IgE Antibodies to Inhalants
Development of positive Dermatophagoides
pteronyssinus IgE Values at 5 yrs of age
RAST IgEs at
six months of age
n
No.
%
Specific IgE for egg white
Positive finding
Negative finding
54
54
46
8
85*
15
31
94*
77
29
25
32
16
92
16
38
100*
41
Specific IgE for cow's milk
Positive finding
Negative finding
Specific IgE for soy
Positive finding
Negative finding
* p<0.001, by chi-square test
Reference: Data from Sasai et al., J Pediatr 1996; 128: 834-840
Asymptomatic Skin Sensitization to Birch May
Predict Development of Birch Pollen Allergy in
Adults
• Methods:
Asymptomatic adults were followed through use of daily diary cards
during 3 consecutive birch pollen seasons
15 +SPT for birch
15 non-atopic controls
6 birch pollen–allergic patients
At the 3-year follow-up visit, conjunctival and nasal challenges,
intradermal late-phase reaction evaluation, and measurement of
birch specific IgE were performed.
JACI 2003;111:149-54.
Asymptomatic Skin Sensitization to Birch May
Predict Development of Birch Pollen Allergy in
Adults
Results:
– Asymptomatic +SPT subjects had both birch specific IgE levels and
positive conjunctival provocation testing.
– Sixty percent (n = 9) of the asymptomatic sensitized subjects
developed clinical allergy in the three year period.
– The development of clinical allergic disease was associated with an
initial birch skin prick test wheal diameter of >4 mm.
– IgE antibodies ≥ 0.7kU/L (class 2) was 87.5% predictive of allergy
development
Conclusion: Positive skin prick test in an asymptomatic patient may
indicate potential for development of allergy in the future.
JACI 2003;111:149-54
A Comparison of SPT, ICT and IgE
Serology in the Diagnosis of Cat Allergy
Methods:
• 120 patients with asthma, with or without a history of cat allergy were
challenged with a characterized cat challenge model after a clinical history,
SPT, ICT and IgE Serology (ImmunoCAP® System).
• Challenge was positive if upper respiratory symptom score was >0.5, mean
lower respiratory symptoms score was > 0.4 or maximum fall in FEV1 was
> 15%
RA Wood, et al. JACI 1999;103:773
Diagnosis of Clinically Significant Cat
Sensitivity
Category
Positive Cat Challenge
SPT +
SPT ICT +
ICT IgE anti-Cat Serology +
IgE anti-Cat Serology -
38/41 (92.7%)
10/39 (25.6%)
6/26 (23.1%)
4/13 (30.8%)
27/27 (100%)
11/44 (25.0%)
• In patients with a negative SPT, there was no correlation between
positive or negative ICT and challenge results
RA Wood, et al. JACI 1999;103:773
Utility of In vivo and In vitro Diagnostic
Methods for Cat Allergy: Conclusions
• Both the SPT and IgE antibody serology (Immuno-CAP System) exhibited
an equivalent excellent efficiency (83.1%, 83.4%) in the diagnosis of cat
allergy.
• ICT results added little to the diagnostic evaluation, exhibiting a low
diagnostic efficiency (38.5%)
RA Wood, et al. JACI 1999;103:773
Quantification of IgE Antibodies in
Diagnosing Food Allergy
Objective:
Compare results of CAP system FEIA to outcome
of SPTs and Double Blind Placebo Controlled
Food Challenge (DBPCFC)
Population:
196/320 well characterized pediatric patients;
Age: mean 5.2 years [range: 0.6-18 years]
Gender: 117 male; 79 female
Evaluation:
IgE mediated reactions by history, SPTs,
DBPCFC and open challenges
Sampson and Ho 1997 100: 444-51
Performance Characteristics of
ImmunoCAP® at Cut-off 0.35 kU/L
No. pts pos/neg
egg
milk
peanut
soy
wheat
fish
145/51
95/101
136/60
34/162
23/173
52/144
sensitivity
98
100
97
94
96
94
specificity
45
30
38
25
20
65
Positive Predictive
value
84
57
78
21
14
49
Negative Predictive
value
88
100
85
95
97
97
Sampson, Ho.1997;100
Tests for Diagnosis of Food Allergy
Skin tests vs Challenge Test
• PPV of positive SPT - <50% vs DBPCFC
• NPV of negative SPT - >95% vs DBPCFC
Performance Characteristics of SPT at 3mm
vs DBPCFC
egg
milk
peanut
soy
wheat
fish
No. pts pos/neg
sensitivity %
specificity %
90/34
98
53
53/53
96
51
20/2199
0
29
29/78
76
47
19/659
90
51
11/79
0
57
Predictive value
Positive
Negative
85
90
66
93
55
75
35
84
35
94
77
80
Sampson, Ho, 1997;100
Size of SPT with 100% Likelihood of
Positive Open Challenge
milk
egg
peanut
Children 0-2yrs
≥6mm
≥ 5mm
≥ 4mm
Children all ages
≥ 8mm
≥ 7mm
≥ 8mm
Sporik et al Clin Exp Allergy 2000;30
Predictive Values for CAP RASTS vs
Challenges
95 % predictive value
– Egg:
7 Ku/L (2 Ku/L*)
– Milk:
15 Ku/L (5 Ku/L*)
– Peanuts: 14 Ku/L
– Fish:
20 Ku/L
Negative Predictive value = 95%
Sampson H. Ho D. JACI 2001
Diagnosis of Allergic Diseases
Summary
• The decision that the patient’s symptoms and clinical
signs represent an allergic disease is made by an
experienced clinician on the basis of the case history,
physical examination, and symptoms following
allergen exposure.
• Measurement of IgE antibodies by SPT or serological
assays confirm the presence of specific IgE antibodies
and are an essential adjunct in making a definitive
diagnosis of allergic disease.
World Allergy Organization (WAO)
For more information on the World Allergy Organization
(WAO), please visit www.worldallery.org or contact the:
WAO Secretariat
555 East Wells Street, Suite 1100
Milwaukee, WI 53202
United States
Tel: +1 414 276 1791
Fax: +1 414 276 3349
Email: [email protected]