1st Edition
PathologyForum
Allergy Investigations
06
Section 1:
An Introduction
to Diagnostic
Investigations for
Allergies
Section 2:
Interpretation of
IgE-mediated Allergy
Tests
08
26
Section 3:
A Practical Diagnostic
Approach to Inhalant
Allergies
12
28
14
20
Section 4:
A Practical Diagnostic
Approach to Food
Allergies
Section 5:
A Practical Diagnostic
Approach to Drug
Allergies
38
22
34
Section 6:
A Practical Approach
to Urticaria and
Angioedema
Section 7:
Contact Dermatitis:
Skin Patch Testing
Section 8:
Component Testing:
A New Era in Allergy
Diagnostics
Section 9:
Coeliac Disease and
other Gluten Related
Disorders
Section 10:
PathCare Allergy Test
Request Form
“Pathology that Adds Value”
www.pathcare.co.za
Pathology Forum Vol 4 No.3
Editorial Team
Editor
Elandi Bishop
Consulting Editor
Dr Dawie de Beer
Design and Layout
Thula Ngcobo
Lindsay Willenberg
Tara Willey
e-mail [email protected]
Management
CEO
Dr John Douglass
Chief Financial Officer
Ms Julie Buissinne
Human Resources Director
Mr Dumisani Ndebele
Chief Systems Officer &
Director of Special Operations
Dr Pierre Schoeman
Director of Pathology Operations
Dr Marthinus Senekal
A list of PathCare pathologists
is available on our website at
www.pathcare.co.za
From the Editor
With this issue of the PathCare Pathology Forum we aim to provide the clinician with a broad
overview of the current rationale on the work-up of allergic conditions and the laboratory
investigations available to identify specific allergens implicated by the patient’s history. In Section 1 of the Forum we provide a list of the test principles of the most common
diagnostic tests available in South Africa. Section 2 covers the interpretation and limitations of allergen specific-IgE tests and
in Sections 3 – 9 we look at diagnostic algorithms and systematic approaches to the
investigations of inhalant, food, and drug allergies as well as coeliac disease, angioedema
and urticaria. Lastly we include and example of our new PathCare Allergy Request Form available to
clinicians as well as our PathCare Patient Brochure on Allergies available via our depots. If you are interested in the Allergy Request Form or would like some Patient Brochures to
display in your waiting rooms, please let us know via email at [email protected] or
contact your local Client Services Officer.
We trust you will find this Pathology Forum informative and that it will be useful to you in
your day-to-day dealings with your patients.
Elandi Bishop
Main Features
Introduction Published March 2014 by:
Drs Dietrich, Voigt, Mia & Partners,
PathCare Business Centre,
PathCare Park ,
Neels Bothma Street, N1 City 7460,
Private Bag X107, N1 City 7463
Tel : (021) 596 3400
Fax : (021) 596 3726
Pictures and medical images are for
illustration purposes only and the
opinions expressed are those of the
authors
2
Pathology Forum Vol 4 No.3
4
Section 1:
An Introduction to Diagnostic Investigations for Allergies
6
Section 2:
Interpretation of IgE-mediated Allergy Tests
8
Section 3: A Practical Diagnostic Approach to Inhalant Allergies
12
Section 4: A Practical Diagnostic Approach to Food Allergies
14
Section 5: A Practical Diagnostic Approach to Drug Allergies
20
Section 6:
A Practical Approach to Urticaria and Angioedema
22
Section 7: Contact Dermatitis: Skin Patch Testing
26
Section 8: Component Testing: A New Era in Allergy Diagnostics
28
Section 9:
Coeliac Disease and other Gluten Related Disorders
34
Section 10: PathCare Allergy Test Request Form
38
Appendix 40
Main Author: Dr Mariana Lloyd
Acknowledgements:
We hereby gratefully acknowledge the following people who assisted with proofreading the articles in this forum: Dr Madaleen Olivier, Dr Esme Hitchcock, Dr S Jansen van Vuuren, Dr Wessel Meyer,
Dr Roberto Mattana, Dr Kevin Longmore, Dr S Weyers
March 2014
Questionnaire





his questionnaire has been accredited for 3 CPD points and you have to obtain a score of 70% or more to qualify for the points.
T
A certificate will be sent to you via email upon successful completion of the quesitonnaire.
Please note that only questionnaires submitted via the PathCare website will be accepted.
Please visit our website at www.pathcare.co.za to complete the electronic questionnaire.
Click on the "Media Centre" button at the bottom righthand side of the Home page on the PathCare website, to access the link to the
electronic questionnaire.
Indicate whether the following statements are TRUE or FALSE:
1.
The prevalence of allergic diseases worldwide is decreasing dramatically in both developed and developing countries.
2.
Allergic conditions markedly affect the quality of life of patients and their families, with a subsequent negative impact
on the socio-economic welfare of society.
3.
The diagnosis of allergy is solely based upon special laboratory investigations.
4.
Laboratory investigations for allergy are broadly divided into IgE-mediated and cell-mediated mechanisms.
5.
AST (Radioallergosorbent test) immunoassays for IgE-mediated allergies have largely been replaced by ImmunoCAP®
R
immunoassays.
6.
Serum tryptase can be used as a marker of mast cell activation in anaphylaxis.
7.
Skin prick tests are the qualitative in vivo alternative for an in vitro allergen-specific-IgE test.
8.
epending on the half-life time of the drug, antihistamines should be discontinued 2-3 days before an allergen-specific
D
IgE blood test (previously called RAST).
9.
The concentration of IgE antibodies (reported in kU/L) in the blood is considerably lower than those of IgG, IgA and IgM
antibodies (reported in g/L).
TRUE
FALSE
10. T
he likelihood of clinical reactivity (allergy) to an allergen is influenced by the allergen in question, degree of positivity
of the allergen specific-IgE and the patient’s clinical history.
11. D
isadvantages of skin prick tests for the confirmation of inhalant allergens include: unavailability of test, expensive and
drugs with antihistamine properties need to be discontinued before the test.
12. The Phadiatop® inhalant test can be used to confirm the presence of an individual allergen specific-IgE.
13. T
he term food allergy is reserved for immune-mediated adverse food reactions, whereas the term food intolerance is
used to refer to non-immune mediated reactions.
14. Food protein-induced enterocolitis (FPIES) is an example of a non-IgE mediated food allergy.
15. M
easurement of IgG-antibodies against food substances are accepted by the most allergy societies for the diagnosis of
food allergy.
16. In vitro tests available for the investigation of drug hypersensitivity reactions include: drug specific-IgE, basophil
activation tests (CAST) and lymphocyte stimulation tests (MELISA). 17. T
he type of laboratory investigation in the case of drug reactions is based upon the clinical manifestation and the
timing of the reaction after exposure to the drug in question.
18. C
hronic urticaria is defined as superficial oedematous skin lesions lasting for less than 24 hours, with attacks occurring
on most days of the week for more than 3 weeks.
19. Routine laboratory investigations are recommended in patients presenting for the first time with acute urticaria.
20. Isolated angioedema, in the absence of urticaria are always allergy-related, and should respond to systemic
antihistamines and corticosteroids.
21. The most common cause of chronic urticaria is possibly undiagnosed autoimmune urticaria.
22. T
he first line investigation in patients with suspected hereditary angioedema (HAE) includes Complement4 (C4) and
C-inhibitor concentration.
23. C
ontact dermatitis is a typical example of delayed immune response allergic reaction, and is typically diagnosed with
skin patch testing.
24. S
pecific-IgE to allergen-components may add additional diagnostic information by the prediction of cross-reactivity,
prediction of risk to cause symptoms or severe reactions and additional information on the heat-stability and
biodegradability of certain allergens in a multi-sensitised patient.
25. P
atients with a clinical milk allergy and specific-IgE antibodies only to the whey components of milk, will not be able to
tolerate any form of milk-containing food, as whey-proteins are heat stable and not destroyed in the cooking process.
26. A
patient sensitised to a peanut-specific component are more prone to severe allergic reactions following exposure to
or ingestion of peanuts compared to a patient sensitised to a cross-reacting peanut component.
27. A patient sensitised to the ovomucoid component of egg cannot tolerate any form of food containing egg.
28. The ISAC (Immuno solid-phase allergen chip) test is a 1st line investigation for severely allergic patients.
29. Patient sensitised to airborne house dust mite allergens may present later in life with food allergy to shrimp.
30. The initial screening test for coeliac disease is tissue transglutaminase IgA antibodies (TTG-IgA)
3
Pathology Forum Vol 4 No.3
Introduction
Allergy Investigations: Major
Irritation or Minor Aggravation?
Allergic diseases have shown a dramatic worldwide increase
DR MARIANA LLOYD
MBChB (UP), FCFP (SA),
FCPath (Chem) (SA),
MMed Chem. Path (UFS)
Chemical Pathologist
Tel: 051 401 4600 (Switchboard)
051 401 4676 (Direct)
Email: [email protected]
during the last two decades. In South Africa almost twentyfive per cent of the population are affected by an allergic
condition. This increasing prevalence represents a significant
load on the burden of disease in South Africa.
The effect on the individual suffering from an allergic
disease can be substantial. Allergic conditions can range
from common chronic conditions such as allergic rhinitis,
asthma, eczema and urticaria, to life-threatening conditions
such as acute asthma and anaphylactic reactions. Despite
the obvious significant impact that allergic diseases have
on an individual’s quality of life, these conditions are often
misdiagnosed, mismanaged or maltreated. Ineffective
diagnosis and management of allergic conditions may
drain resources over a prolonged period of time. The socioeconomic costs of allergic diseases can only be estimated,
and should not only take into consideration direct health
costs, but also indirect costs such as days lost in work or
school and lifestyle modification. Early accurate diagnosis
Definition of Allergy:
Allergy is a hypersensitivity reaction initiated
by immunological mechanisms. Allergy
can be antibody- or cell-mediated. In the
majority of cases the antibody typically
responsible for an allergic reaction belongs
to the IgE isotype and these individuals
of allergies can improve quality of life and reduce health
expenditure by early introduction of optimal management
such as allergen avoidance, and appropriate pharmacoand/or immunotherapy.
Diagnosing allergic conditions may be difficult, partly
because several other conditions share similar symptom
profiles, but also because there is no single gold standard
to achieve a reliable diagnosis of allergy. The diagnosis of an
may be referred to as suffering from an IgE-
allergic condition should be based on:
mediated allergy. IgE-mediated disease is
1. A careful evaluation of the patient’s exposure history
most typical for allergic rhinitis and asthma
but many variants of food and drug allergy
(description of the type of symptoms, timing between
exposure and symptoms and severity of symptoms, in
relation to an eliciting factor),
involve IgG and T-cell mechanisms.
2. Findings at physical examination,
Quoted from: ALLSA handbook of practical allergy, 3rd edition
Allergy tests need to be interpreted carefully. Their
3. Appropriately requested and interpreted laboratory test
results.
limitations should be realised and the results should always
be correlated with specific clinical reference, as a positive
allergen specific-IgE or skin test denotes only a sensitised
state (Figure 1). 4
Pathology Forum Vol 4 No.3
March 2014
List of figures – flaws fixed
HISTORY OF ALLERGIC
REACTION
DEMONSTRATION OF
SENSITISATION
Clinical signs and symptoms of
allergic reactivity to allergen
suggested by history
Presence of allergen specific-IgE
antibodies (or validated alternative
test) to allergen in question
ALLERGY
Symptomatic individual after
allergen exposure +
demonstration of sensitisation in
the individual
Figure 1. Allergy diagnosis is made based upon demonstration of sensitisation correlating with clinical symptoms in an individual.
The aim of this document is to provide clinicians with a broad
overview of the current rationale on the work-up of allergic
References
conditions and the laboratory investigations available to
identify specific allergens implicated by the patient history.
1. Green R, Motala C, Potter PC. ALLSA Handbook of practical
allergy. 3rd ed. The Republic of South Africa: Paarl Media; 2010.
A list with the test principles of the most common diagnostic
tests available in South Africa will be provided, followed by
2.
Potter PC. Investigation of the allergic patient: the importance of
3.
Motala C, Hawarden D on behalf of the Allergy Society of South
early diagnosis. CME 2005; 23(9):444-447.
a section on the interpretation and limitations of allergen
specific-IgE tests. Diagnostic algorithms and systematic
Africa. Diagnostic testing in allergy. SAMJ 2009; 99(7):531-535.
approaches to the investigations of inhalant, food, and drug
allergies as well as coeliac disease, angioedema and urticaria
4.
Morris A. Is allergy testing cost effective? Curr All & Clin Immunol
Figure 2: Schematic representation of an
2006; 19(1): 2-5.
will also be covered.
allergen specific-IgE assay principle.
The
allergen/allergen-components are covalently
the solid phase antibody. The patient’s
With a good history of allergic disease bound
and anto
understanding
serum containing IgE antibodies against the
of the allergy tests available, allergy diagnosis does not need
target allergen is added. The non-bound IgE
to be aggravating to the patient NOR
an irritation
to the away, and the bound IgE
antibodies
are washed
antibodies are detected by a signal (either
clinician.
radiolabel or enzyme-colorimetric label).
5
Pathology Forum Vol 4 No.3
Section 1
An Introduction to Diagnostic
Investigations for Allergies
The increasing global prevalence of allergic
diseases has become a major challenge for the
medical practitioner in South Africa. It is estimated
that 1 in 4 persons are affected by allergic
diseases that include asthma, allergic rhinitis,
atopic dermatitis, food allergy and anaphylaxis.
Early diagnosis of allergy and identification of
the allergic trigger may lead to appropriate
management of the patient, improving quality of
life for the patient, and reducing the burden on
the health system.
Diagnostic investigations (‘Allergy testing’) serves only to
confirm an allergic trigger suspected on the basis of the
patient’s clinical history. The different allergy tests are based
on the mechanism of the allergic reaction, which is generally
divided into two groups (Table 1):
A. IgE-mediated (Type I or immediate hypersensitivity)
allergy tests. This group includes tests such as total IgE,
allergen specific-IgE, skin prick tests and component
tests. Most of the inhalant allergies are IgE-mediated,
whereas approximately 50-60% of food allergies and less
than 5% of drug allergies are IgE-mediated.
B. Non IgE-mediated (Type III & IV or delayed
hypersensitivity) allergy tests. This group includes tests
such as basophil activation tests (CAST), T-cell mediated
tests such as MELISA and skin patch testing.
Summary:
Different allergy tests are offered by clinical laboratories to
aid in the diagnosis of an allergy. Knowledge of the available
allergy tests together with a careful, exposure-specific patient
history may lead to cost-effective allergy test requests.
Abbreviations and explanation of various in vitro
and in vivo allergy test methods:
Total IgE:
Specific-IgE:
6
he total IgE immunoassay quantitate the
T
total concentration of IgE antibodies in the
patient’s serum in kU/L units.
Specific-IgE refers to the measurement of a
group of IgE antibodies in the blood that
Pathology Forum Vol 4 No.3
recognises a specific allergen, reported
in kU/L. PathCare employs ImmunoCAP® (Thermofisher, Sweden) immunoassays.
RAST:
R
adioAllergoSorbent
Test.
The
first
immunoassays used to measure specificIgE’s employed radiolabeled indicators,
which has since been replaced by enzyme
labels. The name ‘RAST’ are sometimes still
used to refer to specific-IgE tests.
CAST:
Cellular Antigen Stimulation Test, also
called BAT (Basophil Activation Test).
Different reference ranges and units apply
to different methods/laboratories.
MELISA:
MEmory Lymphocyte Immune-Stimulation
Assay.
Phadiatop:
Phadia Differential Atopy Test is a
multi-allergen inhalant screening test
(ThermoFisher, Sweden – previously
Phadia).
ImmunoCAP®: A commercial immunoassay for measuring
specific-IgE (ThermoFisher, Sweden). Most
publications and clinical decision points
are based on ImmunoCAP® immunoassay
methods. Other immunoassays are
available, but there are no standardisation
between the different methods, and the
ImmunoCAP® decision points may not
apply to the other methods.
ISAC:
Immuno Solid-phase Allergen Chip
measures allergen components semiquantitatively in ISU units.
SPT:
Skin Prick Test.
Tryptase:
Histamine and tryptase are released from
mast cells during anaphylaxis but the
short half life of histamine (1-2 minutes)
make it impractical as marker for diagnosis
of anaphylaxis. The half life of tryptase is
approximately 90 minutes.
References and further reading:
1. Potter PC. Investigation of the allergic patient: the importance of
2.
3.
early diagnosis. CME 2005; 23(9):444-447.
reen R, Motala C, Potter PC. ALLSA Handbook of practical
G
allergy. 3rd ed. The Republic of South Africa: Paarl Media; 2010.
Motala C, Hawarden D on behalf of the Allergy Society of South
Africa. Diagnostic testing in allergy. SAMJ 2009; 99(7):531-535.
March 2014
Table 1. Summary of available diagnostic investigations for allergies, grouped according to allergy mechanism.
OTHER
CELL MEDIATED
Delayed hypersensitivity
IGE-MEDIATED ALLERGY - RAST
Type I hypersensitivity
TEST
PRINCIPLE
SPECIAL PRECAUTIONS
Increased total IgE levels can suggest allergy as a cause of
symptoms, but has limited specific diagnostic value. There is
a large degree of overlap between IgE levels in persons with
and without allergic disease, limiting the utility of total IgE in
diagnosing allergy. Specific clinical situations in which total
IgE levels may be helpful include:
Total IgE
• Parasitic infections, allergic bronchopulmonary
aspergillosis, hyperimmunoglobulin E syndrome and
occasionally haematological malignancies
• Evaluation of patients eligible for anti-IgE treatment
(not yet available in RSA).
The Phadiatop ImmunoCAP® assay is the most reliable in
vitro test to screen for possible allergy to inhalant allergens.
Phadiatop inhalant
A positive test should be followed by a panel of common
screen
inhalant allergen specific skin prick tests or an ImmunoCAP®
specific-IgE test to the relevant individual allergens.
Specific-IgE against a mixture of the most common food
No special preparation or
allergens e.g. nut mix (fx1), seafood mix (fx2), cereal/wheat
arrangements is necessary.
mix (fx3) or paediatric food mix (fx5). A positive result
ImmunoCAP® food
reliably indicates that the patient has allergen specific-IgE to
Medication does NOT interfere
mix screen
one or more of the constituent allergens incorporated in the
with in vitro IgE based tests.
allergen mix, and should be followed with an individual
ImmunoCAP® test to identify the responsible allergen.
Specific-IgE against an individual allergen e.g. pollen, mould,
Individual specific- mites, animal dander, food, drugs, insect venoms etc. The
IgE (ImmunoCAP®) range of allergens is extensive and tests should be requested
selectively according to clinical history.
Specific-IgE against individual allergen components may
Individual allergen yield information regarding allergen avoidance, severity of
component testing reactions, cross-reactivity of allergens or bio-stability of the
allergen in question.
The ISAC® comprehensive allergy profile test for specific-IgE
to 112 allergen components from 51 sources. This test is
Immuno Solid-Phase
recommended for multisensitised patients. It may add
Allergen Chip
additional diagnostic information by predicting cross
(ISAC®)
reactivity and the risk for severe reactions, as well as
additional information on the heat stability and
biodegradability of allergens.
SPT are used to identify immediate IgE-mediated
hypersensitivity against a group of allergens by measuring
Patient should be antihistamine
Skin Prick Tests
the wheal reaction of an allergen against a positive histamine
free for at least 72 hrs prior to
(SPTs)
control. SPT should be offered only by trained and
testing.
experienced personnel. Enquire at your local laboratory
regarding availability of SPT in your region.
Skin Patch Tests
For contact
dermatitis
CAST tests/
Basophil activation
tests
MELISA
Lymphocyte
stimulation test
Tryptase
The suspected contact dermatitis allergens are placed in
small finn chambers and kept in place on the patient’s skin
for 48 hrs with hypoallergenic tape. The patches (allergens)
are removed after 48 hrs, after which the reactions are then
evaluated immediately, at 72 and 96 hrs for a reaction.
Food additive- and drug allergies are most often non-IgEmediated and diagnosis can be confirmed by measuring the
basophil activation after stimulating the cells in vitro with the
allergen in question.
Tests mainly for metal allergies (e.g. amalgam in
prosthesis/dental implants), and some drug and food
allergies by measuring the lymphocyte proliferation after in
vitro stimulation with the allergen in question.
Patient should be systemic
steroid free for at least 2-4 weeks
(systemic steroids) prior to
testing. Pre-arrangement with the
laboratory is necessary.
Serum tryptase can be used as a marker of mast cell
activation in anaphylaxis, although the diagnosis of
anaphylaxis remains a clinical diagnosis. A significant rise in
serum tryptase levels from the individual’s baseline levels
are regarded as confirmation of anaphylaxis (mast cell
degranulation). Serum tryptase may also be increased in
systemic mastocytosis.
For the confirmation of
anaphylaxis three measurements
are recommended: 1st shortly
after the reaction (1 - 2 hrs), the
next 3 - 4 hours later, and the
last specimen 14 hrs after the
reaction.
Patient should be systemic
steroid free for at least 3-6 weeks
prior to testing. Testing should be
postponed for approximately 2
weeks after an anaphylactic/
severe reaction. Pre-arrangement
with the laboratory is necessary.
7
Pathology Forum Vol 4 No.3
Section 2
Interpretation of IgE-mediated
Allergy Tests (RAST)
Laboratory assays for allergen specific-IgE (sIgE)
are most often used to confirm the suspected
clinical diagnosis of allergic disease. This is a
relatively new test in laboratory medicine, as
the IgE antibody was only discovered in the
late 1960’s. The methods used to analyse IgE
antibodies require considerable experience as it
is complicated by several factors:
 The concentration of IgE antibodies in the
blood is considerably lower (ng/L vs g/L) than
other antibodies in the serum
 Each allergen protein contains multiple
allergenic components or epitopes that IgE
antibodies may recognise
 The allergen used in the assay should be
standardised to ensure reproducibility
between batches and methods.
The allergen sIgE assay should therefore
be sensitive to capture low concentrations
of antibodies and also use allergens from
standardised sources that contain all of the
allergenic epitopes related to the specific
allergen.
The initial laboratory assays for quantifying serum sIgE used a
radioisotope for labelling antibodies in the immunoassay. This
methodology, known as Radioallergosorbent test (RAST) has
since been replaced with newer technology, where enzyme
labelled indicators are used as markers in the assays. Although
it is incorrect, the term ‘RAST’ is still used to refer to allergen
sIgE tests.
Allergen specific-IgE tests have specific limitations that might
diminish its value:
 Cross-reactivity may occur, leading to clinically irrelevant
positive test results
 Negative results may occur as not all allergens and
allergen components have yet been characterised, and
some allergens’ allergenicity may be altered during
reagent preparation
 A positive result does not predict the presence of allergy
nor the severity of the reaction.
Interpretation of sIgE results:
Ideally a laboratory-test for a specific condition should yield
either a positive or a negative result with a 100% sensitivity
and specificity. Unfortunately, despite the development of
current generation of assays for IgE, the role of the laboratory
in the diagnosis of allergic diseases remains limited. It
functions mainly to confirm strongly suspected clinical
diagnoses based on patient history and physical exam. When
using published ‘decision points’ for certain sIgE tests it is
important to take the following factors into consideration:
1.Prevalence of allergic disease in the population being
tested
The predictive value of an allergy test is the probability
that a subject with a positive test have an allergic
condition, or the probability that a subject with a negative
Figure 2: Schematic representation of an allergen specific-IgE assay
principle. The allergen/allergen-components are covalently bound to
the solid phase antibody. The patient’s serum containing IgE antibodies
against the target allergen is added. The non-bound IgE antibodies are
washed away, and the bound IgE antibodies are detected by a signal
(either radiolabel or enzyme-colorimetric label).
8
Pathology Forum Vol 4 No.3
test does not have an allergy (refer to Tables 2 and 3). The
predictive value of a test is influenced by the prevalence
of the disease investigated in the specific population.
If we use an allergy test with a sensitivity of 90% and a
specificity of 90% in: March 2014
-
An asthmatic population with a prevalence of allergic disease of 70% - the PPV of the test will
increase
to1 96%
and the 10:14:17
NPV
willAM
to 79%
(refer todisease
Table 5).of 70% - the PPV of the test will
2014/02/25
- An
asthmatic
population
with
adecrease
prevalence
of allergic
increase to 96% and the NPV will decrease to 79% (refer to Table 5).
When
sIgEpopulation
test resultswith
it is athus
important
consider
the prevalence
of allergy
thetest
patient
- interpreting
An asthmatic
prevalence
oftoallergic
disease
of 70% - the
PPV ofinthe
will
the
population
being
tested:
the
higher
the
prevalence
of
allergic
disease
in
the
patient
population
group,
increase
to
96%
and
the
NPV
will
decrease
to
79%
(refer
to
Table
5).
When interpreting sIgE test results it is thus important to consider the prevalence of allergy in the patient
higher
the predictive
valuethe
of ahigher
positive
test. of allergic disease in the patient population group, the
population
being and
tested:
theallergy
prevalence
Table 2. Definitions
abbreviations
of sensitivity,
specificity, predictive values and prevalence.
When
interpreting
sIgE
test
results
it
is
thus
important
to consider the prevalence of allergy in the patient
higher the predictive value of a positive allergy test.
Positive
predictive
value
(PPV)
Proportion
of true
test
results
among
all positive
test results
Table
2. Definitions
abbreviations
of sensitivity,
specificity,
predictive
valuesinand
population
being and
tested:
the higher
the
prevalence
of positive
allergic
disease
theprevalence.
patient
population
group, the
Negative
predictive
value
(NPV)
Proportion
of
true
negative
test
results
among
all
negative
test
results
higher
the
predictive
value
of
a
positive
allergy
test.
Positive
predictiveand
value
(PPV)
Proportionspecificity,
of true positive
test results
among
all test results
Table
2. Definitions
abbreviations
of sensitivity,
predictive
values and
prevalence.
FIGURES 1.pdf
Sensitivity
(Sens) value
Proportion
results
among
patients
with
the
disease
Negative
predictive
value(PPV)
(NPV)
Proportion
true
results
among
patients
with
the disease
Positive predictive
Proportion of
of positive
true negative
positive
test
results
among
all test
results
Table
2. Definitions
abbreviations
of sensitivity,
predictive
values
and patients
prevalence.
Sensitivity
(Sens) and
Proportionspecificity,
of negative
positive
results
among
patients
with
the
Specificity
(Spec)
Proportion
results
among
healthy
patients
Negative
predictive
value
(NPV)
Proportion
of
true
negative
results
among
withdisease
the disease
Specificity
(Spec)
Proportion
of true
negative
results
among
patients
Positive
predictive
Proportion
of
test
results
among
all test
Sensitivity
(Sens)
positive
results
among
with
theresults
disease
Prevalence
(Prev) value (PPV)
The
total number
ofpositive
existing
cases
in patients
ahealthy
population
Prevalence
(Prev) value (NPV)
The total number
of
existing
cases
in
ahealthy
population
Negative
predictive
of true
negative
results
among
patients
with the disease
Specificity
(Spec)
negative
results
among
patients
TP
= True positive,
TN = True negative, FNProportion
= False negative,
FP
= False
positive
TP
=
True
positive,
TN
=
True
negative,
FN
=
False
negative,
FP
=
False
positive
Sensitivity
(Sens)
Proportion
of
positive
results
among
patients
with the disease
Prevalence (Prev)
The total number of existing cases in a population
Specificity
(Spec) TN = True negative, FNProportion
of negative
results
among healthy patients
TP
= True positive,
= False negative,
FP = False
positive
Table
3. Classification
of positive and negative
tests
results
using definitions
of sensitivity, specificity, positive- and
Prevalence
(Prev)
The total
number
of existing
cases in a population
negative
predictive
values.
TP
=
True
positive,
TN
=
True
negative,
FN
=
False
negative,
FP
=
False
positive
Table 3. Classification of positive and negative tests results using definitions of sensitivity, specificity, positive- and
negative
predictive values. Positive result
Classification
Negative result
Total
Table 3. Classification of positive and negative tests results using definitions of sensitivity, specificity,Sensitivity%
positive- and
Classification
Positive
result
Negative
result
Total
TP+FN
Patients
with values.
TP
FN
negative
predictive
Sensitivity%
True Positive
False Negative
(Prevalence)
allergy
Patients with
TPresult
FN result
TP+FN
Classification
Positive
Negative
Total
allergy
True Positive
False Negative
(Prevalence)
Specificity%
Sensitivity%
Patients
FP
TN
Patientswithout
with
TP
FN
TP+FN
FP+TN
Specificity%
allergy
False
Positive
True Negative
allergy
True Positive
False
Negative
(Prevalence)
Patients
without
FP
TN
FP+TN
allergy
False
Positive
TrueTN+FN
Negative
Total
TP+FP
TP+TN+FP+FN
Specificity%
Patients without
FP
TN
Negative
Predictive
value%
Positive
Predictive
value%
FP+TN
Total
TP+FP
TN+FN
TP+TN+FP+FN
allergy
False Positive
True Negative
Negative Predictive value%
Positive Predictive value%
Total
TP+FP
TN+FN
TP+TN+FP+FN
Negative
Predictive
value%
Positive Predictive value%
Table 4. Classification of positive and negative tests results in a healthy population (n = 100) with an allergy prevalence
of 20%,
an allergy
with and
90%negative
sensitivity
andresults
90% specificity.
Table
4.using
Classification
oftest
positive
tests
in a healthy population (n = 100) with an allergy prevalence
of 20%,
using an allergy test with
90% result
sensitivity and 90% specificity.
Classification
Positive
Negative result
Total
Table
4.
Classification
of
positive
and
negative
tests results in a healthy
prevalence
Patients with
18
2 population (n = 100)
20with an allergy
Sensitivity%
Classification
Positive
result
Negative result
Total
of 20%,
using an allergy test with
90%
allergy
TP sensitivity and 90% specificity.
FN
Prevalence
= 90%
Patients with
18
2
20
Sensitivity%
Patients
without
8
72
Specificity%
allergy
TP
FN
Prevalence
= 90%
80
Classification
Positive
result
Negative
result
Total
allergy
FP
TN
= 90%
Patients
without
8
72
Specificity%
Patients with
18
2
20
Sensitivity%
80
Total
26
74
100
FP
TN
allergy
TP
FN
Prevalence
= 90%
Positive Predictive
value%
Negative Predictive
value%
Patients
without
8
72
Specificity%
Total
26
74
100
80
69%
97%
allergy
FP
TN
= 90%
Positive Predictive
value%
Negative Predictive
value%
Total
26
74
100
69%
97%
Predictive
value% testsNegative
value%population (n = 100) with an allergy
Table 5. Classification Positive
of positive
and negative
results Predictive
in an asthmatic
69%
97%specificity.
prevalence
of
70%,
using
an
allergy
test
with
90%
sensitivity
and
90%
Table 5. Classification of positive and negative tests results in an asthmatic population (n = 100) with an allergy
prevalence
of 70%, using an allergy
test
with 90% sensitivity Negative
and 90% specificity.
Classification
Positive
result
result
Total
Table
5. Classification
of positive 63
and negative tests results in an
asthmatic population70(n = 100) with
an allergy
Patients
with
7
Sensitivity%
Classification
Positive result
Negative result
Total
allergy
FNspecificity.
Prevalence
= 90%
prevalence
of 70%, using an allergyTP
test with 90% sensitivity and 90%
Patients with
63
7
70
Sensitivity%
Patients without
3
27
Specificity%
allergy
TP result
FN
Prevalence
= 90%
30
Classification
Positive
Negative
Total
allergy
FP
TN result
= 90%
Patients
3
27
Specificity%
Patientswithout
with
63
7
70
Sensitivity%
30
Total
66
34
100
FP
TN
allergy
TP
FN
Prevalence
= 90%
Positive Predictive
value%
Negative Predictive
value%
Patients
without
3
27
Specificity%
Total
66
34
100
30
96%
79%
allergy
FP
TN
= 90%
Positive Predictive
value%
Negative Predictive
value%
Total
66
34
100
96%
79%
2. Test method and reference
Positiveranges
Predictive value%
Negative Predictive value%
is96%
particularly important to consider
the test method when using published
79%
2. For
Testcertain
methodsIgE
and allergens
referenceitranges
‘decision
points’,
as there isitno
of quantitative
results
different
testusing
methods.
Most
For certain
sIgE allergens
is standardisation
particularly important
to consider
thebetween
test method
when
published
the
published
data
are
based
on
the
ImmunoCAP®
assay
(ThermoFisher,
Sweden).
PathCare
uses
the
2. of
Test
method
and
reference
ranges
‘decision points’, as there is no standardisation of quantitative results between different test methods. Most
ImmunoCAP®
method
for
all
allergen
sIgE
tests.
For
certain
sIgE
allergens
it
is
particularly
important
to
consider
the
test
method
when
using
published
of the published data are based on the ImmunoCAP® assay (ThermoFisher, Sweden). PathCare uses the
‘decision
points’,
as there
is no
standardisation
ImmunoCAP®
method
for all
allergen
sIgE tests. of quantitative results between different test methods. Most
of the published data are based on the ImmunoCAP® assay (ThermoFisher, Sweden). PathCare uses the
PathCare:ImmunoCAP®
Allergy investigations
10 December
2013
7
method
for all allergen
sIgE tests.
PathCare: Allergy investigations 10 December 2013
7
PathCare: Allergy investigations 10 December 2013
7
9
Pathology Forum Vol 4 No.3
List of figures – flaws fixed
HISTORY OF ALLERGIC
REACTION
DEMONSTRATION OF
SENSITISATION
ALLERGY
Symptomatic individual after
Clinical signs and symptoms of
Presence of allergen specific-IgE
allergen exposure +

A healthy population
of allergic(or validated
3.Other
factors
allergic
reactivity
to allergenwith a prevalence
antibodies
alternative
demonstration of sensitisation in
suggested
history
diseaseby
of 20%
- the PPV (positive predictive
value)
inTquestion
he likelihood of clinical reactivity is
theinfluenced
individualby
test)
to allergen
of the test will be 69% and the NPV (negative
the degree of positivity, the allergen in question, and
predictive value) 97%, which means that the
the specific patient’s clinical history. The higher the
will have a clinical allergy is only 69%, but the
to experience symptoms upon exposure to the allergen
Figure 1. Allergy
diagnosis
based
demonstration
of sensitisation
correlating
with
symptoms
inisan individual.
probability
thatis amade
subject
withupon
a positive
test
concentration
of antibodies,
theclinical
more likely
the patient

probability that a subject with a negative test will
(Figure 3). However, low concentrations of antibodies to a
not have an allergy is 97% (refer to Table 4) specific allergen still denote a certain degree of probability
An asthmatic population with a prevalence of
for a clinical reaction, which is the case in especially drugs,
allergic disease of 70% - the PPV of the test will
venoms and nuts. The exact relationship between sIgE
increase to 96% and the NPV will decrease to 79%
and disease activity is not clearly understood, and further
(refer to Table 5).
studies are needed to investigate this relationship.
When interpreting sIgE test results it is thus important to
consider the prevalence of allergy in the patient population
Reporting of allergen sIgE results:
being tested: the higher the prevalence of allergic disease in
ImmunoCAP® sIgE results are reported in quantitative units
the patient population group, the higher the predictive value
namely kU/L. The assay’s lower limit of detection is 0.10 kU/L,
of a positive allergy test.
therefore undetectable sIgE concentrations are reported as
less than 0.10 kU/L. Previously the lower limit of detection on
2.Test method and reference rangesFigure
2: Schematic representation
of anwas 0.35 kU/L, and older studies will
the older immunoassays
allergenimportant
specific-IgE
assay
The
For certain sIgE allergens it is particularly
to
quote aprinciple.
positive sIgE as
> 0.35 kU/L. Detectable allergen levels,
allergen/allergen-components
covalently is below 0.35 kU/L should always
consider the test method when using
published ‘decision
even if are
the concentration
boundoftoquantitative
the solid phase antibody.
Thewith
patient’s
points’, as there is no standardisation
be correlated
clinical symptoms, as some allergens may
serum
containing
IgE
antibodies
against
the
results between different test methods. Most of the
cause clinical symptoms
even at low concentrations. For most
target
allergen
is
added.
The
non-bound
IgEof clinical symptoms does increase
published data are based on the ImmunoCAP® assay
allergens, the likelihood
antibodies are washed away,
and the bound IgE
(ThermoFisher, Sweden). PathCare uses the ImmunoCAP®
at higher concentrations of sIgE (Table 6). Diagnostic cut-off
antibodies are detected by a signal (either
method for all allergen sIgE tests.
points have been proposed in a number of studies with a 95%
radiolabel or enzyme-colorimetric label).
Figure 3. The relationship between sIgE antibody and the probability of a clinical reaction. The higher the
concentration of sIgE, the higher the probability to be allergic to the specific allergen. The diagnosis of
allergy remains mainly dependent on the clinical history, limiting the diagnostic role of the laboratory test.
10
Pathology Forum Vol 4 No.3
1
March 2014
FIGURES 2.pdf
1
2014/02/25
10:46:22 AM
Table 6. Generic reference ranges for sIgE (ImmunoCAP®, ThermoFisher).
Range (kU/L)
Class
Level
< 0.10
Undetectable
0.10 – 0.35
Detectable, low
0.36 – 0.69
1
Low
0.70 - 3.49
2
Moderate
3.50 – 17.40
3
High
17.50 – 49.0
4
50.0 – 99.0
5
>100.0
6
Very high
Interpretation and management options
Consider causes other than IgE-mediated allergy to explain the symptoms
In rare cases patients with antibody levels in this range may experience
clinical symptoms. Correlate with clinical findings.
Increased sIgE to an allergen only indicates sensitisation. A diagnosis of
IgE-mediated allergy requires evidence of both sensitisation and clinical
reactivity. Consider
- Allergen avoidance
- Desensitisation
- Symptomatic treatment
PPV for the major food allergens. The studies also discriminate
between age groups for certain allergen sIgE e.g. egg and
References and further reading:
cow’s milk proteins (refer to Section 4, Table 9). It is important
to note that the studies were performed on the ImmunoCAP®
1.
sIgE method, and that different reference ranges and
of the clinical use of specific-IgE antibody testing in allergic
predictive values may apply to different sIgE methods.
diseases. Allergy 2003; 58:921-8.
2.
Lopata A. Laboratory methods in allergology. Curr All Clin
3.
Plebani M. Clinical value and measurement of specific-IgE. Clin
Conclusion:
The selection of allergy diagnostic tests and interpretation of
allergen sIgE antibody results MUST be guided and viewed
Söderström L, Kober A, Ahlstedt S et al. A further evaluation
Immunol 2006; 19(3):152-4.
Biochem 2003; 36:453-469.
within the context of the patient’s clinical history, regardless
of reported diagnostic cut-off points.
11
Pathology Forum Vol 4 No.3
Section 3
A Practical Diagnostic Approach
to Inhalant Allergies
Airborne or inhalant allergens usually cause either respiratory (e.g. rhinitis and/or asthma) or
ophthalmological (e.g. conjunctivitis) symptoms in sensitised patients. Airborne allergens cause mainly
IgE-mediated allergies, and both in vivo (skin prick test) and in vitro (allergen specific-IgE) methods are
used to demonstrate sensitisation. A diagnostic algorithm for the identification of inhalant allergens is
demonstrated in Figure 4.
Section 3
 Ito
n most
regions in
South Africa always consider testing for
The importance of a patient’s
exposure and
clinical history
A Practical
Diagnostic
Approach
Inhalant
Allergies
house dust mites, cat and dog dander, grass pollen and
cannot be emphasized enough. Preluding knowledge of
allergens
the
possible
in usually
the patient’s
Airborne
orinhalant
inhalantallergens
allergens
causeenvironment,
either respiratory (e.g.mould
rhinitis
and/or asthma) or ophthalmological (e.g.

Tree
andmainly
weed pollen
indigenous
to theand
geographical
that
may be responsible
symptoms,
canAirborne
make allergens
conjunctivitis)
symptomsforinhis/her
sensitised
patients.
cause
IgE-mediated
allergies,
both in
area
where
the patient resides
should beAadded
to the
allergy
testing
lesstest)
expensive
rewarding.
General methods are
vivo (skin
prick
and in and
vitromore
(allergen
specific-IgE)
used
to demonstrate
sensitisation.
diagnostic
inhalant
test 4.
panel.
guidelines
allergens are:
algorithmfor
forinhalant
the identification
of inhalant allergens is demonstrated
in Figure
History and clinical suspicion of inhalant allergy
Allergic rhinitis,
Asthma, and/or
Conjunctivitis
High suspicion of allergy & no clear history
of individual suspected inhalant allergen
Low suspicion of allergy
High suspicion of allergy & clear history of
individual suspected inhalant allergen
‘Screening’ tests
± Total IgE
levels*
Skin Prick Tests (SPTs)
Negative
PHADIATOP inhalant screen
Positive
Negative
Individual, allergen
specific-IgE tests
Positive
Negative
Positive
Correlate with clinical
findings: Confirms inhalant
allergy
Inhalant allergy unlikely
Correlate with clinical findings:
Confirms inhalant allergy for
specific allergen
TREATMENT including avoidance
measures and immunotherapy (if
indicated)
∗
Total IgE may be positive in non-allergic conditions e.g. parasite infestation, and total IgE may be well within normal limits even in the face of
a severe allergy in a small organ (e.g. the nose), 40% of all atopic children have normal total IgE levels.
Figure 4. Approach to the identification of inhalant allergens.
12
The importance of a patient’s exposure and clinical history cannot be emphasized enough. Preluding knowledge of
the possible inhalant allergens in the patient’s environment, that may be responsible for his/her symptoms, can make
allergy testing less expensive and more rewarding. General guidelines for inhalant allergens are:
∗ In most regions in South Africa always consider testing for house dust mites, cat and dog dander, grass pollen
and mould allergens
Pathology Forum Vol 4 No.3
March 2014
the sIgE tests are that they are more standardised, results are quantitative, medications and skin conditions do not
interfere, and expert personnel are not needed on site. The cost of sIgE is a major disadvantage, but considerable
costs may be saved if tests are selected according to the patient-history or when a patient is being worked-up for
desensitisation therapy.
Table 7. Drugs that may inhibit the wheal-and-flare reaction of a SPT, leading to false negative results.
Drugs that inhibit SPTs reactions
Corticosteroids: Low dose inhaled and short-term corticosteroids generally don’t suppress the
wheal and flare reaction, although larger doses may do so.
Histamine H2-receptor antagonists: e.g. cimetidine or ranitidine have a limited inhibitory effect
1st generation antihistamines
2nd generation antihistamines
Anticholinergic agents, phenothiazine and tricyclic antidepressants
Abstention period
No Abstention
1 Day
2 Days
3 – 10 Days
2 Weeks
Table 8. This table compares SPT with sIgE testing.
IN VIVO TEST: SKIN PRICK TESTS (SPTS)
IN VITRO TEST: SPECIFIC -I G E TESTS
Description of test:
Description of test:
Purified allergen extract is placed on the skin. The skin is then
pricked with a special lancet, in a standardised manner. The test
site is then evaluated after 20 minutes for a wheal-and-flare
reaction (secondary to histamine release from mast cells).
Allergen sIgE is quantified with an immunoassay method. The test
is standardised, reproducible and quality control measures are
usually applied. Medications do not interfere with test.
Interpretation:
-
Types of sIgE tests:
Mixed allergen sIgE: This is used to screen for increased
specific-IgE against a ‘group of allergens’. A positive result
indicates that a patient has allergen sIgE to one or more of
the constituent allergens incorporated in the allergen mix,
and the serum sample should be analysed for individual sIgEs
to allergens included in the group test. A negative result
reliably excludes any of the allergens included in the group
Individual allergen sIgE: This is used to confirm or exclude
increased IgE to a specific allergen.
The wheal and erythema surrounding each reaction is evaluated
after 15-20 minutes. A positive reaction is interpreted as a wheal 3
mm or larger than the ‘negative control’. The presence of a
reaction at the ‘positive (histamine) control’ is necessary to
confirm the absence of antihistamines in the subject’s system.
Prerequisites:
-
Experience is needed for the performance and interpretation
of SPTs
Facilities to manage possible anaphylactic reactions are
essential
Patient need to discontinue drugs with antihistamine
properties 3 to 5 days (depending on t½) prior to the test.
Contraindications:
-
Skin: dermatographism, eczema on testing area, SPT may be
difficult to interpret on a very darkly pigmented skin
Allergens: certain allergens such as penicillins, bee venom,
peanut etc. have a high risk for anaphylactic reactions
Drugs: Antihistamines may suppress SPT reactions
Age: SPT may be difficult to do and/or interpret in very young
or old patients
Pregnant patients: SPT should generally be avoided due to
risk of systemic reactions.
-
Phadiatop inhalant screen consists of:
A mixture of inhalant allergens, which may include: house dust
mites, grass, tree, and weed pollens, animal epidander and
moulds.
Indications for blood tests:
-
Patients with a clinical history that indicate increased risk of
anaphylaxis
Patients taking long-acting antihistamines, tricyclic
antidepressants, or drugs that inhibit the response to
allergens in skin tests
Very young or very old patients may have a reduced
histamine reactivity in SPTs
Patients with any other contraindication for SPT.
-
-
Profile consists of:
Positive and negative controls, cat and dog epidander, feather mix,
house dust mite, moulds, grass, tree and weed pollens applicable
to specific regions.
Both the skin prick tests (SPT) and the allergen specific-IgE
Summary:
Summary:
(sIgE)
tests
have
similar
diagnostic
properties.
Advantages
of
the SPT
and the sIgE
can besuspected
used to identify
the
Both the SPT and the sIgE tests can be used to identify theBoth
allergen
responsible
fortests
clinically
inhalant
the
SPT
include
immediate
results,
lower
cost
and
it
is
useful
allergen
responsible
for
clinically
suspected
inhalant
allergies.
allergies. The pros and cons of each test should be considered when selecting the test.
to motivate the patient, as they are involved in diagnostic
The pros and cons of each test should be considered when
process. Disadvantages
include the need to withhold
References
and further reading:
selecting the test.
1. Motala
C, Hawarden
D on behalf
of the(see
Allergy
Society
of South Africa. Diagnostic testing in allergy. SAMJ 2009; 99(7):531-535.
medications
with
antihistamine
properties
Table
7) and
rd
2. Green
R, Motalaskin.
C, Potter
PC. ALLSA personnel
Handbook ofare
practical
3 ed. The Republic of South Africa: Paarl Media; 2010.
requiring
a rash-free
Experienced
also allergy. References
and2005;
further
reading:
3. Potter PC. Investigation of the allergic patient: the importance of early diagnosis. CME
23(9):444-447.
required to do and interpret the test. Advantages for the
4. Potter PC. Common indoor and outdoor aeroallergens in South Africa. CME 2010; 28(9): 426-432.
1. Motala
C, Hawarden D on behalf of the Allergy Society of South
sIgE tests
that they are more standardised, results
are by: dr SP Jansen
Written
by: M.are
Lloyd
Reviewed
van Vuuren
quantitative, medications and skin conditions do not interfere,
PathCare: Allergy investigations 10 December 2013
and expert personnel are not needed on site. The cost of sIgE
is a major disadvantage, but considerable costs may be saved
if tests are selected according to the patient-history or when a
patient is being worked-up for desensitisation therapy.
2.
3.
4.
Africa. Diagnostic testing in allergy. SAMJ 2009; 99(7):531-535.
Green R, Motala C, Potter PC. ALLSA Handbook of practical allergy.
10
3rd ed. The Republic of South Africa: Paarl Media; 2010.
Potter PC. Investigation of the allergic patient: the importance of
early diagnosis. CME 2005; 23(9):444-447.
Potter PC. Common indoor and outdoor aeroallergens in South
Africa. CME 2010; 28(9): 426-432.
13
Pathology Forum Vol 4 No.3
Section 4
A Practical Diagnostic Approach
to Food Allergies
Any abnormal reaction resulting from the ingestion of a food is considered an adverse food reaction.
In the evaluation of a patient with a history of an adverse reaction to food, one must consider the broad
differential diagnosis before labelling the patient as ‘allergic to food’. Adverse food reactions are broadly
divided into toxic and non-toxic reactions (Figure 5). Toxic substances in food may affect any exposed
individual, whereas non-toxic reactions are highly individual, and depends on genetic, epigenetic
and environmental factors. Non-toxic reactions are grouped in immune mediated and non-immune
mediated reactions. The term food allergy is reserved for adverse reactions that involve the immune
system. The term food intolerance is generally used in relation to non-immune mediated reactions. While
the scientific basis of toxic and allergic (immune mediated) reactions to food is well established, the nonimmune mechanism of some types of food intolerance is less well defined.
Food allergy:
Food allergy may be due to IgE-mediated, non IgE-mediated or a combination of IgE- and non IgE-mediated reactions involving
the skin, gastrointestinal tract, respiratory tract and/or cardiovascular system. The prevalence of food allergy is approximately 6% in
children less than 5 years of age, and about 3.5 - 4% in the general population.
IgE mediated food allergy:
The best characterised food allergies involve the IgE-mediated immune mechanism. A failure to develop oral tolerance to food
allergens (antigens) may lead to an excessive production of IgE-antibodies to the specific food. IgE-mediated allergies present
Adverse reactions to food
Non-Toxic
Toxic
e.g. Food poisoning
Immune mediated
FOOD ALLERGY
Non-immune mediated
FOOD INTOLERANCE
IgE-mediated
Non IgE-mediated
Enzymatic
Pharmacological
Undefined
e.g. anaphylaxis to
food
e.g. Coeliac’s disease,
food protein induced
enterocolitis
e.g. Lactose or
histamine
intolerance
e.g. Reaction to food
additives
e.g. Irritable bowel
syndrome
Figure 5. The classification of adverse food reactions, as proposed by the EAACI-Position paper on Adverse Reactions to Food.
14
Pathology Forum Vol 4 No.3
Obtain history: dates of administration, drug formulation, dosage, route of administration, type of reaction
Specific-IgE (RAST) against drug (if available)
March 2014
Table 9. The Big 8 food allergens and ImmunoCAP® (RAST) food group tests.
Individual sIgE
The BIG 8 food allergens
Egg white, Milk, Fish, Wheat, Peanut, Soy, Shellfish, Tree nuts
Mixed nuts (Fx1)
Mix of Peanut, Hazel nut, Brazil nut, Almond, Coconut
Mixed seafood (Fx2)
Mix of Cod fish, Shrimp, Blue mussel, Tuna, Salmon
Mixed cereal (Fx3)
Mix of Wheat, Oat, Maize, Sesame seed, Buckwheat
Paediatric food mix (Fx5)
Mix of Egg white, Milk, Fish, Peanut, Soy and Wheat
Group tests
typically within minutes to hours after ingestion of the
predictive values (PPV) are listed in Table 10. In cases where
specific food. Patients presents typically with the following
the sIgE concentration exceed the ‘decision point’ (95% PPV),
symptoms/conditions:
the chance of being clinically allergic to that specific food
 Generalised: anaphylaxis, food dependent exercise-
substance is 95% for that specific individual. It is worthwhile
induced anaphylaxis
 Cutaneous: urticaria, angioedema, flushing, acute contact
urticaria
 Gastrointestinal: oral allergy syndrome, gastrointestinal
anaphylaxis, colic, vomiting & diarrhoea
to note that the 95% PPVs in most studies were determined
using the ImmunoCAP® immunoassays. There is currently no
standardisation between sIgE methods, therefore different
cut-off FIGURES
points 4.pdf
will be1 applicable
different
2014/02/25with
10:12:22
AM methods.
Confirm with your local laboratory which method they use.
 Respiratory: acute rhinoconjunctivitis, allergic asthma.
The prevalence of food hypersensitivity is the greatest during
the first few years of life. In infancy and childhood the most
common food allergens include egg, milk, fish, wheat, soya
and peanut. In older children and adults the range of food
allergens causative of hypersensitisation broadens to include
seafood, tree nuts and fruits. Most children develop tolerance
to food allergens by the age of 5 - 6 years, except in the
majority cases of peanut, tree nut and seafood allergy.
Table 10. 95% PPV for food allergies
Food
Egg
Milk
Peanuts
Fish
Tree nuts
Wheat
Soy
Specific-IgE in kU/L
>7 (>2 for infants and toddlers)
>15 (>7 for infants and toddlers)
>15
>20
>15
>80
>65
The diagnosis of an IgE-mediated allergy remains a clinical
exercise dependent upon a clinical history, selective in
Cross-reactivity of IgE-mediated food allergies:
vivo tests (skin prick tests) or in vitro measurement of food
The presence of sIgE in a patient’s blood may be due to
specific-IgE (sIgE), appropriate exclusion diet, and blinded
antibodies to a protein specific to a food source, or due to
provocation. To screen for food hypersensitivity against
antibodies formed against a protein that is present in food
specific food groups, the ImmunoCAP® sIgE (RAST) group
related sources (cross reacting antibodies). Sensitisation
tests for food mixes may be used (Table 9). A positive
to certain fruit or vegetables is often associated with
ImmunoCAP® sIgE food mix test will give the clinician a good
sensitisation to other foods belonging to the same or closely
indication of which group of individual allergens should be
related botanical family. Another example of cross-reactivity
tested for. With a high index of suspicion of a specific food
is that of inhalant allergens and food allergens. Patients
allergen, it will be more cost-effective to request an individual
with sensitisation to common inhalants such as pollen and
sIgE test instead of group tests.
house dust mites, have the possibility of reacting to food
allergens that cross-react with the inhalant allergens. Cross-
Presumptive diagnosis of food allergy based on sIgE test
reacting allergens may not always be of clinical relevance,
results is not acceptable as the presence of sIgE antibodies
and therefore the food group should not be eliminated from
only indicates sensitisation to the specific food. Over one
a patient’s diet without clinical correlation, or confirmation
quarter of all patients with positive sIgE antibodies to
with an elimination diet. Refer to section 9 for more detail on
food will unnecessarily alter their eating habits based on
cross-reacting components.
misinterpretations of food sIgE blood tests. There are no
specific diagnostic cut-off values for sIgE (Section 2); the higher
the sIgE concentration, the higher the likelihood of clinical
allergy. However, some food allergens may produce clinical
reactivity at low concentrations, therefore the importance of
clinical correlation. Published decision points at 95% positive
15
Pathology Forum Vol 4 No.3
FIGURES 5.pdf
1
2014/02/25
10:13:23 AM
Table 11. Cellular Allergen Stimulation Tests (CAST) tests available for food additives.
Preservatives
Tartrazines, sodium benzoate, sodium nitrite, potassium-metabisulphite, sodium
salicylate, monosodium glutamate, potassium sorbate etc.
Food colourant group I
Quininoline yellow, Sunset yellow FCF, Cromotrope B, Armaranth, New coccine
etc.
FIGURES 6.pdf
1
2014/02/25
Food colourant group II
10:08:29 AM
Erythrosine, Patent blue V, Indigo carmine, Brilliant black etc.
Table 12. Examples of non-allergic adverse reactions to food.
Condition
Symptoms
Mechanism
Lactose intolerance
Bloating, abdominal pain,
diarrhoea
Lactase enzyme deficiency
Fructose intolerance
Inhibition or deficiency of the diamine oxidase (DAO)
enzyme, leading to an accumulation of histamine.
Diarrhoea, nausea & vomiting,
headache, nasal congestion,
itching of eyes and nose,
wheezing, hypotension,
tachycardia, urticaria, pruritis,
flushing etc.
Foods rich in histamine: cheeses, processed meat,
some fish, yeast extracts, tomato ketchup, alcohol etc.
Scombroid fish
poisoning
Flushing, angioedema, hives,
abdominal pain, symptoms
similar to histamine
intolerance.
Fish from the Scombridae family i.e. tuna and
mackerel (dark meat fish) contains large amounts of
histidine, which is converted to histamine by bacteria
in spoiled fish.
Tyramine
Migraine
Pharmacologic effect in susceptible individuals
Caffeine
Tremors, cramps, diarrhoea
Pharmacologic effects of caffeine in susceptible
individuals
Monosodium glutamate
Asthma, ‘Chinese restaurant
syndrome’, urticaria
Pharmacologic effects of glutamate in susceptible
individuals
Panic disorder
Subjective reactions upon
smelling or seeing the specific
food
Psychological mechanism
Histamine intolerance
16
Fructase enzyme deficiency
Pathology Forum Vol 4 No.3
Foods with histamine releasing properties: citrus,
papaya, strawberries, pineapple, tomato, spinach,
chocolate, peanuts and tree nuts, fish, shellfish, pork,
egg white, additives, liquorice, spices etc.
March 2014
- Immediate/ IgE-mediated reactions: food specific-IgE or skin prick tests
- Delayed/ cell-mediated reactions: basophil activation tests (CAST) or skin patch testing
There are many other ‘diagnostic’ allergy tests, performed by non-accredited laboratories and health practitioners.
Examples include IgG-measurements against a variety of food groups, Vega testing and ALCAT, to name just a few.
These tests are not currently recommended by the Allergy Society of South Africa (ALLSA).
History and clinical suspicion of non-toxic adverse reaction to food:
Symptoms and signs, amount of food ingested, timing of reaction after ingestion, most recent
reaction, most severe reaction, treatment taken, personal and family history of allergy
History is consistent with nonimmune adverse reaction to food
History is consistent with IgEmediated food allergy
History is consistent non-IgE
mediated or mixed mechanisms
Food Specific-IgE (RAST)
Depending on the history consider:
CAST tests, sIgE, serology for coeliac
disease, biopsy, or other supportive
investigations e.g. stool examination
or
skin prick test (if available)
FOOD INTOLERANCE
Consider:
- Enzyme deficiencies:
lactose/ fructose/
histamine intolerance
- Pharmacologic effect:
tyramine, caffeine, MSG ,
sulphites etc
- Scombroid fish poisoning
- Psycological effect
Test result POSITIVE
> 95% PPV* cut-off
and convincing clinical
history (or anaphylaxis)
Test result NEGATIVE
< 95% PPV* cut-off
Trial of elimination diet;
foods selected based on
history and results of tests
results
IgE mediated FOOD
ALLERGY
POSSIBLE FOOD ALLERGY
Resolution of symptoms
after elimination diet
Strict dietary food avoidance
Nutritional support
Re-evaluate diet history for
possible ‘missed’ or hidden
food allergens, consider nonIgE-mediated allergy.
No
±Anaphylaxis treatment plan
Periodic reassessments
Consider Oral Food
Challenge
Yes
Non IgE-mediated FOOD
ALLERGY or MIXED
mechanism FOOD ALLERGY
Figure 6. Diagnostic algorithm for investigation of non-toxic adverse food reactions. *95% PPV in table 10.
Conclusion:
In all cases of suspected
food allergy, as with all allergy testing,
a full
clinical9)history
is indispensable
in orderFood
to
disease
(section
and dermatitis
herpetiformis. Non-IgE-mediated
food allergy:
facilitate appropriate and cost effective test requests. A positive
sIgE
test
merely
indicates
sensitisation
against
the
induced contact dermatitis is often seen in an occupational
Non-IgE-mediated allergic reactions are less well defined than
allergen, and the diagnosis needs to be confirmed by a clear clinical history, or by supervised food challenge testing.
setting amongst food handlers that handle raw fish, shellfish,
IgE-mediated reactions. The diagnosis of these conditions
Not all food allergies are IgE-mediated, and a delayed sensitivity mechanism test should be considered in selected
meat, such
eggs as
andIgG
spices.
Nonagainst
IgE-hypersensitivity
to cow’s
milk,
remains
a
challenge,
as
the
clinical
picture
is
not
so
obvious
cases, especially in food additives. Alternative, non-accredited tests
testing
food allergens
are not
and
infrequently
to
egg
and
pork,
are
responsible
for
the
than
the IgE-mediated allergies, and laboratory investigations
recommended.
are not always suitable. These reactions usually occur hours to
References and further reading:
rare syndrome of food-induced pulmonary hemosiderosis.
such
as food
days after
to the food
allergen.
manifestations
1. exposure
Lock R, Unsworth
DJ. Food
allergy:Typical
which tests
are worth doing and Hidden
which areallergens
not? Ann Clin
Biochem
2011;additives
48:300-309.(Table 11) may
2. Potter PC. Investigation
of the allergic
patient: the importance of early
CME 2005;
alsodiagnosis.
be responsible
for23(9):444-447.
some of the non-IgE-mediated food
of non-IgE-mediated
allergic conditions
include:
rd
3. Green R, Motala C, Potter PC. ALLSA Handbook of practical allergy. 3 ed. The Republic of South Africa: Paarl Media; 2010.
reactions.
food protein-induced enterocolitis
4. Motala C, Hawarden D on behalf of the Allergy Society of South Africa. Diagnostic testing in allergy. SAMJ 2009; 99(7):531-535.
(FPIES),
proctocolitits,
Coeliac’s
disease,
5. Kock allergic
J. Investigation
of immediate-onset
IgE-mediated
food allergy. CME 2012; 30(7): 257-259.
6. Bruijnzeel-Koomen
Ortolani C, Aas K et al. Position paper of the European
academy
of allergology
and clinicalcases
immunology
on a high
Diagnosis
of the
non-IgE-mediated
involve
gastrointestinal
motilityC,disorders
adverse reactions to food. Allergy 1995; 12: 357–378.
 Gastrointestinal:
 Cutaneous: contact dermatitis, dermatitis herpetiformis
by: Mariana Lloyd
Written
Respiratory:
pulmonary
hemosiderosis
clinical index of suspicion (history), elimination diets, skin
by: Dr Wtesting,
Meyer
cell-mediated
(Heiner’s Reviewedpatch
PathCare:
Allergy investigations 10 December 2013
syndrome).
in vitro tests, biopsy and
14to
histology, and serology in the case of coeliac’ disease (refer
Section 9 for coeliac disease investigations).
Cow’s milk and soy protein are the most common food
allergens indicated in FPIES and allergic proctocolitis
syndromes in infants and children. Food containing gluten
is associated with autoimmune conditions such as coeliac’
17
Pathology Forum Vol 4 No.3
Combined IgE and non IgE-mediated food allergy:
as caffeine and tyramine and enzyme deficiencies causing
Both IgE and non-IgE immune mediated mechanisms are
lactose intolerance or histamine sensitivity. The mechanisms
involved in allergic conditions presenting with:
for some of the food intolerances remain unclear. The
 Cutaneous: atopic dermatitis, contact dermatitis
diagnosis of food chemical intolerance is largely based on
 Gastrointestinal: allergic eosinophylic oesophagitis and
history and elimination diets.
gastroenteritis
 Respiratory: asthma.
Testing for food allergy:
The diagnosis of food allergy is largely based on the clinical
Diagnosis is based on patient’s history together with
history and physical examination (figure 6). Based upon the
demonstration of food sIgE antibodies, cell-mediated
clinical history laboratory investigations may be considered.
reactivity to specific food, occasionally allergen specific patch
Elimination diets and provocation testing may also be utilized
tests, elimination diets and oral food challenges.
in the diagnosis of food allergy. Laboratory investigations
available for food allergy testing depend on the immune
Food intolerance:
mechanism involved, and the availability of the tests:
Food allergy must be distinguished from a variety of adverse
 Immediate/ IgE-mediated reactions: food specific-IgE or
reactions to foods that do not have an immune basis but may
resemble it in clinical manifestations. Mechanisms of adverse
reactions include pharmacologic effects to substances such
18
Pathology Forum Vol 4 No.3
skin prick tests
 Delayed/ cell-mediated reactions: basophil activation
tests (CAST) or skin patch testing
March 2014
There are many other ‘diagnostic’ allergy tests, performed
by non-accredited laboratories and health practitioners.
References and further reading:
Examples include IgG-measurements against a variety of food
groups, Vega testing and ALCAT, to name just a few. These
1.
tests are not currently recommended by the Allergy Society
Lock R, Unsworth DJ. Food allergy: which tests are worth doing
and which are not? Ann Clin Biochem 2011; 48:300-309.
of South Africa (ALLSA).
2.
Potter PC. Investigation of the allergic patient: the importance of
Conclusion:
3.
Green R, Motala C, Potter PC. ALLSA Handbook of practical allergy.
early diagnosis. CME 2005; 23(9):444-447.
In all cases of suspected food allergy, as with all allergy testing,
a full clinical history is indispensable in order to facilitate
3rd ed. The Republic of South Africa: Paarl Media; 2010.
4.
appropriate and cost effective test requests. A positive sIgE
test merely indicates sensitisation against the allergen, and
5.
the diagnosis needs to be confirmed by a clear clinical history,
or by supervised food challenge testing. Not all food allergies
Motala C, Hawarden D on behalf of the Allergy Society of South
Africa. Diagnostic testing in allergy. SAMJ 2009; 99(7):531-535.
Kock J. Investigation of immediate-onset IgE-mediated food
allergy. CME 2012; 30(7): 257-259.
6.
Bruijnzeel-Koomen C, Ortolani C, Aas K et al. Position paper of the
are IgE-mediated, and a delayed sensitivity mechanism test
European academy of allergology and clinical immunology on
should be considered in selected cases, especially in food
adverse reactions to food. Allergy 1995; 12: 357–378.
additives. Alternative, non-accredited tests such as IgG testing
against food allergens are not recommended.
19
Pathology Forum Vol 4 No.3
Section 5
A Practical Diagnostic Approach
to Drug Allergies
Adverse drug reactions (ADRs) are a common cause of patient morbidity and mortality. ADRs are inevitable
consequences of pharmacotherapy, since all drugs carry the potential to produce both desirable and
undesirable effects. The term ‘drug allergy’ refers to adverse immunological reactions, either antibody- or
cell-mediated. It should be distinguished from the ‘complications’ of the drug’s pharmacological effect
or other non-allergic adverse reactions. Accurate diagnosis of drug allergies are important not only to
prevent serious or even life-threatening reactions, but also to avoid unnecessary drug restrictions that
may affect the patient’s health, may result in poor management or may cause an increase in medical costs.
To be able to understand the rationale behind testing for drug allergies, a comprehensive knowledge of the pharmacological
properties of the drug and the immune-pathogenesis that may play a role in the drug hypersensitivity reaction (HSR), is required.
Although the immunologic processes underlying allergic reactions have been studied extensively, we still have a limited
understanding of the molecular and chemical processes involved in allergic reactions to drugs. No single ‘perfect’ diagnostic test
currently exists to assist the clinician in the diagnosis of drug allergy. The available laboratory diagnostic tests are based on the
immunological reactions as described by the Gell and Coombs’ classification system (Table 13). An example of an algorithm for the
diagnosis of immediate and non-immediate allergic reactions is provided in Figure 7.
Diagnostic methods for the diagnosis of drug
hypersensitivity reactions:
Since the pharmacological properties of each drug differ
markedly, as well as the immunological mechanism that
underlies the reaction, there is no single diagnostic approach
that can be recommended for investigation of a possible drug
allergy. The choice of the appropriate diagnostic test should
be made only after careful consideration of the specific drugs
involved, the specific clinical history, a detailed history of
any specific incident and consultation with an allergologist /
specialist.
The following diagnostic modalities are available:
 In vitro tests:
sIgE
Basophil activation tests (also known as “CAST” test)
Lymphocyte stimulation test (also known as MELISA
test)
 In vivo tests:
Skin prick test (SPT)
Skin patch test
Intradermal test (IDT)
Drug provocation test
The sIgE, SPT, IDT and CAST tests may be helpful in an
immediate (Type I hypersensitivity) reaction. The MELISA, skin
patch test and drug provocation tests may be considered in a
delayed (Type IV hypersensitivity) reaction.
20
Pathology Forum Vol 4 No.3
Factors to consider when selecting a diagnostic test
for a patient with a possible drug hypersensitivity
reaction:





atient’s age
P
Type of drug(s) administered
Timing of reaction
Severity of reaction
Availability of on-site support facilities, e.g. resuscitation
facilities, experienced and trained personnel, laboratory
support etc. Since the CAST and MELISA tests are only
available at reference laboratories and research centres,
and due to the requirement for the test to be performed
in vitro on viable cells within 24 hrs after blood collection,
it may not be available at some peripheral laboratories
due to logistical constraints.
Conclusion:
Drug allergy encompasses a spectrum of immunologicallymediated hypersensitivity reactions with varying mechanisms
and clinical presentations. This type of adverse drug reaction
may affect the patient’s quality of life, may also lead to delayed
treatment, unnecessary investigations, and even mortality.
Diagnostic tests for evaluation of possible drug allergy should
be selected according to the clinical history (e.g. immediateor delayed- hypersensitivity), the type of drug, and severity of
reaction and resources/laboratory facilities available. Referral
to an allergologist experienced in the identification, diagnosis
and management of drug allergy is recommended in all cases
where a drug-induced allergic reaction is suspected.
To be able to understand the rationale behind testing for drug allergies, a comprehensive knowledge of the
pharmacological properties of the drug and the immune-pathogenesis that may play a role in the drug
hypersensitivity reaction (HSR), is required. Although the immunologic processes underlying allergic March
reactions
have
2014
been studied extensively, we still have a limited understanding of the molecular and chemical processes involved in
allergic reactions to drugs. No single ‘perfect’ diagnostic test currently exists to assist the clinician in the diagnosis of
drug allergy. The available
diagnostic
Adverse laboratory
reactions to
food tests are based on the immunological reactions as described by the
Gell and Coombs’ classification system (Table 13). An example of an algorithm for the diagnosis of immediate and
non-immediate allergic reactions is provided in Figure 7.
Non-Toxic
Toxic
Table
Classification
e.g.13.
Food
poisoning of immune-mediated allergic drug reactions according to Gell and Coombs’ system.
Immune reaction
Mechanism
Clinical manifestations
Timing of reaction
Type I
IgE-mediated
Type II
Cytotoxic
Immune
mediated
Drug-IgE
complex
binding to mast cells and basophils with
release
of histamine
FOOD
ALLERGYand inflammatory mediators.
Specific IgG or IgM antibodies directed at drug-hapten
coated cells (phagocytes, NK-cells).
Anaphylaxis, urticaria,
Non-immune mediated Minutes to hours
angioedema, bronchospasm,
after exposure to
FOOD
INTOLERANCE
pruritus.
drug.
Haemolytic anaemia,
cytopaenia,
Variable.
thrombocytopaenia.
Tissue deposition
drug-antibody complexes (FcR
Non of
IgE-mediated
Enzymatic Serum sickness,
Pharmacological
vasculitis,
Type IgE-mediated
III
complement
e.g. anaphylaxis topositive cells)
e.g. with
Coeliac’s
disease, activation and
e.g. Lactose or
e.g. Reaction to food
Immune complex
food
Type IV
Delayed, cell
mediated
fever, rash, arthralgia.
inflammation.
food protein
induced
histamine
additives
MHC presentation
of
drug
molecules
to
T-cells
with
enterocolitis
intolerance Contact sensitivity, skin
cytokine and inflammatory mediator release; may also be
rashes, organ tissue damage,
associated with activation and recruitment of eosinophils,
DRESS, SJS/TEN, AGEP.
monocytes, and neutrophils.
1 to 3 Undefined
weeks after
e.g. Irritable
bowel
exposure
to drug.
syndrome
2 to 7 days after
exposure to drug.
Abbreviations: Ig- immunoglobulin, DRESS- Drug reaction with eosinophilia and systemic symptoms, SJS- Stevens Johnson Syndrome, TEN- Toxic epidermal
Figure 5. The classification of adverse food reactions, as proposed by the EAACI-Position paper on Adverse Reactions to Food.
necrolysis, AGEP- Acute generalised exanthematous pustulosis, NK-cells- Natural killer cells, MHC- Major histocompatibility complex.
Diagnostic methods for the diagnosis of drug hypersensitivity reactions:
Since the pharmacological
properties of each drug differ markedly, as well as the immunological mechanism that
Obtain history: dates of administration, drug formulation, dosage, route of administration, type of reaction
underlies the reaction, there is no single diagnostic approach that can be recommended for investigation of a possible
drug allergy. The choice of the appropriate diagnostic test should be made only after careful consideration of the
Specific-IgE
(RAST)
against
drug (if available)
specific drugs involved, the specific
clinical
history,
a detailed
history of any specific incident and consultation with an
allergologist / specialist.
Negative
Positive
The following diagnostic modalities are available:
ALLERGY =
CAST (if available)
- In vitroDRUG
tests:
Positive- testsIgE
PLUS clinical symptoms
Discuss availability with chemical pathologist
- Basophil activation tests (also known as “CAST” test)
Positive
- Lymphocyte stimulation
test (also known as MELISANegative
test)
- In vivo tests:
ALLERGY =
MELISA (if available)
- Skin DRUG
prick test
(SPT)
Positive test PLUS clinical symptoms
Discuss availability with chemical pathologist
- Skin patch test
- Intradermal test (IDT)
Negative
Positive
- Drug provocation test
DRUG ALLERGY =
SPT by experienced allergist
test tests
PLUS clinical
symptoms
The sIgE, SPT, IDTPositive
and CAST
may be
helpful in an immediate (TypeAnaphylaxis
I hypersensitivity)
The MELISA, skin
treatmentreaction.
facilities essential
patch test and drug provocation tests may be considered in a delayed (Type IV hypersensitivity) reaction.
Negative
Positive
PathCare: Allergy investigations 10 December 2013
15
If still high index of suspicion:
Do drug provocation test in appropriate facility
DRUG ALLERGY =
Positive test PLUS clinical symptoms
Negative
Positive
DRUG ALLERGY =
Positive test PLUS clinical symptoms
DRUG ALLERGY UNLIKELY
Figure 7. Example of an algorithm for the diagnosis of immediate and non-immediate allergic reactions to a specific drug.
References and further reading:
2
1. Warrington R, Silviu-Dan F. Drug allergy. Allergy, Asthma & Clinical Immunology 2011; 7(s1):s10.
2. Rive CM, Bourke J, Phillips EJ. Testing for drug hypersensitivity syndromes. Clin Biochem Rev 2013; 34:15-38.
3. Green R, Motala C, Potter PC. ALLSA Handbook of practical allergy. 3rd ed. The Republic of South Africa: Paarl Media; 2010.\
21
Pathology Forum Vol 4 No.3
Section 6
A Practical Diagnostic Approach
to Urticaria and Angioedema
Urticaria is a common disorder, affecting 15-25%
of the population at some stage. Identifying the
cause of the urticaria or angioedema can be
challenging and often leads to inappropriate test
requests. A thorough medical history and physical
examination, as well as methodical investigation,
are necessary to identify the possible cause of the
condition.
 Associated itching or sometimes burning, but not pain
 Superficial lesion that tends to migrate, fleeting in nature
with a return to normal in 1 – 24 hours
 40% of urticarial lesions are accompanied by angioedema
Urticarial vasculitis is a subtype of urticaria with the following
distinctions:
 Lesions is often painful (rather than itchy or burning)
 Lesions leave bruising or pigmentation changes (purpuric
or ecchimotic)
 Lesions last longer than 24 to 36 hours
 Often associated with systemic symptoms such as fever,
arthralgia, arthritis, bone pain, lymphadenopathy.
The first diagnostic step is to distinguish clinically
between isolated angioedema, urticaria with or
without angioedema or urticarial vasculitis:
Angioedema may occur in isolation or together with urticaria.
Angioedema is defined by:
 Sudden, pronounced swelling of the lower dermis and
Urticarial lesions are characterised by the rapid appearance of
subcutis (deeper swelling than urticaria) with frequent
wheals which have three typical features:
involvement of the mucous membranes
 Central swelling (wheal) of variable size surrounded by
 Resolution of lesions is slower than for urticaria – up to 72
erythema (flare)
hours
Oedematous skin lesions
ANGIOEDEMA
Deep swelling beneath skin
URTICARIA
Superficial oedematous skin lesions
Individual lesions
lasting > 24hrs
Individual lesions
lasting < 24hrs
Attacks < 6 weeks
With urticaria
Attacks > 6 weeks
Urticarial
vasculitis
Isolated
angioedema
Acute
urticaria
Chronic
urticaria
Figure 8. Simplified diagnostic algorithm for urticaria and angioedema.
22
No urticarial lesions
Pathology Forum Vol 4 No.3
IgE antibody
Allergy excluded
March 2014
Urticarial vasculitis (UV)
Acute urticaria (AU)
Chronic urticaria (CU)
Most common causes of UV include:
Most common causes of AU include:
Most common causes of CU include:
IDIOPATHIC
INFECTIONS
Viral / bacterial / parasitic
CHRONIC IDIOPATHIC URTICARIA (CIU)
No identifiable cause in 75-80% of CU cases
DRUG REACTIONS
Medications from most drug classes
have been associated with UV
IgE MEDIATED ALLERGIC REACTIONS
Medications e.g. penicillins
Stinging and biting insects
Latex
Foods
Contact with allergens
Aeroallergens (rare)
PHYSICAL URTICARIA
Accounts for up to 5-10% of CU cases:
Dermatographism, cholinergic, cold or heat
induced, aquagenic, exercise induced,
delayed pressure.
INFECTIONS
Hepatitis B and C
EBV
Lyme disease
NON-IgE MEDIATED ALLERGIC REACTIONS
Food additives
Drugs
Some foods/preservatives
COMPLEMENT DISORDERS
Inherited deficiencies of C3 and C4
Secondary C3 deficiency due
presence of C3-nephritic factor
DIRECT MAST CELL ACTIVATION
Narcotics and opiates
Muscle relaxants
Vancomycin
Radiocontrast media
Certain foods e.g. tomato, strawberry
Contact with ‘stinging nettle’ plant
AUTOIMMUNE DISORDERS
SLE
Sjögren syndrome
Other connective tissue disorders
to
MALIGNANCIES
Lymphoma, IgA myeloma, leukaemia,
metastatic adenoca of the colon,
metastatic testicular teratomas
etc
MISCELANEOUS
Monoclonal gammopathies
Idiopathic thrombocytopenic purpura
Polycythemia vera, cryoglobulinemia
Inflammatory bowel disease.
OTHER:
Physical stimuli
Serum sickness
Progesterone associated urticaria
More than 2/3rds of new onset urticaria
cases prove to be self-limited (acute).
CHRONIC AUTOIMMUNE URTICARIA (CAU)
Associated conditions include (4-5% of CU):
Thyroid disorders
Coeliac disease
Sjögren syndrome
SLE
Rheumatoid arthritis
Type I diabetes mellitus
OTHER
Chronic persisting infections (1-2% of CU)
Allergies (< 1% of CU)
Malignancies (1-2% of CU)
Drugs (1-2 % of CU)
Mastocytosis (< 1% of CU)
The most common theory regarding the
cause of chronic auto-immune urticaria
includes the presence of anti-IgE antibodies,
or antibodies against the IgE-receptor that
can trigger histamine and other cytokine
release from the mast cell and thus urticarial
symptoms (refer to figure 10).
Laboratory investigations for UV:
Laboratory investigations in AU:
Laboratory investigations in CU:
Investigations should be guided by a
good clinical history and examination:
- FBC & diff and ESR
- CRP
- Skin biopsy on a fresh (new) lesion
- RF, ANA ± other autoimmune tests
- Serum protein electrophoresis
- Viral studies (e.g. hepatitis B and C)
- Complement: C3 and C4
- Cryoglobulin test.
Routine laboratory screening tests
independent of the patient’s history and
physical examination should be
discouraged. The following may be
considered depending on history:
- FBC and ESR
- Allergy tests according to history:
The diagnosis is based on a thorough
clinical history and physical examination.
Based on this, the following laboratory
tests may be considered:
- FBC & diff and ESR
- CRP
- RF, ANA ± other autoimmune tests
- TSH ± thyroid antibodies (anti-TPO)
- Serum protein electrophoresis
- Serology for chronic infections
- Autologous Serum Skin Test (ASST)
- Allergy tests according to history.
-
-
Specific IgE (RAST) for immediate
reactions (food and drugs)
CAST for delayed reactions (drugs
and preservatives)
Other tests e.g. microbiology
according to history.
Figure 9. List of aetiologies and examinations that can be done for urticarial vasculitis, acute- and chronic urticaria.
23
Pathology Forum Vol 4 No.3
IgE antibody
and receptor
Mast cell
Histamine
granules
Anti-IgE
antibody
Anti-IgE receptor
antibody
Figure 10. Graphical representation of auto-immune antibodies directed against the IgE-antibodies and IgE receptor on the
mast cell.
 Angioedema is a result of increased vascular permeability,
Chronic auto-immune urticaria is caused by auto-antibodies
the surrounding tissues
to the IgE- receptor, or IgE antibodies that lead to mast cell and
 Angioedema may be mediated by histamine, bradykinin
or other mediators:

Histaminergic
presents
of chronic idiopathic urticaria is believed to be autoimmune.
with urticaria and/or pruritus and will respond
The Autologous Serum Skin Test (ASST) is a screening test
to
where the patient’s own serum is injected intradermally on
conventional
treatment
usually
with
antihistamines,
B
radykinin-mediated angioedema on the other hand
healthy skin together with a histamine and saline control.
The skin is evaluated for a reaction (wheal) after 30 minutes.
does not typically present with urticaria, and does not
A wheal diameter larger than 1.5 to 2 mm than the negative
respond to conventional agents such as antihistamines
control, in the presence of a positive control (histamine), is
or corticosteroids.
indicative of a possible auto-immune urticaria.
The next step is to classify urticaria and angioedema into
urticarial vasculitis, acute or chronic urticaria or isolated
angioedema according to the clinical examination and the
duration of the lesions (figure 8):
Urticaria:
After identifying and classifying the type of urticaria, one
can consider the possible causes for each group of urticaria (figure 9).
24
basophil activation, giving rise to the release of histamine and
other pro-inflammatory mediators (Figure 10). Up to 30-40%
angioedema
corticosteroids or epinephrine
What is autoimmune urticaria?
with subsequent extravasation of intravascular fluid into
Pathology Forum Vol 4 No.3
March 2014
Angioedema:
Angioedema in the absence of urticaria is rare. It should alert the physician to an alternative diagnosis, such as
hereditary (HAE) or acquired angioedema, idiopathic angioedema, or angioedema associated with angiotensinconverting enzyme inhibitors (ACE-I). Laboratory investigations that may be considered in isolated angioedema
include C4- and C1 esterase inhibitor (C1-INH) concentration (and function – if available). An algorithm for the
investigation of angioedema without urticaria is provided in Figure 11.
Angioedema without urticaria
History: medications, family history, medical history, number of attacks, duration of attacks, associated symptoms etc.
Causative agent identified
No causative agent identified
Angioedema due to specific cause e.g. ACEinhibitor induced angioedema
Measure C4 and C1-inhibitor concentration
[C4] - low
[C1-INH] - low
Family history or young age of onset
Yes
HAE type I
Normal
No
Measure C1q
level*
[C4] - low
[C1-INH] - normal/elevated
[C4] - normal
[C1-INH] - normal
Measure C1-INH function*
Family history
Normal
Consider other
causes of C4
consumption
Low
HAE type II
Yes
Consider HAE
type III
No
Consider
Idiopathic
Angioedema
Low
Acquired C1INH deficiency
N OTE :
-
ONLY 75% OF HAE TYPES I AND II HAVE A POSITIVE FAMILY HISTORY
APPROXIMATELY 85% OF ALL HAE IS TYPE I, AND 15% IS TYPE II
Figure 11. Algorithm for investigations in patients presenting with isolated angioedema. Abbreviations: HAE = hereditary angioedema;
C1-INH = C1 esterase inhibitor. * = Tests not routinely available, contact laboratory for more information.
In conclusion:
Approximately one quarter of the population are affected by urticaria at some stage during their lives. Of these:
Angioedema:
- Approximately 2/3rds are acute, self-limiting urticaria (routine laboratory tests are discouraged in this group)
References and further reading:
Angioedema in the absence of
urticaria is rare. It should alert
- The remaining 1/3rd of urticaria cases are chronic, where in most cases a cause is never identified. In this group
the physician
to an alternative
diagnosis,
suchbeasguided
hereditary
of patients,
investigations
should
by history and examination.
Green R, Motala
C, Potter
PC. ALLSA
Handbookexamination
of practical allergy.
(HAE)
or
acquired
angioedema,
idiopathic
angioedema,
Isolated angioedema are never allergy related, and again 1.
a thorough
medical
history,
physical
and
3rd ed.of
The
Republic
of South Africa: Paarl Media; 2010.
ormethodical
angioedema
associated are
with
angiotensin-converting
investigation
necessary
to identify the possible cause
the
condition.
2. EAACi/GA2LEN/EDF/WAO guideline: definition, classification and
enzyme inhibitors (ACE-I). Laboratory investigations that may
References
and
further
reading:
diagnosis of urticaria. Allergy 2009; 64:1417-1426.
be considered in isolated angioedema include C4- and C1
rd
1. Green R, Motala C, Potter PC. ALLSA Handbook of practical allergy.
3 ed. The Republic of South Africa: Paarl Media; 2010.
3. Busse PJ, Buckland MS. Non-histaminergic angioedema: focus on
esterase inhibitor (C1-INH)
concentration (and function – if
2
2. EAACi/GA LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria. Allergy 2009; 64:1417-1426.
bradykinin-mediated
angioedema.
2013;
43:385-394.
available).
algorithm
for the
of angioedema
3. An
Busse
PJ, Buckland
MS. investigation
Non-histaminergic
angioedema: focus on bradykinin-mediated
angioedema.
ClinClin
ExpExp
All All
2013;
43:385-394.
2
2
4.
EAACi/GA
LEN
task
force
consensus
report.
The
autologous
serum
skin
test
in
urticaria.
Allergy
2009;
64:
1256-1268.
4.
E
AACi/GA
LEN
task
force
consensus
report.
The
autologous
without urticaria is provided in Figure 11.
5. Emanuel S, Hawarden D. ABC of Allergy: Urticaria and Angio-oedema. Curr All & Clin Immunol 2013; 26(1):31-2.
serum skin test in urticaria. Allergy 2009; 64: 1256-1268.
In conclusion:
5. Emanuel S, Hawarden D. ABC of Allergy: Urticaria and AngioWritten by: Mariana Lloyd
Reviewed by: Dr R Mattana
oedema. Curr All & Clin Immunol 2013; 26(1):31-2.
Approximately one quarter of the population are affected by
urticaria at some stage during their lives. Of these:
 Approximately 2/3rds are acute, self-limiting urticaria
(routine laboratory tests are discouraged in this group)
 The remaining 1/3rd of urticaria cases are chronic, where
in mostAllergy
cases investigations
a cause is never
identified. In
PathCare:
10 December
2013this group of
patients, investigations should be guided by history and
19
examination.
Isolated angioedema are never allergy related, and again
a thorough medical history, physical examination and
methodical investigation are necessary to identify the
possible cause of the condition.
25
Pathology Forum Vol 4 No.3
Section 7
Contact Dermatitis: Skin Patch
Testing
‘Contact dermatitis’ is a generic term applied to acute or chronic inflammatory reactions to substances
that come into contact with the skin. Contact dermatitis can be differentiated into two groups:
i. Irritant contact dermatitis which is caused by a chemical irritant (NOT an allergic reaction), and
ii. Allergic contact dermatitis caused by an allergen that elicits a type IV (delayed or cell mediated)
hypersensitivity reaction.
26
Contact allergy caused by Nickel in earrings
Patch tests in position for 48 hrs (2 days)
Removal of patches after 48 hrs
Apositive reaction (read after 48, 72 and 96 hrs)
Pathology Forum Vol 4 No.3
During the patch test
The patient may experience itching, burning and discomfort. In rare cases where severe discomfort
is experienced,
March 2014
the test should be terminated and treatment given. Patches are removed after 48 hours, and the position of the
patches are re-marked with a felt pen so that positive reactions can be clearly identified. The first reading is
performed 30 minutes after removal of the tape, and again after 72 and 96 hours. The reactions are graded as
detailed in Table 14.
Table 14. Recording of patch test reactions
Score
Morphology
No reaction
?+
Erythema, infiltration, possibly papules
++
Erythema, infiltration, vesicles
+++
Intense erythema and infiltration and coalescing vesicles
IR
Irritant reactions of different types
NT
Interpretation
Negative
Weak positive reaction
Strong positive reaction
Extreme positive reaction
Irritant Reaction
Not Tested
Allergens included in the patch test
chromate, allergens
benzocaine, suspected
fragrance mixes,
colophony,allergic
epoxy contact
Patch testing
is used
to document
and validate
The standard
TroLab
patch
test includes
45 aofdiagnosis
the most common
of causing
resins, quinolone
mixes,are:
balsam
of Peru, wool
cobalt, formaldehyde,
of allergic
contactofsensitisation,
to identifyin
thethe
causative
dermatitis.
Examples
allergensand
included
standard patch
test panel
nickel,
alcohols, neomycin,
paraben
mixes,
black
rubber
mixes,
phenylediamine,
agent.
Patch
tests
are
not
the
same
as
skin
prick
tests,
which
chromate, benzocaine, fragrance mixes, colophony, epoxy resins, quinolone mixes, balsam ofthioram
Peru, cobalt,
mixes, mercapto
mixes,mixes,
preservatives
and topical
anaesthetics
are usedparaben
to diagnosemixes,
IgE mediated
formaldehyde,
blackallergies.
rubber mixes, phenylediamine,
thioram
mercapto
mixes,
preservatives
(refer
to
Appendix
F).
In
theory
any
substance
can
be
used
for
and topical anaesthetics (refer to Appendix F). In theory any substance can be used for patch testing. Individual
patch
Patch test principle
patch testing. Individual patch tests for a specific occupation,
Low concentrations of the various suspected allergens are
substance or environment (e.g. hairdressing chemicals, latex
placed on the skin in shallow cups (Finn chambers) and kept in
gloves, sunscreens, shoes etc.) can be arranged with the
position with hypoallergenic tape. The patches are removed
laboratory.
PathCare: Allergy investigations 10 December 2013
20
after 48 hours and assessed for any reactions. These are
reassessed at 72 and 96 hours for possible delayed reactions.
In conclusion:
Preparations and precautions
reaction. Allergens are applied in low concentrations to the
Skin patch tests are used to test for delayed hypersensitivity
An appointment should be made at the local laboratory for
skin for 48 hrs, and possible reactions are assessed thereafter
patch testing. The patches are usually applied on a Monday,
24 hourly up to 96 hours post application for reactions.
removed on a Wednesday and assessed and re-assessed on
Individualised patch tests can be arranged.
Thursday and Friday.
Oral steroids should be avoided for approximately 2-4 weeks
prior to testing, until the last reaction has been read at 96 hrs.
Topical steroid creams and ointments should not be used on
or near the test area. Antihistamines may be used.
During the patch test
The patient may experience itching, burning and discomfort.
In rare cases where severe discomfort is experienced, the
References and further reading:
1.
Green R, Motala C, Potter PC. ALLSA Handbook of practical allergy.
3rd ed. The Republic of South Africa: Paarl Media; 2010.
2.
TroLab patch test allergens. Package insert, last updated June
2009.
3.
Fitzpatrick TB et al. Colour atlas & synopsis of clinical dermatology.
4th ed. United States of America: McGraw-Hill companies; 2001.
test should be terminated and treatment given. Patches are
removed after 48 hours, and the position of the patches are
re-marked with a felt pen so that positive reactions can be
clearly identified. The first reading is performed 30 minutes
after removal of the tape, and again after 72 and 96 hours. The
reactions are graded as detailed in Table 14.
Allergens included in the patch test
The standard TroLab® patch test includes 45 of the most
common allergens suspected of causing allergic contact
dermatitis. Examples of allergens included in the standard
patch test panel are: nickel, wool alcohols, neomycin,
27
Pathology Forum Vol 4 No.3
Section 8
Component Testing: A New Era in
Allergy Diagnostics
Introduction:
Since the discovery of the IgE antibody in the late 1960’s considerable advances have been made in the
development of in vitro allergy diagnostics. Allergen specific-IgE tests were developed in the early 1970’s.
Initially radio-immunoassays (RAST) were used for the measurement of allergen specific-IgE, but have
been replaced by enzyme-linked immunoassays (ELISA) in the late 1980’s. The first allergens were cloned
(recombinant allergens) in the early 1990’s and that allowed researchers to study allergenic structures
more closely. The first allergen component specific-IgE tests were available in the late 1990’s, and the
first microarray specific-IgE tests were available early in the 2000’s. Although we have entered a new era
of component resolved diagnostics (CRD) or molecular diagnosis in allergy, not all allergen components
have been characterised yet. Research in the field of IgE-epitope mapping is a continuous process.
EVOLUTION OF ALLLERGY TESTS
r = recombinant
r Ara h 2
(Biogenetically engineered allergens)
n = native
(Allergens are purified from natural food extracts)
Scientific acronym of allergen source e.g.
Arachis hypogaea (peanut)
Figure 12. Allergen component nomenclature explained.
28
Pathology Forum Vol 4 No.3
Allergen
component
number
March 2014
Common name: Peanut
Latin name: Arachis hypogaea
ImmunoCAP allergen name: f13
Ara h 1
Storage protein
Peanut specific marker
Ara h 2
Storage protein
Peanut specific
Ara h 5
Profilin
Marker of grass pollen
cross-reactivity, low clinical
Ara h 8
PR-10 protein
Marker of tree pollen
cross-reactivity
Ara h 6
Storage protein
Peanut specific marker
Ara h 9
nsLTP
Marker of peach
cross-reactivity
Ara h 3
Storage protein
Peanut specific marker
Figure 13. Peanut allergen components.
Figure 13.resolved
Peanut allergen
components.
Component
diagnostics
(CRD):
plant and animal food allergens, or injected allergens:
Almost any substance containing proteins can be an allergen
1.Indoor allergens (mites, animal allergens, cockroach
source. Each allergen source may contain many different
and moulds): proteolytic enzymes (serine and cysteine
allergenic proteins. Each allergenic protein may have several
proteases),
different epitopes. An epitope is a three-dimensional binding
tropomyosins, albumins, calcium-binding proteins and
site for the corresponding antibody. Antibodies may be formed
protease inhibitors
lipocalins
(ligand-binding
proteins),
Gluten-related disorders
2.Outdoor allergens (grass, tree and weed pollens, and
to one, some or all of the allergenic epitopes in a specific
Pathogenesis
allergenic protein. Each epitope (or allergen component) also
mould spores): plant pathogenesis related (PR-10)
have different characteristics that may contribute additional
proteins, pectate lyases, β-expansin, calcium-binding
proteins (polcalcins), defensin-like proteins and trypsin
information concerning the management of the allergic
Autoimmune
patient.
Non-autoimmune
Allergic
(?Possibleinhibitors
innate immunity)
Dermatitis
1.
Allergen component Coeliac
names and
acronyms
disease
nuts,
milk, eggs, shellfish and fish): lipid-transfer
Gluten
sensitivity
Wheat allergy
Gluten ataxia
herpetiformis
Allergen component names can be confusing. The
proteins, profilins, seed storage proteins, lactglobulins
(whey), caseins, tropomyosins and parvalbumins
nomenclature used in component diagnostics follows a
logical approach, where allergens are described using the
Asymptomatic
Symptomatic
Classical
for the species
and an Arabic numeral to indicate the
Non-Classical
3.Plant and animal food allergens (fruits, vegetables,
4.Injected
allergens
(insect
venoms allergy
and some
Respiratory
therapeutic proteins): phospholipases,
hyaluronidases,
Food allergy
first three letters of the genus, followed by a single letter
pathogenesis-related proteins andWDEIA
asparaginase.
chronological order of allergen purification (Figure 12).
Refer to figures 14 and 15 for more information
on component
Contact urticaria
protein families and nomenclature.
allergens have
biochemical disorders
names according
that
FigureMany
16. Classification
of gluten-related
to pathogenesis. Adapted from Sapone et al. Abbreviations: WDEIA = wheat
dependent
exercise
induced
anaphylaxis.
2.Allergen component protein properties
describe their biological function and which precede
the allergen nomenclature. Examples include egg
As mentioned previously, all proteins contain different
allergens (ovomucoid and ovalbumin); insect allergens
epitopes that act as binding sites for corresponding
(phospholipases and hyaluronidases); and tropomyosins
antibodies. Every allergenic species contain different
from shrimp, mite and cockroach. Sequence homology
allergenic epitopes, some of which are species-specific
searches have assigned allergens to particular protein
and some with a similar structure to epitopes in other
families
to
allergen sources. Antibodies formed against a species-
their biological function. To some extent, allergens
specific epitope will only bind to allergenic epitopes in that
segregate among protein families that are based on
specific species. However antibodies formed against an
whether they are indoor allergens, outdoor allergens,
epitope with a similar structure found in other biologically
and
have
provided
important
clues
29
Pathology ForumLabile
Vol 4proteins
No.3
Stabile proteins
Severe reactions
Mild reactions
Rosacea family or between tree nuts. For example, profilins are proteins with a highly similar structure in
pollens and plants, contributing to cross-reactions between botanically unrelated species (Figure 14).
Increasing risk for severe reactions
Labile proteins
Mild reactions
Profilin
PR-10
ns-LTP
Profilins
Pathogenesis-related protein 10
Non-specific lipid transfer protein
Profilin is a pan-allergen occurring
in tree-, grass- and weed- pollen as
well as in plant-related foods.
are
widely
PR-10
proteins
distributed in tree- and weedpollens, as well as in plant-related
foods (in the pulp of some fruit).
ns-LTP is a major cross-reactive
allergen present in tree- and
Increasing risk for severe
weed- pollens, as well as in the
majority of plant-derived foods.
PR-10 proteins are heat-labile
proteins and cooked/processed
foods are PR-10
usually well tolerated.
Patients often present with local
symptoms restricted to the oral
cavity
(OAS).
Pathogenesis-related
protein 10
ns-LTP are stable to heat and
digestion, causing reactions to
cooked
foods.
ns-LTP ns-LTP is
concentrated in the peel of fruits,
rather than the pulp.
Profilins are sensitive to heat
denaturation
and
gastric
digestion; they cannot cause
Profilin
sensitisation
via the GI tract.
Reactions are usually restricted to
the oral cavity (OAS).
Stabile proteins
SevereStorage
reactionsproteins
Storage proteins
Storage proteins are dominant
allergens found in seeds, nuts and
reactions
legumes. They are categorised into
2S albumin, 7/8 globulin and 11s
globulin storage proteins.
Storage proteins are very stable to
causing
heat Storage
and digestion,
proteins
reactions to cooked foods, with a
high frequency of severe systemic
reactions.
Patients
with lipid
ns-LTP
IgE antibodies
Non-specific
transfer
protein
Profilins
Storage proteins
Patients
with
profilin-sIgE
can often tolerate peeled-off fruits
2S albumin proteins occur in:
antibodies are either sensitised or
Patients displaying PR-10 sIgE
and certain
such
as carrots,
ns-LTP
is a food
major
cross-reactive
mustard
rapeare
seed,
Brazil
Storage seed,
proteins
dominant
are
widely
Profilin is a pan-allergen occurring
PR-10
proteins
antibodies are sensitised or at risk
at risk of developing multiple
bananas, potatoes
allergen
present and
in melon,
tree- but
and
nut,
peanut,
walnut,
sesame
seed,
allergens
found
in seeds,
nuts
and
distributed in tree- and weedin tree-, grass- and weed- pollen as
of developing multiple pollen
pollen sensitisation and pollenare at pollens,
risk of developing
cashew
nutThey
and are
pistachio.
weedas well as severe
in the
legumes.
categorised into
pollens, as well as in plant-related
well as in plant-related foods.
sensitisation,
and
pollenassociated food allergy.
reactionsofupon
ingestion of
nuts.
majority
plant-derived
foods.
2S albumin, 7/8 globulin and 11s
foods (in the pulp of some fruit).
associated food allergy.
7/8S
globulin
globulin
storageproteins
proteins.occur in:
Profilins are sensitive to heat
Plant foods
most often
involved
Plant foods most often involved
peanut, lentil, pea, hazelnut,
ns-LTP
are
stable
to
heat
and
and
gastric
PR-10 proteins are heat-labile
denaturation
include: strawberry,
apricot,
Plant foods most often involved
are: strawberry, apple, cherry,
walnut,
cashew
nutto
digestion,
causing apple,
reactions
to
Storage sesame
proteinsseed,
are very
stable
digestion; they cannot cause
proteins and cooked/processed
cherry, plum,
and
include: peach, apricot, cherry,
almond, peach, pear, hazelnut,
cooked
foods. peach,
ns-LTP pear,is
heatpistachio.
and digestion, causing
sensitisation via the GI tract.
foods are usually well tolerated.
raspberry, grape,
tomato,
melon, banana, celery, carrot,
strawberry, raspberry, apple, pear,
concentrated
in thecitrus,
peel of
fruits,
reactions to cooked foods, with a
Reactions are usually restricted to
Patients often present with local
cabbage,
asparagus,
11S
in:
rather
than thelettuce,
pulp.
litchi, pineapple, orange, bell
hazelnut, carrot, celery, gold kiwi,
high globulin
frequencyproteins
of severeoccur
systemic
the
oral
cavity
(OAS).
symptoms
restricted
to
the
oral
chestnut, hazelnut, walnut, wheat
peanut,
pepper, tomato and soybean.
peanut and soybean.
reactions.Brazil nut, hazelnut,
cavity (OAS).
and maize.
sesame seed, cashew nut and
Patients
with ns-LTP IgE antibodies
Patients
with
profilin-sIgE
pistachio.
can often tolerate peeled-off fruits
2S albumin proteins occur in:
antibodies are either sensitised or
Patients displaying PR-10 sIgE
and certain food such as carrots,
mustard seed, rape seed, Brazil
at risk of developing multiple
antibodies are sensitised or at risk
bananas, potatoes and melon, but
nut, peanut, walnut, sesame seed,
pollen 14.
sensitisation
pollen- protein
of developing
multiple
pollen stability
are at and
risk of
severe
cashew
nut and
pistachio.
Figure
Example and
of allergen
groups with
their allergen
riskdeveloping
of reaction.
OAS = Oral
Allergy
Syndrome
.
associated food allergy.
sensitisation,
and
pollenreactions upon ingestion of nuts.
associated food allergy.
7/8S globulin proteins occur in:
Immuno
Allergen Chip Test (ISAC):
Plant foods most often involved
Plant foodsSolid-Phase
most often involved
peanut, lentil, pea, hazelnut,
include:ImmunoCAP®
strawberry, apple, apricot,
are: strawberry,
apple, cherry,
Plant are
foodsnot
most
often involved
sesame seed,
nut
Some
of the allergen
components
available
as individual
tests, but walnut,
are contained
incashew
the ISAC
cherry, plum, peach, pear,
and pistachio.
almond, peach, pear, hazelnut,
include: peach, apricot, cherry,
test
profile.
Thecelery,
ISAC carrot,
test is a strawberry,
multiplexraspberry,
microchip
which IgE
is detected
to multiple recombinant allergen
grape,
citrus, tomato,
melon,
banana,
apple,array
pear, in raspberry,
asparagus,
lettuce,
11S globulin test
proteins
occur in:
litchi, pineapple,Theorange,
bell
hazelnut,
carrot,
gold
kiwi,
components.
test measures
specific
IgE celery,
to 112
different
components.
This iscabbage,
a semi-quantitative
reported
in
chestnut, hazelnut, walnut, wheat
peanut, Brazil nut, hazelnut,
pepper,
tomato and soybean.
peanut
and soybean.
ISU
(International
Standardised
Units)
units. This test is recommended
for
multisensitised
patients:
it
will
add
and maize.
sesame seed, cashew nut and
additional diagnostic information by prediction of cross-reactivity, prediction of risk to cause
symptoms or severe
pistachio.
reactions and additional information on heat-stability and biodegradability of certain allergens. Refer to table 15 for a
list
of allergen components available as individual tests, and to appendix G for a list of the components included in
Figure 14. Example of allergen protein groups with their allergen stability and risk of reaction. OAS = Oral Allergy Syndrome.
the ISAC profile.
Immuno Solid-Phase Allergen Chip Test (ISAC):
Table 15. Allergen components available as individual sIgE tests.
Some of the allergen components are not available as individual ImmunoCAP® tests, but are contained in the ISAC
rPen m1 Shrimp tropomyosin
rTri a19
Wheat omega-5 gliadin
rApi m1
Honey bee venom phosholipase A2
test profile. The ISAC test is a multiplex microchip array in which IgE is detected to multiple recombinant allergen
rCyp c1
Carp parvalbumin
nBos d4
rCor a8
Hazelnut LTP
Milk α-lactalbumin
components.
The test measures specific
IgE to 112
different components.nGly
Thism4
is a semi-quantitative
test reported in
rGad c1
Cod parvalbumin
nBos d5
Milk β-lactoglobulin
Soy PR-10 protein
ISU
(International
Standardised
Units)
units.
This
test
is
recommended
for
multisensitised
patients:
it will add
nGal d1
Egg ovomucoid
nBos d8
Milk Whey
nGly m5
Soy storage protein
additional
information by
of cross-reactivity,
of risk
causeprotein
symptoms or severe
nGal d2 diagnostic
Egg ovalbumin
rAraprediction
h2
Peanut
Storage protein prediction
nGly m6
Soytostorage
reactions
on heat-stability
andred
biodegradability
of certain
allergens.pineapple
Refer to table 15 for a
nGal d3 and
Eggadditional
conalbumininformation
Alpha-gal
nAna
c2
Bromelein,
α-1,3-Gal,
meat
list of allergen components available as individual tests, and to appendix G for a list of the components included in
PathCare: Allergy investigations 10 December 2013
24
the
ISAC profile.
related species, may bind to a similar structure, and cause
not peanut specific and may be associated with cross-
cross-reactivity
both in vitro
and in
vivo. Antibodies
reactions in plant-related food species.
Table
15. Allergen components
available
as individual
sIgE tests.
rPenagainst
m1 aShrimp
tropomyosin
Wheat omega-5 gliadin
rApi m1
Honey bee venom phosholipase A2
species-specific
epitoperTri
are a19
usually associated
rCypwith
c1 a risk
Carp
nBos d4
a8
Hazelnut
LTP
Milktoα-lactalbumin
forparvalbumin
severe reactions, whereas
antibodies
an
3.AllergenrCor
component
protein stability
rGad c1
Cod parvalbumin
nBos d5
Milk β-lactoglobulin
nGly m4
Soy PR-10 protein
epitope with a similar structure in other allergen sources
Knowledge of the stability of the allergen protein
nGal d1
Egg ovomucoid
nBos d8
Milk Whey
nGly m5
Soy storage protein
or noh2clinical Peanut
reaction.
adds another
valuable
aspect to
component resolved
nGalare
d2usually
Eggassociated
ovalbuminwith milderrAra
Storage
protein
nGly m6
Soy storage
protein
nGalAsd3an example
Egg conalbumin
Alpha-gal
nAna
c2
Bromelein,
pineapple
some peanut allergenic
components
are red meat diagnostics.
Allergens
that are stable
to heat and digestion
α-1,3-Gal,
shown in figure 13. The Ara h1, 2 and 3 storage proteins
PathCare: Allergy investigations 10 December 2013
are peanut-specific allergens, and are associated with
30
are more likely to cause severe reactions, whereas heat
24
and digestion labile allergens are more likely to be
primary peanut sensitisation. They are associated with a
tolerated or only cause mild/local reactions. Refer to figure
risk of severe reactions. The Ara h5, 8, and 9 allergens are
14 for examples of some protein-allergen characteristics.
Pathology Forum Vol 4 No.3
March 2014
IgE-mediated allergy tests have traditionally been based
of milk will react to all forms of food containing milk. The
on a crude extract of pollen or plant food that contains
knowledge of which allergen component the patient
a complex mixture of allergens, some with minor clinical
is sensitised to may prevent serious morbidity (e.g.
significance, some with cross-reacting properties, and
malnutrition) and even mortality. Refer to figure 15 for
some with prognostically significant implications. A
examples of common food allergen components.
positive sIgE to a specific food (e.g. milk) will not be
able to discriminate between the allergen-components.
4.Cross-reactivity between allergen components
Knowledge of the allergen components to which the
Allergen components can be classified as belonging to
patient has formed IgE antibodies may add valuable
different protein families according to their function and
information regarding the management of the patient. In
structure. IgE antibodies in the same protein family often
the case of a patient allergic to milk, for example, with a
show cross-reactivity. Cross-reactivity between closely
positive milk sIgE test, it may be of value to know whether
related molecular structures may shed light on several
the patient is sensitised to the whey or the casein
clinical syndromes such as the oral allergy syndrome
components of milk. Whey components (α-lactalbumin
(OAS), latex-fruit syndrome as well as the well-known
and β-lactglobulin) are heat-labile, and are denatured
cross-reactivity between fruits of the Rosacea family or
during the cooking process. Patients allergic to the whey
between tree nuts. For example, profilins are proteins
component will be able to tolerate pasteurised milk, or
with a highly similar structure in pollens and plants,
food containing cooked milk. Casein on the other hand is
contributing to cross-reactions between botanically
heat-stabile, and patients allergic to the whey component
unrelated species (Figure 14).
31
Pathology Forum Vol 4 No.3
f1 (Gallus domesticus), Egg white components
f1
Gal d1, Ovomucoid
Gal d2, Ovalbumin
Gal d3, Conalbumin
Gal d4, Lysozyme
Egg white
Heat stable protein.
Risk of reaction to cooked egg,
Highly allergenic, associated
with persisting egg allergy.
Heat labile protein.
Risk of reaction to raw/
slightly cooked egg.
Heat labile protein.
Risk of reaction to raw/
slightly cooked egg.
Heat labile protein.
Risk of reaction to raw/
slightly cooked egg.
f2 (Bos domesticus), Milk- components
f2
Milk
α-lactalbumin
Bos d4
β-lactoglobulin
Bos d5
Albumin (BSA)
Bos d6
Casein
Bos d8
Bos d lactoferrin
Whey proteins
Heat labile protein.
80% of milk proteins.
Heat labile protein
Heat labile protein.
Risk for reactions to
fresh milk.
Heat stabile protein.
Risk of reactions
to fresh milk.
Risk of reactions to fresh milk.
Main allergen in beef.
f3 (Cod), Fish components
f3
Crustacean components
f24
Parvalbumins
Cyp c1, Gad c1
Fish
Risk of severe reactions
to all forms of milk.
Tropomyosin
Pen m1, Ani s3, Der p10, Bla g7
Shrimp
Tropomyosin is a very heat stable muscle protein that is found in:
Crustaceans: shrimp, lobster, crayfish and crab;
Arachnids: House dust mite; Insects: Cockroach and
Parasites: Anisakis simplex (Herring worm)
The parvalbumin proteins
have a large degree of
cross-reactivity between
fish species.
Honey bee venom components
f14 (Glycine max), Soybean- components
f14
Soybean
i1
Storage proteins
Gly m5, Gly m6
PR-10 proteins
Gly m4
Associated with severe
reactions.
Stable to heat and
digestion.
Associated with both systemic
and local reactions (crossreact with plant pollen).
Honey bee
venom
Phospholipase A2
Api m1
Api m1 can confirm that the
sensitisation to honey bee venom
are not due to cross-reactive
components from wasp venom.
f4 (Triticum aestivum), Wheat components
f4
Wheat
Gliadin
α, β, γ, and ω-gliadins
ω-5-Gliadin
Tri a19
Lipid transfer protein
Tri a14
Risk marker for systemic reactions
and persistent wheat allergy.
Risk marker for systemic reactions
and persistent wheat allergy.
Associated with local and systemic
reactions.
Stable to heat and digestion.
f13 (Arachis hypogaea), Peanut components
f13
Peanut
Storage proteins
Ara h1, Ara h2, Ara h3
PR-10 proteins
Ara h8
Lipid transfer protein
Ara h9
Profilin
Ara h5
Associated with severe
reactions.
Stable to heat and
digestion.
Associated with local
reactions (cross-react with
plant pollen).
Labile to heat and
digestion.
Associated with both severe
and local reactions (crossreact with peach-related
fruits).
Stable to heat and digestion.
Marker of grass pollencross-reactivity.
Low clinical relevance.
Figure 15. Important food allergen components.
PathCare: Allergy investigations 10 December 2013
32
Pathology Forum Vol 4 No.3
25
March 2014
Immuno Solid-Phase Allergen Chip Test (ISAC):
Knowledge of the allergen protein family can also predict the
Some of the allergen components are not available as
severity of the reaction, as well as add information regarding
individual ImmunoCAP® tests, but are contained in the
the stability of the allergen to heat and digestion. CRD or MD
ISAC test profile. The ISAC test is a multiplex microchip
is an important support tool in the management of a severely
array in which IgE is detected to multiple recombinant
allergic or multisensitised patient, leading to targeted therapy
allergen components. The test measures specific IgE to
and advice regarding avoidance measures. Since not all
112 different components. This is a semi-quantitative test
allergen components have been identified and characterised
reported in ISU (International Standardised Units) units. This
to date, CRD or MD should be evaluated together with the
test is recommended for multisensitised patients: it will add
clinical picture of the patient.
additional diagnostic information by prediction of crossreactivity, prediction of risk to cause symptoms or severe
reactions and additional information on heat-stability and
biodegradability of certain allergens. Refer to table 15 for a list
of allergen components available as individual tests, and to
appendix G for a list of the components included in the ISAC
profile.
In conclusion:
References and further reading:
1.
2.
4.
Kock J. Investigation of immediate-onset IgE-mediated food
5.
Hauser M, Roulias A, Ferreira F, Egger M. Panallergens and
allergy. CME 2012; 30(7): 257-259.
their impact on the allergic patient. Allergy, Asthma & Clinical
components are classified into protein families based on their
function and structure. Allergens can further be classified as
species-specific (primary) or cross-reactive to proteins with
similar structures. This information may help to evaluate the
Treudler R. Update on in vitro allergy diagnostics. JDDG 2012; 10:
1-9.
allergy diagnosis, known as component resolved diagnostics
(CRD) or molecular diagnostics (MD) in allergy. Allergen
Sastre J. Molecular diagnosis in allergy. Clin Exp All 2010; 40: 14421460.
3.
Continuous development and progress in the rapidly evolving
field of recombinant allergens have led to a novel concept in
Green R, Motala C, Potter PC. ALLSA Handbook of practical allergy.
3rd ed. The Republic of South Africa: Paarl Media; 2010.
Immunology 2010; 6 (1): 1-14.
6.
Ferreira F, Hawranek T, Gruber P, Wopfner N, Mari A. Allergic crossreactivity: from gene to clinic. Allergy 2004; 59: 243-267.
risk of reaction upon exposure to different allergen sources.
33
Pathology Forum Vol 4 No.3
r = recombinant
r Ara h 2
(Biogenetically engineered allergens)
n = native
Allergen
component
number
Scientific acronym of allergen source e.g.
Arachis hypogaea (peanut)
(Allergens are purified from natural food extracts)
Section 9
Coeliac Disease and Other Gluten
Related Disorders
Figure 12. Allergen component nomenclature explained.
A number of disorders have been linked to gluten, a protein complex found in wheat, rye and barley.
Gluten-related conditions include coeliac disease, wheat allergy and non-coeliac gluten sensitivity. The
Common
Peanut environmental factor, gliadin, leading to a
immune system reacts in different ways
to thename:
triggering
Latin name: Arachis hypogaea
diverse spectrum of gluten-induced ImmunoCAP
conditions.allergen
Figure
16 highlights
the pathophysiology
name:
f13
Ara h 2 behind the
Ara h 1
Storage protein
Peanut specific marker
most common
gluten-related
disorders.
Storage
protein
Peanut specific marker
Wheat allergy (WA)
Ara h 8
Ara h 5
Profilin
WA is an adverse
reaction to wheat proteins. Depending on the underlying immunological
mechanisms and the
PR-10immunologic
protein
Marker of grass pollen crossroute
of allergen
exposure,
WA is classified into classic food allergy, wheat-dependent exercise
induced
anaphylaxis
(WDEIA),
Marker
of tree pollen
cross-reactivity
reactivity, low clinical
relevance
occupational asthma (baker’s asthma) or contact urticaria. WAs usually involve IgE antibodies to one or more of the wheat protein
Ara h 9 and gluten (gliadin and glutenin). The majority of IgE-mediated reactions
Ara h 6 to wheat involve the
fractions namely albumin, globulin
nsLTP
Storage protein
albumin and globulin
fractions,
the glutens can also induce IgE-mediated
Ara h 3 reactions. Peanut specific marker
Marker
of peachalthough
cross-reactivity
Storage protein
Peanut specific marker
Non-coeliac Gluten sensitivity (GS)
GS individuals may suffer from symptoms similar to those of coeliac disease patients (with a predominance of extra-intestinal
symptoms)
after ingestion
gluten containing food. There are currently no laboratory biomarkers specific for GS. The diagnosis
Figure
13. Peanut
allergen of
components.
is based on exclusion criteria. An elimination diet (of gluten-containing foods) followed by an open gluten-food challenge, is most
often used to evaluate whether symptoms resolve after elimination of gluten from the patient’s diet.
Gluten-related disorders
Pathogenesis
Autoimmune
Non-autoimmune
Allergic
(?Possible innate immunity)
Dermatitis
herpetiformis
Coeliac disease
Symptomatic
Classical
Non-Classical
Gluten ataxia
Gluten sensitivity
Asymptomatic
Wheat allergy
Respiratory allergy
Food allergy
WDEIA
Contact urticaria
Figure 16. Classification of gluten-related disorders according to pathogenesis.
Adapted from Sapone et al. Abbreviations: WDEIA = wheat dependent exercise induced anaphylaxis.
4
34
Pathology Forum Vol 4 No.3
March 2014
spectrum of gluten-related disorders. The characteristics of the three main forms of gluten reactions are summarised
in Table 16.
Table 16. Characteristics of the three best known gluten-related disorders.
Onset of symptoms
Pathogenesis
Genetic
Background
(HLA class II
antigens)
Autoantibodies:
tTG, EMA, Gliadin
Enteropathy
(Histology)
Coeliac Disease
Weeks to years
Autoimmunity
Gluten Sensitivity
Wheat Allergy
Hours to days
Minutes to hours
Possibly innate immunity
Allergic immune response
GS and WA are not associated with the presence of HLADQ2/8 antigens. HLA-DQ2 is present in 20-30% and DQ8
in 10 % of the general asymptomatic population. Only 3%
of HLA-DQ2/8 positive individuals will develop CD.
HLA-DQ2 is positive in > 90% and
HLA-DQ8 is positive in 5-10% of CD patients.
Almost always present
(See Table 17)
Enteropathy almost always present
(Increased intraepithelial lymphocytes, crypt hyperplasia,
villous atrophy)
GIT symptoms (classical presentation):
Chronic or recurrent diarrhoea, anorexia, vomiting,
abdominal pain and distension, constipation,
malabsorption, failure to thrive/weight loss.
Symptoms and
complications
Co-existing
conditions
Non-GIT symptoms + complications
(atypical presentation):
Dental enamel defects, osteopenia/osteoporosis, short
stature, delayed puberty, infertility, iron deficiency
anaemia resistant to oral iron replacement, unexplained
liver disease, neurologic problems, stomatitis etc.
Endocrine: type 1 diabetes, autoimmune thyroiditis,
Addison disease, reproductive disorders, alopecia areata
Neurologic: Cerebellar ataxia, neuropathy, epilepsy,
migraine
Cardiac: Idiopathic dilated cardiomyopathy, autoimmune
myocarditis
Hepatic: Primary biliary cirrhosis, autoimmune hepatitis
and cholangitis
Other: Anaemia, osteoporosis, selective IgA deficiency,
Sjögren’s syndrome, juvenile chronic arthritis, Turner’s,
Down’s, and Williams’ syndromes, dental enamel
defects, dermatitis herpetiformis
Always absent
Always absent
No enteropathy
(± slight increase in
intraepithelial
lymphocytes)
No enteropathy
(± eosinophils in the lamina
propria)
Both intestinal and extraintestinal symptoms;
gastrointestinal symptoms
are not always
distinguishable from those
of CD and WA.
Long term complications
unlikely.
Classic food allergy:
Skin, GIT, respiratory
system affected
WDEIA
Occupational asthma and
rhinitis
(Baker’s asthma)
Contact urticaria
Absence of coexisting
conditions.
Absence of coexisting
conditions.
Adapted from: Celiac Disease (NEJM, Dec 2012). Abbreviations: tTG = tissue transglutaminase, EMA = endomysial antibody, GIT = gastrointestinal tract; WDEIA =
wheat-dependent exercise induced anaphylaxis
Who should be investigated for CD?
1. Symptomatic individuals presenting with classic gastrointestinal symptoms such as chronic or recurrent
white children, but now it is known to affect persons of
Coeliac
disease
(CD)
diarrhoea,
malabsorption,
weight loss, abdominal distension and pain or patients with a differential diagnosis of
different
ages and ethnic groups, and may manifest without
CD is
a
systemic
immune-mediated
multi-system
disorder
irritable bowel syndrome
any gastrointestinal
symptoms.anaemia
The prevalence
of CDoris
triggered
by dietary
gluten in genetically
susceptible persons.
2.
Individuals
presenting
with extra-intestinal
clinical conditions
such as unexplained
(iron, folate
B12 deficiency),
dermatitis
herpetiformis,
neuropathy,
bone density, short stature,
approaching
1% inreduced
most populations.
CD isvitamin
characterised
by a broad range
of clinical
presentations,peripheral
delayed puberty, reproductive disorders, low birthweight infants, persistent aphtous stomatitis, dental enamel
a specific serum autoantibody response, and variable degrees
hypoplasia, non-hereditary cerebellar ataxia, persistent elevation in serum aminotransferases (AST and ALT) or
The diagnosis of CD is established on serological and HLA
of small-intestine mucosa l inflammation, villous atrophy and
hypoalbuminaemia
testing,
biopsy
and observation
of deficiency,
the patient’s
cryptAsymptomatic
hyperplasia. Expression
of the
HLA-DQ2
HLA-DQ8condition:
3.
individuals
with
a CD and
associated
type duodenal
1 diabetes
mellitus,
selective IgA
response
to a GFD.
The reactions
to gluten
areanot
autoimmune
thyroiditis,
liver
Williams’
or Turner’s
syndromes
and
1st limited
degreeto
molecules
is an essential
geneticautoimmune
component of
the disease,
disease, Down’s,
relative
with for
proven
CD
CD, and we need to appreciate the existence of a spectrum of
being
necessary
the immune
reaction against gluten
(explaining the familial occurrence). The onset of symptoms
gluten-related disorders. The characteristics of the three main
Investigations for CD:
forms of gluten reactions are summarised in Table 16.
is usually
andof
characterised
a limeand
lag pathological
of month
The
widegradual
variability
CD-related by
findings
processes make it difficult to conceptualise the diagnostic
or years into
aftera gluten
introduction.
Thealgorithm.
treatment Considering
of the
process
single rigid
diagnostic
the clinical picture, the following factors should also be
Who should be investigated for CD?
taken
intoisaccount
when
making
condition
a gluten free
diet
(GFD). the diagnosis of CD in a patient:
1. Positivity and titre of CD auto-antibodies (Table1.
17)Symptomatic individuals presenting with classic
2.
HLA-DQ2
and/or
HLA-DQ8
genotypes
gastrointestinal symptoms such as chronic or recurrent
The frequency of the disorder is increasing due to various
3. Coeliac enteropathy confirmed on small bowel biopsy
diarrhoea, malabsorption, weight loss, abdominal
factors such as the westernisation of diets, changes in
4. Response to a GFD
distension and pain or patients with a differential
wheat production and preparation, increased awareness,
a better understanding
of the
pathogenesis
PathCare:
Allergy investigations
10 December
2013 of the disorder
and improved diagnostic skills. Coeliac disease was once
considered a gastro-intestinal disorder that affected mainly
diagnosis of irritable bowel syndrome
28
2. Individuals presenting with extra-intestinal clinical
conditions such as unexplained anaemia (iron, folate
or vitamin B12 deficiency), dermatitis herpetiformis,
35
Pathology Forum Vol 4 No.3
Table 17. Blood tests for the investigation of CD.
Test
Sensitivity %*
Specificity %*
Comments
st
Recommended as 1 line screening test, test may be false negative
in IgA deficiency and in young children
IgA anti-tTG antibodies
90-98%
95-97%
IgG anti-tTG antibodies
12.6–99.3%
Differ between
studies
86.3-100%
Differ between
studies
Useful in patients with IgA deficiency
IgA anti-EMA
85-98%
97-100%
Useful in patients with an uncertain diagnosis, false negatives may
occur in IgA deficiency and in young children
78%
85%
Lower sensitivity and specificity than IgA anti-tTG
>90.0%
>90.0%
Useful in patients with IgA deficiency and young children
±91.0
±54.0
High negative predictive value
IgA anti-gliadin
(new generation DGP)
IgG anti-gliadin
(new generation DGP)
HLA-DQ2 and/or
HLA-DQ8 genotypes
*Data for sensitivity and specificity are obtained from different studies - see references.
Abbreviations: tTG = tissue transglutaminase, EMA = endomysial antibodies, DGP = deaminated gliadin peptides
History and Physical Examination
suggestive of gluten-related disorder
Differential diagnosis: wheat allergy
Differential diagnosis: coeliac disease or gluten sensitivity
Wheat sIgE tests (RAST):
Wheat (f4) and Gluten (f79)
Screen: IgA-tTG antibodies plus total IgA (if not tested before)
Wheat sIgE component testing:
ω-5-gliadin (Tri a19), gliadins (f98),
LTP (Tri a14)
Normal total IgA and elevated IgA tTG
IgA-tTG > 10 x ULN
Gluten food challenge:
3g gluten/day for 2 weeks then reevaluate
Tests and/or challenge positive
Low total IgA
IgA-tTG < 10 x ULN
Do IgG-tTG & IgG-antigliadin
Do EMA & HLA
Both EMA and
HLA-DQ2 or HLA-DQ8
positive
Positive for
IgG-tTG or
antigliadin
Negative for
IgG-tTG and
antigliadin
Consider OEGD & biopsy
No
Biopsy suggestive of CD
Yes
No
Confirms
wheat allergy
Rule out wheat
allergy
Yes
No
Yes
Consider gluten
sensitivity
Confirms
coeliac disease
Double-blind gluten challenge
positive
Yes
Confirms
gluten
sensitivity
No
Consider other
diagnoses e.g.
irritable bowel
syndrome
Figure 17. Proposed algorithm for the differential diagnosis of gluten-related disorders. Abbreviations: OEGD = oesophageal gastroendoscopy; tTG = tissue Transglutaminase; EMA = edomesial antibodies; LTP = lipid transfer protein; ULN = upper limit of normal
36
PathCare: Allergy investigations 10 December 2013
Pathology Forum Vol 4 No.3
29
March 2014
peripheral neuropathy, reduced bone density, short
stature, delayed puberty, reproductive disorders, low
birthweight infants, persistent aphtous stomatitis, dental
enamel hypoplasia, non-hereditary cerebellar ataxia,
persistent elevation in serum aminotransferases (AST and
ALT) or hypoalbuminaemia
3. Asymptomatic
individuals
with
a
CD
associated
condition: type 1 diabetes mellitus, selective IgA
deficiency, autoimmune thyroiditis, autoimmune liver
disease, Down’s, Williams’ or Turner’s syndromes and a 1st
degree relative with proven CD
Investigations for CD:
The wide variability of CD-related findings and pathological
processes make it difficult to conceptualise the diagnostic
process into a single rigid diagnostic algorithm. Considering
the clinical picture, the following factors should also be taken
into account when making the diagnosis of CD in a patient:
1. Positivity and titre of CD auto-antibodies (Table 17)
2. HLA-DQ2 and/or HLA-DQ8 genotypes
3. Coeliac enteropathy confirmed on small bowel biopsy
4. Response to a GFD
Key points on diagnosis of CD:
 IgA tTG antibodies remain the preferred initial screening
test for detection of CD in individuals over the age of two
years, because of its high sensitivity and specificity. CD is
unlikely in patients with a low IgA tTG and a normal total
IgA concentration.
 IgA deficiency is more common in patients with CD than
in the general population. The IgA-based serology tests
Summary and conclusion:
Reactions to gluten are not limited to CD, but involve a
broad spectrum of gluten-related disorders. The clinical
presentation of CD varies greatly from asymptomatic to
severe malnutrition, which may make case finding difficult.
The diagnosis of CD is not always straightforward, despite
the high sensitivity and specificity of serological tests. False
negative serological tests may occur, especially in patients
on a GFD. Testing for HLA-DQ2 and HLA-DQ8 may be useful
in patients at risk. HLA testing has a high negative predictive
value, meaning that CD is unlikely to develop in individuals
who are negative for HLA-DQ2 and HLA-DQ8. The diagnosis
of CD usually requires a small bowel biopsy with histology
suggestive of CD. Exceptions can be made in patients with
strong clinical, serological and genetic evidence of CD. The
cornerstone treatment for all the gluten-related disorders
remains the implementation of a strict GFD.
Nomenclature and abbreviations:
CD
DGP
EMA
GFD
GIT
GS
HLA
IgA
IgG
OEGD
Ttg
ULN
WA
Coeliac disease
Deaminated gliadin peptides
Endomesial antibodies
Gluten free diet
Gastrointestinal
Gluten sensitivity
Human leukocyte antigen
Immunoglobulin A
Immunoglobulin G
Oesophageal gastroendoscopy
Tissue transglutaminase
Upper limit of normal
Wheat allergy
(IgA tTG and IgA EMA) may be falsely negative in CD
patients with IgA deficiency as well as in young children.
IgG-based serology tests (IgG tTG and IgG anti-gliadin)
should be requested in this patient group
 The diagnosis of CD is confirmed by means of upper
References and further reading:
1.
endoscopy with duodenal biopsy, but recent guidelines
M, Mäki M, Ribes-Koninckx C, Ventura A, Zimmer KP. European
Society of Pediatric Gastroenterology, Hepatology, and Nutrition
suggest that biopsy may be omitted in patients with
Guidelines for the Diagnosis of Coeliac Disease. Journal of
strong clinical and serological evidence of CD (tTG-IgA
elevated > 10 times upper limit of normal and EMA
serology positive and HLA-DQ2 or HLA-DQ8 positive)
 The cornerstone of treatment CD is the implementation
Pediatric Gastroenterology and Nutrition 2012; 54:136-160.
2.
Fasano A, Catassi C. Celiac Disease. NEJM 2012; 367:2419-2426.
3.
Sapona A, Bai JC, Ciacci C, Dolinsek J, Green PHR, Hadjivassiliou
M, Kaukinen K, Rostami K, Sanders DS, Schumann M, Ullrich R,
of a strict gluten-free diet for life. CD patients on a
Villalta D, Volta U, Catassi C, Fasano A. Spectrum of gluten-related
disorders: consensus on new nomenclature and classification.
gluten-free diet should report significant symptom
improvement, together with normalisation of CD-specific
antibodies on serology investigations (usually after 12
months on a gluten free diet)
 A proposed algorithm to the investigation of CD is
depicted in figure 17.
Husby S, Koletzko S, Korponay-Szabó IR, Mearin ML, Phillips A,
Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman
Biomedcentral Medicine 2012; 10:13.
4.
Duggan JM. Coeliac Disease: the great imitator. Medical Journal of
5.
Bürgin-Wolff A, Mauro B, Faruk H. Intestinal biopsy is not always
Australia 2004; 180: 524-526.
required to diagnose celiac disease: a retrospective analysis of
combined antibody tests. Gastroenterology 2013; 13(19):1-6.
37
Pathology Forum Vol 4 No.3
Section 10
PathCare Allergy Test Request
Form
The PathCare allergy test request form is designed to give an overview of the most frequent allergy tests requested. The request
form guides the clinician through the types of tests available, and is divided in three groups:
 IgE-mediated allergies, which is subdivided into screening/group tests, confirmation/quantification of individual allergen sIgE
and allergen component sIgE testing
 Delayed hypersensitivity tests, including basophil- and lymphocyte activation tests as well as patch tests
 Other allergy tests.
1
Patient and account information:
It is the requesting physician’s and patient’s obligation to
confirm with the specific medical aid which allergy tests
will be reimbursed. This differs between medical aids, and
plan options. Sometimes a motivation will be requested
for approval of allergy test reimbursement.
Clinical information:
Suspect aero-allergens if clinical symptoms are consistent
with: allergic rhinitis, asthma or allergic conjunctivitis.
2
Suspect food or ingestant allergens if clinical symptoms
are consistent with: GIT symptoms, skin rash, urticaria or
oral cavity symptoms.
With food and drug allergy it is important to distinguish
between:
- Immediate
reactions
(consider
IgE-mediated mechanism), or
- Delayed reactions (consider cell-mediated mechanism).
IgE-mediated screening/group tests:
If the clinical history is vague, with a low clinical index of
suspicion, screening or group tests are advised. Skin Prick
Tests for inhalant allergens are more cost-effective screens
for inhalant allergens than blood tests, if there are no
contra-indications present.
sIgE group tests contain a mixture of allergens with the
purpose to screen for a specific group allergens e.g.
Phadiatop inhalant-, paediatric-, nut-, seafood- and cerealmixes. If the screening test is positive, an option is available
to request allergens in the specific group test.
IgE-mediated confirmatory/quantitative tests:
This option will be more cost-effective to select if there is
a high index of suspicion of the suspected allergen. e.g. if
history is positive for peanut allergy: instead of selecting
the nut group test, select the peanut sIgE RAST.
Allergen Component sIgE testing:
The most common components are listed here.
3
IgE-mediated allergies include:
- Inhalant allergies
- Food allergies that cause symptoms within minutes to
hours
- Insect venom allergies
- Some drug allergies (anaphylaxis).
Delayed hypersensitivity tests:
This group includes the most common food additives,
drugs, metal and contact dermatitis allergens.
Tests not on the request form:
The lists of available allergy tests are too broad to place on a single allergy test request form. The backside of the test request form does
have a comprehensive list of IgE-specific allergens. Please contact your local laboratory if a test is not on the request form, it may be
available.
38
Pathology Forum Vol 4 No.3
4
5
6
7
March 2014
Allergy Test Request Form
PRACTICE NO. 5200539
If urgent, please complete below
BARCODE STICKER
Contact
Person
Please tick no. supplied (ü) Tel
PathCare
Code
Referring
Doctor
PATIENT DETAILS
File No.
Patient
Title
Tel. (h)
Cell
Tel. (w)
E-mail
F
M
I certify that the above information is correct and give specific consent for selected test(s) to be done. I authorise
you to disclose these results to my medical aid administrators and/or insurance company. I undertake to pay all
outstanding monies not covered by medical aid. I fully understand the implication of the test and have received
adequate pre-test counselling.
SIGNATURE : PERSON RESPONSIBLE FOR PAYMENT
IF DIFFERENT FROM PATIENT
SIGNATURE : PATIENT / GUARDIAN
Date
Collected by
DD
SPECIMEN INFORMATION
MM
On Ice
Time
Location code
YY
Venous
:
Arterial
Guarantor
ID No.
Title, Initials
and Surname
Postal
Address
(initials & surname)
( compulsory - please complete)
Mr Mrs Ms Dr Prof
Tel. (h) / cell
Tel. (w)
E-mail
Medical
Aid
Medical Aid
No.
Other:
In Foil
,
URINE
Date
DD
MM
YY
Time
HEPARIN
:
Allergy specific history:
Consider Aero-allergens if:
Allergic rhinitis
Asthma
Conjunctivitis
Consider Food allergens if:
GIT symptoms
Skin rash
Urticaria
Oral symptoms
Consider IgE mediated mechanism if reactions are IMMEDIATE (minutes to hrs)
Consider non-IgE-mediated mechanism in the case of DELAYED reactions (hrs to days)
Other allergy history:
E1103
CITRATE
EDTA
4ml
6ml
TEST COUNT
GEL
CLOTTED FLUORIDE
ACD
OTHER - please specify
Other allergy tests:
ICD 10 CODE
Step 1. SCREENING/GROUP TESTS: Vague clinical history
INHALANTS SCREENING
W1106
FOOD SCREENING
B2265
Fx5 Paediatric food mix
QFT D2263
if Fx5 is positive
Include: cat, dog, house dust mites, feathers, moulds, grass-, weed- and tree pollens
Patient needs to be 72 hrs antihistamine free before test. Confirm with local laboratory for
availability of test and area specific inhalant panel
R2255
Fx1 Nut mix
QFT T2254
if Fx1 is positive
Phadiatop inhalant mix
W2164
Fx2 Seafood mix
QFT D2033
if Fx2 is positive
Skin Prick Test
QFT R2209
if Phadiatop mix is positive
Phadiatop panel consists of: House dust mites: D. pteronyssinus d1; Grass pollens: Bermuda
g2, Timothy g6; Weed pollen mix: wx7; Mould mix: mx1; Animal dander: Cat e1, dog e5;
Tree pollen mix: tx4 and tx7
Egg white, milk, fish, wheat, peanut, soybean
Peanut, hazel nut, brazil nut, almond, coconut
Fish, shrimp, blue mussel, tuna, salmon
Q2178
Fx3 Cereal/wheat mix
QFT S2177
Wheat, oats, maize, sesame seed, buckwheat
if Fx3 is positive
902461 SKELETON A4 ENG
OTHER SPECIFIC IgE ALLERGENS
C2067
Amoxicilloyl c6
K2068
Ampicilloyl c5
A2119
Cefaclor c7
G2281
Penicilloyl G
G2281
Penicilloyl V
M3524
Pholcodine c261
Morphine c260
L1307
Q2040
Succinylcholine c202
B2196
Honey bee venom i1
N2266
Paper wasp i4
L2135
Common wasp i3
W2072
Ascaris p1
N2151
Echincoccus p2
N2335
Anisakis p4
Q2224
Latex k82
Fx5 Paediatric
Other foods
Fx2 Seafood
Fx1 Nut mix
D.pteronyssinus d1
H2203
F2146
D.farinae d2
G2074
Aspergillus mould m3
N2128
Cladosporium mould m2
V2064
Alternaria mould m6
Z2130
Cockroach i6
Y2260
Olive tree t9
A2257
Oak tree t7
V2087
Bermuda grass g2
T2047
Timothy grass g6
D5207
Mugwort weed w6
M2144
Dandelion weed w8
P2147
Dog epidander e5
E2115
Cat epidander e1
See list of additional allergens on reverse side of request form
Z2199
Horse epidander e3
Step 3. ALLERGEN SPECIFIC COMPONENT TESTING: Define/characterize the allergy
Soy components
Cow's milk components
Egg white components
Peanut specific component
C2228
nGly m5 f431
B2058
Whey β-lactglobulin f77
B2219
Ovalbumin nGal d2 f232
J5211
rAra h2 f423
Z2337
nGly m6 f432
X2057
Whey
α-lactalbumin
f76
H4687
Ovmucoid
nGal
d1
f233
Wheat specific component
N2312
rGly m4 f353
L2112
Casein nBos d8 f78
Q5214
Conalbumin nGal d3 f323
Z5212
Omega-5 gliadin f416
Immuno Solid-Phase Allergen Chip
Seafood specific components
Detect
112
allergen
components
Other components are available – enquire at your local laboratory
N2220
Parvalbumin rGad c1 (fish)
Q1235
ISAC
S5213
Tropomyosin rPen a1 (shrimp)
Preservative
grp
DELAYED HYPERSENSITIVITY: Basophil or Lymphocyte activation tests – arrange with laboratory before specimen collection
CAST Drugs
CAST Drugs
CAST Preservatives
W5200
Preservative grp (7 analytes)
K5196
Penicillin grp (6 analytes)
E5013
Aspirin (ASA)
J5004
Tartrazine
J4015
Penicilloyl G c1
P4332
Indomethacin
A5201
Sodium benzoate
S4017
Penicilloyl V c2
Z1578
Ibuprofen
A5017
Metabisulphite
Z3671
Benzylpenicilloyl/PPL
Z3372
Paracetamol
T5014
Sodium salicylate
E5197
Ampicillin
J1577
Diclofenac
W5016
Sodium
Nitrite
N4014
Amoxycillin
G5202
Mefenamic acid
R5015
MSG
J3670
Minor determinant mix
M5203
Naproxen
H1674
Sorbate
R5199
Clavulanic Acid & Amoxicillin
Y5204
Articaine
CAST Colorants
S3350
Sulfomethoxazole
F5205
Bupivacaine
S5006
Colorant group I
V4341
Trimetroprim
E3794
Lignocaine
Yellow, red, orange
N2956
Cefuroxime
P5206
Mepivacaine
Q5007
Colorant group II
T5198
Rifampicin
V4686
Chlorhexidine
Blue, red, black
Insects
FOOD ALLERGENS
J2152
Egg white f1
X2241
Milk f2
V2133
Fish f3
Y3985
Wheat f4
K2275
Peanut f13
Y2030
Soybean f14
S2154
Egg yolk f75
T2070
Apple f49
Z2222
Kiwi f84
Y2007
Potato f35
X2172
Gluten f79
B2081
Banana f92
X2287
Tomato f25
P2262
Orange f33
F2169
Garlic f47
Parasi
FOOD ALLERGENS
K2275
Peanut f13
G2189
Hazel nut f17
A2096
Brazil nut f18
H2065
Almond f20
Q2132
Coconut f36
V2133
Fish (Cod) f3
W2026
Shrimp f24
T2093
Blue mussel f37
Q2293
Tuna f40
K2022
Salmon f41
Y3985
Wheat f4
G2258
Oat f7
R2232
Maize f8
T2024
Sesame seed f10
F2100
Buckwheat f11
Pen Group
IgE-Mediated Allergy
Immediate hypersensitivity reaction
Non-IgE mediated allergy
Delayed hypersensitivity
6
INHALANT ALLERGENS
Phadiatop allergens
Drugs
Step 2. CONFIRMATORY / INDIVIDUAL ALLERGENS: High clinical index of suspicion of a specific allergen or previous positive screening test
4
7
3rd Copy
Doctor
SPECIMEN INFORMATION AND COUNT
Received
by
3
5
2 Copy
Doctor
No Cuff
Site
Priority
2
Hospital
& Ward
(initials & surname)
Fx3 Wheat
1
(initials & surname)
Print
PERSON RESPONSIBLE FOR PAYMENT OF ACCOUNT
Patient
First Name
*
Cell
1st Copy
Doctor
nd
Patient
ID No. / DOB
Patient
Surname
Fax
MELISA Metals
X3644
Nickel
M2282
Manganese
X2494
Titanium
A3660
Chromium
B4634
Aluminium
A4718
Mercury
J3647
Cobalt
SKIN PATCH TEST (Contact dermatitis)
X4633
Standard 45 allergen
More allergens are available; contact
your local laboratory for information.
Z: \ 01 FORMS REVIEW\ 04 NOV 2013 TT \ ALLERGY TEST REQUEST FORM 26/02/2014 LW
39
Pathology Forum Vol 4 No.3
Appendix
Allergy Investigations: Major
Irritation or Minor Aggravation?
APPENDIX
40
PAGE
Appendix A: Example of Allergy Case History Report
41
Appendix B: PathCare Allergy Test Requisition Form 42
Appendix C: PathCare Allergy Test Fees 2014
43
Appendix D: List of most Common Allergens (Specific-IgE)
44
Appendix E: Standard Inhalant Skin Prick Test Panel
45
Appendix F: List of most Common Standarised CAST and MELISA Tests Available (2014)
46
Appendix G: Contact Dermatitis Standard Patch Test Panel
47
Appendix H: Allergen Components Included in the ISAC 112 Test Profile (two pages)
48
Appendix I: Patient Information Brochure
50
Pathology Forum Vol 4 No.3
March 2014
Appendix A:
Example of Allergy Case History Report
Patient
Details
Patient Name: ……………………………………………………………………………………………. Date of Birth: …………………………………… Gender: …………………………………….
Address: ……………………………………………………………………………………………………………………………………………………………………… Contact nr: ……………………………….
…………………….………………………………………………………………………………….…Code: ………………………………………………… Date: ……………………………….........
Personal &
Family history
Appendix A: Example of Allergy Case History Report for Clinicians
Occupation: ……………………………………………………………………………. Hobbies: …………………………………………………………………………………………………………………….
Other relevant exposures: ………………………………………………………………………………………………………………………………………………………………………………………………..
Family history (parents and siblings): Asthma/ Eczema/ Rhinitis and sinusitis/ Conjunctivitis/ Urticaria / Other: ……………………………………………………………
Personal allergy history: Asthma/ Eczema/ Rhinitis and sinusitis/ Conjunctivitis/ Urticaria / Other: ………………………………………………………………………………
Current and past medications used for allergy: ……………………………………………………………………………………………………………………………………………………………….
Respiratory-related symptoms:
Allergic rhinitis: blocked nose/ itchy nose or throat/ runny nose/ sneezing
Allergic conjunctivitis: itchy or red/ swollen eyes/ shiners/ lacrimation
Asthma: chronic cough/ shortness of breath/ wheezing
Other symptoms:
…………………………………………………………………………………………………………
Occurrence of symptoms:
Seasonal variation (symptomatic months): J/ F/ M/ A/ M/ J/ J/ A/ S/ O/ N/ D
Weekly variations – worst on: weekdays or weekends
Daily variation - worst at: day or night
Environmental effect – worst: Indoors or Outdoors/ Inland or Coastal regions
Symptoms with animal contact – cat/ dog/ horse/ rabbit/ birds
Duration of symptoms – sporadic/ seasonal/ months/ years
Gastro-intestinal symptoms:
Symptoms:
Diarrhoea/ abdominal pain or cramps/ nausea & vomiting
Swelling/ tingling/ itching of lips and mouth (?Oral Allergy Syndrome)
Other symptoms: ………………………………………………………………………………………………………..
Period of time between ingestion of suspected food and symptoms:
Minutes……………………Hours…………………… Days……………………………………..
Associated foods/ food additives:
Eczema/ Dermatitis:
Relevant Clinical History
Atopic eczema – food or contact allergens associated with symptoms?
Contact dermatitis – any associated triggers?
……………………………………………………………………………………………………………………………….
Urticaria ± Angioedema (AE)
Acute urticaria ± AE (lesions present for < 24 hrs for less than 6 weeks)
Infections – parasite/ bacterial/ viral
Clear Association with - Certain food/ preservatives/ menstruation/ physical
stimuli (heat/ cold/ water/ pressure)/ drugs
No identifiable trigger
Chronic urticaria ± AE (lesions present for most days for more than 6 weeks)
Auto-immune diseases? ……………………………………………………………………………..
Chronic infections (bacterial, parasitic, viral)……………………………………………….
Other:…………………………………………………………………………………………………………..
Isolated AE (No urticaria, unresponsive to antihistamines or steroids)
Family history………………………………………………………………………………………………
Age of onset………………………………………………………………………………………………..
Medications e.g. ACE-Inhibitors …………………………………………………………………
Suspected drug allergy:
Acute reaction (anaphylaxis, immediate reaction) or
Delayed reaction (e.g. vague skin rash/ other symptoms)
Symptoms & signs: ……………………………………………………………………………………………………………
Suspected drug: …………………………………………………………………………………………………………………..
Suspected insect venom allergy:
Date of last reaction: ………………………………………………………………………………………………..
Insect identified: honey bee/ paper wasp/ common wasp/ other
Time delay from sting to symptoms: ………………………………………………………………………….
Symptoms - Localized swelling/ Difficulty in breathing/ Swelling of tongue or glottis
Anaphylaxis:
Symptoms: …………………………………………………………………………………………………………………
Suspected allergen: ……………………………………………………………………………………………………
Other allergy relevant history:
PathCare: Allergy investigations 10 December 2013
Consider the following investigations:
Skin Prick Test - no antihistamine
containing drugs for 2-3 days
Phadiatop Inhalant screen – Screening test
Specific-IgE (RAST) for suspected allergens
Component testing in ‘complex’ cases.
Most common allergens:
Cat-/ Dog-/ Horse- dander
House dust mites (indoors)
Grass pollens (seasonal/ outdoors)
Tree- / Weed pollens (seasonal/outdoors)
Maize pollen (rural/ seasonal/ outdoors)
Moulds (coastal/ moist regions).
Remember: Immediate reactions are mostly IgE
based (RAST), delayed reactions are most likely a
cellular mechanism (CAST, MELISA or Patch test).
Consider the following investigations:
- Specific-IgE group tests for screening e.g.
paediatric(fx5)-, nut(fx1)-, seafood(fx2)- and
cereal(fx3) mix
- Individual specific-IgE (RAST) for food (high
index of suspicion of specific food)
- CAST for food additives (3-6 weeks steroid
free).
Most common food allergens:
- Specific-IgE (RAST): Milk, egg white, fish,
peanut, tree nut, wheat, soy, seafood.
- CAST: preservatives and food colorants.
Investigations should be guided by history:
Acute urticaria:
- Routine tests not recommended. Investigate
according to history e.g. infections/ RAST/
CAST tests.
Chronic urticaria:
- FBC, ESR, CRP, thyroid antibodies, autoimmune (RF, ANA etc.), protein electrophoresis, infection investigations.
- Chronic urticaria with vasculitis: All of the
above plus viral & complement studies.
Isolated AE:
- Unlikely allergy. Consider hereditary
angioedema (HAE) or ACE-inhibitor. C4 and
C1-inhibitor studies indicated.
Consider the following investigations:
- If acute reaction: consider sIgE (RAST) tests
- If delayed reaction: consider CAST tests.
- Arrange with laboratory for individualised
tests.
Consider the following investigations:
sIgE (RAST) for insect venom e.g. honey bee
venom, paper wasp, common wasp.
Venom specific component tests may be
indicated (e.g. r Api m1 for honey bee) if
desensitisation therapy are considered.
Consider testing:
sIgE (RAST) or CAST tests but remember
tests may be false negative 4-6 weeks after
anaphylaxis.
E.g. Latex allergy or
Multiple allergies e.g. inhalant and food
allergies, consider sensitisation to cross- 33
reactive component (ISAC test indicated).
41
Pathology Forum Vol 4 No.3
Appendix B:
PathCare Allergy Test Requisition Form
Allergy Test Request Form
PRACTICE NO. 5200539
If urgent, please complete below
BARCODE STICKER
Contact
Person
Please tick no. supplied (ü) Tel
PathCare
Code
Referring
Doctor
PATIENT DETAILS
File No.
Patient
ID No. / DOB
Patient
Surname
Cell
1st Copy
Doctor
(initials & surname)
Hospital
& Ward
2nd Copy
Doctor
(initials & surname)
3rd Copy
Doctor
Print
(initials & surname)
PERSON RESPONSIBLE FOR PAYMENT OF ACCOUNT
Patient
Title
Patient
First Name
*
Fax
Tel. (h)
Cell
Tel. (w)
E-mail
F
M
I certify that the above information is correct and give specific consent for selected test(s) to be done. I authorise
you to disclose these results to my medical aid administrators and/or insurance company. I undertake to pay all
outstanding monies not covered by medical aid. I fully understand the implication of the test and have received
adequate pre-test counselling.
SIGNATURE : PERSON RESPONSIBLE FOR PAYMENT
IF DIFFERENT FROM PATIENT
SIGNATURE : PATIENT / GUARDIAN
Date
Collected by
DD
SPECIMEN INFORMATION
MM
On Ice
Time
Location code
YY
Venous
:
Arterial
Guarantor
ID No.
Title, Initials
and Surname
Postal
Address
Mr Mrs Ms Dr Prof
Tel. (h) / cell
Tel. (w)
E-mail
Medical
Aid
Medical Aid
No.
No Cuff
Site
Priority
( compulsory - please complete)
Other:
In Foil
SPECIMEN INFORMATION AND COUNT
,
Received
by
URINE
Date
DD
MM
YY
Time
HEPARIN
:
Allergy specific history:
Consider Aero-allergens if:
Allergic rhinitis
Asthma
Conjunctivitis
Consider Food allergens if:
GIT symptoms
Skin rash
Urticaria
Oral symptoms
Consider IgE mediated mechanism if reactions are IMMEDIATE (minutes to hrs)
Consider non-IgE-mediated mechanism in the case of DELAYED reactions (hrs to days)
Other allergy history:
E1103
TEST COUNT
GEL
CLOTTED FLUORIDE
ACD
OTHER - please specify
Other allergy tests:
ICD 10 CODE
Step 1. SCREENING/GROUP TESTS: Vague clinical history
INHALANTS SCREENING
W1106
CITRATE
EDTA
4ml
6ml
FOOD SCREENING
B2265
Fx5 Paediatric food mix
QFT D2263
if Fx5 is positive
Include: cat, dog, house dust mites, feathers, moulds, grass-, weed- and tree pollens
Patient needs to be 72 hrs antihistamine free before test. Confirm with local laboratory for
availability of test and area specific inhalant panel
R2255
Fx1 Nut mix
QFT T2254
if Fx1 is positive
Phadiatop inhalant mix
W2164
Fx2 Seafood mix
QFT D2033
if Fx2 is positive
Skin Prick Test
QFT R2209
if Phadiatop mix is positive
Phadiatop panel consists of: House dust mites: D. pteronyssinus d1; Grass pollens: Bermuda
g2, Timothy g6; Weed pollen mix: wx7; Mould mix: mx1; Animal dander: Cat e1, dog e5;
Tree pollen mix: tx4 and tx7
Egg white, milk, fish, wheat, peanut, soybean
Peanut, hazel nut, brazil nut, almond, coconut
Fish, shrimp, blue mussel, tuna, salmon
Q2178
Fx3 Cereal/wheat mix
QFT S2177
Wheat, oats, maize, sesame seed, buckwheat
if Fx3 is positive
Pathology Forum Vol 4 No.3
Drugs
Insects
Parasi
Fx5 Paediatric
Preservative
grp
DELAYED HYPERSENSITIVITY: Basophil or Lymphocyte activation tests – arrange with laboratory before specimen collection
CAST Drugs
CAST Drugs
CAST Preservatives
W5200
Preservative grp (7 analytes)
K5196
Penicillin grp (6 analytes)
E5013
Aspirin (ASA)
J5004
Tartrazine
J4015
Penicilloyl G c1
P4332
Indomethacin
A5201
Sodium benzoate
S4017
Penicilloyl V c2
Z1578
Ibuprofen
A5017
Metabisulphite
Z3671
Benzylpenicilloyl/PPL
Z3372
Paracetamol
T5014
Sodium
salicylate
E5197
Ampicillin
J1577
Diclofenac
W5016
Sodium Nitrite
N4014
Amoxycillin
G5202
Mefenamic acid
R5015
MSG
J3670
Minor determinant mix
M5203
Naproxen
H1674
Sorbate
R5199
Clavulanic Acid & Amoxicillin
Y5204
Articaine
CAST Colorants
S3350
Sulfomethoxazole
F5205
Bupivacaine
S5006
Colorant group I
V4341
Trimetroprim
E3794
Lignocaine
Yellow, red, orange
N2956
Cefuroxime
P5206
Mepivacaine
Q5007
Colorant group II
T5198
Rifampicin
V4686
Chlorhexidine
Blue, red, black
902461 SKELETON A4 ENG
42
Other foods
Fx3 Wheat
Fx2 Seafood
Fx1 Nut mix
INHALANT ALLERGENS
FOOD ALLERGENS
FOOD ALLERGENS
OTHER SPECIFIC IgE ALLERGENS
Phadiatop allergens
J2152
Egg white f1
C2067
Amoxicilloyl c6
K2275
Peanut f13
D.pteronyssinus d1
H2203
X2241
Milk
f2
K2068
Ampicilloyl c5
G2189
Hazel nut f17
F2146
D.farinae d2
V2133
Fish f3
A2119
Cefaclor c7
A2096
Brazil nut f18
G2074
Aspergillus mould m3
Y3985
Wheat f4
G2281
Penicilloyl G
H2065
Almond f20
K2275
Peanut f13
N2128
Cladosporium mould m2
G2281
Penicilloyl V
Q2132
Coconut f36
Y2030
Soybean f14
M3524
Pholcodine c261
V2064
Alternaria mould m6
V2133
Fish (Cod) f3
S2154
Egg
yolk
f75
Morphine c260
L1307
W2026
Shrimp f24
Z2130
Cockroach i6
T2070
Apple
f49
Q2040
Succinylcholine c202
T2093
Blue
mussel
f37
Y2260
Olive tree t9
Z2222
Kiwi f84
B2196
Honey bee venom i1
Q2293
Tuna f40
A2257
Oak tree t7
Y2007
Potato f35
N2266
Paper wasp i4
K2022
Salmon f41
V2087
Bermuda grass g2
L2135
Common wasp i3
X2172
Gluten f79
Y3985
Wheat f4
T2047
Timothy grass g6
W2072
Ascaris p1
B2081
Banana
f92
G2258
Oat f7
D5207
Mugwort weed w6
N2151
Echincoccus p2
X2287
Tomato
f25
R2232
Maize
f8
M2144
Dandelion weed w8
N2335
Anisakis p4
P2262
Orange f33
T2024
Sesame seed f10
P2147
Dog epidander e5
Q2224
Latex k82
F2169
Garlic f47
F2100
Buckwheat f11
E2115
Cat epidander e1
See list of additional allergens on reverse side of request form
Z2199
Horse epidander e3
Step 3. ALLERGEN SPECIFIC COMPONENT TESTING: Define/characterize the allergy
Soy components
Cow's milk components
Egg white components
Peanut specific component
C2228
nGly m5 f431
B2058
Whey β-lactglobulin f77
B2219
Ovalbumin nGal d2 f232
J5211
rAra h2 f423
Z2337
nGly m6 f432
X2057
Whey α-lactalbumin f76
H4687
Ovmucoid nGal d1 f233
Wheat specific component
N2312
rGly m4 f353
L2112
Casein nBos d8 f78
Q5214
Conalbumin nGal d3 f323
Z5212
Omega-5 gliadin f416
Immuno
Solid-Phase
Allergen
Chip
Seafood specific components
Detect 112 allergen components
Other components are available – enquire at your local laboratory
N2220
Parvalbumin rGad c1 (fish)
Q1235
ISAC
S5213
Tropomyosin rPen a1 (shrimp)
Pen Group
Non-IgE mediated allergy
Delayed hypersensitivity
IgE-Mediated Allergy
Immediate hypersensitivity reaction
Step 2. CONFIRMATORY / INDIVIDUAL ALLERGENS: High clinical index of suspicion of a specific allergen or previous positive screening test
MELISA Metals
X3644
Nickel
M2282
Manganese
X2494
Titanium
A3660
Chromium
B4634
Aluminium
A4718
Mercury
J3647
Cobalt
SKIN PATCH TEST (Contact dermatitis)
X4633
Standard 45 allergen
More allergens are available; contact
your local laboratory for information.
Z: \ 01 FORMS REVIEW\ 04 NOV 2013 TT \ ALLERGY TEST REQUEST FORM 26/02/2014 LW
March 2014
Appendix C:
PathCare Allergy Test Fees 2014
Allergy Test Price List
The fees listed below are valid until 31 December 2014.
A 15% discount applies to cash payments. Fees may differ for patients with medical aid
cover as these fees are negotiated individually with the medical schemes.
PRACTICE NO. 5200539
Step 1. SCREENING/GROUP TESTS: Vague clinical history
INHALANTS SCREENING
W1106
Skin Prick Test R360.50
FOOD SCREENING
B2265
Fx5 Paediatric food mix
QFT
QFT D2263 if Fx5
R1058.40
is positive
R2255
QFT
QFT T2254 if Fx1
R882.00
is positive
QFT
QFT D2033 if Fx2
is positive
R882.00
QFT
QFT S2177 if Fx3
R705.60
is positive
Egg white, milk, fish, wheat,
R347.90
peanut, soybean
Include: cat, dog, house dust mites, feathers, moulds, grass-, weed- and tree pollens
Patient needs to be 72 hrs antihistamine free before test. Confirm with local laboratory for
availability of test and area specific inhalant panel
E1103
Phadiatop
inhalant mix
QFT
W2164
QFT R2209 if Phadiatop
R2273.60
mix is positive
R529.30
Fx2 Seafood mix
Fish, shrimp, blue mussel,
tuna, salmon
Phadiatop panel consists of: House dust mites: D. pteronyssinus d1; Grass pollens: Bermuda
Q2178
g2, Timothy g6; Weed pollen mix: wx7; Mould mix: mx1; Animal dander: Cat e1, dog e5;
R347.90
Fx3 Cereal/wheat mix
Wheat, oats, maize, sesame
seed, buckwheat
R347.90
Tree pollen mix: tx4 and tx7
Step 2. CONFIRMATORY / INDIVIDUAL ALLERGENS: High clinical index of suspicion of a specific allergen or previous positive screening test
R176.40
J2152
Egg white f1 R176.40
X2241
Milk f2
R176.40
C2067
Amoxicilloyl c6
R176.40
K2068
Ampicilloyl c5
V2133
Fish f3
R176.40
R176.40
A2119
Cefaclor c7
Y3985
Wheat f4
R176.40
R176.40
G2281
Penicilloyl G
R176.40
R176.40
G2281
Penicilloyl V
R176.40
Y2030
Soybean f14 R176.40
M3524
Pholcodine c261
R176.40
S2154
Egg yolk f75 R176.40
L1307
Morphine c260
R176.40
T2070
Apple f49
R176.40
Q2040
Succinylcholine c202 R176.40
D.pteronyssinus d1
R176.40
G2189
Hazel nut f17
R176.40
F2146
D.farinae d2
R176.40
A2096
Brazil nut f18
R176.40
G2074
Aspergillus mould m3
R176.40
H2065
Almond f20
R176.40
N2128
Cladosporium mould m2 R176.40
Q2132
Coconut f36
R176.40
K2275
Peanut f13
V2064
Alternaria mould m6
R176.40
V2133
Fish (Cod) f3
R176.40
Z2130
Cockroach i6
R176.40
W2026
Shrimp f24
R176.40
Y2260
Olive tree t9
R176.40
T2093
Blue mussel f37 R176.40
Fx2 Seafood
Fx1 Nut mix
H2203
Oak tree t7
R176.40
Q2293
Tuna f40
R176.40
Z2222
Kiwi f84
R176.40
B2196
Honey bee venom i1 R176.40
Bermuda grass g2
R176.40
K2022
Salmon f41
R176.40
Y2007
Potato f35
R176.40
N2266
Paper wasp i4
R176.40
T2047
Timothy grass g6
R176.40
Y3985
Wheat f4
R176.40
X2172
Gluten f79
R176.40
L2135
Common wasp i3
R176.40
D5207
Mugwort weed w6
R176.40
G2258
Oat f7
R176.40
B2081
Banana f92 R176.40
W2072
Ascaris p1
R176.40
M2144
Dandelion weed w8
R176.40
R2232
Maize f8
R176.40
X2287
Tomato f25 R176.40
N2151
Echincoccus p2
R176.40
P2147
Dog epidander e5
R176.40
T2024
Sesame seed f10
R176.40
P2262
Orange f33
R176.40
N2335
Anisakis p4
R176.40
E2115
Cat epidander e1
R176.40
F2100
Buckwheat f11
R176.40
F2169
Garlic f47
R176.40
Q2224
Latex k82
R176.40
Z2199
Horse epidander e3
R176.40
Other foods
A2257
V2087
Drugs
OTHER SPECIFIC IgE ALLERGENS
Peanut f13
Insects
FOOD ALLERGENS
K2275
Parasi
FOOD ALLERGENS
Fx5 Paediatric
INHALANT ALLERGENS
Phadiatop allergens
Fx3 Wheat
IgE-Mediated Allergy
Immediate hypersensitivity reaction
Fx1 Nut mix
Peanut, hazel nut, brazil nut,
R347.90
almond, coconut
See list of additional allergens on reverse side of request form
Step 3. ALLERGEN SPECIFIC COMPONENT TESTING: Define/characterize the allergy
Cow's milk components
Peanut specific component
J5211
rAra h2 f423
R176.40
Wheat specific component
Z5212
Omega-5 gliadin f416
R176.40
Seafood specific components
B2058
Whey β-lactglobulin f77
R176.40
X2057
Whey α-lactalbumin f76
R176.40
L2112
Casein nBos d8 f78
R176.40
N2220
Parvalbumin rGad c1 (fish) R176.40
Immuno Solid-Phase Allergen Chip
Detect 112 allergen components
S5213
Tropomyosin rPen a1 (shrimp) R176.40
Q1235
ISAC
Egg white components
B2219
Ovalbumin
nGal d2 f232
H4687
Ovmucoid
nGal d1 f233
Q5214
Conalbumin
nGal d3 f323
R2822.40
Soy components
R176.40
R176.40
C2228
nGly m5 f431
R176.40
Z2337
nGly m6 f432
R176.40
N2312
rGly m4 f353
R176.40
R176.40
Other components are available – enquire at your local laboratory
R2370.60
R395.10
R395.10
R395.10
R395.10
CAST Preservatives
E5013
Aspirin (ASA)
R395.10
P4332
Indomethacin
R395.10
Z1578
Ibuprofen
R395.10
Z3372
Paracetamol
R395.10
J1577
Diclofenac
R395.10
G5202
Mefenamic acid R395.10
R395.10
M5203
Naproxen
R395.10
Y5204
Articaine
R395.10
R395.10
R395.10
F5205
Bupivacaine
R395.10
E3794
Lignocaine
R395.10
R395.10
P5206
Mepivacaine
R395.10
R395.10
V4686
Chlorhexidine
R395.10
R395.10
R395.10
W5200
MELISA Metals
Preservative
grp (7 analytes)
R2765.70
J5004
Tartrazine
R395.10
A5201
Sodium benzoate
R395.10
A5017
Metabisulphite
R395.10
T5014
Sodium salicylate
R395.10
W5016
Sodium Nitrite
R395.10
R5015
MSG
R395.10
H1674
Sorbate
R395.10
CAST Colorants
Colorant group I
R395.10
Q5007
Colorant group II
R395.10
Blue, red, black
X3644
Nickel
R734.50
M2282
Manganese
R734.50
X2494
Titanium
R734.50
A3660
Chromium
R734.50
B4634
Aluminium
R734.50
A4718
Mercury
R2938.00
J3647
Cobalt
R734.50
SKIN PATCH TEST (Contact dermatitis)
S5006
Yellow, red, orange
Preservative grp
CAST Drugs
Pen Group
Non-IgE mediated allergy
Delayed hypersensitivity
DELAYED HYPERSENSITIVITY: Basophil or Lymphocyte activation tests – arrange with laboratory before specimen collection
CAST Drugs
K5196
Penicillin grp
(6 analytes)
J4015
Penicilloyl G c1
S4017
Penicilloyl V c2
Z3671
Benzylpenicilloyl/PPL
E5197
Ampicillin
N4014
Amoxycillin
J3670
Minor determinant
mix
R5199
Clavulanic Acid &
Amoxicillin
S3350
Sulfomethoxazole
V4341
Trimetroprim
N2956
Cefuroxime
T5198
Rifampicin
X4633
Standard 45
R983.10
allergen
More allergens are available; contact
your local laboratory for information.
Z:\01 FORMS REVIEW \04 NOV 2013 TT \ ALLERGY REQUEST FORM \ ALLERGY TEST PRICE LIST_2014 22/01/2014 LW
Hints for cost-effective and best practice in allergy test requests:
1. Use single allergens where possible
Allergen mixes such as the inhalant mix (Phadiatop), paediatric
food screen (fxS) etc. have limited utility except to 'rule out' allergic
disease in patients with a low pre-test probability of allergic disease.
Appropriate selection of specific allergens provides more useful
information than allergen mixes.
2. Requests should address the clinical question
A few selective questions may identify the allergens of interest. For
example the associations and persistence of symptoms (seasonal or
all year-round, worse indoors or outdoors) may distinguish between
testing for grass pollens or indoor allergens such as house dust
mites, cat or dog dander
43
Pathology Forum Vol 4 No.3
Appendix D:
List of most Common Allergens (Specific-IgE)
Appendix C: List of most Common Allergens (Specific IgE)
More allergens are available – enquire at your local laboratory
INHALANT ALLERGENS
Inhalant mix
Phadiatop
Phad
Mix of inhalant allergens
Grass pollens
Grass mix
gx2
g2, g5, g6, g8, g10, g17
g17
Bahia grass
g2
Bermuda grass
g10
Johnson grass
g202
Maize pollen
g8
Meadow grass
g5
Rye grass
g6
Timothy grass
Tree pollens
Temperate tree mix
tx4
t7, t8, t11, t12, t14
Tropical tree mix
tx7
t9, t12, t16, t18, t19, t21
t19
Acacia
t25
Ash
t3
Birch
t23
Cypress, Italian
t214
Date palm
t8
Elm
t18
Eucalyptus, Gum-tree
t17
Japanese cedar
t21
Melaeuca, Cajeput-tree
t20
Mesquite (Prosopis)
t7
Oak
t9
Olive
t22
Pecan Hickory
t73
Pine, Australian
t11
Plane (London, Maple leaf)
t14
Poplar, Cottonwood
t10
Walnut tree
t16
White pine
t12
Willow
Weed pollens
Weed pollen mix
wx7
w7,w8,w9,w10,w12
w7
Daisy
w8
Dandelion/ Khakibos
w9
English plantain
w10
Goosefoot
w12
Goldenrod
w20
Nettle
Epidermals and animal proteins
Animal epidermal mix
ex1
e1, e3, e4, e5
Feathers mix
ex73
e70, e85, e213
e77
Budgie droppings
e78
Budgie feathers
e201
Canary feathers
e1
Cat dander
e218
Chicken droppings
e85
Chicken feathers
e219
Chicken serum proteins
e4
Cow dander
e5
Dog dander
e86
Duck feathers
e80
Goat epithelium
e70
Goose feathers
e6
Guinea pig epithelium
e84
Hamster epithelium
e3
Horse dander
e71
Mouse epithelium
e76
Mouse serum protein
e72
Mouse urine
e197
Parakeet droppings
e196
Parakeet feathers
e213
Parrot feathers
e7
Pigeon droppings
e215
Pigeon feathers
e82
Rabbit epithelium
e87
Rat mix
e81
Sheep epithelium
e83
Swine epithelium
e89
Turkey feathers
INHALANT ALLERGENS (cont)
Mites
hx2
d1
d2
d74
d71
d201
h2
Moulds
mx1
m1
m2
m3
m6
m14
House dust mite mix
h2, d1, d2, i6
D.pteronyssinus (HDM)
D.farinae (HDM)
E.maynei (HDM)
L.destructor (Storage mite)
B.tropicalis (HDM)
House dust
Mould mix
m1, m2, m3, m6
Penicillium notatum
Cladosporium herbatum
Aspergillus fumigatus
Alernaria alternata
Epiccocum purpurascens
INSECTS & VENOMS
Insects
i1
i3
i4
i6
i208
Honey bee venom
Common wasp venom
Paper wasp venom
Cockroach
rApi m1, Phospholipase A2,
Honey bee venom component
DRUGS
Drugs
c6
c5
c7
c8
c71
c70
c260
c1
c2
c261
c202
Amoxicilloyl
Ampicilloyl
Cefaclor
Chlorhexidine
Insulin bovine
Insulin porcine
Morphine
Penicilloyl G
Penicilloyl V
Pholcodine
Suxamethonium
PARASITES
Parasites
p4
Anisakis
p1
Ascaris
p2
Echinococcus
OCCUPATIONAL
Occupational
k80
Formaldehyde
k77
Isocyanate HDI
k76
Isocyanate MDI
k75
Isocyanate TDI
k82
Latex
k84
Sunflower seed
FOOD MIXES
Food mixes
Nut mix
fx1
f13, f17, f18, f20, f36
fx2
fx3
fx5
Seafood mix
f3, f24, f37, f40, f41
Cereal/wheat mix
f4, f7, f8, f10, f11
Paediatric food mix
f1, f2, f3, f4, f13, f14
FOOD ALLERGENS
Pathology Forum Vol 4 No.3
FOOD ALLERGENS (cont)
Fruits & vegetables
f49
Apple
f237
Apricot
f96
Avocado
f92
Banana
f319
Beetroot
f211
Blackberry
f288
Blueberry
f260
Broccoli
f217
Brussels sprouts
f216
Cabbage
f31
Carrot
f291
Cauliflower
f85
Celery
f242
Cherry
f244
Cucumber
f289
Date
f276
Fennel, fresh
f328
Fig
f47
Garlic
f259
Grape
f209
Grapefruit
f263
Green pepper
f292
Guava
f84
Kiwi
f208
Lemon
f215
Lettuce
f348
Litchi
f302
Mandarin (tangerine)
f91
Mango
f87
Melon
f342
Olive (black, fresh)
f48
Onion
f33
Orange
f293
Papaya
f294
Passion fruit
f95
Peach
f94
Pear
f210
Pineapple
f255
Plum
f35
Potato
f225
Pumpkin
f343
Raspberry
f322
Red currant
f330
Rose hip
f214
Spinach
f44
Strawberry
f54
Sweet potato
f25
Tomato
f329
Watermelon
Spices and Herbs
f271
Anise
f269
Basil
f280
Black pepper
f279
Chilipepper
f268
Clove
f317
Coriander
f281
Curry (Santa Maria)
f219
Fennel seed
f270
Ginger
f263
Green pepper
f274
Marjoram
f332
Mint
f89
Mustard
f283
Oregano
f218
Paprika, Sweet pepper
f86
Parsley
f344
Sage
f273
Thyme
f234
Vanilla
Meat
f27
Beef
f88
Mutton
f26
Pork
Miscellaneous foods/other
u865
Alpha-gal (1,3-gal)
f93
Cacao
f296
Carob (E410)
f221
Coffee
f247
Honey
f324
Hop (fruit cone)
f90
Malt
f212
Mushroom (champignon)
o214
MUXF3 CCD, Bromelain
f222
Tea
Explanation of specific IgE codes:
o201
Tobacco leaf
f5
f45
Baker’s Yeast
The letter indicates the allergen group, e.g. f=food,
The number indicates the number in the
t=tree, m=mould etc. An x in the code indicate a
group of allergens e.g. f2 = cow’s milk
mixture of allergens e.g. fx5
PathCare: Allergy investigations 10 December 2013
44
FOOD ALLERGENS (cont)
Egg & fowl
f83
Chicken meat
f75
Egg yolk
f1
Egg white
Milk products
f81
Cheese, cheddar
f82
Cheese, mold type
f236
Cow's whey
f300
Goat milk
f2
Cow's milk
Seeds, legumes & nuts
f20
Almond
f6
Barley
f18
Brazil nut
f11
Buckwheat
f202
Cashew nut
f309
Chick pea
f36
Coconut
f55
Common millet
f79
Gluten
f315
Green bean
f17
Hazel nut
f235
Lentil
f182
Lima bean
f333
Linseed
f345
Macadamia nut
f8
Maize, corn
f7
Oat
f12
Pea
f13
Peanut
f201
Pecan nut
f253
Pine nut
f203
Pistachio
f224
Poppy seed
f226
Pumpkin seed
f9
Rice
f5
Rye
f10
Sesame seed
f14
Soybean
f299
Sweet chestnut
f256
Walnut
f4
Wheat
f15
White bean
Fish, shellfish & molluscs
f346
Abalone
f313
Anchovy
f37
Blue mussel
f369
Cat fish
f23
Crab
f320
Crayfish
f264
Eel
f3
Fish (cod)
f42
Haddock
f307
Hake
f205
Herring
f60
Jack mackerel, Scad
f80
Lobster
f206
Mackerel
f59
Octopus
f290
Oyster
f58
Pacific squid
f413
Pollock
f381
Red snapper
f41
Salmon
f61
Sardine (Japanese Pilchard)
f338
Scallop
f24
Shrimp
f314
Snail
f337
Sole
f304
Spiny Lobster (Langoustine)
f258
Squid
f312
Swordfish
f204
Trout
f40
Tuna
35
March 2014
Appendix E:
Standard Inhalant Skin Prick Test Panel
Appendix D: Standard Inhalant Skin Prick Test Panel
Nr
1
Allergen
Negative control
Afrikaans name
Negatiewe kontrole
Latin name/Description
Saline
2
5 Grass mix
5 Grasmengsel
Dactylis (Orchard grass), Lolium
(Rye), Phleum pratense (Timothy
grass), Festuca (Meadow grass),
Poa pratensis (Kentucky Blue)
3
Bermuda grass
Bermuda gras
Cynodon dactylon
4
Plantain weed pollen
Plantaan onkruid stuifmeel
Plantago Lanceolata
5
Maize pollen
Mielie stuifmeel
Zea Mays
6
Dog Dander
Hondehaar/epiteel
Canis familiaris
7
Cat Dander
Kathaar/epiteel
Felis domesticus
8
Feather mix
Vere mengsel
Duck, Chicken
9
House dust mite mix
Huisstofmiet mengsel
Dermatophyte mix
10
Plane tree pollen
Plantaanboom stuifmeel
Platanus acerifolia
Cladosporium swam
Cladosporium
Aspergillus swam
Aspegillus Mould mix III
Alternaria swam
Alternaria Alternaria
Olyfboom stuifmeel
Olea Europica
11
12
13
14
15
16
Cladosporium mould
Aspergillus mould
Alternaria mould
Olive tree pollen
Cockroach
Kakkerlak
Positive control
Positiewe kontrole
PathCare: Allergy investigations 10 December 2013
Result in mm
Blatella Germanica
Histamine
36
45
Pathology Forum Vol 4 No.3
Appendix F:
List of most Common Standarised CAST and
Appendix E: List of Most Common Standardised CAST and MELISA Tests Available (2013)
MELISA
Tests Available (2014)
CAST (Basophil activation tests) for delayed hypersensitivity reactions
Antibiotics
Amoxicillin
Amoxicillin plus Clavulanic acid
Ampicillin
Benzylpenicillin, MDM
Benzylpenicilloyl, PPL
Penicillin G
Penicillin V
Cefaclor
Ceftriaxone
Cefuroxime
Cephalosporin C
Ciprofloxacin
Clarithromycin
Levofloxacin
Rifampicin
Sulfomethoxazole
Tetracycline
Trimetroprim
General anaesthetics
Atracurium
Cistrcurium
Pancuronium
Suxamethonium (Scoline)
Rocuronium
Vecuronium
Propofol
Contrast media
Iobitridol
Iohexol
Iomeprol
Iopamidol
Iopromide
Ioxaglate
Ioxitalamate
Local Anaesthetics
Lidocaine, Lignocaine
Articaine
Bupivacaine
Mepivacaine
Analgesics/ Anti-Inflammatories
Aspirin
Paracetamol
Mefenamic acid
Diclofenac
Ibuprofen
Indomethacin
Dipyrone
Naproxen
Food Preservatives
Tartrazine
Sodium benzoate
Sodium nitrite
Potassium metabisulfite
Sodium salicylate
Monosodium glutamate
Potassium Sorbate
Food colorant mix I
Quininoline Yelow
Sunset Yellow FCF
Cromotrope B
Armaranth
New Coccine
Food colorant mix II
Erythrosine
Patent Blue V
Indigo Carmine
Brilliant black
Notes: Other CAST analytes may be available; enquire at your local laboratory.
Specimen requirements: EDTA (purple top) tube. This specimen must be analysed within 24hrs after specimen collection.
Analyses are only done on weekdays. Contact your local laboratory for arrangements.
MELISA (Memory Lymphocyte Immune Stimulation Assay) for delayed hypersensitivity reactions
Metals
Aluminium
Cadmium
Chromium
Cobalt
Copper
Gold
Lead
Manganese
Mercury
Metals
Molybdenum
Nickel
Palladium
Platinum
Silver
Tin
Titanium
Vanadium
Zinc
Notes: Other MELISA analytes may be available; enquire at your local laboratory.
Specimen requirements: 1-2 Citrate (light blue top) tube per allergen. This specimen must be analysed within 24hrs after
specimen collection. Analyses are only done on weekdays. Contact your local laboratory for arrangements.
PathCare: Allergy investigations 10 December 2013
46
Pathology Forum Vol 4 No.3
37
March 2014
Appendix G:
Appendix F: Contact
Dermatitis Standard
Patch TestTest
Panel Panel
Contact Dermatitis
Standard
Patch
TroLab standard range patch test allergens used:
Reaction (hrs)
Allergen
Nr
48
72
96
Allergen
Nr
1
Potassium Dichromate
24
Turpentine Peroxides (liquid)
2
Paraphenylenediamine
25
Naphtyl Mix
3
Thiuram Mix
26
PCMX (Dettol)
4
Neomycin Sulphate
27
Lanolin
5
Cobalt Chloride
28
Thiomersal (Preservative)
6
Benzocaine
29
Propylene Glycol
7
Nickel Sulphate
30
Chlorhexidine (liquid)
8
Clioquinol (Vioform/Chinoform)
31
Kathon CG/Cl + Me-isothiazolinone
9
Colophony
32
Mercaptobenzothiazole (MBT)
10
Paraben Mix
33
Sesquiterpene Lactone mix
11
IPPD
34
Cetyl Stearyl Alcohol
12
Wool Alcohols
35
Euxyl K400 (Preservative)
13
Mercapto Mix
36
Musk Mix
14
Epoxy Resin
37
Formaldehyde Resin
15
Balsam of Peru
38
Taraxacum Officianale (dandelion)
16
p-Tert-butylphenol formalin
39
Woodmix (pine/spruce/birch/teak)
17
Carba Mix
40
Tixocortol Pivalate
18
Formaldehyde (liquid)
41
Budesonide
19
Fragrance Mix
42
Sodium Thiosulfatoaurate (Gold)
20
Ethylene Diamine HCL
43
Compositae Mix (5.0% Pet)
21
22
23
Quartinium 15 (Preservative)
Chloroscresol (PCMC)
Imidazolidinyl Urea
44
45
46
47
Fragrance Mix II 14%
Dibromodicyanobutane 0.3%
Sodium Laurelsulfate (Irritant control)
Petrolateum (Negative control)
Reaction (hrs)
48
72
96
KEY TO PATCH TEST INTERPRETATION
?
+
++
+++
Doubtful
Weak (nonvesicular) erythema, infiltrated
Strong (vesicular) plus papules & vesicles
Extreme (bullous)
IR
NT
C
Negative
Irritant Reaction
Not Tested
Control
Other path test panels are available including:
Hairdressing series
Sunscreen series
Cosmetic series
– contact your local laboratory for more information.
PathCare: Allergy investigations 10 December 2013
38
47
Pathology Forum Vol 4 No.3
Appendix H:
Allergen Components Included in the ISAC 112
Appendix G:pages)
Allergen Components Included in the ISAC 112 Test Profile
Test Profile (two
INHALANT / AERO- ALLERGEN COMPONENTS INCLUDED IN THE IMMUNOCAP ISAC TEST
Mites
Cockroach
(House dust and
Storage)
Moulds
Animal Dander
Weed Pollen
Tree Pollen
Grass Pollen
Group
Source
Latin name
R/N
Component
Protein Family or Function
Bermuda grass
Cynodon dactylon
Timothy grass
Phleum pratense
Alder
Ainus glutinosa
Birch
Betula verrucosa
Hazel
Japanese cedar
Cypress
Corylus avellana
Cryptomeria japonica
Cupressus arizonica
Olive
Olea europaea
n
r
r
n
r
r
r
r
r
r
r
r
r
r
n
n
n
n
r
r
n
r
n
n
n
r
r
r
r
n
r
r
r
r
r
n
r
n
r
n
r
r
r
r
r
r
n
n
n
n
n
n
n
n
n
n
n
Cyn d1
Phl p1
Phl p2
Phl p4
Phl p5
Phl p6
Phl p7
Phl p11
Phl p12
Aln g1
Bet v1
Bet v2
Bet v4
Cor a1
Cry j1
Cup a1
Ole e1
Ole e7
Ole e9
Pla a1
Pla a2
Pla a3
Amb a1
Art v1
Art v3
Che a1
Mer a1
Par j2
Pla l1
Sal k1
Can f1
Can f2
Can f3
Can f5
Equ c1
Equ c3
Fel d1
Fel d2
Fel d4
Mus m1
Alt a1
Alt a6
Asp f1
Asp f3
Asp f6
Cla h8
Blo t5
Der f1
Der f2
Der p1
Der p2
Der p10
Lep d2
Bla g 1
Bla g2
Bla g5
Bla g7
Grass pollen group 1 allergen
Grass pollen group 1 allergen
Grass pollen group 2 allergen
Berberine bridge enzyme
Grass pollen group 5 allergen
Grass pollen group 6 allergen
Calcium binding protein
Ole e1 related protein
Profilin
PR-10 protein
PR-10 protein
Profilin
Calcium binding protein
PR-10 protein
Pectate lyase
Pectate lyase
Trypsin inhibitor
LTP
Glucanase
Invertase inhibitor
Polygalacturonase
LTP
Pectate lyase
Defensin
LTP
Trypsin Inhibitor
Profilin
LTP
Pectate lyase
Pectin methylesterase
Lipocalin
Lipocalin
Serum Albumin
Arginine esterase/kallikrein
Lipocalin
Serum Albumin
Uteroglobin
Serum Albumin
Lipocalin
Lipocalin
Acidic glycoprotein
Enolase
Mitogillin family
Peroxysomal protein
Mn superoxides dismutase
Mannitol dehydrogenase
Group 5 mite allergen
Cysteine protease
NPC2 family
Cysteine protease
NPC2 family
Tropomyosin
NPC2 family
Cockroach group 1 allergen
Aspartic protease
Gluthatione S-transferase
Tropomyosin
Plane
Platanus acerifolia
Ragweed
Amrosia artemisifolia
Mugwort
Artemesia vulgaris
Goosefoot
Annual Mercury
Wall pellitory
Plaintain (English)
Saltwort
Chenopodium album
Mercurialis annua
Parietaria judacia
Plantago lanceolata
Salsola kali
Dog
Canis familliaris
Horse
Equus caballus
Cat
Felis domesticus
Mouse
Mus musculus
Alternaria
Alternaria alternata
Aspergillus
Aspergillus fumigatus
Cladosporium
Blomia tropicalis
Cladosporium herbatum
Blomia tropicalis
D. Farinae
Dermatofagoides
farinae
D. Pterosinyssus
Dermatophagoides
pteronyssinus
Lepidoglyphus
Lepidoglyphus destructor
Cockroach
Blattella germaina
Abbreviations: PR-10 = Pathogenesis Related protein-10; LTP = Lipid Transfer Protein; NPC2 = Niemann–Pick type C2 protein;
CCD = Carbohydrate Cross-reactive Determinant; R = recombinant; N = native
Specimen requirements: 1 x SST (yellow top) tube blood.
48
Pathology Forum Vol 4 No.3
Source
Specific?
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
March 2014
Appendix G: Allergen Components Included in the ISAC 112 Test Profile (Continue)
FOOD ALLERGEN COMPONENTS INCLUDED IN THE IMMUNOCAP ISAC TEST
Milk, Egg and Meat
Group
Source
Latin name
Egg white
Gallus domesticus
Egg yolk/chicken
Gallus domesticus
Cow's milk
Bos domesticus
Cod
Gadus calarias
Shrimp
Penaeus monodon
Cashew nut
Brazil nut
Anacardium occidentale
Bertholletia excelsa
Hazel nut
Corylus aveillana
R/N
Component
Protein Family or Function
n
n
n
n
n
n
n
n
Gal d1
Gal d2
Gal d3
Gal d5
Bos d4
Bos d5
Bos d6
Bos d8
Bos d
Ovomucoid
Ovalbumin
Conalbumin/Ovotransferrin
Livetin/Serum Albumin
Alpha-lactalbumin
Beta-lactglobulin
Serum Albumin
Casein
Fruit
Cereal
Legumes
Seeds and Nuts
Fish and
Seafood
n
Walnut
Juglans regia
Sesame
Sasamum indicum
Peanut
Arachis hypogaea
Soy bean
Glycine max
Buckwheat
Fagopyrum esulentum
Wheat
Triticum aestivum
Kiwi
Actinidia delicosa
Celery
Apple
Apium graveolens
Malus domestica
Peach
Prunus persica
r
n
n
n
r
r
r
r
n
n
n
n
n
r
r
r
n
n
r
r
n
n
n
r
r
n
n
n
n
r
r
r
r
r
Lactoferrin
Gad c1
Pen m1
Pen m2
Pen m4
Ana o2
Ber e1
Cor a1
Cor a8
Cor a9
Jug r1
Jug r2
Jug r3
Ses i1
Ara h1
Ara h2
Ara h3
Ara h6
Ara h8
Ara h9
Gly m4
Gly m5
Gly m6
Fag e2
Tri a14
Tri a19
Tri aA-TI
Act d1
Act d2
Act d5
Act d8
Api g1
Mal d1
Pru p1
Pru p3
Source
Specific?
Transferrin
Parvalbumin
Tropomyosin
Arginine kinase
Sarcoplasmic Calcium Binding Protein
Storage protein, 11S globulin
Storage protein, 2S albumin
PR-10
LTP
Storage protein, 11S globulin
Storage protein, 2S albumin
Storage vicilin-like protein, 7S globulin
LTP
Storage protein, 2S albumin
Storage protein, 7S globulin
Storage protein, 2S albumin
Storage protein, 11S globulin
Storage protein, 2S albumin
PR-10
LTP
PR-10
Storage protein, Beta-conglycinin
Storage protein, Glycinin
Storage protein, 2S albumin
LTP
Omega-5-gliadin
Alpha-Amylase/Trypsin inhibitor
Cysteine protease
Thaumatin-like protein
Kiwellin
PR-10
PR-10
PR-10
PR-10
LTP
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
Honey bee venom
Apis mellifera
Paper wasp venom
Common wasp venom
Pilostes dominulus
Vespula vulgaris
Anisakis
Anisakis simplex
Latex
Insect venom
and
Parasite
OTHER ALLERGEN COMPONENTS INCLUDED IN THE IMMUNOCAP ISAC TEST
Latex
Hevea brasiliensis
CCD
Bromelain
Bromelain Sugar epitope
n
n
r
r
r
r
r
r
r
r
r
n
Api m1
Api m4
Pol d5
Ves v5
Ani s1
Ani s3
Hev b1
Hev b3
Hev b5
Hev b6.01
Hev b8
MUXF3
Phospholipase A2
Melittin
Antigen 5
Antigen 5
Serine protease inhibitor
Tropomyosin
Rubber elongation factor
Small rubber particle protein
Acidic protein
Prohevein
Profilin
CCD marker
*
*
*
*
*
*
*
*
Abbreviations: PR-10 = Pathogenesis Related protein-10; LTP = Lipid Transfer Protein; NPC2 = Niemann–Pick type C2 protein;
CCD = Carbohydrate Cross-reactive Determinant; R = recombinant; N = native
Specimen requirements: 1 x SST (yellow top) tube blood.
49
50
Pathology Forum Vol 4 No.3
Information for Patients
Allergy Testing:
•
•
•
•
Inhaled - pollens, cat and dog epidander, house dust mites,
cockroaches and mould spores
Infants and children - egg, milk, peanut, soy, wheat and fish
Adults - shellfish, peanut, tree nuts and fish
Other - insect venom, food additives and drugs.
What are the most common allergens?
Allergy tests should always be guided by a good clinical history of
exposure to an allergen. It should only serve to confirm the
suspected source of the allergen causing the symptoms. It is not
always necessary to test for allergies. In some cases the cause of the
allergy can be identified by a good clinical history and demonstration of symptoms upon exposure alone. By identifying the source
of the allergen (e.g. house dust mites), steps can be taken to reduce
exposure to the allergen and/or treatment can be initiated for the
specific allergy. The management of allergies or allergic symptoms
can improve your quality of life significantly, and reduce further
health expenses.
Why test for allergy?
Allergic conditions show an increasing incidence in South-Africa
and across the world. Allergy symptoms may range from an itching
nose to severe life threatening anaphylaxis.
Common allergy symptoms include:
• Nose - blocked, runny nose, itching
• Eyes - itching, red eyes
• Lungs - asthma, cough, wheezing
• Abdominal - cramps, vomiting, diarrhoea
• Skin - eczema and sometimes urticaria
• Anaphylactic shock
What is allergy?
Allergy occurs when a person's immune system reacts to
substances in the environment that are usually harmless for most
people. These substances are known as allergens (antigens) and
are found in sources such as house dust mites, pets, pollens,
moulds, insects and insect venoms, foods, food additives and some
medicines. The body has several types of immune responses to
allergens. The most common response is when the immune
system reacts by producing antibodies called immunoglobulin E
(IgE). When exposed to an allergen, the IgE antibodies recognise
and bind the allergens in order to eliminate them from the body. In
the process chemicals such as histamine are released leading to
allergic inflammation causing redness, swelling and itching.
Compiled and printed: October 2013
[email protected]
www.pathcare.co.za
“Pathology that Adds Value”
More information regarding allergies and allergen avoidance can
be obtained from the website of the South African Allergy Society
at www.allergysa.org.
The diagnosis of allergy is not based on a laboratory test alone.
Allergy tests results are complicated and should only be interpreted together with a good clinical history. For example: an
individual with increased allergen specific-IgE antibodies are
sensitised to the allergen, and not necessary allergic to the allergen.
After testing, a follow-up consultation with the referring clinician is
recommended for interpretation of the results.
Interpretation of allergy tests
Allergy tests can be expensive if the specific allergy test request is
not guided by a good clinical history. It is therefore recommended
that you consult your clinician to limit unnecessary allergy
investigations.
Cost of allergy tests
Beware of allergy tests offered by non-accredited laboratories, as
some of these tests are not scientifically validated and not
recommended by the Allergy Society of South Africa (ALLSA).
Types of allergy tests
There are different types of allergy tests available. The specific test
depends on the allergen and the type of allergic reaction.
• A Skin prick test (SPT) is a quick, cost-effective method to
identify inhalant (airborne) allergens. Your doctor may ask
you to stop your antihistamines two to three days before
the test. You need to make an appointment with your local
laboratory for a SPT.
• Allergen specific-IgE blood tests (ImmunoCAP RAST®) can be
used to identify most inhalant, food, insect venom and
some drug allergens. Antihistamines do not interfere with
this test.
• Some allergy blood tests (mainly for drug and food
additives) need special arrangements, and the laboratory
should be contacted beforehand.
• Skin patch testing can be used to diagnose the allergen
causing contact dermatitis.
Pathology Forum Vol 4 No.3
Appendix I:
Patient Information Brochure
“Pathology that Adds Value”
www.pathcare.co.za
PATHOLOGISTS CONTACT DETAILS
CHEMICAL PATHOLOGY, ALLERGY & ENDOCRINOLOGY
HISTOLOGY & CYTOPATHOLOGY
Dr Wessel Meyer
Dr Mariana Lloyd
Dr Kevin Longmore
Dr Esmé Hitchcock
Dr Younus Essack
Dr John Stanfliet
Dr Clive Harrison
Dr Kabasele Kasongo
Dr Ross Millin
Dr Karl Vermeulen
Dr Rustum Solomon
Dr Nick van Diggelen
Dr Chris Eedes
Dr Dotti von Ulmenstein
Dr Karen Brundyn
Dr Gillaume Swart
Dr Pieter Bloem
Dr Jackie de Jager
Dr Michael Hofmeyr
Dr David Marx
Dr Izak Loftus
Dr Linda Steyn
Dr Casper J van Rensburg
Dr Nerissa Lazarus
Dr Bongani Zulu
Dr Berna de Bruin
Dr Debbie Maartens
Dr Marie-Leen Shaw
Bellville, Cape Town
Bloemfontein
Goodwood, Cape Town
Goodwood, Cape Town
Goodwood, Cape Town
Goodwood, Cape Town
Port Elizabeth
Port Elizabeth
021 596 3400
051 401 4600
021 596 3400
021 596 3400
021 596 3400
021 596 3400
041 391 5700
041 451 4423
Bloemfontein
Bloemfontein
Claremont, Cape Town
Constantiaberg, Cape Town
Goodwood, Cape Town
Goodwood, Cape Town
Goodwood, Cape Town
Klerksdorp
Paarl
051 401 4600
051 401 4600
021 674 2643
021 797 3785
021 596 3400
021 596 3400
021 596 3400
018 468 9000
021 872 5158
HAEMATOLOGY
Dr Engela le Roux
Dr Teresa Nel
Dr Louis Jacobs
Dr Melonie Johnson
Dr Werner Slazus
Dr Alicia Els
Dr Ntsiki Baartman
Dr Roberto Mattana
Dr Illse Louw
CLINICAL PATHOLOGY
Dr Madaleen Olivier
Dr Fanie Weyers
Dr Johan Rood
Dr Marais Venter
Dr Erina Pretorius
Dr Peter Soldin
Dr Riaan Writes
Dr Joanna van Lathem
Dr Braam van Greunen
Dr Henriëtte Roux
Bloemfontein
Bloemfontein
Bloemfontein
George
Port Elizabeth
Vereeniging
Vereeniging
Vereeniging
Windhoek
Windhoek
051 401 4600
051 401 4600
051 401 4600
044 803 8200
041 391 5700
016 440 6300
016 440 6300
016 440 6300
00264 (61) 431 3000
00264 (61) 431 3000
HISTO AND CYTOPATHOLOGY
Dr Mada Crause
Dr Frik Botha
Dr Willem Brummer
Dr Annette Smith
Dr Bruce Matelakengisa
Dr Ellen Bolding
Dr Colin Mostert
Dr Stephen Price
Dr Carolyn Baigrie
Dr Kathy Taylor
Dr Christopher Walker
Dr. Lesiba Mogotlane
Dr David Laing
Dr Ryan Soldin
Dr Attie Louw
Dr Elmarie Potgieter
Dr Rudi Botha
Bethlehem
Bloemfontein
Bloemfontein
Bloemfontein
Claremont, Cape Town
Claremont, Cape Town
Claremont, Cape Town
Claremont, Cape Town
Claremont, Cape Town
Claremont, Cape Town
Claremont, Cape Town
East London
George
George
Klerksdorp
Klerksdorp
Kimberley
058 303 4961
051 401 4600
051 401 4600
051 401 4600
021 670 5700
021 670 5700
021 670 5700
021 670 5700
021 670 5700
021 670 5700
021 670 5700
043 701 5900
044 803 8200
044 803 8200
018 468 9000
018 468 9000
053 830 8960
Goodwood, Cape Town
Goodwood, Cape Town
Goodwood, Cape Town
Goodwood, Cape Town
Goodwood, Cape Town
Goodwood, Cape Town
Goodwood, Cape Town
Goodwood, Cape Town
Mossel Bay
Port Elizabeth
Port Elizabeth
Port Elizabeth
Somerset West
Somerset West
Somerset West
Vereeniging
Vereeniging
Welkom
Somerset West / Windhoek
Windhoek
021 596 3400
021 596 3400
021 596 3400
021 596 3400
021 596 3400
021 596 3400
021 596 3400
021 596 3400
044 691 1399
041 391 5700
041 391 5700
041 391 5700
021 852 3144
021 852 3144
021 852 3144
016 440 6300
016 440 6300
057 391 0400
021 852 3144
00264 (61) 431 3000
FORENSIC PATHOLOGY
Dr Izak Loftus
Somerset West
021 852 3144
MICROBIOLOGY, VIROLOGY, SEROLOGY & MOLECULAR
DIAGNOSTICS
Dr Ossie van Rensburg
Dr Nasser Mia
Dr Delene Brink
Dr Pierre Schoeman
Dr Elizabeth Wasserman
Dr Marthinus Senekal
Dr Jamie van Zyl
Dr Siseko Martin
Dr Reinhard Böhmer
Dr Inéz Rossouw
Bellville, Cape Town
Gatesville, Cape Town
George
Goodwood, Cape Town
Goodwood, Cape Town
Panorama, Cape Town
Potchefstroom
Port Elizabeth
Somerset West
Welkom
021 917 8000
021 633 5391
044 803 8200
021 596 3400
021 596 3400
021 937 9111
018 293 0573
041 391 5700
021 852 3144
057 391 0400
Goodwood, Cape Town
Goodwood, Cape Town
021 596 3400
021 596 3400
HUMAN GENETICS
Dr Nico de Villiers
Dr Oubaas Pretorius
NEUROPATHOLOGY
Dr Richard Hewlett
Cape Town
021 596 3400
Goodwood, Cape Town
Tygerberg, Cape Town
021 596 3400
021 938 6159
ORAL PATHOLOGY
Prof Vince Phillips
Prof Jos Hille
CONTACT DETAILS - MAIN & REGIONAL LABORATORIES
Reference Lab, N1 City, Cape Town
021 596 3400
Bethlehem
058 303 4961
Bloemfontein
051 401 4600
East London
043 701 5900
George
044 803 8200
Kimberley
053 830 8960
Klerksdorp
018 468 9000
Paarl
021 872 5158
Port Elizabeth
041 391 5700
Somerset West
021 852 3144
Upington
054 332 2653
Vereeniging
016 440 6300
Welkom
057 391 0400
Worcester
023 347 1021
Windhoek
00264 61 283 6000
PathCare’s Electronic
Results Delivery Products
Applications for Apple and Android Phones and Pads
Features and Benefits:
1.Patient’s pathology results pushed to your device
anywhere at anytime
2.Strong cumulative report formats to track your
patient's progress
3. Email results to your colleagues and patients
4. Request further testing on-line
5. Capture patient notes
6. Store patient results on your device
Visit the iStore or Android Store to download the Apps. Contact the IT Help Desk for more support on 021 596 3820
“Pathology that Adds Value” | www.pathcare.co.za