How allergy is diagnosed?
Clinical history plays a very important part in allergy diagnosis. This history, aided by physical examination and objective tests of IgE sensitivity (either skin tests or IgE measurements), focus on addressing the following questions:
- Is the patient atopic?
- Does allergy contribute to the patient’s symptoms?
- What are the clinically relevant allergens?
Suggested Flow for Allergy Diagnosis
Diagnosis Flow of Allergic Rhinitis
A careful history taking is the basis for diagnosis and management of allergic diseases. The principle of history taking is the same for any medical problem (When, Where & What). General points of particular importance are:
- Family and patient’s history should be explored
- Patients should be allowed to give their own account of their symptoms in their own time
- Home, work, and outdoor environmental risk factors should be discussed, e.g. pets, carpet in bedroom, mildew, etc.
- The work environment, e.g. chemicals, irritants
- Groups of particular allergy risk such as healthcare, rubber industry workers, or children with spina bifida whom latex allergy is particularly prevalent should be identified
- Dietary factors: e.g. hives within 1 hour of eating
- Frequency, severity, day, night, duration, at work, at home and seasonality of symptoms should be ascertained, with particular reference to triggering factors, life threatening events, and effects of avoidance measures
- Hobbies and interests: e.g., horse allergy in keen rider
- Medication, especially less obvious OTC preparations
- Patients should be asked about any treatment they are currently having, particularly about antihistamines, topical and oral corticosteroids, and adrenalin autoinjectors
Several pitfalls in History
- Absence of known contact with pets does not exclude sensitization to animals or symptoms on exposure. Several recent studies show very high level of cat allergens in homes without cats, at school, in offices, cinemas and even doctor’s office.
- Patients with perennial disease have most of their symptoms in the bedroom during the early morning although the causal agent is not necessarily in the bedroom.
- Patients who have strong aeroallergen sensitivity and chronic low dose exposure to the allergen, e.g. house dust mite or cat may not notice immediate symptoms at home, but will notice symptoms from irritants (due to a nonspecific nasal hyperactivity) like smoke, cold air and perfumes. The patient will then assume these are the allergens, when they are merely secondary irritant triggers. Therefore, case history is rarely informative with regards to house dust mite allergy. A carefully taken history should be followed by an appropriate physical examination.
Skin Prick Test
Allergy Skin testing (SPT) is a well-established diagnostic procedure which has been in vogue for more than 100 years. It is a bioassay that facilitates the exposure to the antigen and indicates the presence of specific IgE antibodies on the surface of the sensitized mast cells. The tested subject develops a wheal and flare over a period of 15–20 min following the introduction of the allergen to which he is sensitized. It is worthy to note that “sensitization” is an immunologic term; it does not mean the person is “allergic”. SPT detects only sensitization, and correlation of SPT with clinical history will determine allergy.
Current evidence suggests skin allergy testing as a safe procedure, although in extremely rare occasions, fatalities have been observed with both skin provocation tests and – with a slightly higher rate with intradermal tests (Rev Alerg Mex 2014;61:24–31).
Practical points of SPT
- Skin prick testing requires training, both for performance and interpretation of results
- Check that patient is not taking antihistamines
- Oral corticosteroids do not (significantly) inhibit skin prick tests
- Skin prick tests may be performed on the flexor aspect of the forearm (or back) using sterile lancets
- The procedure should be painless and not draw blood
- Test sites, which should be 2–2.5 cm apart to avoid overlapping reactions from occurring, should be marked for allergen identification
- Wheal size should be measured at 15–20 minutes and recorded as the mean of the longest diameter and the orthogonal diameter
- The possibility of either false negative or false positive results in skin testing should always be considered and appropriate controls be placed to evaluate these situations (e.g. a positive control with histamine (10 mg/mL) and a negative control with saline)
- To be deemed as positive, allergen-induced wheals should have a maximum diameter at least 3 mm greater than the appropriate negative control.
- Demographism may confound results (although it is evident as a positive response with the negative control solution)
- Skin tests should not be performed in the presence of severe eczema
- Skin test can provide useful confirmatory evidence for a diagnosis made on clinical grounds. A positive skin prick test merely identifies sensitization to a particular allergen. It does not predict clinical relevance independent of the history.
- To be informative, the skin prick tests must be related to the clinical context of the patient’s history and the physical examination. The selection of the antigens and the administration of tests require experience and knowledge. A skin test may be positive both before the allergy is clinically apparent and years after cessation of symptoms.
Point-of-care ALFA test
ALFA (Allergy Lateral Flow Assay) is a rapid assay for the qualitative determination of allergen specific immunoglobulin E (sIgE) in human serum, plasma or whole blood. ALFA is a screening test, which enables the user to perform an allergy test very fast and reliable. By choosing appropriate allergen solutions a symptom based diagnosis is possible.
To perform the test the patient´s sample is transferred to the sample application point of the Basis Set. Immediately afterwards, the desired allergen solution is applied. During incubation of 15-20 min the liquid is driven through the device by capillary flow. The allergen specific IgE of the sample binds specifically to its corresponding allergens of the allergen solution. The labelled allergens are retained at the test line (T) by a capture molecule. At the same time, the sIgE bound to the allergen is bound by an antibody coupled to coloured particles (conjugate). The intensity of the colour reaction at the test line is proportional to the amount of immune complexes consisting of ligand tagged allergens, sIgE, and IgE specific conjugate. The signal intensity ranges from faintly pink (low titre of sIgE) to dark ruby (high titre of sIgE). Access conjugate, which is not bound at the test line, forms a dark ruby control line (C) after 20 min of incubation.
Although SPT is known as a reliable method for allergy diagnosis, it has some drawbacks, including nonspecific reactions in subjects with urticarial dermographism, inconclusive results in case of drug intake with antihistaminic activity, and serious side eﬀects in rare cases. Therefore, rapid allergy tests may represent a promising alternative to SPT
In vivo provocation tests
The clinical history may occasionally not provide a clear diagnosis. Additionally, there will be instances when the clinical history of allergic disease does not match skin testing or sIgE assays. In these situations, in vivo provocation testing can be considered to assess further the relationship between symptoms and physiological end points.
Such tests may use pharmacological agents and allergens, or the presumed allergen may be used in certain in vivo diagnostic assessment such as double-blind, placebo-controlled food challenges (DBPCFC) utilized to evaluate symptoms presumed to be caused by ingestion of foods or other substances via the gastrointestinal tract.
Organ challenge tests can be performed to assess whether a specific allergen is causing a specific constellation of symptoms suggestive of an allergic reaction. The site of organ challenge is based on the patient’s history and may include the conjunctiva, upper or lower respiratory tract, or skin for allergic contact dermatitis or insect sting. These tests are usually reserved for the situation where skin test or in vitro allergen IgE results do not correspond to patient history or clinical situation. Most often, these tests are performed in a controlled research setting because of the possible risk of severe, life-threatening reactions to direct organ allergen challenge.
Serum Specific IgE test
In the past decades, measurement of allergen-specific IgE was performed using the radioallergosorbent test (RAST); nowadays, new tools are developed that supersede this method. The basic concept is that an allergen is linked to a solid phase to which a patient’s serum is added. With incubation, the patient’s allergen-specific IgE binds to the allergen-linked solid phase. After washing of unbound patient antibody from the allergen-linked solid phase, a labelled human anti-IgE antibody is added; this will then bind to the patient’s IgE that is bound to the allergen-linked solid phase. Detection of this human anti-IgE antibody bound to the patient’s allergen-specific IgE provides the readout for this assay.
The test measures the circulating IgE that is directed to a specific allergen. It is appropriate for those patients who present with a good history of sensitivity to a particular allergen, and yet produce consistently negative skin test results. While skin tests are generally considered to be more sensitive than serum specific IgE test, its specificity is lower. Moreover, the concentration of specific IgE may not correlate to wheal size of the skin test nor to the symptoms of the patient.
Indications for serum specific IgE (over skin prick test)
- Patient has severe generalized eczema
- When a patient demonstrates demographism
- Clinic does not have the labour and space to perform skin test and ALFA test
- When a patient is on antihistamines, which for some reason cannot be temporarily discontinued.
- Patients apprehensive about skin prick test.
Basophil histamine release test
Allergy screening may also be performed by assessing histamine released from blood basophils after the addition of allergen extract. In this test, blood samples, which may be as small as 20 μL for each allergen, are pipetted into the wells of an ELISA plate pre-coated with the suspected allergens. The plate is then incubated at 37°C for up to 1 hour and the resultant histamine release is estimated. As about 5% of basophils do not release histamine in vitro, a positive response to anti-IgE, used as a positive control, is absolutely necessary to validate a negative result.
There are three major advantages of basophils testing compared with provocation testing:
- The patient is not exposed to allergen. This saves both the patient and the health care system for resources, and requires only good manufacturing and laboratory procedures.
- A number of single allergen molecules can be tested simultaneously as 75-100 μl blood is required for a single test, and allergen components can be combined to mirror a real life exposure.
- CD63 upregulation is a precise marker of anaphylactic degranulation, and thus has a potential to reflect the severity of allergic reaction (Allergy 2015;70:1393-1405).
Golden rules of allergy diagnosis
- An accurate clinical history is the mainstay of allergy diagnosis
- Skin prick/serum IgE tests provide objective confirmation of IgE sensitivity
- Skin prick/serum IgE tests must always be interpreted in the context of the history
- If you do not need the result of a test then don’t do the test. It is not advised to go for a big screening panel for more than 10 to 15 allergens. Indiscriminate skin prick/serum IgE ‘panels’ are more likely to confuse rather than inform diagnosis and should be avoided. Based on the clinical experience in both Europe and southern China, a screening panel of 6 to 8 allergens should be good enough to cover >90% of sensitizations among rhinitis and asthma patients.
Is it cold or an allergy
There is no absolute way to tell the difference between allergy symptoms of running nose, coughing, and sneezing and cold symptoms. Allergy symptoms, however, may last longer than cold symptoms. Anyone who has any respiratory illness that lasts longer than a week or two should consult a health service provider. Below is a reference for preliminary screening:
General aches, pains
Rate or never
3 to 14 days
Weeks (for example, 6 weeks for ragweed orgrass pollens seasons)
Antihistamines – OTC or by prescription
Specific allergen immunotherapy
Wash your hands often
Avoid those things that you are allergic to
Avoid close contact with anyone with a cold
Middle ear infection
U.S. Department of Health and Human Services, 2005