Compliance with the provisions in this LCD may be monitored and addressed
through post payment data analysis and subsequent medical review audits.  
  
 **History/Background and/or General Information  
  
** Allergy is a form of exaggerated sensitivity or hypersensitivity to a
substance that is either inhaled, ingested, injected, or comes in contact with
the skin or eye. The term allergy is used to describe situations where
hypersensitivity results from heightened or altered reactivity of the immune
system in response to external substances. Allergic or hypersensitivity
disorders may be manifested by generalized systemic reactions as well as
localized reactions in any part of the body. The reactions may be acute,
subacute, or chronic, immediate or delayed, and may be caused by a variety of
offending agents; pollen, molds, mites, dust, feathers, animal fur or dander,
stinging insect venoms, foods, drugs, etc.  
  
Allergy testing is performed to determine a patient's immunologic sensitivity
or reaction to particular allergens for the purpose of identifying the cause
of the allergic state, and is based on findings during a complete medical and
immunologic history and appropriate physical exam. There are several different
types of diagnostic modalities available for allergy testing. Positive and
negative controls should be performed with all tests and tests used should
have proven efficacy as demonstrated through scientifically valid medical
studies published in peer review journals.1,2,3,4  
  
This policy addresses immediate (IgE-mediated) hypersensitivity and delayed
(cell mediated) hypersensitivity and includes in vivo testing (skin tests),
organ challenge tests, in vitro testing, limitations, and provider
qualifications. The specific allergy testing described below is considered
medically reasonable and necessary in accordance with the criteria noted in
accordance with evidence-based guidelines.  
  
 **Covered Indications  
  
** **A. In Vivo Testing (skin tests):  
  
** In vivo testing (skin tests) include the performance and evaluation of
selective cutaneous and mucous membrane tests in correlation with history,
physician examination, and other observations of the patient. The tests are
performed to determine body sensitivity and reaction to the antigen for the
purpose of diagnosing the presence of allergic reaction to antigenic stimuli.
Prick/puncture tests or intracutaneous tests are the preferred techniques for
immunoglobulin E (IgE)-mediated hypersensitivity.1  
  

  1. Percutaneous testing (scratch, puncture, prick), immediate type reaction, will be considered medically reasonable and necessary when used to evaluate IgE mediated hypersensitivity to inhalants, foods, Hymenoptera (stinging insects), chemicals, and specific drugs (e.g., penicillins and macromolecular agents).1  
  

  2. Intracutaneous (intradermal) testing, immediate type reaction, will be considered medically reasonable and necessary when used to evaluate IgE mediated hypersensitivity to inhalants, Hymenoptera venoms (e.g., bee venom), drugs (e.g., penicillin, insulin, heparin, muscle relaxants) and/or chemicals.1,2  
  

  3. Patch testing is used to differentiate allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD). Patch testing is the gold standard method of identifying the cause of allergic contact dermatitis. This testing is indicated to evaluate a nonspecific dermatitis, allergic contact dermatitis, pruritus, and other dermatitis to determine the causative antigen. It is a diagnostic test reserved for patients with skin eruptions for which a contact allergy source is likely.1,2  
  
The patch test procedure can induce an eczematous reaction in miniature by
applying suspect allergens to normal skin, allowing the physician to determine
a specific patient allergy. Patch tests are applied to the skin on the
patient's back and left in place for 48 hours. The test is interpreted after
48 hours, and typically once again at 72 hours or 96 hours, and the reactions
are systemically scored and recorded. The patient is then informed and
educated regarding specific allergies and avoidance of exposure. Avoidance of
the identified allergen(s) is critical to patient improvement and resolution
of the dermatitis.1  
  
Allergy patch testing will be considered medically reasonable and necessary
when used to diagnose allergic contact dermatitis for patients with a clear-
cut clinical suspicion of contact allergy, and they are tested with the
chemicals relevant to the problem, which may include the following:

  *     * Dermatitis due to detergents, oils and greases, solvents, drugs and medicines in contact with skin, other chemical products, food in contact with skin, plants (except food), cosmetics, and metals, such as nickel and rubber additives (this is not an all-inclusive list).1,2,3

  4. Photo patch testing will be considered medically reasonable and necessary to evaluate unique allergies resulting from photosensitization (e.g., photo-allergic contact dermatitis).1  
  

  5. Photo testing will be considered medically reasonable and necessary to evaluate skin abnormalities (e.g., itching, blisters, hives) resulting from exposure to sunlight.1  
  

  6. Intracutaneous (intradermal) Dilutional Testing (IDT) (also known as Skin Endpoint Titration [SET]), immediate type reaction is intradermal testing of sequential and incremental dilutions of a single antigen. The endpoint is determined by intradermal testing with the use of approximately 0.1 ml of serial five-fold dilution extract. The endpoint is the weakest dilution that produces a positive skin reaction and initiates progressive increase in the diameter of the wheals with each stronger dilution. For example, if Hymenoptera venom sensitivity is suspected, initial prick/puncture tests followed by serial endpoint titration with intracutaneous tests may be required.1,5

  *     * Intracutaneous (intradermal) dilutional testing will be considered medically reasonable and necessary when used for determining the starting dose for immunotherapy for individuals with Hymenoptera venom sensitivity and significant aeroallergen sensitivity.

  7. **** Intracutaneous (intradermal) testing, delayed reaction

  *     * Intracutaneous (intradermal) testing will be considered medically reasonable and necessary when used in epidemiologic testing of susceptible populations exposed to bacterial and fungal pathogens (e.g., tuberculin skin test). The tuberculin skin test is elicited by the intracutaneous injection of 0.1 mL of standardized purified protein derivative (PPD) starting with the intermediate strength of 5 tuberculin units. **** The size of the delayed skin test response is measured 48 hours after antigen challenge, and the largest diameter of the palpable firm area that outlines the induration reaction should be measured to the nearest millimeter.1

**  
B. Organ Challenge Tests:  
  
**Controlled challenges or supervised exposure are considered the gold
standard for assessing whether clinical sensitivity is present. When tests for
IgE-mediated immunity are ambiguous, organ challenge testing is used to
determine if clinical sensitivity exists. Organ challenge test material may be
applied to the mucosae of the conjunctivae, nares, GI tract, or bronchi. All
organ challenge tests should be preceded by a control test with diluent and,
if possible, the procedure should be performed on a double blind or at least
single, blind basis. Considerable experience with these methods is required
for proper interpretation and analysis. Specific organ challenge tests will be
considered medically reasonable and necessary under the following
conditions1,4,6:

  1. Ophthalmic mucous membrane challenge tests and direct nasal mucous membrane challenge tests provided that levels of allergic mediators (such as histamine and tryptase) are measured.

  2. Inhalation bronchial challenge tests to evaluate new allergens and to substantiate the role of allergens in patients with significant symptoms. Results of these tests are ordinarily evaluated by objective measures of pulmonary function and occasionally by characterization of bronchoalveolar lavage samples.

  *     * Inhalation bronchial challenge tests should be performed as dose-response assays wherein provocation concentration thresholds can be determined on the basis of allergen concentration required to cause a significant decrease in pulmonary function measurements.

  3. Oral food challenge (OFC) testing is a physician-supervised oral provocation procedure where a patient ingests gradually increasing amounts of a food under medical supervision until an age-appropriate serving is reached or the feeding is terminated because of symptoms. Prior to conducting an OFC, the patient's medical history, age, past adverse food reactions, skin prick testing (SPT), and serum food allergen-specific IgE results must be considered.

  *     * Oral food challenge testing will be considered medically reasonable and necessary when the diagnosis is uncertain for:  
  

      * Food allergy dermatitis
      * Anaphylactic shock due to an adverse food reaction
      * Allergy to medicinal agents
      * Allergy to foods

****

**C. In Vitro Testing:  
  
** **Specific IgE In Vitro Tests**

  * Examples include1,7: 
    * ELISA (Enzyme linked immunosorbent assay)
    * MAST (Multiple thread allergosorbent test)
    * IP (Immuno-peroxidase test)
    * PRIST (Paper radioimmunosorbent test)
    * CAP (ImmunoCap assay)  
  

Specific IgE immunoassays detect antigen-specific IgE antibodies in the
patient's serum. Testing must be based on a careful history/physical
examination which suggests IgE- mediated disease. The choice of specific
allergen specificities for testing should be guided by a comprehensive
physical exam that includes objective symptoms to select appropriate testing.
In situations in which a high pretest probability has been determined,
confirmation of sensitization is frequently conducted by IgE antibody testing
due to the possible risk of life-threatening anaphylaxis and/or the
possibility of starting a course of immunotherapy. Specific IgE in vitro tests
are useful when testing for inhalant allergens (pollens, molds, dust mites,
animal dander), specific foods, insect stings, and other allergens such as
drugs or latex, when direct skin testing is impossible due to extensive
dermatitis, or in marked dermatographism.1,5,7  
  
In-vitro allergen specific IgE testing will be considered medically reasonable
and necessary under the following conditions1,5,7:

  * Direct skin testing is not possible due to extensive dermatitis, dermographism, ichthyosis, or generalized eczema.
  * For patients who cannot be safely withdrawn from medications that interfere with skin testing (such as long-acting antihistamines, tricyclic antidepressants).
  * Testing of uncooperative patients with mental or physical impairments.
  * As adjunctive laboratory testing for disease activity of allergic bronchopulmonary Aspergillosis (ABPA) and certain parasitic diseases.
  * The evaluation of cross-reactivity between insect venoms (e.g., fire ant, bee, wasp, yellow jacket, hornet).
  * When the pretest probability of Hymenoptera venom allergy is strong and the skin test result is negative, serological detection of IgE antibodies is recommended for vespid, wasp, honeybee, bumblebee, and fire ant venoms.
  * When clinical history suggests an unusually greater risk of anaphylaxis from skin testing than usual (e.g., when a patient has a history of a previous systemic reaction to skin testing or when an unusual allergen is not available as a licensed skin test extract).
  * Measurements of total IgE serum levels are not appropriate in most general allergy testing which is performed to determine a patient's immunologic sensitivity or reaction to particular allergens for the purpose of identifying the cause of the allergic state. Total serum IgE levels will only be considered medically reasonable and necessary for the following1:  
  

    * Follow up of bronchopulmonary Aspergillosis (ABPA),
    * Select immunodeficiency such as the syndrome of hyper-IgE,
    * Eczematous dermatitis,
    * Recurrent pyogenic infections, or
    * Evaluation for omalizumab therapy.  
  

**Limitations  
**

  1. The number of allergy tests performed should be judicious and dependent upon the patient's history, physical findings and provider's clinical judgment. All patients should not necessarily receive the same tests or the same number of sensitivity tests. Rather, testing should be patient specific based on the history and physical examination.1

  *     * Per evidence-based guidelines, the number of skin tests (e.g., _<_ 70 prick/puncture and 40 intracutaneous tests) for inhalant allergens is justified as an initial diagnostic evaluation. Also, up to 80 patch tests may be required for ACD diagnosis.1,8-10

  2. In-vitro testing performed in addition to skin testing for the same antigen is not usually necessary, except in the case of suspected latex sensitivity, Hymenoptera, or nut/peanut sensitivity where both the skin test and the in-vitro test may be performed.1
  3. Intracutaneous (intradermal) tests for food sensitivity are not recommended because of numerous false-positive test findings and possible risks.1
  4. Food allergy tests are inappropriate for investigation of chronic idiopathic urticaria (CIU) or angioedema.1
  5. Routine utilization of a large number of skin tests or routine annual tests without a discernable indication is not acceptable.1
  6. Please refer to the CMS IOM Publication 100-03, _Medicare National Coverage Determinations (NCD) Manual_ , Chapter 1, Part 2, Section 110.11 Food Allergy Testing and Treatment, Section 110.12 Challenge Ingestion Food Testing, and Section 110.13 Cytotoxic Food Tests for additional limitations.
  7. Please refer to the CMS IOM Publication 100-03, _Medicare National Coverage Determinations (NCD)_ _Manual_ , Chapter 1, Part 4, Section 230.10 Incontinence Control Devices for additional limitations.  
  

**The following tests are considered not medically reasonable and necessary:**

    * Allergen specific IgE; qualitative, multiallergen screen and multiplex microarray chip for IgE antibody detection are non-specific screening tests that do not identify a specific antigen.1,5 These tests are screening tools and therefore are not covered by Medicare.
    * Provocation-neutralization1,11
    * Electrodermal testing1,6,11
    * Applied kinesiology1,6,11
    * Iridology1
    * Hair analysis1,6,11
    * Lymphocyte proliferation test1,11
    * Basophil activation tests (BAT) to diagnose food or drug allergies1,6,11,12
    * T-cell proliferation assay6
    * Facial thermography6
    * Breath condensate analysis1
    * In vitro tests for delayed hypersensitivity to contact allergens (e.g., metals and bone cement)3
    * Immunoglobulin G (IgG) allergy testing13
    * Tests to diagnose Food Allergy:

  *     *       * Food specific IgG, IgG4, and IgG/IgG4 antibody tests1,6,11
      * Atopy patch tests to diagnose non-contact food allergy1,11
      * Intradermal testing to diagnose food allergy6
      * Component-resolved diagnostics (CRD) to diagnose food allergy6
      * Epitope binding testing to diagnose food allergy6
      * T-cell responses to food allergens6
      * Platelet activating factor (PAF) to diagnose food allergy6
      * Gastric juice analysis6,11
      * Mediator release assay (LEAP diet)11
      * Cytotoxic food testing1,11
      * Please refer to the CMS IOM Publication 100-03, _Medicare National Coverage Determinations (NCD) Manual_ , Chapter 1, Part 2, Section 110.11 Food Allergy Testing and Treatment, Section 110.12 Challenge Ingestion Food Testing, and Section 110.13 Cytotoxic Food Tests for additional coverage restrictions.



**Provider Qualifications  
  
 __**Services will be considered medically reasonable and necessary when all
aspects of care are within the scope of practice of the provider 's
professional licensure; and when all procedures are performed by appropriately
trained providers in the appropriate setting.  
  
 __  
 **Notice** : Services performed for any given diagnosis must meet all of the
indications and limitations stated in this LCD, the general requirements for
medical necessity as stated in CMS payment policy manuals, any and all
existing CMS national coverage determinations, and all Medicare payment rules.

Multiple guidelines and appropriate use criteria are available for allergy
testing.  
  
Pretest probability is used to determine if allergy testing is appropriate and
is based on the patient's clinical history.  
  
A literature search was conducted using the following key words: allergy;
allergen; allergy testing; guideline; practice parameters; meta-analysis;
systematic review; diagnosis; IgE; pretest probability; clinical history; skin
testing; skin prick tests; food allergy; drug allergy; venom allergy; insect
hypersensitivity; Hymenoptera venom; anaphylaxis; urticaria; in vitro allergy
tests; in vivo allergy tests; specific IgE antibodies; allergic contact
dermatitis; patch testing; oral food challenge; immediate IgE-mediated
hypersensitivity; delayed (cell mediated) hypersensitivity; atopic dermatitis;
multiallergen screen; photoallergy; allergic rhinitis; asthma; cockroach;
house dust mites; and inhalant allergy.  
  
 **Evidence-based guidelines  
  
** **Skin Tests (prick/puncture and intracutaneous)  
  
** Bernstein et al has provided practice parameters for allergy diagnostic
testing. There are many diagnostic methods for use in diagnosing
hypersensitivity disorders. Positive and negative controls should be performed
with all allergy tests and tests used should have proven efficacy as
demonstrated through scientifically valid medical studies.1  
  
 **Prick/Puncture Tests and Intracutaneous Tests  
  
** Prick/puncture tests or intracutaneous (intradermal) tests, which have an
immediate type reaction, are the preferred techniques for IgE-mediated
hypersensitivity.14 Skin tests (prick/puncture and intracutaneous) are
beneficial to verify sensitivity caused by aeroallergens, foods, some drugs,
and a few chemicals.11 Skin test allergens utilized for prick/puncture tests
should also be potent and stable. The dependability of prick/puncture tests
rests on the skill of the tester, the test instrument, color of the skin, skin
reactivity on the day of the test, potency, and stability of test reagents.
The diagnostic validity of prick/puncture tests has been proven not only in
patients subjected to allergens under natural conditions but also in patients
undergoing controlled organ challenge tests. Many studies have confirmed the
sensitivity and specificity of prick/puncture tests for both inhalant and food
allergens when correlated with nasal and oral challenge tests. Skin tests
should not be conducted on skin locations with active dermatitis or severe
dermatographism. Literature indicates that life-threatening, generalized
systemic reactions are rarely generated by prick/puncture tests. In a recent
retrospective survey, one death was reported in a patient who received 90 food
prick/puncture tests at one time. In general, skin prick/puncture testing is
more sensitive for detecting sensitization to inhalant allergens and
confirming clinical allergy. However, specific IgE assays with defined
quantifiable threshold levels can also predict positive respiratory responses
following allergen exposure.1  
  
Intracutaneous (intradermal) tests will recognize a greater number of patients
with lower skin test sensitivity and are utilized when increased sensitivity
is the main goal of testing.1 Intracutaneous tests are beneficial for
evaluation of anaphylaxis, particularly drug (e.g., penicillin) and
Hymenoptera venom anaphylaxis. They have been assessed and validated in
analysis of several significant IgE-mediated drug reactions, including
anaphylactic reactions caused by penicillin, succinylcholine analogs, and
cancer chemotherapeutic agents.  
  
 **Intracutaneous (Intradermal) Dilutional Testing (skin endpoint titration)  
  
** Intracutaneous (intradermal) dilutional testing (also known as skin
endpoint titration [SET]) is intradermal testing of sequential and incremental
dilutions of a single antigen. The endpoint is determined by intradermal
testing with the use of approximately 0.1 ml of serial five-fold dilution
extract. The endpoint is the weakest dilution that produces a positive skin
reaction and initiates progressive increase in the diameter of the wheals with
each stronger dilution.1 In comparison with specific nasal challenge, skin
endpoint titration (SET) is equivalent to prick/puncture skin tests. This type
of testing is beneficial for determining the starting dose for immunotherapy
for individuals with Hymenoptera venom sensitivity and significant
aeroallergen sensitivity. For example, if Hymenoptera venom sensitivity is
suspected, initial prick/puncture tests followed by serial endpoint titration
with intracutaneous tests may be required.  
  
The sensitivity of intracutaneous tests may be greater than prick/puncture
tests for penicillin, insect venom, or certain drug classes (e.g., insulin,
heparin, muscle relaxants) hypersensitivity. Concurrent medications may affect
the validity of prick/puncture and intracutaneous tests (e.g., antihistamines,
tricyclic antidepressant doxepin, histamine antagonists, oral prostaglandin D2
inhibitors). The dependability of intracutaneous tests rests on the same
variables as those described for prick/puncture tests; the age of the skin,
the location of the body where the tests are applied, skin pigmentation,
concurrent medications, and potency and biologic stability of the allergen
test extracts. Prompt systemic reactions are more common with intracutaneous
tests.  
  
The late-phase cutaneous reaction is an extension of the prick/puncture or
intracutaneous testing, generally the latter, and is described by erythema,
induration or edema, and dysesthesia.1 The late-phase cutaneous reaction can
occur following immune and nonimmune activation. Numerous allergens have been
implicated. The late-phase cutaneous reaction should be read between the 6th
and 12th hours after the skin tests are performed; measurements of average
diameter and/or area of induration or edema should be documented.  
  
 **Delayed-Type Hypersensitivity Skin Testing  
  
** Delayed-type hypersensitivity skin testing is key in epidemiologic
screening of susceptible populations exposed to bacterial and fungal
pathogens.1 The standardized purified protein derivative (PPD) antigen has a
long history for use as a predictor of active or latent tuberculosis
infection. Variables, such as vulnerable populations and cross-sensitization
with other atypical mycobacterial species affect the diagnostic accuracy of
the tuberculin skin test and, by extrapolation, other delayed-type
hypersensitivity tests. A late phase cutaneous reaction and a delayed-type
hypersensitivity reaction might not look entirely different except that the
latter typically has prolonged induration. No life-threatening occurrences or
deaths have been reported as a result of late-phase cutaneous reactions in
recent surveys.  
  
Purified protein derivative (PPD) of tuberculin is the prototype antigen
recall test and offers explicit evidence that hypersensitivity, as opposed to
toxicity, is elicited by the antigens in Mycobacterium hominis or related
mycobacterial species. The tuberculin skin test is elicited by the
intracutaneous injection of 0.1 mL of standardized PPD starting with the
intermediate strength of 5 tuberculin units. Recall antigen skin tests are
used to assess cellular immunity in patients with infection (e.g., life-
threatening sepsis), cancer, pretransplantation screening, and end-stage
debilitating diseases. Decreased or absent recall antigen tests are termed
anergy, which develops frequently in certain diseases, such as hematogenous
tuberculosis, sarcoidosis, and atopic dermatitis. The size of the delayed skin
test response is measured 48 hours after antigen challenge, and the largest
diameter of the palpable firm area that outlines the induration reaction
should be measured to the nearest millimeter.1  
  
When a single intracutaneous antigen (other than PPD) is utilized to assess
prior sensitization to a potential pathogen, a reaction of 5 mm or larger may
serve as the cutoff point for a positive test, but smaller reactions (2 to 4
mm) may be clinically significant. The absence of delayed-type
hypersensitivity to all the test antigens would imply an anergic state. The
largest application of recall antigen testing is the recognition of anergy and
as an in vivo clinical correlate of cell-mediated immunoincompetency.1
Although the standardized PPD antigen has been used for many years as a
predictor of active or latent tuberculosis infection, confounders, such as
susceptible populations, bacilli Calmette-Guerin (BCG), a vaccination for
tuberculosis that is not widely used in the United States, and cross-
sensitization with other atypical mycobacterial species, have all affected the
diagnostic accuracy of the tuberculin skin test and, by extrapolation, other
delayed-type hypersensitivity tests.  
  
 **Patch Tests  
  
** The epicutaneous patch test is considered to be the definitive diagnostic
method for the diagnosis of allergic contact dermatitis (ACD), which is a
unique form of delayed hypersensitivity.1 Leading triggers of ACD are
chemicals, plant resins, and lipid components. Direct irritants may cause
irritant contact dermatitis (ICD), which often is indistinguishable from ACD;
however, the clinical presentation of ICD is more limited to the skin site
directly in contact with the offending agent(s) with little or no extension
beyond the site of contact. Irritant contact dermatitis is generally the
result of nonimmunologic, direct tissue reaction and must be clearly
differentiated from ACD. Irritant contact dermatitis is usually a
multifactorial response that involves contact with a substance that chemically
abrades, physically irritates, or damages the skin. Irritation is usually a
direct cytotoxic reaction produced by a multitude of various agents (e.g.,
chemicals, detergents, solvents, alcohol, creams, lotions, ointments, and
powders) and by contributing physical factors that include excessive
scrubbing, washing, overhydration, improper drying, perspiration, and
temperature extremes. Patch testing is recommended for any dermatitis for
which contactant exposure, either natural or secondary to topical agents,
might be implicated. The diagnosis of ACD is suspected from the clinical
presentation of the rash, which then must be supported by a history of
exposure to a causative agent and subsequently confirmed by patch testing.
Patch tests are most beneficial for patients with a clear-cut clinical
suspicion of contact allergy, and they are tested with the chemicals relevant
to the problem; these conditions satisfy the prerequisites of high pretest
probability.  
  
Patch tests are recommended for patients with chronic, pruritic, eczematous,
or lichenified dermatitis if underlying or secondary ACD is speculated.
Contact dermatitis is a frequent concern following exposure to topical
medications, including lanolin, para-aminobenzoic acid (PABA), caine
derivatives, antihistamines, iodochlorhydroxyquin, nonsteroidal anti-
inflammatory drugs (NSAIDs), and corticosteroids. When clinical evaluations
imply that exposure to a specific contactant has occurred either in an
occupational or nonoccupational setting, patch testing may be used to confirm
the diagnosis.8,10 As indicated previously, patch tests should be used for
patients based on a clear-cut clinical inference of contact allergy, and
tested with the chemicals pertinent to the issue; these conditions satisfy the
prerequisites of high pretest probability. Certain contactants (e.g.,
antibiotics, PABA) may induce photo contact ACD or phototoxic contact
dermatitis (CD) (e.g., carrot, celery, fennel, lemon-lime, grapefruit). If
photosensitization is suspected, photo patch tests should be performed by a
physician with expertise in UV radiation. If photo contact sensitivity is
suspected, the appropriate allergens should be subjected to photo patch test
primarily in the UV-A range of 320 to 400 nm. Photosensitizers are substances
that lead to photobiologic reactions after UV exposure, showing either toxic
or allergic reaction patterns. Cutaneous manifestations in photoallergic
reactions are predominantly eczematous lesions. Photo patch testing is the
diagnostic testing recommended for photosensitization, whereas, photo tests
are used to evaluate skin abnormalities (e.g., itching, blisters, and hives)
resulting from exposure to sunlight. Patch test findings are affected by oral
corticosteroids but not by antihistamines. Usually, patch tests stay in place
for 48 hours. Following the 48-hour patch test reading, additional readings at
3 to 4 days and, in some instances, 7 days following the original application
of the patch generate the greatest overall reading reliability.  
  
 **Specific IgE Immunoassays  
  
** Under specific circumstances, IgE immunoassays may be preferable to skin
testing, such as widespread skin disease, patients receiving skin test
suppressive therapy, uncooperative patients, or when the patient's history
proposes an extraordinarily greater risk of anaphylaxis from skin testing.
Also, antihistamines and drugs such as tricyclic antidepressants decrease or
block skin test reactivity. Therefore, when a patient cannot be safely
withdrawn from a medication that would interfere with skin testing, an
immunoassay may be appropriate. The sensitivity of these immunoassays compared
with prick/puncture skin tests range from less than 50% to greater than 90%,
with the mean at about 70% to 75% for most studies. Consequently, skin tests
are highly beneficial for the diagnosis of IgE-mediated sensitivity.1,14  
  
As indicated previously, skin prick/puncture testing is more sensitive for
recognizing sensitization to inhalant allergens and proving clinical allergy.
However, specific IgE assays with defined quantifiable threshold levels can
also predict positive respiratory responses following allergen exposure.1  
  
Diagnostic skin and/or specific IgE tests are utilized to verify sensitivity
to venoms in a patient with a history of a prior systemic reaction. While
diagnostic tests distinguish species specificity of venom sensitization, they
do not reliably predict severity of the sting reaction. A small percentage of
individuals (1%) with negative findings to both skin and in vitro tests may
experience anaphylaxis following a field sting.1  
  
Assessment of drug-specific IgE antibodies caused by many high-molecular-
weight and several low-molecular-weight agents is often beneficial for
validating the diagnosis and prediction of future IgE-mediated reactions, such
as anaphylaxis and urticaria.1  
  
Examples of specific IgE in vitro tests include1,7:

  * ELISA (Enzyme linked immunosorbent assay) 
  * MAST (Multiple thread allergosorbent test)
  * IP (Immuno-peroxidase test)
  * PRIST (Paper radioimmunosorbent test)
  * CAP (ImmunoCap assay)

**  
Total Serum IgE  
  
** The clinical applications of total serum IgE are of limited value. Elevated
serum IgE concentrations occur in allergic bronchopulmonary Aspergillosis
(ABPA). Total serum IgE is recommended to assess select immunodeficiency
syndromes such as hyper-IgE, eczematous dermatitis, and recurrent pyogenic
infections. Total serum IgE is also recommended to evaluate the
appropriateness of a patient for omalizumab therapy and to establish the
initial dose.1 Allergic bronchopulmonary Aspergillosis is an inflammatory
disease of the lungs distinguished by severe asthma, sputum production,
peripheral blood eosinophilia, and an increased total serum IgE concentration.
If untreated, it could progress to central bronchiectasis and, eventually,
pulmonary fibrosis and death. Following suitable treatment with
corticosteroids, total serum IgE levels generally decrease. Total serum IgE
should be monitored during the disease as an increase in IgE may signal a
relapse.  
  
 **Food Allergy Testing**

Tests for food specific IgE antibodies include percutaneous skin tests
(prick/puncture tests) and serum assays. Overall, these tests are very
sensitive (generally 85%) but modestly specific (approximately 40% to 80%) and
therefore are recommended for use when a specific food is highly suspected.1
They are not effective for indiscriminate screening (e.g., using panels of
tests without consideration of likely causes) and therefore generally should
not be used for that purpose.  
  
The probability distribution of specific IgE for several anaphylactogenic
foods (peanuts, egg whites, cow's milk, and codfish) can outline sensitivity
as confirmed by double-blind oral challenge tests.1  
  
 **Organ Challenge Tests  
  
** Controlled challenges or supervised exposure are considered the gold
standard for assessing whether clinical sensitivity is present. In challenge
testing, a suspected allergen in a clinically relevant exposure is
administered in an attempt to reproduce symptoms. Challenge tests have been
broadly applied under research conditions for many years, but they may also be
useful in clinical situations for confirmation of clinical disease. For
example, when tests for IgE-mediated immunity are ambiguous, organ challenge
testing may be used to determine if clinical sensitivity exists. Specific
organ challenge tests may facilitate or support clinical diagnosis under
certain conditions: 1) investigation of potential "new" allergens, 2)
validation of diagnosis when the history is suggestive but skin and/or in
vitro test findings are negative, 3) verifying food allergy, and 4) monitoring
of therapy, either pharmacologic or immunologic. In general, these tests
require cooperative patients with respect to both age and mental status. The
site of the specific organ challenge is history dependent (i.e., conjunctival,
nasal, bronchial, or skin) (e.g., patch tests for ACD; supervised insect
stings).1  
  
Respiratory challenge tests are utilized when an objective gold standard for
determining clinical sensitivity is indicated. Conjunctival challenge tests
are generally performed for suspected localized eye allergy but they may also
be helpful in assessing nasal allergy. Conjunctival challenge tests are
assessed by symptoms of itching and objective indices, including tear volume,
amount of mucus, and palpebral or bulbar erythema. Nasal challenge testing is
rare but may be used to offer objective evidence of sensitivity when the
diagnosis is uncertain or to evaluate the effectiveness of therapeutic
management. Nasal challenge reactions are assessed by subjective symptoms and
objective measurements of nasal airway resistance, the number of sneezes, and
the measurement of inflammatory mediators in nasal secretions (such as
histamine and tryptase). Specific (allergic) bronchial challenge yields a
measure of lower airway clinical sensitivity when there is doubt. Possible new
asthma triggers can be investigated and confirmed with specific bronchial
challenge. Since late-phase asthmatic responses may occur, arrangements should
be made for peak flow monitoring or direct observation of such reactions,
which usually appear 6 to 12 hours later.1  
  
Many inflammatory correlates can be assessed and studied serially in
respiratory and other body fluids, such as nasal smears or lavage, induced
sputum, and bronchoalveolar lavage (BAL).1 These may identify specific
phenotypes or in some cases predict severity.  
  
 **Number and Frequency of Tests  
  
** The number of skin tests and the allergens chosen for skin testing should
be based on the patient's age, history, environment and living conditions
(e.g., region of the country), occupation, and activities.1 Regular use of a
significant number of skin tests or routine annual tests without a distinct
clinical indication are clearly not necessary. Evidence-based sources should
be used to determine whether specific allergen tests based on pretest
probability are likely to confirm a suspected clinical diagnosis. Because ACD
is frequently caused by unsuspected substances, up to 80 patch tests may be
required for diagnosis.8-10 The Joint Task Force on Practice Parameters
concludes the number of skin tests (e.g., _<_ 70 prick/puncture and 40
intracutaneous tests) for inhalant allergens is justified as an initial
diagnostic evaluation.1 However, routine annual tests without a definite
clinical indication are clearly not indicated.  
  
If Hymenoptera venom sensitivity is suspected, initial prick/puncture tests
followed by serial end point titration with intracutaneous tests may be
required.1  
  
If a patient presents with idiopathic anaphylaxis, up to 30 screening
prick/puncture tests have been reported to distinguish causal foods in a small
percentage of such individuals.1 A subsequent overview of this study
questioned whether the diagnostic yield of such a strategy was useful.
However, in the diagnostic assessment of speculated anaphylaxis, it would be
wise to spread the total number of tests over several clinic visits to prevent
the likelihood of severe anaphylaxis if multiple reactions occurred.  
  
 **Unproven Tests  
  
** The role of lymphocyte proliferation as measured in vitro in the
pathogenesis of the delayed-type hypersensitivity tissue reaction and delayed-
type hypersensitivity skin reactions is unclear.1  
  
Procedures for which there is no evidence of diagnostic validity include
cytotoxic tests, provocation-neutralization, electrodermal testing, applied
kinesiology, iridology, hair analysis, and food specific IgG, IgG4, and
IgG/IgG4 antibody tests. Also, atopy patch tests, lymphocyte proliferation
tests, and basophil activation tests are additional diagnostic tests for drug
allergy. However, further studies are required to confirm their clinical
utility in the evaluation of drug allergic patients.1  
  
Intracutaneous (intradermal) skin tests for foods are potentially dangerous as
they can provoke a systemic reaction (seldom a concern for prick test), are
overly sensitive, increase the chance of a false-positive test result, and are
not recommended.1  
  
Food allergy tests are inappropriate for investigation of chronic idiopathic
urticaria (CIU) or angioedema.1  
  
Although breath condensate analysis is an evolving noninvasive method for
evaluation of asthma, results are still variable and further refinements are
required before it can be accepted as a valid diagnostic method.1  
  
A positive multiple allergen test result does not provide adequate information
to make a specific diagnosis or to initiate therapy. In addition, a negative
multiple allergen test finding does not exclude clinical sensitivity since the
commercially-available multiallergen screening tests only screen for
approximately 15 aeroallergens.1  
  
Unproven tests, such as immunoglobulin G (IgG) testing or an indiscriminate
battery of immunoglobulin E (IgE) tests, should not be conducted in the
evaluation of allergy as these tests may lead to inappropriate diagnosis and
treatment.13  
  
 **Evidence-Based Guideline for Drug Allergy Testing  
  
** An evidenced-based updated practice parameter for drug allergy testing2
provides important considerations in the assessment of drug hypersensitivity
which includes the patient's history, physical exam, objective clinical and
laboratory tests, previous and current drug use, toxicity and allergenicity of
previous current drug use and the timing between initiation of therapy and
onset of symptoms. All body systems potentially responsible for symptoms
should be assessed. Cutaneous manifestations are the most common presentation
for drug allergic reactions. Although drug allergic reactions may present with
noncutaneous physical findings, these findings are generally nonspecific and
are not nearly as helpful in diagnosis and management decisions.  
  
The immediate hypersensitivity skin test is considered the most useful test
for detecting IgE-mediated drug reactions caused by many large-molecular-
weight biologicals and penicillin.2  
  
Limited trials with small numbers of individuals have assessed the specificity
and sensitivity of third-generation assays for detection of penicillin
specific IgE in vitro. These studies show relatively high specificity
(97%-100%) but lower sensitivity (29%-68%) for penicillin specific IgE.
Consequently, although a positive in vitro test result for penicillin specific
IgE is highly predictive of penicillin allergy, a negative in vitro test
result does not adequately exclude penicillin allergy. The basophil activation
test is a recently described method of evaluating expression of CD63 on
basophils after stimulation with an allergen. Data is limited for this method
to assess patients with possible allergies to -lactam antibiotics and
nonsteroidal anti-inflammatory drugs (NSAIDs). Further confirmatory studies,
especially with commercially available tests, are needed before its general
acceptance as a diagnostic tool.2  
  
The most dependable method for diagnosis of contact dermatitis caused by
topically applied drugs is patch testing. Recent literature indicates concerns
regarding the diagnostic utility of patch tests with systemically administered
drugs in non-IgE-mediated cutaneous drug reactions. While drug patch testing
may be beneficial for certain types of cutaneous drug reactions, including
maculopapular exanthems, acute generalized exanthematous pustulosis, and fixed
drug eruptions, generally drug patch testing is not helpful for Stevens-
Johnson syndrome (SJS) or urticarial eruptions.2  
  
 **Evidence-Based Guidelines for Contact Dermatitis  
  
** Fonacier et al provided an updated practice parameter for contact
dermatitis. These evidence-based guidelines signify that patch testing (PT) is
the gold standard to confirm the diagnosis in individuals suspected of
allergic contact dermatitis (ACD). The consideration of ACD is recommended in
the differential diagnosis of individuals with chronic eczematous or
noneczematous dermatitis. Patch testing for patients with the following
conditions/situations is recommended: 1) hand dermatitis; 2) generalized and
anatomically localized skin eruptions (such as the hands, face, eyelids); 3)
facial rash involving the periorbital areas (e.g., eyelids); 4) lip dermatitis
(cheilitis) and perioral dermatitis; 5) dermatitis that involves the scalp and
neck; 6) acute or chronic hand eczema; 7) axillary dermatitis; 8) anogenital
dermatitis; 9) a generalized ACD rash from systemic exposure (e.g., ingestion,
infusion, or transcutaneous exposure) of a drug, chemical, or food to which
the patient previously experienced ACD; 10) chronic dermatitis involving the
lower extremities, feet and/or soles; 11) preoperative patch testing for metal
sensitization in patients with a significant history of metal allergy; and 12)
in patients with joint replacement failure after infection and biomechanical
causes have been excluded.3  
  
Currently, there are no guidelines or recommendations for symptomatic patients
with positive PT to metals or bone cement components.3 Therefore, a
determination concerning an implant revision after a positive PT test must be
made following a conversation between the patient and their healthcare team.
Furthermore, in addition to the probability of metal sensitization as a
possible cause of joint replacement failure, reports also show implant failure
associated with bone cement or its components including benzoyl peroxide,
hydroquinone, methyl methacrylate, and n-dimethyl para-toluidine.  
  
 **Tests Not Recommended for Hypersensitivity to Contact Allergens  
  
** In vitro tests are available for delayed hypersensitivity to contact
allergens (i.e., metals and bone cement). However, routine use of such assays
is not currently recommended as their sensitivity and specificity for
diagnosing ACD has not been determined and should be considered
investigational.3  
  
 **Evidence-Based Guidelines for Atopic Dermatitis  
  
** Schneider et al provided an evidenced-based, updated practice parameter for
atopic dermatitis (AD). These evidence-based guidelines indicate that atopic
dermatitis (AD) is often the first manifestation of allergic disease. Most
patients with AD will also have another atopic disorder, such as allergic
rhinitis, asthma, or food allergy. Pruritus and chronic or relapsing
eczematous lesions with typical morphology and distribution in patients with a
history of atopy are essential for diagnosis. In older children and adults,
the skin lesions often involve lichenification (thick, leathery skin, usually
the result of constant scratching and rubbing) and are usually localized to
the flexural folds of the extremities. Factors that can exacerbate symptoms in
patients with AD include temperature, humidity, irritants, infections, food,
inhalant and contact allergens, and emotional stress.4  
  
The diagnosis of AD is based on its clinical presentation rather than the
results of diagnostic testing. Potential causes of AD can be verified by
percutaneous skin tests or in vitro tests for specific IgE antibodies and in
some situations by using patch tests that can produce immediate or delayed
reactions to protein allergens. To establish the significance of specific food
ingestion to symptoms, double-blind food challenges are frequently needed. It
has been established that most patients with AD have increased serum IgE
levels that correlate with the degree of disease severity.4 Management of AD
involves a combination of trigger avoidance, measures to restore skin barrier
function, and anti-inflammatory medication.  
  
 **IgE Testing  
  
** Hamilton et al provided a clinical management review to examine the role
that IgE antibody measurements play in the diagnostic algorithm when
considering the pretest likelihood of disease on the basis of the patient's
clinical history. In this regard, the choice of specific allergen
specificities for testing should be guided by a comprehensive physical exam
that includes objective symptoms to select appropriate testing.  
  
In situations in which a high pretest probability has been determined,
confirmation of sensitization is frequently conducted by IgE antibody testing
due to the possible risk of life-threatening anaphylaxis and/or the
possibility of starting a course of immunotherapy.5 Verification of
sensitization may also encourage the patient to avoid situations for improved
quality of life and provide a baseline for future monitoring of IgE antibody
levels.  
  
The multiallergen screen is recognized as a serological test with the highest
negative predictive value for ruling out allergic sensitization. The
multiallergen screen is a single test that detects IgE antibody to a balanced
mixture of extracted aeroallergens (n =~10) including selections of tree,
grass, and weed pollens, molds, dust mites, pet epidermals, but not foods,
drugs, or venoms. These specific aeroallergen specificities have been chosen
for inclusion on the multiallergosorbent following research to distinguish the
group of aeroallergens that principally contributes to sensitization in
individuals in North America with allergic asthma and rhinitis symptoms. This
is considered a screening assay, and does not identify the precise allergen
specificity or the quantitative level of IgE antibody to which the patient is
sensitized.5 Also, the allergen specificities are highly targeted and
consequently they will not detect sensitization (IgE antibody) to less common
aeroallergens and food allergens.  
  
A quantitative singleplex IgE antibody assay assessment can be beneficial in
situations in which there is a moderate pretest likelihood of aeroallergen-
related allergic disease and the suspected allergen can be distinguished from
the patient's history.5 The age of the individual is considered in selecting
the specific IgE antibody assay used to determine sensitization (skin test or
serology). Serological assays are typically used for children possibly because
pediatricians seldom conduct skin testing and serology can decrease the fear
of potential risk of adverse events after allergen administration. While skin
tests are performed more frequently for adults.  
  
The intradermal skin test is the diagnostic test of choice for assessment in
patients with a potential Hymenoptera venom allergy.5 This test is recommended
regardless of the level of pretest probability for individuals who do not
qualify for skin testing due to dermatographism or antihistamine premedication
or if there is a suspected false-negative skin test result due to a recent
sting reaction. Also, in situations in which the pretest probability of
Hymenoptera venom allergy is strong and the skin test result is negative,
serological detection of IgE antibodies is recommended for vespid, wasp,
honeybee, bumblebee, and fire ant venoms.  
  
A World Allergy Organization survey reported that the most frequently tested
drugs for IgE antibody-mediated reactions using serology assays were the
penicillins (93.7%; beta-lactam antibiotics), cephalosporins (61.9%), general
anesthetic agents (36.5%), and nonsteroidal anti-inflammatory drugs.
Infrequently tested drug specificities included platinum-based
chemotherapeutic agents, quinine, and sulfamides. However, evidenced-based
guidelines indicate that intradermal skin testing is currently the diagnostic
test of choice for the assessment in individuals for sensitization to these
drugs. Studies of penicilloyl-specific IgE antibody analysis have documented a
high diagnostic specificity (97%-100%) but low diagnostic sensitivity
(29%-68%) of clinically used tests. Consequently, when a serological IgE
antipenicilloyl measurement is positive, it is highly predictive of penicillin
allergy when in agreement with the patient's medical history.5 However, a
negative test (absence of IgE antibody) result does not rule out penicillin
allergy.  
  
IgE antibody serology is frequently used in pediatrics for the detection of
sensitization to foods. In this regard, molecular allergen tests have been
used in the assessment of food allergies for the recognition of several
defined allergenic protein families. The five chief food related allergen
families include the pathogenesis-related proteins (PR10, Bet v 1 homologue);
the nonspecific lipid transfer proteins, which are present in tree pollen,
fruits, nuts, vegetables, and legumes; the parvalbumins in fish; tropomyosins
in crustaceans; and possibly most important, the storage proteins in seeds and
nuts. The most commonly used application of molecular allergen (component)
resolved diagnostics has been the testing of IgE antibodies to five peanut
allergen molecules. However, panel testing is not without issues. For
instance, when the outcome of panel testing is positive (clinically irrelevant
positive IgE antibody response) for a food that has been safely consumed by
the individual with no obvious symptoms, the result is a clinical false-
positive result. Therefore, a comprehensive history is imperative to guide the
appropriate selection of allergen in testing for IgE antibody to confirm
allergic sensitization.5  
  
Currently, individual single allergenic molecules on a singleplex autoanalyzer
such as the ImmunoCAP or Immulite are most frequently used.5 Also, literature
indicates that the use of extracts in IgE antibody assays will remain the
principal source of allergen used in serological IgE antibody assay
allergosorbents due to their comprehensive nature.  
  
The multiplex microarray chip is an impressive technology that detects IgE
antibody to a broad spectrum of clinically relevant allergenic molecules using
a small quantity of serum. However, using this type of panel testing
encourages abuse by providing measurements of unwanted or unneeded IgE
antibody specificities that are not indicated by the patient's clinical
history. Also, this chip-based microarray tends to be less quantitative and
potentially less analytically sensitive than singleplex autoanalyzers.  
  
 **Food Allergy Testing  
  
** Kattan et al performed a review of evidenced-based literature to assess
current testing methods used to diagnose food allergy and methods under study
that show potential to diagnose food allergy. In this regard, the National
Institute of Allergy and Infectious Diseases-sponsored expert panel published
recommendations (2010) on the diagnosis of food allergy, endorsing use of the
medical history and physical examination, elimination diets, skin prick
testing (SPT), serum food specific IgE (sIgE) levels, and oral food challenges
(OFCs). The OFC is recommended when the diagnosis is uncertain.6  
  
Skin prick testing (SPT) is particularly sensitive and has a negative
predictive value of greater than 90% and is frequently able to quickly rule
out an IgE-mediated food allergy.6 Also, SPT can assist to verify a food
allergy when positive results correlate with the patient's recent medical
history of an acute allergic reaction to the tested food. In addition, studies
suggest that the likelihood of a reaction to the tested food increases with
increasing SPT wheal size. While skin tests offer quick results and are
considered highly sensitive, they require the patient to be off antihistamines
and to have an area of skin free of rash for testing. Furthermore, studies
show that predictive values may differ according to various foods, ages, and
populations, and that skin test results cannot be used as an isolated
diagnostic tool without a thorough history and possibly other testing.

Serum immunoassays that measure food-specific IgE antibodies are sometimes
used in the assessment of IgE-medicated food allergy with higher
concentrations of food sIgE being associated with a higher risk of true food
allergy. However, as with skin testing, predictive values may differ among
populations for various reasons. Also, sIgE levels do not always correlate
with reaction severity.6 Therefore, the routine use of measuring total serum
IgE should not be used to make a diagnosis of food allergy.11  
  
An OFC may be performed to determine if a patient is sensitized to an allergen
or is clinically reactive to the allergen. An OFC is a physician-supervised
oral provocation procedure conducted in a hospital or outpatient office, where
a patient ingests gradually increasing amounts of a food under medical
supervision until an age-appropriate serving is reached or the feeding is
terminated because of symptoms. Prior to conducting an OFC, the patient's
medical history, age, past adverse food reactions, SPT, and serum food
allergen-specific IgE results must be considered. The OFC may be conducted as
an open feeding or as a single blind, or double-blind, placebo-controlled food
challenge (DBPCFC).11 Currently, the DBPCFC is considered the gold standard
test for diagnosing food allergy; however, due to the time and labor intensive
nature of this approach it is typically only performed in research studies and
select cases in clinical practice.6  
  
 **Tests Under Investigation that Require Further Evaluation  
  
** In recent years, several testing modalities have been under investigation
that may improve food allergy diagnostics, including component-resolved
diagnostics (CRD), epitope binding, T-cell responses, basophil activation
studies, T-cell proliferation assays, and measurement of platelet activating
factor (PAF).6  
  
The allergen CRD test measures IgE to individual allergen proteins. This
method has been used on a variety of food allergens, including peanuts,
hazelnuts, eggs, milk, wheat, soy, fruits, cow's milk, hen's eggs, and shrimp.
However, the results from these studies have differed, possibly due to varying
study populations and methods, manners of sensitization, environmental
exposures, and degree of sensitization to various food components.
Consequently, CRD is not considered ready to be used solely in ruling out a
food allergy on its own.6  
  
Similar to immune responses against various proteins within a food, the
location (epitope) and strength of binding (affinity) of IgE antibodies within
a protein can also have clinical implications. Having IgE antibodies directed
to a greater number of epitopes, or to epitopes that are not easily destroyed
by denaturation and digestion (e.g., sequential or linear epitopes rather than
ones dependent upon folding and conformation) may be linked with clinical
allergy. Studies for epitope binding testing have been performed in relation
to cow's milk, shrimp, eggs, and wheat allergies. Studies for epitope binding
assays continue to evolve in diagnosing food allergy.6  
  
Studies have recently investigated T cell responses to food allergens and
reported that assessment of allergen-specific T-cell responses may be
beneficial in differentiating sensitization from clinical reactivity. These
studies have primarily focused on peanut allergens. Additional studies are
needed to verify the efficacy of T-cell proliferative responses in the
diagnosis of food allergy.6  
  
A few studies have reported that markers of basophil activation, particularly
upregulation of cell-surface molecules such as CD63 and CD203c using flow
cytometry, may be useful in the diagnosis of food allergy. Studies have
focused mainly on allergies related to eggs and cow's milk. Additional studies
are needed to clarify the effectiveness of basophil activation in the
diagnosis of food allergy.6  
  
Santos et al12 indicates that the basophil activation test (BAT) is an
emerging diagnostic test for food allergy. The BAT is a flow cytometry-based
assay in which the expression of activation markers is calculated on the
surface of basophils after stimulation with allergen. A positive BAT is
described as an in vitro surrogate of an acute allergic reaction in vivo.
However, there is a large degree of inconsistency in the basophil response to
allergens between patients. Additional issues in transforming the BAT from a
research technique to a diagnostic test for a broader application is
associated with standardization of the assay and its reproducibility as well
as the cost-effectiveness of using this method for patients with suspected
food allergy. Additional studies are needed to define and validate diagnostic
cut-off values for the BAT.  
  
Currently, there's no established method to accurately predict the severity of
an allergic reaction. In this regard, studies have assessed serum platelet
activating factor (PAF) and PAF acetylhydrolase (PAF-AH) levels as potential
markers of allergy severity. The PAF is a pro-inflammatory phospholipid
synthesized and secreted by mast cells, basophils, monocytes, and macrophages.
It has a variety of biological activities, including platelet activation,
airway constriction, hypotension, and vascular permeation. Circulating levels
of PAF are somewhat controlled by the activity of PAF-AH, an enzyme that
controls activity by cleaving PAF, leaving it inactive. Additional studies are
needed to determine the role of PAF and its associated catabolic enzymes in
the prediction and validation of anaphylaxis in regard to food allergy.6  
  
 **Unproven/Not Recommended Tests for the Diagnosis of Food Allergy  
  
** Several tests have been investigated and a determination has been made that
these tests are unproven/not recommended in the diagnosis of food allergy: a)
intradermal testing-the intradermal injection of allergens is too sensitive
and involves a greater risk of adverse reactions than SPT; b) per the National
Institute of Allergy and Infectious Diseases expert guidelines published in
2010, atopy patch testing (APT) should not be utilized in the assessment of
non-contact food allergy as the sensitivity and specificity fluctuates between
studies and there is no agreement on the suitable reagents or methods to use,
or on how to interpret these tests; c) a measurement of the total serum IgE
level is not recommended for routine use as studies have shown no benefit when
comparing the predictive value of the ratio of serum food specific IgE (sIgE)
used in a double-blind, placebo-controlled food challenge (DBPCFC) to a
measurement of the total IgE for the diagnosis of food allergy; and d) other
non-standardized tests which are not recommended in the diagnosis of food
allergy include facial thermography, gastric juice analysis, applied
kinesiology, allergen-specific IgG4 levels, hair analysis, and electrodermal
testing.6,11

Allergy and hypersensitivity conditions are widespread and may be caused by a
variety of offending agents; pollen, molds, mites, dust, feathers, animal fur
or dander, stinging insect venoms, foods, drugs, etc. Allergy is a form of
exaggerated sensitivity or hypersensitivity to a substance that is either
inhaled, ingested, injected, or comes in contact with the skin or eye. The
term allergy is used to describe situations where hypersensitivity results
from heightened or altered reactivity of the immune system in response to
external substances. Allergic or hypersensitivity disorders may be manifested
by generalized systemic reactions as well as localized reactions in any part
of the body. The reactions may be acute, subacute, or chronic, immediate or
delayed with varying severity and usually have a considerable effect on the
quality of life for the individual affected.  
  
Allergy testing is performed to determine a patient's immunologic sensitivity
or reaction to particular allergens for the purpose of identifying the cause
of the allergic state and is based on findings during a complete medical and
immunologic history and appropriate physical exam. There are several different
types of diagnostic modalities available for allergy testing. Positive and
negative controls should be performed with all tests and tests used should
have proven efficacy as demonstrated through scientifically valid medical
studies published in peer reviewed journals. The number of skin tests and the
allergens chosen for skin testing should be based on the patient's age,
history, environment and living conditions (e.g., region of the country),
occupation, and activities. In this regard, regular use of a significant
number of skin tests or routine annual tests without a distinct clinical
indication are clearly not necessary.1,2,3,4  
  
The value of in vivo allergy skin tests, which include skin prick tests,
intracutaneous (intradermal) tests, and skin patch tests, is well established
as safe diagnostic tools. These tests have been used for more than 100 years
and are recognized worldwide. These tests are the preferred techniques for
IgE-mediated hypersensitivity. Concerning this, evidence-based guidelines
recommend percutaneous testing (scratch, puncture, prick), immediate type
reaction, to evaluate IgE mediated hypersensitivity to inhalants, foods,
Hymenoptera (stinging insects), chemicals, and specific drugs (e.g.,
penicillins and macromolecular agents). Also, evidence-based guidelines
recommend intracutaneous (intradermal) testing, immediate type reaction to
evaluate IgE mediated hypersensitivity to inhalants, Hymenoptera venoms (e.g.,
bee venom), drugs (e.g., penicillin, insulin, heparin, muscle relaxants)
and/or chemicals.  
  
Per evidence-based guidelines, the epicutaneous patch test is considered to be
the definitive diagnostic method for the diagnosis of allergic contact
dermatitis (ACD), which is a unique form of delayed hypersensitivity. Direct
irritants may cause irritant contact dermatitis (ICD), which often is
indistinguishable from ACD; however, the clinical presentation of ICD is more
limited to the skin site directly in contact with the offending agent(s) with
little or no extension beyond the site of contact.  
  
Evidence-based guidelines recommend patch tests for patients with chronic,
pruritic, eczematous, or lichenified dermatitis if underlying or secondary ACD
is speculated. Patch tests should be used for patients based on a clear-cut
clinical inference of contact allergy, and tested with the chemicals pertinent
to the issue; these conditions satisfy the prerequisites of high pretest
probability. Evidence-based guidelines support the use of allergy patch
testing to diagnose allergic contact dermatitis after the following exposures:
dermatitis due to detergents, oils and greases, solvents, drugs and medicines
in contact with skin, other chemical products, food in contact with skin,
plants (except food), cosmetics, and metals (this is not an all-inclusive
list). Also, photo patch testing is recommended to evaluate unique allergies
resulting from photosensitization (e.g., photo-allergic contact dermatitis).
Additionally, photo testing is recommended to evaluate skin abnormalities
(e.g., itching, blisters, hives) resulting from exposure to sunlight.  
  
Evidence-based guidelines indicate intracutaneous (intradermal) testing,
delayed reaction **** tests are key in epidemiologic testing of susceptible
populations exposed to bacterial and fungal pathogens (e.g., tuberculin skin
test). The standardized purified protein derivative (PPD) antigen has a long
history for use as a predictor of active or latent tuberculosis infection.  
  
Intracutaneous (intradermal) dilutional testing (IDT) (also known as skin
endpoint titration [SET]) has an immediate type reaction and consists of
sequential and incremental dilutions of a single antigen. The endpoint is the
weakest dilution that produces a positive skin reaction and initiates
progressive increase in the diameter of the wheals with each stronger
dilution. Evidence-based guidelines indicate this type of testing is
beneficial for determining the starting dose for immunotherapy for individuals
with Hymenoptera venom sensitivity and significant aeroallergen sensitivity.  
  
Specific IgE immunoassays detect antigen-specific IgE antibodies in the
patient's serum. Testing must be based on a careful history/physical
examination which suggests IgE- mediated disease. Specific IgE immunoassays
are useful when testing for inhalant allergens (pollens, molds, dust mites,
animal dander), foods, insect stings, and other allergens such as drugs or
latex, when direct skin testing is impossible due to extensive dermatitis, or
in marked dermatographism. In this regard, evidence-based guidelines recommend
in-vitro allergen specific IgE testing under the following conditions: 1)
Direct skin testing is not possible due to extensive dermatitis,
dermographism, ichthyosis, generalized eczema, 2) For patients who cannot be
safely withdrawn from medications that interfere with skin testing (such as
long-acting antihistamines, tricyclic antidepressants), 3) Testing of
uncooperative patients with mental or physical impairments, 4) The evaluation
of cross-reactivity between insect venoms (e.g., fire ant, bee, wasp, yellow
jacket, hornet), 5) As adjunctive laboratory testing for disease activity of
allergic bronchopulmonary Aspergillosis and certain parasitic diseases, and 6)
When clinical history suggests an unusually greater risk of anaphylaxis from
skin testing than usual (e.g., when a patient has a history of a previous
systemic reaction to skin testing or when an unusual allergen is not available
as a licensed skin test extract).  
  
Measurements of total IgE serum levels are not suitable in most general
allergy testing, which is performed to determine a patient's immunologic
sensitivity or reaction to particular allergens for the purpose of identifying
the cause of the allergic state. In this regard, evidence-based guidelines
recommend total IgE diagnostic evaluations for patients with the following
conditions: 1) Allergic bronchopulmonary Aspergillosis (ABPA), 2) Select
immunodeficiency syndromes, such as hyper-IgE, 3) Eczematous dermatitis, 4)
Recurrent pyogenic infections, and 5) To evaluate the appropriateness of a
patient for omalizumab therapy and to establish the initial dose.  
  
Organ challenge tests (also referred to as controlled challenges or supervised
exposure tests) are considered the gold standard for assessing whether
clinical sensitivity is present. In challenge testing, a suspected allergen in
a clinically relevant exposure is administered in an attempt to reproduce
symptoms. When tests for IgE-mediated immunity are ambiguous, organ challenge
testing is used to determine if clinical sensitivity exists. Organ challenge
test material may be applied to the mucosae of the conjunctivae, nares, GI
tract, or bronchi. All organ challenge tests should be preceded by a control
test with diluent and, if possible, the procedure should be performed on a
double blind or at least single, blind basis. Considerable experience with
these methods is required for proper interpretation and analysis.  
  
Specific organ challenge tests may facilitate or support clinical diagnosis
under certain conditions: 1) investigation of potential "new" allergens, 2)
validation of diagnosis when the history is suggestive but skin and/or in
vitro test findings are negative, 3) verifying food allergy, and 4) monitoring
of therapy, either pharmacologic or immunologic. In general, these tests
require cooperative patients with respect to both age and mental status. The
site of specific organ challenge is history dependent (i.e., conjunctival,
nasal, bronchial, or skin) (e.g., patch tests for ACD; supervised insect
stings).  
  
Evidenced-based guidelines recommend the following for challenge tests: 1)
Ophthalmic mucous membrane challenge tests and direct nasal mucous membrane
challenge tests provided levels of allergic mediators (such as histamine and
tryptase) are measured and a placebo control is performed. This test is
usually performed in the office setting with the provider present to observe
objective measurement of reactions which might include redness of the eyes,
tearing and sneezing. 2) Inhalation bronchial challenge tests to evaluate new
allergens and to substantiate the role of allergens in patients with
significant symptoms. This test should be performed as a dose-response assay
wherein provocation concentration thresholds can be determined on the basis of
allergen concentration required to cause a significant decrease in pulmonary
function measurements. 3) Challenge ingestion food testing for food allergy
dermatitis, anaphylactic shock due to an adverse food reaction, allergy to
medicinal agents, and allergy to foods.  
  
The quality of evidence in the literature is insufficient to support the
diagnostic validity regarding allergy testing for the following procedures: 1)
Allergen specific IgE qualitative, multiallergen screen and multiplex
microarray chip for IgE, 2) Provocation-neutralization, 3) Electrodermal
testing, 4) Applied kinesiology, 5) Iridology, 6) Hair analysis, 7) Lymphocyte
proliferation test, 8) Basophil activation tests (BAT) to diagnose food or
drug allergies, 9) T-cell proliferation assay, 10) Facial thermography, 11)
Breath condensate analysis, and 12) In vitro tests for delayed
hypersensitivity to contact allergens (e.g., metals and bone cement). In this
regard, the following tests are not considered appropriate in testing for food
allergy: 1) Food specific IgG, IgG4, and IgG/IgG4 antibody tests, 2) Atopy
patch tests to diagnose non-contact food allergy, 3) Intracutaneous
(intradermal) testing to diagnose food allergy, 4) Component-resolved
diagnostics (CRD) to diagnose food allergy, 5) Epitope binding testing to
diagnose food allergy, 6) T-cell responses to food allergens, 7) Platelet
activating factor (PAF) to diagnose food allergy, 8) Gastric juice analysis,
9) Mediator release assay (LEAP diet), and 10) Immunoglobulin G (IgG) testing.
Further research is needed to clarify the utility and efficacy of these
procedures for allergy testing.