What is h on an allergy test

Allergy Diagnostic Testing

Updated: July
Originally posted: November

Dr. John Oppenheimer
Director of Clinical Research,
Pulmonary and Allergy Associates
Denville, NJ, USA

Prof. Stephen Durham
Department Allergy and Respiratory Medicine,
Imperial College, London, UK

Dr. Harold Nelson
National Jewish Medical and Research Center
Denver, CO, USA

Dr. Ole D. Wolthers
Clinical Institute, Health, Aarhus University
Asthma and Allergy Clinic, Children’s Clinic Randers
Randers, Denmark

Credit for the first skin testing goes to Charles H.

Blackley, who in abraded a quarter-inch area of his skin with a lancet, applied grass pollen on a piece of wet lint, and covered the scarified area with an occlusive bandage. This resulted in intense itching and a extremely large cutaneous response.

Percutaneous skin test ranks first in confirming the presence of IgE-mediated sensitization in the allergist's office. This should come as no surprise, as it has numerous advantages. Skin testing is minimally invasive, and when it is performed correctly it has excellent reproducibility, is easily quantified, and allows the evaluation of multiple allergens at one session.

The results correlates within vivochallenges.in vitrotesting is an alternative, generally a back up tool for diagnosing allergic illness. Skin testing alone or in combination within vitrotesting is relied upon for the evaluation of allergic rhinitis, asthma, eczema, food allergy, insect sting allergy, drug allergy (especially beta-lactam and local anesthetic allergy), occupational disease and anaphylaxis. However, the reliability of these tests depends on a number of factors. In the case of skin testing, it is significant that the technician performing the skin tests and the clinician ordering or interpreting these tests are aware of the advantages and pitfalls of the type of skin testing, the device used, the location of the tests on the body, the extracts used and the potential for suppression of the skin response by medications used to treat allergies or depression.

These issues own been reviewed elsewhere in greater detail.1Forin vitrotesting, it is imperative that quality standards be met. These include calibration of the assay, training and experience of the technician and the use of quality allergens in the solid phase.2As in any diagnostic test, it is of paramount importance that the clinician consider the positive and negative predictive worth of the tests performed.

These tests should always be considered as adjuncts to the medical history and physical exam in formulating the diagnosis in each individual case, bearing in mind that both test types can yield untrue positive or, less commonly, untrue negative results.

Skin Testing Devices

Whereas intradermal skin tests are always performed using a hypodermic syringe and needle, percutaneous tests may be performed with a variety of devices. Comparisons of percutaneous devices own been reviewed elsewhere in greater detail.5 Some devices own a single stylus with one or several points, whereas others own multiple heads and permit up to 10 tests to be accomplished with one application.

The degree of skin trauma created by these devices for percutaneous testing varies and so may result in differences in the size of positive reactions, and the likelihood of producing a reaction at the site of the negative control. Thus, they require diverse criteria for what constitutes a positive reaction (see Table 1).

Table 1. Wheal size indicating a positive response to skin tests using various devices.a

a Positive response is defined as a wheal greater than 99% of wheals generated by the istration of saline to the subject's back by the same operator.

Adapted from ref.
b HS = Hollister Steir, Greer = Greer laboratories, Lincoln = Lincoln Diagnostics, ALK = ALK America, ALO = Labs of Ohio

Comparing in vivo to in vitro Testing:

The preponderance of comparative studies protest skin tests to be more sensitive thanin vitrotests. However, the majority of these studies were performed with earlier generationin vitrotests. The newerin vitrotests produce higher test sensitivity and specificity13by using a matrix capsule containing antigen bound to a hydrophilic carrier to produce enhanced specific IgE binding with lower nonspecific IgE binding.2Levels of specific IgE measured by diverse commercial assays are not equivalent, as each assay differs in the composition of allergen reagents, methods of measurement and standardization procedures.

The advantages ofin vitrotesting are largely related to use in patients with extensive dermatoses (e.g., atopic dermatitis), resulting in an inability to act out tests on unaffected skin, or in patients who are unable to discontinue medicines that block the histamine response, i.e., antihistamines or tricyclic antidepressants.

The disadvantages ofin vitrotesting include a potential decrease in sensitivity, added cost, and lack of immediate and visible response. Performing bothin vitroandin vivotests may yield improved sensitivity.15

Proficiency Testing

Like every other laboratory tests, it is imperative that quality assurance standards be met to ensure that the testing technique produces precise results. To confirm such standards, it is recommended that every technicians performing skin testing undergo evaluation of their technique.11 Certainly, it would be comforting to know that skin test technicians achieve some degree of consistency in skin test performance.

Although there are no formal standards available for skin test proficiency testing, several publications propose some possible criteria. European publications propose a coefficient of variation of less than 20% following repeated skin test control applications, and the Childhood Asthma Management Program study requires that a coefficient of variation of less than 30% be attained with repeated testing with histamine and consistently negative reactions to saline to confirm proficiency in skin testing.

The National Committee for Clinical Laboratory Standards recommends quality control procedures for daily performance ofin vitroallergy testing, with a recommended coefficient of variation of less than or equal to 15%.2Even with such calibration and the increased use of automation,in vitroassays still own flaws.

Williams and colleagues examined the performance of 6 large commercial laboratories on tests of blinded samples of the same sera, both diluted and non-diluted.12They found that only two of the laboratories demonstrated acceptable precision and accuracy.

Methods of Skin Testing

Skin testing may be performed using either the prick/puncture (percutaneous) or intradermal (intracutaneous) technique. Intradermal testing is far more sensitive than prick/puncture testing, which means that it requires about fold less concentrated extracts than those used for prick/puncture testing to achieve a similar response.

Although direct comparisons indicate that intradermal testing is more reproducible than percutaneous testing, there are numerous factors that favor the routine use of percutaneous allergy tests. These include economy of time, patient comfort and patient safety. Percutaneous testing allows the use of extract in 50% glycerin, which provides greater extract stability. Intradermal testing cannot use this diluent, as it may incite a false-positive irritant response. However, the most significant consideration is that results of percutaneous testing correlate better with clinical allergy. The higher sensitivity of intradermal skin tests does not generally offer added benefit, since the results of skin prick tests performed with potent extracts are of sufficient sensitivity for use in clinical practice.

Two studies reinforce this concept.3,4Each study compared intradermal with skin prick tests by correlating their results with patients' responses to natural exposure to allergen as well as by allergen challenge testing.

In the first study, three groups of patients with seasonal rhinitis were compared. These subjects were classified into 3 groups based on their degree of sensitization to Timothy grass pollen. They were either skin prick test positive, only intradermal test positive, or were negative by both skin prick and intradermal testing. Both nasal allergen provocation testing and symptom scores during the pollen season correlated best with a positive skin prick test (>60% of subjects with positive skin prick tests had symptoms on allergen exposure). The frequency of positive nasal provocation (11%) and symptom scores (21%) in subjects with positive intradermal testing alone were not diverse from subjects who were skin prick test and intradermal test negative.

The authors conclude that under the conditions of this study, the presence of a positive intradermal skin test response to Timothy grass in the presence of a negative skin prick test did not indicate the presence of clinically significant sensitivity to this grass.

In the second study, patients were challenged with cat exposure for one hour.4Both positive skin prick tests andin vitrotests to cat were highly predictive of the development of symptoms upon allergen exposure in the cat challenge room.4Subjects with a negative skin prick test were just as likely to own a positive challenge result if they had a negative intradermal skin test (31%) as subjects with a positive intradermal skin test (24%).

The authors conclude that, at least with regard to cat allergy, major therapeutic decisions, such as environmental control or immunotherapy, should never be based on a positive intradermal skin test alone.

Both of these studies were performed in adults and both relied upon skin testing with relatively potent allergens (Timothy grass and cat). The clinical applicability of these results to less potent allergens, such as dog, or to younger patients (especially infants) is a matter of clinical judgment, because no specific evidence is available for these groups.

Recording and Scoring of Skin Test Results

Skin test results are often reported by clinicians in semi-quantitative terms.

What is h on an allergy test

They may record results only as positive or negative, or express them on a 0 to 4+ scale without any indication of the size of the reactions that these numbers represent. However, allergy patients may own to change their allergist for numerous reasons, and it is significant that records of prior allergy testing be interpretable by the receiving physician. At the extremely least, a record of skin testing should contain sufficient information to permit another physician to interpret the results and avoid the need to repeat skin testing.

Standardized forms own been developed and are available through the American Academy of Allergy Asthma and Immunology website (for an exampleAAAAI's Skin Test and Immunotherapy Forms).

Although the area of the wheal and erythema are the most precise measurements, the longest diameter or two diameters at correct angles to each other correlate with area (r > ).8The importance of performing such measurements is exemplified by the study of McCann and Ownby in which allergists were asked to interpret photographs of skin test reactions.

The scoring and interpretation of the skin test results varied greatly.9The authors of this study reinforce the thought that the most dependable method of reporting a skin test reaction is to measure and record the reaction size.

What is h on an allergy test

At the extremely minimum, skin test results should be graded 0 to 4+, and the criteria for each grade of reaction clearly stated along with the skin test results.

Various investigators propose diverse criteria for interpreting a skin test response as positive. To assess the reliability of diverse means of interpreting the results of skin prick testing, Vanto and colleagues studied a group of children sensitive to dogs.10A determination of sensitivity to dog was based on a composite score derived from the history, RAST, and bronchial or conjunctival allergen challenges. Although in this study the overall efficacy was greatest with the histamine reference method (in which the allergy skin test response is compared to a histamine control, with a positive response considered to be a response at least as grand as that of the histamine control), maximal sensitivity was achieved when using a cutoff of a wheal 3 mm.

If a clinician wishes to maximize sensitivity, the latter criterion would be most useful; however, adjustment must be made for the device used. Therefore, the criteria for a positive test should be: 1) the larger of a 3 mm mean wheal diameter or 2) equal to or greater than the 99th percentile reaction with that device at negative control sites (see Table 1).

"Gold Standard" Confirmation of Allergy

Although there are challenge protocols available in the research setting to confirm allergic rhinitis and asthma, the standard tool available to the clinician is a careful history and physical exam.

Skin testing correlates with results of nasal challenge and with bronchial challenges when allowance is made for nonspecific airway responsiveness.

When evaluating potential food allergy, the clinical history is the initial screening, with skin testing orin vitrotests used to corroborate the history. Oral food challenges represent the "gold standard" for the confirmation of food allergy. These can be performed as open challenges or in a single- or double-blind fashion.

Food challenges are not without risk and thus require that appropriate supportive care be available. Several studies protest that the magnitude of thein vitrotest or the skin test reaction size may be useful in determining the utility of performing a food challenge.16,17One additional advantage of skin testing for food allergies is the ability to act out skin testing with the unused food, "prick-prick" test.

Several reports protest that unused foods provide greater sensitivity for certain foods.18, 19This is particularly significant in assessing allergy to fruit; however, useful results own also been demonstrated for other foods, including seafood, peanut, tree nuts, vegetables, milk and eggs.

Molecular-based allergy diagnostic

It is hoped that the predictive worth of allergy diagnostic testing can be improved with the use of molecular-based allergy diagnostics. This methodology is used to map the allergen sensitization of a patient at the epitope level, using purified natural or recombinant allergenic molecules (components) 20,21Molecular-based allergy diagnostics is available either using singleplex platforms which utilize panels of single allergens together with the corresponding allergen extract or can also be performed using multiplex technology to measure serum IgE antibodies against multiple allergens in a single assay The technique allows for the testing of a large number of allergens using a little quantity of serum (as little as 20 µL; conventional specific IgE tests use 50 µL per allergen).

Currently one multiplex platform is available on the market (the Immuno-Solid phase Allergen Chip (ISAC) platform) 23,24 Though a higher degree of variability in low IgE levels own been found, ISAC results own been similar to those obtained from singleplex platforms 25,26 At low serum IgE levels singleplex platforms may be more sensitive than ISAC and thus this should be considered when interpreting testing using the ISAC. Although more than epitopes own been identified, the clinical relevance of numerous of these is not known.

Evidence, however, has been provided for use of several epitopes in clinical practice, such as peanut.

In numerous cases of peanut sensitization detected solely by prick skin testing or by whole allergen specific IgE it is hard to decide whether true allergy exists versus sensitization with no clinical symptoms as a manifestation of cross reactivity to pollen. In such cases there is excellent evidence for analyzing IgE to the epitopes Ara h 2 (genuine IgE mediated allergy) and Ara h 8 (Bet v 1 (birch pollen) homologue; a marker of cross-reactivity) 27,28 IgE sensitization to Ara h 2 often correlates with positive IgE against Ara h 1 and Ara h 3.

If there were IgE antibodies in serum to Ara h 2 and/or Ara h 1/Ara h 3, more than 95% of patients own reported symptoms when ingesting peanuts 29 If there was IgE only to Ara h 2 and not to Ara h 1, 3 or 8, 87% reported symptoms. Whether there may be a threshold level of serum IgE to Ara h 2 above which peanut allergy may be diagnosed with a sufficient sensitivity and specificity which may forsake the need for oral provocation remains to be prospectively evaluated 30If there was only IgE to Ara h 8 and not to Ara h 1, 2 or 3 only around 18% of patients own reported symptoms, and these were generally extremely mild 29 More serious symptoms cannot be ruled out, however, in Ara h 8 sensitized patients.

In the event of itching and swelling in the mouth and throat both Ara h 2 and Ara h 8 should be sure, and, at the same time, assessment of sensitization to birch pollen should be made by analyzing IgE to Bet v 1.

Bet v 1, PR protein is the major allergen in birch pollen and approximately 95% of birch pollen sensitized patients own specific IgE antibodies to Bet v 1 31 Specific IgE to Bet v 1 may also be found in patients with primary sensitization to other tree pollens (e.g. elm: Aln g 1; hazel pollen: Cor a 1) as well as to foods (hazelnut, apple, soy, peanut (Ara h 8), kiwi, celery).

IgE antibodies to Bet v 2 (profilin) and/or Bet v 4 (calcium-binding protein) are markers of cross-reactivity 31 and as opposed to Bet v 1 if increased are indicators that the patient is primarily sensitized to another pollen. IgE to Bet v 2 is a marker of cross-reactivity with numerous pollens and vegetable foods 32 while IgE to Bet v 4 is a marker of cross-reactivity only with other pollen allergens 33

IgE antibodies to Phl p 1 and Phl p 5 are specific markers for sensitization to Phleum pratense (Timothy grass).

Phl p 7 (calcium-binding protein) and Phl p 12 (profilin) are markers of cross-reactivity with fruits and vegetables. Increased IgE to these components and not to Phl p 1 and/or Phl p 5 indicates primary sensitization to a diverse species of grass pollen than Phleum pratense 34 It has been suggested that if relevant symptoms are present in addition to elevated IgE Phl p 1 and p 5 levels immunotherapy with phleum pratense extract would likely be clinically effective because phleum pratense extracts contain mainly Phl p5 and p6 24,35

Molecular-based allergy diagnostics are also likely to be of utility when considering immunotherapy for dust mite allergy.

Der p 1 and Der p 2 are the most significant component markers for sensitization to home dust mites 36as more than % of patients allergic to home dust mites own IgE antibodies to these epitopes. Approximately 10% of patients allergic to home dust mites, however, own increased IgE levels to Der p 10 37 These patients will not benefit from specific immunotherapy since home mite extracts contain mainly Der p 1 and Der p 2 and variable or low amounts of Der p Whether molecular-based allergy diagnostics may increase the effect ratio of immunotherapy of Phleum pratense and houst dust mite allergic patients has not, however, been tested in prospectively planned trials.

Positive IgE to both bee and wasp venom is often due to cross-reactivity between cross-reactive carbohydrate-determining reagents (CCD) 38 shared in these two species.

In the frequently occurring clinical situation of an uncertain history and positive IgE to both allergens, determination of specific molecular epitopes may be of aid. An increase in both Api m 1 and Ves v 5 would indicate a true double sensitization and immunotherapy with both bee and wasp extracts would be indicated 38,39

Understanding the paucity of data, a recent consensus document concluded that molecular-based allergy diagnosis may be considered for investigation of 20

  1. Williams, PB ; Barnes, J; Szeinbach, S; Sullivan, T Analytic precision and accuracy of commercial immunoassays for specific IgE: Establishing a standard J Every Clin Immunol ;
  2. Valenta R, Hayek B, Seiberler S et al.

    Calcium-binding allergens: from plants to man. Int Arch Allergy Immunol ;

  3. Constantin C, Quirce S, Poorafshar M et al. Micro-arrayed wheat seed and grass pollen allergens for component-resolved diagnosis. Allergy ;
  4. Oppenheimer J, Nelson HS. Skin Testing. Ann Every Asthma Immunol. ;S
  5. Sastre J. Molecular diagnosis in allergy. Clin Exper Allergy ;40(10)
  6. Fernandes J, Reshef A, Patton L, Ayuso R, Reese G, Lehrer SB. Immunoglobulin E antibody reactivity to the major shrimp allergen, tropomysin, in unexposed Orthodox Jews.

    Clin Exp Allergy ;

  7. Sporik, R0, Hill DJ, Hosking, CS0 Specificity of allergen skin testing in predicting positive open food challenges to milk, egg and peanut in children. Clin and Exp Every ;
  8. Ortolani C, Ispano M., Pastorello EA.,. Ansaloni R, Magri GC Comparison of results of skin prick tests (with unused foods and commercial food extracts) and RAST in patients with oral allergy syndrome Jl Every Clin Immunol ;
  9. selected cases of suspected peanut allergy, birch pollen allergy and associated cross-reactivity (Ara h2, h8 (h1, h3) (Bet v1, v2, v4).
  10. Canonica GW, Ansetegui IJ, Pawankar R, et al.

    A WAO-ARIA-GA2LEN consensus document on molecular-based allergy diagnostics. WAOJ ;&

  11. MS Dykewicz, JK Lemmon, DL Keaney. Comparison of the Multi-Test II and Skintestor Omni allergy skin test devices. Ann Allergy Asthma Immunol ;
  12. Ownby DR. Computerized measurement of allergen-induced skin reactions. J Allergy Clin Immunol , ;
  13. Adkinson NF Jr. The radioallergosorbent test in limitations and refinements Jl Every Clin Immunol ;
  14. Nelson HS, Oppenheimer JJ, Buchmeier A, et al. An assessment of the role of intradermal skin testing in the diagnosis of clinically relevant allergy to timothy grass.

    J Allergy Clin Immunol ,

  15. Hiller R, Laffer S, Harwanegg C, Huber M, et al. Microarrayed molecules: diagnostic gatekeepers for allergy treatment. FASEB J ;
  16. Nicolaou N, Murray C, Belgrave D et al. Quantification of specific IgE to whole peanut extract and peanut components in prediction of peanut alergy. J Allergy Clin Immunol
  17. patients and triggering allergens for specific immunotherapy, specifically
    — grass, (Phl p1, p5, p12)
    — home dust mites, (Der p1, p2, p10)
    — hymenoptera venom (Api m1; Ves v5).
  18. Swoboda I, Twaroch T, Valenta R, Grote M. Tree pollen allergens. Clin Allergy Immunol ;
  19. Wood RA, Phipatanakul W, Hamilton RG, Eggleston PA.

    A comparison of skin prick tests, intradermal skin tests, and RASTs in the diagnosis of cat allergy. J Allergy Clin Immunol ,

  20. Yoon I-K, Martin BL, Carr WW. A comparison of two single-headed and two multi-headed allergen skin test devices. Allergy Asthma Proc ;
  21. Flinterman AE, van Hoffen E, den Hartog Jager CF et al. Children with peanut allergy recognize predominantly Ara h 2 and Ara h 6, which remains stable over time. Clin Exp Allergy ;
  22. Dreborg S. ed. Skin tests used in type I allergy testing Position paper. Allergy ;s
  23. Sampson H Update on food allergy Jl Every Clin Immunol ;
  24. McCann WA, Ownby, DR. The reproducibility of the allergy skin test scoring and interpretation by board-certified/board-eligible allergists.

    Ann Every Asthma Immunol ;

  25. Pittner G, Vrtala S, Thomas WR et al. Component-resolved diagnosis of house-dust mite allergy with purified natural and recombinant mite allergens. Clin Exp allergy ;
  26. Rosen JP, Selcow JE, Mendelson LM et al. Skin testing with natural foods in patients suspected of having food allergies: Is it a necessity? Jl Every Clin Immunol ;
  27. Meliol G, Bonifazi F, Bonni S, et al. The ImmunoCAP ISAC molecular allergologyappraoch in adult multi-sensitized Italian parents with respiratory symptoms. Clin Biochem ;
  28. Gadisseur R, Chapelle JP, Cavalier E: A new tool in the field of in-vitro diagnosis of allergy: preliminary results in the comparison of ImmunoCAP© with the ImmucoCAP© ISAC.

    Clin Chem Lab Med ;

  29. Turkeltaub P. Performance standards for allergen skin testing: An approach to proficiency testing in Skin Testing Dolen W (ed): Immunology and Allergy Clinics of North America Philadelphia, WB Saunders , p
  30. Yunginger, J. MD a; Ahlstedt, S; Eggleston, P. et al. Quantitative IgE antibody assays in allergic diseases JACI ;
  31. patients with insect allergy (Api m1; Ves v5).
  32. Oppenheimer J. Devices for epicutaneous skin testing. in Skin Testing Dolen W (ed): Immunology and Allergy Clinics of North America Philadelphia, WB Saunders , p
  33. Bilo BM, Rueff F, Mobech H, Bonifazi F, Oude-Elberink JN.

    Diagnosis of hymenoptera venom allergy. Allergy ;

  34. Droste JH, Kerkhof M, de Monchy JGR et al. Association of skin test reactivity, specific IgE, entire IgE, and eosinophils with nasal symptoms in a community-based population study J Every Clin Immunol ;
  35. Eller E, Bindslev-Jensen C. Clinical worth of component-resolved diagnostics in peanut-allergic patients. Allergy. Feb;68(2) doi: /all Epub Dec
  36. Martinez A, Asturias JA, Monteseirin J et al.

    The allergenic relevance of profilin (Ole e 2) from Olea europaea pollen. Allergy ;57(suppl 71)

  37. Hejl C, Wurtzen PA, Kleine-Tebbe J, Johansen N, Broge L, Ipsen H. Phleum pratense alone is sufficient for allergen-specific immunotherapy against allergy to pooideae grass pollens. Clin Exp Allergy ;
  38. Wolthers OD. Component-resolved diagnosis in pediatrics. ISRN Pediatrics ; doi: // Epub Aug 5.
  39. Vanto T. Efficacy of diverse skin test methods in diagnosis of allergy to dogs.

    Ann Every

  40. Ferrer M, Sanz ML, Sastre et al. Molecular diagnosis in allergologgy: application of the microarray technique. J Investig Allergol Clin Immunol ;19(suppl 1)
  41. Liebermann JA, Glaumann S, Batelson S, Borres MP, Sampson HA, Nilsson C. The utility of peanut components in the diagnosis of IgE-mediated peanut allergy among distinct populations. J Allergy Clin Immunol Pract ; Jan;1(1) doi: / Epub Dec
  42. De Graaf DC, Aerts M, Danneels E, Devreese B. Bee, wasp and ant venomics pave the way for a component-resolved diagnosis of sting allergy.

    J Proteomics ;

Rather than classic testing, alternative molecular-based allergy diagnostics should be seen as an adjunct to the traditional whole allergen specific IgE tests. It is significant to remember that numerous patients can still be sufficiently assessed using conventional prick skin testing or specific IgE to whole allergens in the blood in addition to a thorough history and clinical examination 20 The clinical significance of sensitization detected via molecular-based allergy diagnostics should only be used in relation to the clinical history and physical signs.

What is h on an allergy test

ISAC testing is likely to be most useful in poly-sensitized patients for evaluation of sensitization to cross-reacting food and airborne allergens. Prospectively planned studies should be undertaken to determine to what extent such extensive panel screening may be helpful in clinical practice. Robust evidence has not yet been provided to prove that molecular-based allergy diagnostics can be utilized in lieu of oral challenge testing in food allergy.

ConclusionDiagnostic testing remains an essential tool for the evaluation of the allergic patient.

Several variables should be controlled to produce more dependable skin test results and improve the predictive values of allergy skin testing.

What is h on an allergy test

It is also imperative that allergists ensure that the results of skin testing are dependable by conducting proficiency testing. In addition, the results must be properly documented to make them easily understandable by others. Similar standards must be applied toin vitrotesting; as in the case of skin testing, it is imperative that the ordering physician be familiar with the operating characteristics that thein vitrolab employs. Lastly, it is likely that in the future, molecular based allergy diagnostics will frolic a bigger role in the evaluation of allergic patients.

References

  • Oppenheimer J, Nelson HS.

    Skin Testing. Ann Every Asthma Immunol. ;S

  • Valenta R, Hayek B, Seiberler S et al. Calcium-binding allergens: from plants to man. Int Arch Allergy Immunol ;
  • Constantin C, Quirce S, Poorafshar M et al. Micro-arrayed wheat seed and grass pollen allergens for component-resolved diagnosis. Allergy ;
  • Sampson H Update on food allergy Jl Every Clin Immunol ;
  • Meliol G, Bonifazi F, Bonni S, et al. The ImmunoCAP ISAC molecular allergologyappraoch in adult multi-sensitized Italian parents with respiratory symptoms. Clin Biochem ;
  • Bilo BM, Rueff F, Mobech H, Bonifazi F, Oude-Elberink JN.

    Diagnosis of hymenoptera venom allergy. Allergy ;

  • Rosen JP, Selcow JE, Mendelson LM et al. Skin testing with natural foods in patients suspected of having food allergies: Is it a necessity? Jl Every Clin Immunol ;
  • Ortolani C, Ispano M., Pastorello EA.,. Ansaloni R, Magri GC Comparison of results of skin prick tests (with unused foods and commercial food extracts) and RAST in patients with oral allergy syndrome Jl Every Clin Immunol ;
  • Dreborg S. ed. Skin tests used in type I allergy testing Position paper.

    Allergy ;s

  • Wolthers OD. Component-resolved diagnosis in pediatrics. ISRN Pediatrics ; doi: // Epub Aug 5.
  • McCann WA, Ownby, DR. The reproducibility of the allergy skin test scoring and interpretation by board-certified/board-eligible allergists. Ann Every Asthma Immunol ;
  • Vanto T. Efficacy of diverse skin test methods in diagnosis of allergy to dogs. Ann Every
  • Droste JH, Kerkhof M, de Monchy JGR et al. Association of skin test reactivity, specific IgE, entire IgE, and eosinophils with nasal symptoms in a community-based population study J Every Clin Immunol ;
  • Yoon I-K, Martin BL, Carr WW. A comparison of two single-headed and two multi-headed allergen skin test devices.

    Allergy Asthma Proc ;

  • Ferrer M, Sanz ML, Sastre et al. Molecular diagnosis in allergologgy: application of the microarray technique. J Investig Allergol Clin Immunol ;19(suppl 1)
  • Eller E, Bindslev-Jensen C. Clinical worth of component-resolved diagnostics in peanut-allergic patients. Allergy. Feb;68(2) doi: /all Epub Dec
  • Nelson HS, Oppenheimer JJ, Buchmeier A, et al. An assessment of the role of intradermal skin testing in the diagnosis of clinically relevant allergy to timothy grass.

    J Allergy Clin Immunol ,

  • Swoboda I, Twaroch T, Valenta R, Grote M. Tree pollen allergens. Clin Allergy Immunol ;
  • MS Dykewicz, JK Lemmon, DL Keaney.

    What is h on an allergy test

    Comparison of the Multi-Test II and Skintestor Omni allergy skin test devices. Ann Allergy Asthma Immunol ;

  • Turkeltaub P. Performance standards for allergen skin testing: An approach to proficiency testing in Skin Testing Dolen W (ed): Immunology and Allergy Clinics of North America Philadelphia, WB Saunders , p
  • Liebermann JA, Glaumann S, Batelson S, Borres MP, Sampson HA, Nilsson C. The utility of peanut components in the diagnosis of IgE-mediated peanut allergy among distinct populations.

    J Allergy Clin Immunol Pract ; Jan;1(1) doi: / Epub Dec

  • Wood RA, Phipatanakul W, Hamilton RG, Eggleston PA. A comparison of skin prick tests, intradermal skin tests, and RASTs in the diagnosis of cat allergy. J Allergy Clin Immunol ,
  • Canonica GW, Ansetegui IJ, Pawankar R, et al. A WAO-ARIA-GA2LEN consensus document on molecular-based allergy diagnostics. WAOJ ;&
  • Williams, PB ; Barnes, J; Szeinbach, S; Sullivan, T Analytic precision and accuracy of commercial immunoassays for specific IgE: Establishing a standard J Every Clin Immunol ;
  • Pittner G, Vrtala S, Thomas WR et al. Component-resolved diagnosis of house-dust mite allergy with purified natural and recombinant mite allergens.

    What is h on an allergy test

    Clin Exp allergy ;

  • Hiller R, Laffer S, Harwanegg C, Huber M, et al. Microarrayed molecules: diagnostic gatekeepers for allergy treatment. FASEB J ;
  • Gadisseur R, Chapelle JP, Cavalier E: A new tool in the field of in-vitro diagnosis of allergy: preliminary results in the comparison of ImmunoCAP© with the ImmucoCAP© ISAC. Clin Chem Lab Med ;
  • Flinterman AE, van Hoffen E, den Hartog Jager CF et al. Children with peanut allergy recognize predominantly Ara h 2 and Ara h 6, which remains stable over time. Clin Exp Allergy ;
  • Adkinson NF Jr. The radioallergosorbent test in limitations and refinements Jl Every Clin Immunol ;
  • Oppenheimer J.

    Devices for epicutaneous skin testing. in Skin Testing Dolen W (ed): Immunology and Allergy Clinics of North America Philadelphia, WB Saunders , p

  • Yunginger, J. MD a; Ahlstedt, S; Eggleston, P. et al. Quantitative IgE antibody assays in allergic diseases JACI ;
  • Ownby DR. Computerized measurement of allergen-induced skin reactions. J Allergy Clin Immunol , ;
  • Fernandes J, Reshef A, Patton L, Ayuso R, Reese G, Lehrer SB.

    Immunoglobulin E antibody reactivity to the major shrimp allergen, tropomysin, in unexposed Orthodox Jews. Clin Exp Allergy ;

  • Sporik, R0, Hill DJ, Hosking, CS0 Specificity of allergen skin testing in predicting positive open food challenges to milk, egg and peanut in children. Clin and Exp Every ;
  • Martinez A, Asturias JA, Monteseirin J et al. The allergenic relevance of profilin (Ole e 2) from Olea europaea pollen. Allergy ;57(suppl 71)
  • Hejl C, Wurtzen PA, Kleine-Tebbe J, Johansen N, Broge L, Ipsen H. Phleum pratense alone is sufficient for allergen-specific immunotherapy against allergy to pooideae grass pollens. Clin Exp Allergy ;
  • Nicolaou N, Murray C, Belgrave D et al.

    Quantification of specific IgE to whole peanut extract and peanut components in prediction of peanut alergy. J Allergy Clin Immunol

  • Sastre J. Molecular diagnosis in allergy. Clin Exper Allergy ;40(10)
  • De Graaf DC, Aerts M, Danneels E, Devreese B. Bee, wasp and ant venomics pave the way for a component-resolved diagnosis of sting allergy. J Proteomics ;

What is food allergy?

Food Allergy is a harmful or irritating immune response to a food that is harmless to most people. It should be accurately assessed to minimise risk and maximise quality of life.

Food Allergy is not the same as a food intolerance.

What is food allergy?

Food Allergy is a harmful or irritating immune response to a food that is harmless to most people.

It should be accurately assessed to minimise risk and maximise quality of life.

Food Allergy is not the same as a food intolerance.


What is the treatment for food allergy?

The best treatment for food allergy is to avoid the triggering food.

Severe food allergies need review by an allergy specialist. We will provide significant advice, action plans, and prescribe emergency treatments — including auto-injectors (e.g.

EpiPen or AnaPen).

If you are attending our clinic please read these food allergy instructions.


Gluten Allergy Symptoms?

What is an allergy blood test?

Allergies are a common and chronic condition that involves the body’s immune system. Normally, your immune system works to fight off viruses, bacteria, and other infectious agents. When you own an allergy, your immune system treats a harmless substance, love dust or pollen, as a threat.

To fight this perceived threat, your immune system makes antibodies called immunoglobulin E (IgE).

Substances that cause an allergic reaction are called allergens. Besides dust and pollen, other common allergens include animal dander, foods, including nuts and shellfish, and certain medicines, such as penicillin. Allergy symptoms can range from sneezing and a stuffy nose to a life-threatening complication called anaphylactic shock. Allergy blood tests measure the quantity of IgE antibodies in the blood. A little quantity of IgE antibodies is normal.

A larger quantity of IgE may mean you own an allergy.

Other names: IgE allergy test, Quantitative IgE, Immunoglobulin E, Entire IgE, Specific IgE

We’ve got you covered

Living with allergies or asthma can be irritating, sometimes even life-threatening. Fortunately, Fairview and HealthEast doctors know exactly how to assist you. They’ll work with you to develop a customized treatment plan that minimizes your discomfort, works with your lifestyle and keeps you safe.

How does allergy testing work?

An allergy test determines what triggers your allergy symptoms. During the test, little drops of diverse allergens are placed on your skin with a tender poke. If you’re allergic to the item, the skin around the test area will turn red. The size of the red area is measured. Once every the measurements are done, your doctor will review the results with you.

How do allergy shots work?

Allergy shots, also known as immunotherapy, are used to prevent allergic reactions to things love grass pollen, home dust mites and bee venom.

What is h on an allergy test

Shots are given by injecting a little quantity of the allergen under the skin of the arm. Shots are given in a series, generally once a week for about 30 weeks and then less often for three to five years. The quantity of allergen in the shot is gradually increased each time, causing your immune system to become less sensitive to it and reducing your symptoms. For people with asthma, allergy shots can also assist relieve the allergic reactions that trigger asthma episodes.

How can I get my asthma under control?

We offer finish asthma care. To assist you control your asthma, our doctors will assist you take every the most significant steps, including:

  1. Understanding your asthma
  2. Recognizing asthma signs and symptoms
  3. Learning about your triggers and how to avoid them
  4. Controlling asthma episodes

Our physicians, nurses and respiratory therapists will work with you to create a treatment plan that helps you breathe easier while still enjoying activities that you love.

If medication is necessary, we’ll work to discover the prescription that works best for you.

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This is the first study systematically evaluating the risk of Anisakis allergen sensitization in a representative sample of employees of fish processing facilities and working-age blood donor controls, using highly specific and sensitive serodiagnostic test.

Also tested are associations of Anisakis-sensitization in fish processing workers to a number of sociodemographic, behavioral, health-related, genetic, and professional attributes. Given that the knowledge on risk factors for Anisakis sensitization is incomplete, often contradictory and vague, and since the replication of the study is unlikely as it would own required repeated efforts to achieve formal cooperation of entire industry, we performed exploratory association analysis. Exploratory nature together with a low number of observed events might own affected the precision of some estimates and conditioned the emergence of some false-positive interactions.

Nevertheless, association results presented here are mainly corroborated with the strength of associations, their consistency, biological plausibility, and/or coherence with previous knowledge, as described in detail under. More importantly, we argue that the study exhaustively covered almost every marine fish processing workers in Croatia, precisely reflecting real-time Anisakis sensitization status within the industry. This sets a baseline for the future tracking of sensitization in the sector already under the influence of wide array of allergens.

Risk factors for Anisakis sensitization in fish processing workers

Higher anti-Anisakis seroprevalences in workers (%, 95% CI –%) compared to controls (0%, 0–%) suggests an increased risk of acquiring Anisakis seropositivity in fish processing industry.

This was also postulated in France, Italy, South Africa and Spain [14,15,26–29], but the body of evidence was limited to case reports, studies with little sample size and/or non-representative sample or cross-sectional studies without control groups of individuals exterior of the fish processing industry. However, in our study the highest risk for Anisakis sensitization among the workers was fishing in the free time (OR ), suggesting that the professional exposure in studied environment does not represent a major risk factor for fish-processing workers when appropriate safety measures such as gloves, masks and goggles are in put. Rather, the association between IgE sensitization and fishing in free time, which is found in this subpopulation and accompanied with 5 times higher frequency of eating raw fish in amateur fisherman than in those who do not, implicate this behaviour as risky (Table 2).

The fact that every seropositive workers tested by Trisakis were positive to Ani s 7, which reveals true Anisakis infections [19], confirms that anti-Anisakis IgE antibodies in our study were induced by an unsuspected previous Anisakis infection rather than to an environmental exposition of workers to Anisakis allergens. Although fish workers may be more exposed to Anisakis aeroallergens than normal population, this seems not to be relevant to sensitize against major Ani s 1 and Ani s 7 secretory allergens.

While eating fish per se (OR , 95% CI –, p = ) or eating thermally unprocessed fish (OR , 95% CI –, p = ) were not risk factors in our study, eating meat and the frequency of fish consumption were.

The reason for this contradiction may be that workers who didn’t eat meat actually ate fish more frequently (no vegetarians or vegans were observed, reflecting dietary habits of a typical Croatian).

An alternative explanation for the lack of association between Anisakis IgE sensitization and exposure to Anisakis allergens in the population of fish processing workers is that Ani s 1 and Ani s 7 allergen present in the Trisakis kit are not adequate to measure sensitization by cutaneous and/or respiratory routes.

To cover this possibility, the sera of the entire population working in the fish industry, and reporting allergy status in the questionnaire (n = ), were tested for IgE antibodies to Anisakis CE antigen in indirect ELISA. In this case, an increased number of fish-processing employees has been found positive to Anisakis CE (%, –%) in comparison with Trisakis (%, 95% CI –%). At a first glance, such difference may suggest: i) that the working population might be sensitized to other relevant Anisakis allergens present in CE and not present in the Trisakis kit (Ani s 1 and Ani s 7, only), or alternatively, ii) that some allergens present in the Anisakis CE cross-reacted with other allergens to which some workers are sensitized.

To distinguish between these two possibilities, the frequency of IgE sensitization to Anisakis CE was compared within the subpopulations of workers reporting versus those non-reporting allergic symptoms, as well as between subjects working in direct contact with fish with honor to the remaining subjects working in other tasks. We found no significant differences in the proportion of Anisakis IgE sensitization for any of the above comparisons, which suggests that the greater quantity of positive patients to Anisakis CE, compared to Trisakis, is more probably due to cross-reactivity with other allergens than to sensitizations to Anisakis by skin and/or respiratory routes.

Similarly, but with the lower level of evidence, Mazzucco et al. [14] showed that seroprevalence among fishermen/ sailors compared to fish industry workers was fold greater, whereas the skin contact frequency was same among two groups. Authors unexpectedly found an inverse association between dietary fish intake and seroprevalence, and interpreted the anomaly by potentially reduced fish consumption in workers suffering allergy. Nevertheless, since a grand majority of subjects in that study [14] worked in direct contact with fish ( versus ) a bias could be introduced and this conclusion should be taken with some caution.

Another reason for dominant behavioral instead of occupational risk factors could be that this subpopulation shows a more frequent habit of eating raw little pelagic fish, which unlike the processed anchovy and sardine, does not undergo veterinary inspection.

The protective clothing (goggles, gloves, mask), being a prerequisite for the application of HACCP (Hazard Analysis of Critical Control Points) principles in Croatian fish processing industry [30], could also frolic a role. Workers wearing a face mask seemed to be protected (p<), but because every Anisakis-sensitized workers wore gloves and only 20% of every workers wore masks, we were unable to precisely determine the risk of not wearing protective clothing in Anisakis sensitization. The effect of protective clothing and occupational allergies in general is not fully resolved. It can be insignificant in adults with atopic dermatitis [31] or represent an occupational allergen per se (natural rubber latex, [32]).

Therefore, the odds of protection clothing in Anisakis allergy should be carefully considered in future in a differently designed study.

Unlike for other acute allergic symptoms in workers, the occurrence of urticaria and rhinitis (Table 4) was significantly higher in seropositive than in seronegative individuals (ORs from to ) or controls (ORs from to ). This is not surprising because urticaria is typically associated to helminths and blood-sucking arthropods with a cutaneous phase triggering Th2-type response [33]. We also found implication of other allergens in our study by differentiating between chronic and acute allergy, as seronegative workers reported more frequently every of the listed acute allergic symptoms than the controls.

Similar to our finding, Jeebhay et al. [34] found that asthma and ocular-nasal symptoms are frequent in marine fish processing facilities. The implication of multiple-allergens sensitization and clinical manifestation of the allergy in case of Anisakis is still unresolved. Daschner et al. [35] observed that Anisakis-sensitized patients suffering chronic urticaria had also high prevalence of pollen, mold and dander sensitization. Home dust mites sensitization was less prevalent in those patients, whom then exhibited allergic rhino-conjunctivitis and bronchial asthma, even in a region with a low burden of mites allergens.

No difference in Anisakis sensitization was observed between smoking and non-smoking workers, but ex-smokers were at significantly higher risk of sensitization than smokers, probably due to changes in the nasal mucociliary epithelium typical for ex-smokers.

Namely, while the expelling of cigarette irritants through mucosal ciliature in smokers is inefficient, cigarettes induce coughing that enables the clearing process. In ex-smokers, it can take a year for the cilia to recover after cessation, during which ex-smokers can be susceptible to chest infections [36]. Whether the same mechanism has a role in Anisakis sensitization still remains to be tested.

Older male workers were at higher risk to Anisakis sensitization, contrasting a retrospective survey in French hospitals on anisakiasis incidence which demonstrated female dominance and younger average age of cases [37].

However, the latter encompassed broader range of species (genera Pseudoterranova and Anisakis) and surveyed diverse disease types (“esophageal, gastroduodenal, allergic, eosinophilic granuloma or another form”) in contrast to our study that focuses on sensitization. The predominance of Anisakis-sensitized women was previously found in Japan and South Korea [38,39] related to their increased consumption of raw fish, but not in USA or Croatia [9,40].

This suggests that age and gender susceptibility are strongly influenced by country-specific diversity of sociodemographic, behavioral and occupational habits of the population under study.

Seroprevalence of anti-Anisakis IgE and anti-Trichinella IgG

The Ani s 7 allergen [41] was present in every seropositive individuals, which is in agreement with previous studies that recognize it as the most relevant Anisakis allergen, including patients with Anisakis-induced chronic urticaria [20]. By contrast, Ani s 1 tested positive only in four individuals, but the inclusion of this allergen in the Trisakis is of interest since IgE antibodies to Ani s 1 may be present in a few number of cases not detected by Ani s 7 [20].

The measurement of the IgE response to this allergen is also of interest since in the absence of an additional exposure to infection, IgE levels to Anis s 1 seem to persist, or even increase after sustained oral exposition to Anisakis allergens present in fishery products [10].

Interestingly, when the sensitization to the nematode whole extract presented in ImmunoCAP has been measured in a sera subsample (n = 76; fish-processing employees that were Ani s 1 and Ani s 7 seropositive or seronegative, but suffered one or more allergy symptoms), positive reaction was observed only in seven Trisakisseropositive sera.

This is surprising at the first glance since ImmunoCAP may contain Anisakis allergens recognized by cross-reactive antibodies [23], therefore giving untrue positive results. A possible explanation for these results is that Ani s 1 and/or Ani s 7 major allergens might not be well represented in the current pool of antigens used in ImmunoCAP, which may provoke untrue negative results when the response to these allergens is dominant. The relatively low IgE response observed with ImmunoCAP for some sera with honor to Trisakis (e.g., # in Table 2) is in agreement with this hypothesis.

Moreover, the fact that every ImmunoCAP positive sera fell within the group of Trisakis positive workers reinforces our conclusion that the fish-processing environment per se is not associated with risk of Anisakis-sensitization. Otherwise, it would be expected that a significant number of workers in contact with Anisakis antigens (e.g. through ingestion of processed fish or aerosols in the working environment), tested positive by ImmunoCAP and negative by Trisakis

In our previous study [9] we observed that 60% (6/10 cases) of Trisakispositive sera were also positive to Ascaris sp., Toxocara sp.

or both (tested by a commercial ELISA for detection of IgG, encompassing a pool of antigens with 95% specificity), suggesting that the output was merely a cross-reactivity, rather than the genuine status of seroprevalence. This time we tested Trichinella-sensitization for two reasons; firstly, because of the historical incidence of acute trichinellosis in the coastal area, although with low incidence (–/ , inhabitants in Croatia [42]); and secondly, because the migratory larvae of Trichinella spp.

resembles the human infection model by L3 Anisakis. As Anisakis seropositive sera tested negative for anti-Trichinella IgG, no association was investigated. Cross-reactivity is a major problem in the serological diagnosis of parasitic infections (especially those caused by nematodes), particularly when crude parasite extracts are used, and to a lesser extent the excretory/secretory antigens (ESA). Such cross-reactivity has previously been described among A. simplex and other nematodes [43,44], and among Trichinella spp. and other zoonotic parasites [45,46]. However, studies demonstrated that WBs based on homologous ESA could distinguish between Anisakidae and Trichinella seropositivity [47] and that a WB based on T.

spiralis ESA allows the definition of a unique diagnostic pattern for Trichinella-infected humans [24].

Difference in seroprevalence of healthy population estimated in Mladineo et al. [9] (2%) and in this study (0%) might own arisen from diverse structure of two groups. While the previous recruited persons ongoing professional and systematic medical examination using stratified sampling, the latter recruited blood donors at sites shut to the factories who, by definition, are frequently scrutinized for health and better reflect working population in terms of age.

Compared to the sample from with the mean age of 58 years, participants from this sample were on average 19 years younger (95% CI 17–21).

HLA and Anisakis Sensitization

HLA class I and class II proteins frolic a pivotal role in the adaptive human immune system, the latter mediating specific immunization to the antigen. In this study we identified several HLA class II loci strongly associated with Anisakis seropositivity, majority increasing the risk of acquiring seropositivity. This suggests that identified HLA-alleles might be implicated in functional improvement of MHC class II antigen-presenting role by i.e.

sustained antigen presentation, in line with described hypersensitivity to Anisakis [20]. Similar to our study, Sánchez-Velasco et al. [48] reported that HLA-DRB1* increased the risk of Anisakis allergy by times, while DQB1* was exclusive for Anisakis-allergic patients. Moreover, the epitope-binding motif of HLA molecules coded by HLA DRB1* has been evidenced at least once in the homologous segments of every the characterized allergens of A. simplex [49]. In addition to HLA-alleles already detected by Sánchez-Velasco et al.

[48], we identified seven other risk HLA-alleles (Table 5). While some of these alleles might represent spurious association or be in linkage disequilibrium, several findings support their identification. Specifically, DRB1* allele is involved in presentation of group 2 allergens of Dermatophagoides spp. [50] to which every the Anisakis allergic patients previously showed sensitization [51]. This is not surprising as both Ani s 1 and 7 are encompassed within major allergens group, being products of the nematode excretory and secretory activity [5].

DQB1* that we identified as a strong protective factor against Anisakis sensitization is also a protective factor against home dust mite–sensitive allergic rhinitis [52]. The list of HLA-alleles and haplotypes we found significant for Anisakis sensitization, associated with other disorders, is presented in S3 Table. It suggests that HLA association with Anisakis


What are the symptoms of food allergy?

Common symptoms included hives (urticaria), tingling in the mouth and diarrhoea or stomach pains. Concerning symptoms include swelling of the lips, tongue or throat (angioedema), shortness of breath or wheeze (acute asthma), dizziness or collapse and require immediate medical attention.

Food allergy symptoms generally happen within an hour of eating the food.


How do you test for food allergy?

Common triggers in adults include seafood and nuts however people can be allergic to a wide range of foods.

Food allergy testing may assist identify the cause and prevent further reactions.

Skin prick testing and blood tests are available to assist diagnose food allergies. A careful history of symptoms is required to select the best approach. A positive test, by itself, does not necessarily mean you own an allergy.


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