The Fine Points of Allergy Skin Testing

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					      The Fine Points of Allergy Skin
                 Testing
                               multiple-
                          with multiple-head and single site
                             antigen skin testing devices

                                               Dewey Hahlbohm
                                        President-      AAPA-
                                        President-Elect AAPA-AAI




  Allergy Diagnostic Testing

    Historical perspective
    Definition: percutaneous, intracutaneous tests
    Reliability: variables in skin testing
    Validity and accuracy of testing methods
    Comparative studies
        Wood RA, et al. – cat allergy in subjects with rhinitis/ asthma
        Nelson HS, et al. – grass allergy in subjects with rhinitis
        Reddy PM, et al. – perennial allergic rhinitis
        Brown WG, et al. – general population sample


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    Skin testing: historical perspective
1865: First described by Dr. Charles Blackley
                                                                    pollen,
       Scarified a large area of skin on his forearm, applied grass pollen, and covered
       the area with an occlusive dressing → 2.5 x 1.5 inch wheal raised ¾ inch

1907: von Pirquet introduced cutaneous test for tuberculosis

1912: Schloss introduced scratch test for food allergy testing in children.

Early 1900s: Schick (diphtheria toxin) and Cooke (ragweed) and Hansel
   independently introduced the intracutaneous test as a diagnostic method; Phillips
   correlated size of IDST wheal with safe starting dose for IT.


1950s: Lewis suggested the puncture technique and Squire outlined the quantitative
                                                                  the
   aspects of percutaneous testing.
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Percutaneous allergy testing

Prick testing (Pepys, 1972 ): a sharp instrument is passed through a drop of
extract/ control solution at a 45o or 60o angle to the skin. Skin is then lifted,
                                                              solution
creating a small break in the epidermis through which the solution penetrates.

         testing:
Puncture testing: testing device (usually with a shoulder) is passed through a
drop of extract/ control solution at a 90o angle.

Life-                                                             100,000
Life-threatening generalized systemic reactions are rare: 521 per 100,000 tested
         (Devenney
children (Devenney et al.). 1 death reported in a patient who received 90 food
SPT at one time (Bernstein et al.).

Peak reactivity of prick / puncture tests is 15 – 20 minutes at which time both
                                                                   and
wheal and erythema diameters should be recorded in millimeters and compared
with controls.


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Percutaneous allergy testing
A number of sharp instruments (hypodermic needle, solid bore
                                                   multiple-
needle, lancet with or without bifurcated tip, and multiple-head
devices) may be used for prick/ puncture testing.
                                                             clear-
        An objective comparison has not demonstrated a clear-cut advantage
        for any single or multitest device.
        Interdevice wheal size variability at allergen positive and negative sites
                                                                       proper
        is significant; thus, positive/ negative controls required for proper test
        interpretation.

Variables influencing reliability
        Test instrument, skill of the tester, skin color, age of patient (< 2 years
        or > 65 years), location of testing (back vs. arm), proximity to adjacent
                                                                     potency,
        positive reactions, medications taken by the patient, and potency,
                   allergenicity,
        stability, allergenicity, concentrations of test extracts


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Percutaneous allergy testing:
survey of allergists




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Percutaneous allergy testing:
comparison of commonly used
devices




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Percutaneous allergy testing




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Percutaneous allergy testing




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 Percutaneous allergy testing:
 survey of allergists




   Prick testing: 92.1% used the most concentrated extract available
   Intradermal testing was used by 85.2% of responders.
   Intradermal concentration: 20.8 % 1:100, 10.3 % 1:500, 59.4 % 1:1000.
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Percutaneous vs. Intracutaneous
testing
Percutaneous testing                    Intracutaneous testing
  Safe                                      Sensitive (venoms, drugs)
  Rapid                                     Reproducible
  Little discomfort                         Lower threshold for
                                            histamine response
  Positive and negative easily
                                            Low potency extracts
  distinguished (if low trauma
  device employed)                          Exclude allergy
                                            Confirm borderline SPT
  Good correlation with
  clinical symptoms                         Information for IT starting
                                            dose

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   Skin testing: grading
   Grading system
                                                              comparison
       Mean wheal diameter (D + d/2), longest wheal diameter, comparison to
       histamine. Consensus: wheal of at least 3 mm diameter greater than
                                                 erythema.
       negative control with at least equivalent erythema.
       Only 28.2% measure orthogonal diameter
   Criterion for a positive skin prick test (survey of allergists)
       Wheal of 3 mm greater than the negative control             71.6%
       Wheal same size or greater than histamine control           13.5%
       Other (ie, wheal 5mm > negative control)                    14.9%
   Criterion for positive intradermal test (survey of allergists)
       Wheal of 3 mm greater than the negative control             55.2%
       Wheal same size or greater than histamine control           18.0%
       Other (ie, wheal 5mm > negative control,
                  any wheal > negative control)                    26.8%
       (85% use criterion of >/= 3 mm > negative control)
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   Percutaneous allergy testing




Reference: Vanto et al. Ann Allergy 1982;49:340-4.




Reference: Adinoff et al. J Allergy Clin Immunol 1990;86:766-74.
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   Percutaneous allergy skin testing

                                                                provided
      A 3.0 mm diameter wheal cutoff for a positive test result provided 100%
      sensitivity and 100% negative predictive value
                                                                      were
      When increased symptom scores after nasal allergen challenge were used as
                                                                      test
      the gold standard, a wheal diameter cutoff of 5.5 mm increased test specificity
      to 89%, albeit at the expense of sensitivity (88%).




Zarei et al. Ann Allergy Asthma Immunol 2004;92:604-10.
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  Allergy testing


To optimally define test performance, a method should be
  reproducible and validated against a diagnostic
  benchmark or comparative gold standard (ie, double
  blind placebo controlled food challenge) – difficult to
  attain for inhalant allergy.




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  Percutaneous allergy testing
  Using positive nasal provocation challenges as a standard
                     85-
        Sensitivity: 85-87 %
                     79-
        Specificity: 79-86 %


  Diagnostic validity: confirmed in patients exposed to allergens
  under natural conditions as well as controlled organ challenges.


  Diagnostic accuracy: confirmed in groups of allergic patients
  undergoing specific nasal challenge measured by nasal resistance
  or acoustic rhinometry under controlled laboratory conditions.

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  Percutaneous allergy testing
  Correlate with in vitro tests


  Quantitative relationship with symptoms


                               allergenicity,
  Due to variable constitutive allergenicity, potency, and stability
  among commercial allergen extract reagents, sensitivity and
  positive predictive values tend to be higher among standardized
  extracts.
                                                                   spores,
        Molds most difficult due to allergenic differences between spores,
        hyphae, and secreted products


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  Percutaneous allergy testing

  Single recombinant allergens: highly specific, safe, lower
  sensitivity



                                                         subsequent
  Positive tests in asymptomatic individuals may predict subsequent
  clinical allergy (60%)


  Comparative standard for other tests



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  Percutaneous allergy testing:
  accuracy
  Meta-
  Meta-analysis comparing percutaneous tests to nasal challenge
  revealed the following likelihood ratios:
Allergen              Positive              Negative        Sens./spec. (%)
Cat                    4.93                  0.08              93.6/ 81.0
Tree pollen            16.17                 0.03              97.0/ 94.0
Grass pollen            3.23                 0.04              97.0/ 70.0
Dust mite               4.06                 0.03              97.4/ 76.0
Mold                   11.75                 0.05              95.2/ 91.9
  Alternaria: similar positive and negative likelihood ratios for
  percutaneous and intracutaneous tests when compared to
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  Intracutaneous allergy testing

  Single dilution: strength 100 – 1,000 fold more dilute than
                                                                HAS
  allergen concentration used for percutaneous testing (diluent HAS
  (0.03%) – saline)
                                          0.5-
         0.02 to 0.05 mL of extract via a 0.5- or 1.0 mL 26 – 30 gauge syringe

                                        1940-
  Multiple serial dilutions (Rinkel 1940-1950): serial endpoint
                                                             testing
  titration, serial dilution testing, intradermal dilutional testing
         Endpoint is the first/ weakest dilution producing wheal at least 2 mm >
         negative control, followed by a second wheal at least 2 mm >
         preceding one (through dilution #2)
         SET dilution between #3 & #4 ≈ SPT (gold standard: ragweed nasal
         challenge, history)
                                                                       grass,
         Questionable value of dilution #2 (gold standard: Alternaria, grass,
         nasal challenges)
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Intracutaneous allergy testing



                       0




 Haydon et al. Otolaryngol Clin N Am 2008;41:331-46.

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Intracutaneous allergy testing

Peak reactivity of intracutaneous tests is 10 – 15 minutes at which
time both wheal and erythema diameters should be recorded in
millimeters and compared with controls.

Immediate systemic reactions are more common compared with
SPT: 6 fatalities reported in a retrospective survey (Lockey, et
al.); no fatalities 1990 – 2001(Bernstein, et al.).
       Prescreening with percutaneous tests is advised




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Intracutaneous allergy testing

                                                               (ie,
Standard of care in evaluation of possible anaphylaxis to drug (ie,
                                            (↑
penicillin) and hymenoptera and of ABPA (↑ sensitivity)

                                                          especially
The greater sensitivity of titrated intracutaneous tests, especially
the erythema component, is an advantage for determining
                                                             units.
biologic potency of allergen extracts and biologic allergy units.




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Intracutaneous allergy testing:
accuracy
Will identify a larger number of patients with lower skin test
sensitivity (lower potency extracts, reduced sensitization) and are
used when increased sensitivity is the main goal of testing.

Meta-
Meta-analysis comparing intracutaneous tests to allergen
challenge revealed the following likelihood ratios:
Allergen               Positive          Negative       Sens./ spec. (%)
Cat                     0.89                1.24          60.0/ 32.4
Grass                   1.05                0.98          33.3/ 68.4
Mold (Alternaria)       8.80                0.05           95.2/89.2


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Intracutaneous allergy testing
                                    rhinometry)
Using nasal provocation (& acoustic rhinometry) with grass
pollen as gold standard
        Percutanous tests were more sensitive 85.3% vs. 79.4%
        and more specific 78.6% vs. 67.9% than SET
        SET positive predictive value 75%, negative 73%

Using clinical history as gold standard (dust mite, grass, tree, cat; 30
and 3,000 BU/ mL)
       Intracutaneous positive predictive value: 77%
       Percutaneous positive predictive value: 86%

More dilute intracutaneous concentrations are comparable to
percutaneous tests (gold standard: history)
        SET endpoints between 10-5 and 10-6 g/mL (wt/vol)
                                                 (wt/vol)

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Allergy diagnostic testing


   Introduction of in vitro tests for the measurement of
 total and specific serum IgE has permitted
 correlations to be made between clinical history and
 various skin testing methods.




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 In vitro allergy testing
 Sensitivity of immunoassays compared with percutaneous tests is
 approximately 70 – 75%.
       Similar sensitivity ranges (50 – 90 %) pertain when immunoassays are
       compared with symptoms induced after natural or controlled organ
       challenges.


                                                                excluding
       A negative serologic test result cannot be relied on for excluding
       clinical sensitivity to inhalant allergens.


       Total serum IgE concentrations are reported in international units or
                                                 ng/
       nanograms per milliliter (1 IU/ mL = 2.44 ng/ mL).


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 In vitro allergy testing
 With defined quantifiable threshold levels, specific IgE useful in
                                                          exposure.
 predicting positive respiratory responses after allergen exposure.


 The use of specific IgE levels to support the clinical diagnosis of
 respiratory allergic disease is different for the same allergist
 depending on the particular inhalant allergen and between
 allergists for the same allergen specificity.

 Poor correlation between skin testing and serum specific IgE for
 molds.


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Allergy Skin Testing

• Optimizing allergy skin testing results to
  improve patient outcomes
• Standardization-everybody does it the
  Standardization-
  same way
• Reproducibility



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    Don’t let your patient down
 There’
 There’s more than meets the eye
    Test head quality
    Time is money (Labor & admin. Costs)
                   (Evidence-
    Published data (Evidence-based medicine)
 Need to know medications & herbals.
                   matters-
 Proper technique matters-reproducibility.
          reactions-
 Reading reactions-The best time to read is 20
 minutes to pick up late blooming reactions.
 Why testing controls matter.
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           Why the big deal?
 Skin testing is our primary diagnostic tool
 Patient outcomes are only as good as …

                                                      Glyc
                                Meds           Ctls

                               Herbs        How Fill

                                 Exts                 Blot
                                            Score


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    Medications/Supplements
• Medications that suppress skin whealing
  responses:
  – Anti-H1 histamines (Astelin, Benadryl, Zyrtec)
  – Anti-H2 histamines (Tagamet, Pepcid, Zantac)
  – Tricyclic Antidepressants (Doxepin)
• Herbal Supplements
  – Decreases whealing; Licorice, Green Tea,
    Saw Palmetto, St. John’s Wort, Feverfew
  -Increases whealing; Milk Thistle, Astragalus
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                Medication List
•    Practice Parameters (Annals, July 2008)
    – Allergy Diagnostic testing: An updated
      Practice Parameter, Table 4. suppressant
      Effects of Drugs on Immediate skin tests:
      1.   Brand and Generic (sorted by) names
      2.   How the medication is used/conditions
      3.   Mean days suppressed
      4.   Maximum days suppressed
      5.   Dose

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              Medication List 2
• Benzodiazepines, Atypical
  Antidepressants/Sedatives, SSRI, SNRI,
  and PPI medications
    – Medications that may interfere with Skin Prick
      Testing (SPT)
    – Medications that are unlikely to interfere with
      SPT
    – Source:AAAAI Annual meeting in New
      Orleans, March 1, 2010 by Mayo Clinic.
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           Herbal Supplements

            Affects of Commonly used Herbal
            Supplements on Histamine Skin Prick
            Testing
               Five Herbal Supplements that decrease
               skin whealing from 15-21%
               Two Herbal Supplements that increase
               skin whealing from 15-24%
               16 Herbal Supplements that do not effect
               skin whealing response


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TCA, BABA, & CCB’s

 Tricyclic Antidepressants (Suppress
              3-
 SPT results 3-11 days)
 Beta Adrenergic Blocking Agents (may
 make anaphylaxis more difficult to
 treat)
 Calcium Channel Blockers (potentially
 safe replacements for Beta Blockers)

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Allergy 101-
Points to remember
 Wheal is the true measurement of IgE
 Compare Antigen sites to controls.
 Positive control (1 mg/ml histamine
 base= ≥5 mm wheal at 7 minutes and
 ≥7 mm wheal at 17-20 minutes).
                   17-
 A wheal at ‘-’ control may be caused
 by dermatographia, glycerin &/or
 phenol sensitivity.
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Allergy 101:
Pressure and comfort
 Enough pressure to leave an
 impression of the point pattern
 w/multiple antigen devices
 Gentle rocking motion to ensure
 penetration of all test head points
 Bleeding should not occur
 Minimal discomfort to the patient
 Single vs. Multiple head for children?
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Single Head Devices




Modified-Prick Method            Rotation or Twist Method

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Multiple Head Device




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Extracts and Controls
 Undiluted, non-standardized or
 standardized, glycerinated extracts
 + control is 1 mg/ml histamine base or 2.75
 mg/ml Histamine phosphate per ml
 - control must be in 50% glycerin
 Saline (PNS) ctls/exts evaporate in wells
 Overfilling wells wastes extract on shafts
 Extracts have different loading
 characteristics-evaporation is not a concern

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Reading Test Sites
 Glycerinated histamine peaks at 17 mins.
 Read all test sites at 20 minutes
 Read + & - control sites first
 Is there is a wheal at the – control site?
 Non-specific irritant responses subside at
 20 minutes.
 Wheal is the true indicator of IgE-mediated
 response not flare
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 Positive & Negative Controls




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  Extract usage and
  Sterility
                        357-
    Single site devices 357-3,000 tests/5 ml
    Multiple-         devices-
    Multiple-headed devices-500 tests/5ml
                     method-
    Prick and Wipe method-100 tests/5 ml
    Glycerin (50%) extracts/ controls provide:
    –   Consistent & uniform loads
    –   Protein stabilization
    –   Anti-
        Anti-microbial protection
    –   Protease (proteolytic enzyme) inhibition
    –   Naturally hygroscopic; i.e., inhibits evaporation
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       Where do we mess up?

         Insufficient pressure-no penetration
         No test solution at test site-False negs.
         Using non-glycerinated diagnostics
         Meds/herbal supplement’s suppression
         Reading test sites before 20 minutes
         Using a positive control stronger than 1
         mg/ml
         Negative Control has whealing
         Using lateral lighting to improve grading

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                  Wrap-up
  Evidence-
► Evidence-based  medicine-
                  medicine-Show me studies
► Time is money. What is most efficient?
► What is most reproducible?
► Ask yourself, what would you like.
     side- by-
► Do side-by-side testing to compare devices.
           manufacturer’
► Use the manufacturer’s scoring system
► Compare quality and technical support.

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    Test Heads at 100x




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Where to Get More Information
Read the package insert
Watch the instructional video
Practice
Proficiency testing (c.v.)
Call/email someone in the know
                           in-
If all else fails, request in-service training


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      Questions/Feedback?
Do you need further clarification?
Dewey Hahlbohm
hahlbohmd@earthlink.net




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