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Hypersensitivity and allergy testing

15 min

Skills you'll build3 skills
  • Classify a hypersensitivity reaction by its main effector mechanism
  • Distinguish allergen sensitization from clinical allergy
  • Compare an acute tryptase with the patient's own baseline

Try first

Try first

A jeweler develops an itchy, blistering rash under a new nickel ring. It appears about 48 hours after she first wears it. Which hypersensitivity type fits?

Keep going to see the reasoning.

Keep going to see the reasoning.

Keep going to see the reasoning.

Right. Keep going to follow the reasoning.

Keep going to see the reasoning.

Get the idea

Use the explanation to check your first decision.

Four mechanisms

The Gell and Coombs scheme sorts a hypersensitivity reaction by the immune effector that does most of the damage. Many diseases involve more than one mechanism, and the type names the main one.1

TypeMain effectorTypical timingExample
I, immediateAllergen-specific IgE on mast cells and basophilsMinutesAnaphylaxis to a bee sting
II, antibody against a fixed antigenIgG or IgM bound to a cell, matrix or receptorHours to daysAnti-GBM disease, myasthenia gravis
III, immune complexSoluble antigen-antibody complexes deposited in tissueDays after exposureSerum sickness
IV, cell mediatedSensitized T cells and macrophages24 to 72 hoursContact dermatitis, tuberculin skin test

1

Types II and III both use antibody. In type II the antibody binds antigen fixed in place, such as a basement membrane or a receptor. In type III the complexes form in the circulation and lodge in vessel walls, where they activate complement and can lower C3 and C4.1

Sensitization and allergy

A positive allergen-specific IgE or skin test shows sensitization. The patient has made IgE to that allergen. Whether the IgE explains a reaction depends on the exposure and the reaction history. Many sensitized people tolerate the allergen with no symptoms. Total IgE rises in many conditions and cannot name the allergen responsible.2

Acute and baseline tryptase

Mast cells release tryptase when they degranulate. The acute serum tryptase is drawn as early as practical after a suspected anaphylactic reaction, and a baseline is drawn later when the patient is well. One criterion supporting mast-cell activation is an acute tryptase (ng/mL) greater than 1.2 × baseline tryptase (ng/mL) + 2 ng/mL, with the acute specimen drawn ideally within 2 hours of symptom onset and the baseline when the patient is well. An acute result within the reference interval does not exclude anaphylaxis.3

The criterion compares the acute result with the patient's own baseline. A baseline of 4.0 ng/mL gives a threshold of 6.8 ng/mL, so an acute result of 8 ng/mL can meet the criterion and be within the reference interval. Each result is reported with its collection time, because the two are interpreted as a pair.3

Follow the bench demonstration

Sources for this step
References
  1. Abbas AK, Lichtman AH, Pillai S, Henrickson S. Cellular and Molecular Immunology. 11th ed. Elsevier; 2025. Elsevier.
  2. Ansotegui IJ, Melioli G, Canonica GW, et al. IgE allergy diagnostics and other relevant tests in allergy, a World Allergy Organization position paper. World Allergy Organ J. 2020;13(2):100080. doi:10.1016/j.waojou.2019.100080
  3. Golden DBK, Wang J, Waserman S, et al. Anaphylaxis: a 2023 practice parameter update. Ann Allergy Asthma Immunol. 2024;132(2):124-176. doi:10.1016/j.anai.2023.09.015

Watch one

Read each decision and its explanation.

Imani Dillon, 35, a wedding florist, develops hives and wheezing minutes after eating a cashew. An acute tryptase is drawn in the emergency department. A baseline is drawn 4 weeks later.

Does the acute tryptase meet the criterion for mast-cell activation?

TestResultReference intervalFlag
Tryptase, acute8.1 ng/mL<11.5 ng/mL<11.5
Tryptase, baseline4.0 ng/mL<11.5 ng/mL<11.5

Specimen: H 3, L 10, I 1. Acute serum collected 1 hour 15 minutes after symptom onset; baseline serum collected 4 weeks later

  1. Check the acute collection time first. It was drawn 1 hour 15 minutes after onset, inside the recommended 2 hours.

    Tryptase peaks early and falls over hours, so a late acute draw can miss the rise.

  2. Check the baseline. It was drawn 4 weeks later, when she was well.

    A baseline drawn during the reaction would already be raised and would mask the rise.

  3. Multiply the baseline: 1.2 × 4.0 ng/mL = 4.8 ng/mL.

    The criterion multiplies the patient's own baseline first.

  4. Add 2 ng/mL: 4.8 + 2 = 6.8 ng/mL.

    The added 2 ng/mL allows for normal variation between specimens.

  5. Compare: 8.1 ng/mL is greater than 6.8 ng/mL.

    The acute result is compared with the patient's threshold.

  6. Both results are within the reference interval, so neither is flagged. Reading the flags alone would miss the rise.

    The reference interval comes from a reference population and misses a rise from a low baseline.

Threshold = 1.2 × 4.0 ng/mL + 2 ng/mL = 6.8 ng/mL. The acute tryptase of 8.1 ng/mL exceeds it, which supports mast-cell activation.

Practice this skill

Your turn

Problem 1 of 3 · Hints available

A kidney biopsy shows IgG laid down in a smooth, continuous line along the glomerular basement membrane. The patient's serum contains antibody against a basement membrane collagen. Which hypersensitivity type fits?

Circulating complexes deposit unevenly in a granular pattern. Here the antibody binds collagen that is part of the basement membrane.

Classified all antibody injury as immune-complex disease

Type II injury comes from IgG or IgM bound to a fixed cell, matrix, or receptor, and type III from soluble immune complexes deposited in tissue. Calling every antibody-mediated injury immune-complex disease mislabels immune cytopenias, anti-GBM disease, and receptor antibodies.

The antigen is fixed in the basement membrane, and IgG binds it in place. That gives the smooth linear pattern of anti-GBM disease.

Type IV injury comes from sensitized T cells. This biopsy shows antibody bound to the membrane.

Type I reactions depend on IgE on mast cells. IgG along the basement membrane is a different mechanism.

Hint
  1. Ask where the antigen is located before the antibody binds it.
  2. Compare where the antigen is located in type II and in type III.

Review Hypersensitivity mechanisms

Problem 2 of 3 · Hints available

A serum tryptase collected 1 hour after symptom onset is 9 ng/mL, and the later baseline is 5 ng/mL. Using the criterion 1.2 × baseline + 2 ng/mL, what is the threshold, and does the acute result exceed it?

Incorrect. 1.2 × 5 = 6 ng/mL leaves out the added 2 ng/mL. The threshold is 1.2 × 5 + 2 = 8 ng/mL.

Correct. 1.2 × 5 + 2 = 8 ng/mL, and 9 ng/mL exceeds it, which supports mast-cell activation. The acute specimen was drawn within the recommended 2 hours of symptom onset.

Incorrect. 5 × (1.2 + 2) = 16 ng/mL multiplies the baseline by the sum. The baseline is multiplied by 1.2 first, then 2 ng/mL is added.

Hint
  1. The criterion has two parts. Do them in order.
  2. Scale the baseline first, then add the fixed amount.

Review Type I laboratory findings

Problem 3 of 3 · On your own

A man with seasonal sneezing has a total IgE of 620 IU/mL (reference <100 IU/mL). His provider asks whether the result identifies the allergen causing his symptoms. What does the laboratory tell the provider?

Total IgE rises with many allergens, parasites and other conditions. It does not identify any one allergen.

Many allergic patients have a total IgE within the reference interval. Total IgE cannot exclude allergy either.

Nothing suggests an error in the measurement. A repeat total IgE would not identify an allergen either.

Total IgE has poor specificity for an individual allergy. Specific IgE to the suspected pollens shows sensitization, which is then interpreted with his symptoms.

Review Type I laboratory findings

Use it

Read the case evidence, then make each decision. The step is complete without it.

  • Tomasz Summers, 29, keeps six hives of bees on his roof.
  • Last week a honeybee stung his hand. Within minutes he had hives, wheezing and low blood pressure.
  • The emergency department drew an acute tryptase 1 hour after the sting.
  • A baseline tryptase and venom-specific IgE were drawn 3 weeks later.
  • He says a wasp has never stung him.
TestResultReference intervalFlag
Tryptase, acute10.4 ng/mL<11.5 ng/mL<11.5
Tryptase, baseline6.0 ng/mL<11.5 ng/mL<11.5
Honeybee venom IgE3.2 kU/L High<0.35 kU/L<0.35High
Wasp venom IgE0.9 kU/L High<0.35 kU/L<0.35High

Specimen: H 2, L 8, I 1. Acute serum 1 hour after the sting; baseline and venom IgE serum 3 weeks later

Decision 1 of 3

Which mechanism fits his reaction to the sting?

Immune-complex injury takes days to develop. His reaction began within minutes.

Venom cross-linked IgE on his mast cells, which released their mediators within minutes.

T-cell reactions take a day or more to appear. His started within minutes.

Review Hypersensitivity mechanisms

Decision 2 of 3

Does the acute tryptase meet the criterion for mast-cell activation?

The criterion uses his own baseline. His threshold is 1.2 × 6.0 + 2 = 9.2 ng/mL, and 10.4 ng/mL exceeds it.

Judged an acute tryptase by the population reference limit

The criterion compares the acute tryptase with the patient's own baseline, using 1.2 × baseline + 2 ng/mL. A baseline of 5 ng/mL gives a threshold of 1.2 × 5 + 2 = 8 ng/mL. An acute value of 9 ng/mL exceeds that threshold and falls within a laboratory reference interval, so judging it against the population limit misses mast-cell activation.

1.2 × 6.0 = 7.2 ng/mL leaves out the added 2 ng/mL. The threshold is 9.2 ng/mL.

1.2 × 6.0 ng/mL + 2 ng/mL = 9.2 ng/mL. The acute 10.4 ng/mL exceeds it, which supports mast-cell activation.

6.0 × (1.2 + 2) multiplies the baseline by the sum. The baseline is multiplied by 1.2 first, then 2 ng/mL is added.

Review Type I laboratory findings

Decision 3 of 3

How does the laboratory interpret the wasp venom IgE?

Specific IgE shows sensitization. He has never reacted to a wasp, so nothing links this IgE to a reaction.

Reported sensitization as clinical allergy

Allergen-specific IgE or a positive skin test shows sensitization. Whether that sensitization explains a reaction depends on the patient's exposure and reaction history. Total IgE has poor specificity for an individual allergy. A positive IgE result without a matching history does not show that the patient is allergic.

The IgE shows he has made antibody that binds wasp venom. Venom IgE often cross-reacts, and his history shows no wasp reaction.

The measurement is valid. Sensitization without a reaction history is common and is reported as measured.

Review Type I laboratory findings

The result that matters is his own baseline tryptase. A baseline of 6.0 ng/mL gives a threshold of 9.2 ng/mL, so an acute 10.4 ng/mL shows mast-cell activation even though neither result is flagged. The venom IgE results show sensitization, and only the honeybee result matches a reaction he has had.

For reference

Sources checked