6  Immediate Drug Allergy

For an overview of immediate drug allergy testing, I recommend getting started by watching Immediate Drug Allergy Hypersensitivity Testing.

Skin Testing

Concentrations typically employed for drug skin testing are 1:10, 1:100, and full strength.

Should be performed on healthy, non-pathologic skin. For example skin with altered permeability (e.g. atopic dermatitis), the amount of allergen penetrating the skin is up to 20x greaterh than the average volume of inoculum by SPT.

Skin Prick Testing

Figure 6.1: Skin prick testing

Intradermal Testing

Figure 6.2: Intradermal testing

Controls

To increase the solubility of histamine in water, it is provided in its salt form, such as histamine dihydrochloride or histamine phosphate. In vivo, histamine dissociates into its biologically active form, called “histamine base.”

The histamine and normal saline controls used for skin testing usually also includes 0.4% phenol (also known as carbolic acid) in order to inhibit microbial growth and maintain sterility. Carbolic acid is what Joseph Lister discovered to be an effective antiseptic for surgery.

Increased skin test reactivity - Skin lesion with altered permeability (e.g. atopic dermatitis) - Stress

Decreased skin reactivity - Eczema (but finding is not consistently observed) - Some patients with cancer - Chronic renal failure or on regular hemodialysis - Patients with spinal cord injuries - Peripheral nerve abnormalities (e.g. diabetic neuropathy)

Positive Skin Test

Figure 6.3: Positive skin test

Immediate skin testing reading times

Immediate Reaction

Immediate skin testing starts around 5 minutes and peaks at 15 minutes, resolving around 30 minutes.

Histamine is not the only mediator of the wheal and flare response. Mast cell degranulation also leads to release of the following mediators:

• Tryptase

• Neurogenic Mediators (e.g. substance P, CGRP, neurokinin A)

• Nitric oxide

• Corticotropin-releasing hormone

Late phase reaction

Late phase reaction–if occurs–start around 1-2 hours, peak at 6-12 hours, and resolve at 24-48 hours. Not actively/systematically recorded (instruct patients to notify if does occur); however, the exact clinical significance of late phase reactions is unknown.

Concentrations

Oral Challenge

Rapid Desensitization

Figure 6.4: Rapid Desensitization

Figure 6.5: Rate (mg/min) by time for 1-bag vs 3-bag rapid desensitization protocols

Figure Generated from protocol comparison from (Lee et al. 2020)

Biomarkers

Tryptase

Figure 6.6: Tryptase Gene

Figure 6.7: Tryptase Secretion

Figure 6.8: Tryptase Secretion

Figure 6.9: Acute and Baseline Tryptase

Tryptase is a natural serine protease

average tryptase, average tryptase HAT, average tryptase ISM, average tryptase ASM

Elevated basal tryptase >= 11.5 ng/mL Can get basal tryptase at 24 hrs after anaphylaxis event

Anaphylaxis >= 20% increase from basal tryptase + 2 ng/mL

TPSAB1 increased: HaT, SM CNV (alpha tryptase) alpha or beta tryptase constitutively released (measure of MC burden)

TPSB2 Beta preformed granule release during anaphylaxis/severe MC activation

Total Tryptase = a + B by ImmunoCAP (R) In vitro assay half-life ~90 minutes peak at 1 hr stored primarily in MC

Lee, Jae-Ha, Mira Moon, Young-Chan Kim, Soo Jie Chung, Jihyun Oh, Dong-Yoon Kang, Suh-Young Lee, Kyung-Hun Lee, James Yun, and Hye-Ryun Kang. 2020. “A One-Bag Rapid Desensitization Protocol for Paclitaxel Hypersensitivity: A Noninferior Alternative to a Multi-Bag Rapid Desensitization Protocol.” The Journal of Allergy and Clinical Immunology: In Practice 8 (2): 696–703. https://doi.org/10.1016/j.jaip.2019.10.014.