7  Delayed Drug Allergy

Non-severe Cutaneous Adverse Drug Reactions

Allergic Contact Dermatitis

Allergic contact dermatitis (ACD) secondary to topical medications is characterized by an eczematous eruption–which typically localized to sites of direct exposure. Depending on the severity and chronicity of ACD, eczematous eruptions can range from localized erythema and edema to vesicularization, crusting and weeping. However, ACD can become generalized to non-exposed sites, referred to as “autoeczematization” or “id reaction.”

The differential diagnosis for ACD also includes irritant contact dermatitis as well as other chronic eczematous dermatoses (e.g., atopic dermatitis, psoriasis).

The top 4 drug category causes of ACD are: antibiotics, local anesthetics, corticosteroids, and propylene glycol (techically an excipient).

Important

Antibiotics (e.g., neomycin, bacitracin, polymyxin B) are the most common cause of ACD. Therefore, it is recommended to use petrolatum or other bland emolients for wound care because have equally low infection rate as bacitracin and other topical antibiotics without the risk of ACD.

Co-sensitization—when sensitized to ≥ 2 structurally distinct allergens—often occurs in patients who experience ACD. Therefore, when possible, it is important to test to individual components of a culprit topical drug.

Severe Cutaneous Adverse Drug Reactions

Figure 7.1: Timeline of SCAR

Drug Reaction with Eosinophilia and Systemic Symptoms

Figure 7.2: Signs and symptoms of DRESS

Nikolsky negative blistering on dependent surfaces due to significant underlying edema. Purpura is also found on dependent surfaces (lower extremities).

Lymphadenopathy (cervical, axillary, epitrochlear, inguinal).

Figure 7.3: Polymorphic rashes associated DRESS

Figure 7.4: Typical timing of select laboratory changes seen in DRESS

RegiSCAR criteria

https://doi.org/10.1111/bjd.12501

DRESS Review Paper in NEJM (Blumenthal)

Kroshinsky, Cardones, and Blumenthal (2024)

Mimics of Delayed Drug Allergy

• Lichen planus

• Prurigo nodularis

• Psoriasis

• Atopic dermatitis

• Mycosis fungoides

Note

These underlying chronic dermatoses can be exacerbated by drugs but not primarily driven by delayed drug allergy.

Skin Testing

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

Table 7.1: Utility of patch and intradermal skin testing for delayed drug allergy reaction types

Reaction	Patch Testing	Intradermal Testing
Maculopapular exanthem (MPE)	Useful if positive	Useful if positive
Acute generalized exanthematous pustulosis (AGEP)	Useful if positive	Useful if positive
Stevens-Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN)	Low sensitivity but potentially useful if positive	Contraindicated due to concern for potential reactivation
Drug reaction with eosinophilia and systemic symptoms (DRESS)	Useful if positive	Useful if positive
Fixed drug eruption	Useful if applied to the site of reaction	Useful if positive
Allergic contact dermatitis	Useful if positive	Useful if positive
Symmetrical drug-related intertrigenous and flexural exanthema (SDRIFE)	Useful if positive	Useful if positive
Drug-induced organ injury (e.g., kidney, liver)	Not useful	Not useful

Important

No delayed skin testing method has 100% negative predictive value.

Table 7.2: Shared characteristics of patch and intradermal testing

Characteristic	Details
Timing	Perform at least 6 to 8 weeks after reaction; and 6 months or later after DRESS
Concomitant medications	Most medications okay to continue, including anti-histamines and beta-blockers. Should be off of steroids for ≥ 1 month or prednisone equivalent dose ≤ 10 mg/day

Intradermal Testing

Table 7.3: Characteristics of intradermal testing

Characteristic	Details
Testing site	Volar forearm or extensor upper arm
Testing reagents	Must be sterile; often higher concentrations than those used for immediate skin testing
Reading	At 24 hours
Controls	+ None - Saline
Test interpretation	+ Papule present - Negative

Patch Testing

Figure 7.5: Patch testing

Figure 7.6: Patch testing sites

Figure 7.7: Patch testing placement for fixed drug eruption

Figure 7.8: Patch test reading times

Figure 7.9: Patch test interpretation

Table 7.4: Characteristics of patch testing

Characteristic	Details
Testing site	Back or upper arm (needs to be hairless)
Testing reagents	1% and 10% of reagent grade product; 10% and 30% of trade product; most commonly used vehicle is petrolatum
Controls	+ None - Petrolatum
Shelf-life of patch test mixes	Most antibiotics at room temperature are stable for 1 to 3 months; check with USP Pharmacopeia for verification
Patches	Finn chambers (can be aluminum or molded plastic)
Tape	Use hypoallergenic paper tape
Reading	At 48 hours (85% of drugs-if will be positive-are positive by this point); 72 hours; 96 hours; and 1 week
Test interpretation	- Negative ? Doubtful reaction + Weak reaction, erythema ++ Strong reaction, erythema, papules, or vesicles +++ Extreme, bullous, ulcerative

Human Leukocyte Antigen Testing

Enzyme-linked Immunospot Testing

Figure 7.1: Timeline of SCAR Figure 7.2: Signs and symptoms of DRESS Figure 7.3: Polymorphic rashes associated DRESS Figure 7.4: Typical timing of select laboratory changes seen in DRESS Figure 7.5: Patch testing Figure 7.6: Patch testing sites Figure 7.7: Patch testing placement for fixed drug eruption Figure 7.8: Patch test reading times Figure 7.9: Patch test interpretation

Kroshinsky, Daniela, Adela Rambi G. Cardones, and Kimberly G. Blumenthal. 2024. “Drug Reaction with Eosinophilia and Systemic Symptoms.” Edited by Julie R. Ingelfinger and Clement D. Lee. New England Journal of Medicine 391 (23): 2242–54. https://doi.org/10.1056/NEJMra2204547.