Introduction:
Fixed drug eruption is a well-defined, circular, pigmented one or more lesions in a place after ingesting a drug. It can occur at the same site or at different sites. When a large area is involved with bullous (large bubbles on the skin filled with clear fluid) formation, it is known as generalized bullous fixed drug eruption (GBFDE). The first line of approach for any fixed drug eruption is to identify and remove the causative agent. Failure to remove the causative agent can increase inflammation and pigmentation, leading to lethal generalized bullous FDE (GBFDE).
Who Are Affected With Fixed Drug Eruption?
Fixed drug eruptions are seen in 2 % to 5 % of hospitalized patients and 1 % of outpatients. Fixed drug eruptions are rarer than exanthematous (morbilliform) eruptions, where 95 % of a drug reaction to the skin is seen. Fixed drug eruptions occur in males and females of all age groups. 5 % to 22 % of children report fixed drug eruptions. Fixed drug eruption is commonly seen with oral medications.
What Causes Fixed Drug Eruptions?
Fixed drug eruption is a delayed-type IV hypersensitivity reaction. The reason behind a selected drug reaction remains unknown. The result of many studies using patch tests, auto-transplantation, and demonstration of the causative agents in the lesion and the laboratory studies in FDE has been fascinating yet indecisive.
-
Within 24 hours of intake of culprit medication, the immune cells migrate towards the skin surface and activate the natural killer cells to destroy the skin surface and pigment-producing cells. Once destroyed, the immune cells reverse the function, stop the activation of natural killer cells, and collect the pigment explaining why fixed drug eruptions are self-limiting lesions and produce pigment.
-
Presence of human leukocyte antigen (HLA).
-
FDE to a particular drug is seen in immediate family members, indicating genetic inheritance.
Fixed drug eruptions occur up to one week after the first drug exposure; for following exposures, between 30 minutes and eight hours. It resolves a few weeks after stopping the medication, but the post-inflammatory hyperpigmentation can last up to a few months.
How Is Fixed Drug Eruption Diagnosed?
Fixed drug eruption should be diagnosed based on history and clinical examination. It may be challenging to analyze on the first occasion, but on the next episode, a detailed history of oral intake in the preceding 24 hours may identify the drug involved. The diagnosis is confirmed by microscopic examination of a small punch biopsy specimen, patch test, and lymphocyte transformation test. Oral challenge has been the gold standard of diagnosis but is now usually contraindicated due to the risk of widespread FDE or GBFDE.
1. Oral Challenge Test: A low dose of a suspected drug is ingested and checked for the patch. The oral challenge is contraindicated in generalized bullous fixed drug eruption patients.
2. Biopsy: A biopsy is indicated in patients with an unclear diagnosis or associated systemic symptoms such as fever, malaise, or arthralgia. It is also demonstrated in the unique subtypes of generalized FDE, GBFDE, and mucosal FDE.
3. Patch Testing: Patch testing is the best confirmation method and is more accessible and safer. A patch test is done using the suspected drug in soft paraffin applied to the lesion site and conducted on a highly pigmented area from the previous FDE. However, the sensitivity of patch testing depends on the memory of immune cells to last attack and drug penetration through the skin.
Limitation of Patch Testing-
- Ineffective in patients without visible lesions.
- Sensitive for NSAIDs, but not antibiotics.
- A few weeks after the lesions resolve, it should be done to avoid a false negative result.
4. Lymphocyte Transformation Test (LTT): The lymphocyte transformation test is not confirmatory and is not commonly used. LTT is a laboratory examination that measures a sensitized immune cell response to a drug. LTT is primarily used in confirming drug hypersensitivity reactions, where it has a sensitivity of 60 % to 70 %.
What Are the Clinical Features of Fixed Drug Eruption?
FDE is classified based on clinical morphology as:
-
Localized pigmenting type.
-
Bullous (localized or generalized).
-
Mucosal, non-pigmenting.
-
Generalized.
1. Localized Fixed Drug Eruption: The most common form of fixed drug eruption commonly occurs on the genitals, lips, trunk, hands, and areas of previous skin trauma, such as burns, insect bites, venipuncture, and healed herpes simplex virus (HSV) infection. It appears as a circular lesion with a dusky gray center and red or violet margin, single, localized cluster, or diffuse. Fixed drug eruptions are usually asymptomatic but may be painful or pruritic, and sensations of itching or burning before the lesion starts.
2. Generalized Fixed Drug Eruption (GBFDE): Occur as dusky-red or heavily pigmented oval blisters and erosions. Blistering affects only a small body surface area, and between two large blisters are normal skin surfaces. Erosive mucosal involvement is rare. The patient generally has better overall health (differentiates SJS/TEN).
3. Mucosal Fixed Drug Eruption: Seen in lips, tongue, hard palate, and genital mucosa. Commonly present as blisters and erosions, isolated or localized, or may occur with cutaneous lesions.
4. Non-Pigmenting Fixed Drug Eruption: Often symmetrical lesions resolve without post-inflammatory hyperpigmentation.
5. Generalized Fixed Drug Eruption: Presents with numerous lesions. Lesions may be targetoids resembling erythema multiforme.
How to Treat Fixed Drug Eruption?
-
Drug avoidance is the mainstay of treatment.
-
Antihistamines can reduce associated pruritus.
-
Topical or systemic steroids.
-
Mild oral lesions can usually be managed with viscous Lidocaine, topical corticosteroids, or calcium carbonate.
-
For erosive genital FDE, zinc oxide paste is provided to reduce irritation and the risk of infection.
-
Raising awareness of fixed drug eruptions increases the likelihood of prompt diagnosis leading to resolution within days to weeks after the responsible drug is discontinued.
-
Generalized bullous fixed drug eruption may need intensive care or burns units for aggressive wound care.
What Are the Complications of Fixed Drug Eruption?
-
Blisters, erosions.
-
Post-inflammatory pigmentation.
-
Re-occurrence.
-
Cross-reactivity with medications.
-
Generalized bullous fixed drug eruption can be confused with fluid loss, electrolyte imbalance, and secondary infection.
What Drugs Can Cause Fixed Drug Eruption?
1. Antimicrobials:
-
Antibiotics - Tetracycline, Cotrimoxazole, Penicillins, Quinolones, Metronidazole, Rifampicin, Dapsone, and Erythromycin.
-
Antimalarial - Quinine.
-
Antifungals - Systemic azoles.
2. Analgesics:
-
Paracetamol.
-
Non-steroidal anti-inflammatory drugs (NSAID) - Aspirin, Mefenamic acid, Ibuprofen, Naproxen, and Piroxicam.
3. Sedatives and Anticonvulsants - Carbamazepine, Barbiturates, and Benzodiazepines.
4. Antihypertensive - Calcium-channel blockers, angiotensin-converting enzyme inhibitors.
5. Other Drugs - Cetirizine, Omeprazole, Pseudoephedrine, Sulphasalazine, vaccinations, tonic water Quinine, oral contraceptives, additives or colorants, Tartrazine, laxatives, etc.
6. Exposure to Ultraviolet in the A or B Range (UVA or UVB).
7. Complementary Medicines - Including traditional herbal medications and supplements.
8. Foods - Cashew nuts, asparagus, lentil, kiwi fruit, palm wine, peanut, strawberry, propolis, quinine (tonic water), seafood, tartrazine (yellow rice, cheese crisps, etc.).
What Are the Other Conditions That Resemble Fixed Drug Eruption?
-
The first incidence of single or few lesions - Bullous insect bite reaction, bullous pemphigoid, and other autoimmune bullous disorders.
-
Targetoid lesions - Erythema multiforme.
-
Multiple bullous lesions - Stevens-Johnson syndrome.
-
Oral lesions - Aphthous ulcer, oral autoimmune blistering disease morbilliform exanthem, herpes simplex, urticaria, hypersensitivity syndrome, pseudolymphoma, photosensitivity, pigmentary changes, acute generalized exanthematous pustulosis, lichenoid dermatitis, vasculitis, Stevens-Johnson syndrome.
-
Erythematous plaques - Lichen planus.
-
Localized pigmenting - Psoriasiform epidermal hyperplasia.
Conclusion:
Fixed drug eruptions have been well described in the literature. Still, with the development of many new medications, a broad spectrum of FDEs has been seen that may mimic other more emergent dermatologic entities. We encourage physicians to consider FDEs, specifically non-pigmenting, bullous, and generalized bullous FDEs, when evaluating patients for erythema multiforme, Stevens-Johnson syndrome, TEN, cellulitis, and bullous pemphigoid.
