Authors: Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand, 2001; Updated: Dr Christine Condon, Resident Medical Officer, St Vincent’s Hospital Melbourne, Australia; A/Prof Rosemary Nixon AM, Dermatologist, Skin Health Institute, Carlton, Australia. Copy edited by Gus Mitchell. March 2021
Fixed drug eruption is a distinctive cutaneousallergic reaction that characteristically recurs at the same site(s) on re-exposure to the medication or other chemical agent.
Fixed drug eruption
Targetoid fixed drug eruption
Blistering fixed drug eruption
Who gets fixed drug eruption?
Fixed drug eruption affects both sexes, and affects adults more commonly than children. There are some examples of HLA-associations with fixed drug eruptions due to specific drugs eg, HLA-A30 with cotrimoxazole-induced fixed drug eruption.
What causes fixed drug eruption?
Fixed drug eruption is a delayed type IV hypersensitivity reaction. In the initial phase memory CD8+ T-cells at the dermo-epidermal junction release interferon-gamma when activated by the medication antigen causing epidermal basal layer damage. Recruited T-cells and neutrophils damage melanocytes and keratinocytes. During the resolution phase, dermalmacrophages collect the melanin resulting in the typical post-inflammatoryhyperpigmentation. Regenerating basal keratinocytes release interleukin-15 leading to the formation of resident memory CD8+ T-cells which remain quiescent but in a primed state ready to respond to the chemical antigen again.
Fixed drug eruption is usually due to oral medications, with antimicrobials and non-steroidal anti-inflammatory drugs (NSAID) being the most common culprits. Less common drug exposures may be topical or intravaginal. Fixed food eruptions may be due to antibiotics, flavouring or colouring agents, or preservatives in the food. Herbal supplements and caffeine have also been implicated. For a more detailed list, see the Appendix at the end.
What are the clinical features of fixed drug eruption?
Fixed drug eruption can be categorised by clinical morphology. The most common form is the localised pigmenting type; other presentations include bullous (localised or generalised), mucosal, non-pigmenting, or generalised.
Fixed drug eruption typically presents as a single (or small number of) well-defined, round or oval red or violaceouspatch or plaque which may blister or ulcerate. It is usually asymptomatic but can be itchy or painful. Over the next few days and weeks, the surface may become scaly or crusted before peeling, and the colour fades to leave brown post-inflammatory hyperpigmentation. Post-inflammatory hyperpigmentation tends to be more prominent in skin of colour.
In contrast to many other drug eruptions, the patient remains systemically well.
The hands and feet, eyelids, and anogenital areas are common sites. Lesions in the oral mucosa are usually found on the lips, tongue and hard palate. A fixed drug eruption may occur at the same location as previous skin trauma such as a burn, insect bite, or venepuncture.
On the first occasion, the eruption may develop after weeks to years of regular ingestion of the drug, but subsequent episodes develop within minutes to hours of recommencing the implicated drug. A patch of fixed drug eruption shows a refractory period during which it will not flare even with re-exposure. With subsequent episodes, the original patch may enlarge and more patches may appear. The post-inflammatory hyperpigmentation darkens with each recurrence.
Fixed drug eruption
Fixed drug eruption
Targetoid lesion in fixed drug eruption
Clinical variants of fixed drug eruption
Mucosal fixed drug eruption
Involves lips, tongue, hard palate, genital mucosa
Blisters and erosions are common
Can be isolated/localised or may occur with cutaneous lesions
Oral mucosal lesions commonly due to cotrimoxazole and naproxen
Resolves without post-inflammatory hyperpigmentation
Associated with piroxicam and pseudoephedrine.
Generalised fixed drug eruption
Presents with numerous lesions
Lesions may be targetoid resembling erythema multiforme.
Generalised bullous fixed drug eruption
Rare variant
Recurrent episodes with onset within 24 hours of drug exposure
Numerous large blisters and erosions with normal skin between typically affecting <10% of the skin surface
Relative sparing of mucosal surfaces
Lesions are not targetoid
Fever, malaise and arthralgia may be associated
Resolves with post-inflammatory hyperpigmentation.
What are the complications of fixed drug eruption?
Blisters and erosions
Post-inflammatory hyperpigmentation
Recurrence
Cross-reaction with other medications
Generalised bullous fixed drug eruption can be complicated by fluid loss, electrolyte imbalance, and secondary infection.
How is fixed drug eruption diagnosed?
Fixed drug eruption should be considered on history and examination but may be difficult on the first occasion. On subsequent episodes, a detailed history of oral intake in the preceding 24 hours may identify the culprit.
Investigations may include:
Skin biopsy — shows an interfacedermatitis in an early lesion with scattered apoptotic keratinocytes, vacuolar degeneration, dermal oedema, and a superficial perivascular lympho-eosinophilicinfiltrate. Blisters are subepidermal if present. A late lesion shows upper dermal melanophages.
Oral challenge test — with a low dose of the suspected drug although there is typically a refractory period during which time the patch will not flare. This is contraindicated in patients with generalised bullous fixed drug eruption.
Patch test — using the suspected drug in soft paraffin applied to the lesion site is positive in 50% of cases. Prick testing and patch testing on normal skin is usually negative.
What is the differential diagnosis for fixed drug eruption?
First episode of single or few lesions — bullous insect bite reaction, bullous pemphigoid and other autoimmune bullous disorders
Generalised bullous fixed drug eruption requires intensive care or burns unit
What is the outcome for fixed drug eruption?
Fixed drug eruption is generally a benign self-resolving eruption that recurs on re-exposure, leaving post-inflammatory hyperpigmentation. Subsequent flares can be more severe.
Generalised bullous fixed drug eruption can be life-threatening, and has been reported to have a 20% mortality rate.
Appendix: list of some causes of fixed drug eruption
Adern-Jones MR, Lee HY. Benign cutaneous adverse reactions to drugs. In: Griffiths C, Barker J, Bleiker T, Chalmers R, Creamer D (eds). Rook’s Textbook of Dermatology, 9th edn. Wiley Blackwell, 2016: pp118.11–14.
Byrd RC, Mournighan KJ, Baca-Atlas M, Helton MR, Sun NZ, Siegel MB. Generalized bullous fixed-drug eruption secondary to the influenza vaccine. JAAD Case Rep. 2018;4(9):953–5. doi:10.1016/j.jdcr.2018.07.013. PubMed Central
Fukushima S, Kidou M, Ihn H. Fixed food eruption caused by cashew nut. Allergol Int. 2008;57(3):285–7. doi:10.2332/allergolint.C-07-58. Journal
Mitre V, Applebaum DS, Albahrani Y, Hsu S. Generalized bullous fixed drug eruption imitating toxic epidermal necrolysis: a case report and literature review. Dermatol Online J. 2017;23(7):13030/qt25v009gs. Journal
Mizukawa Y, Shiohara T. Trauma-localized fixed drug eruption: involvement of burn scars, insect bites and venipuncture sites. Dermatology. 2002;205(2):159–61. doi:10.1159/000063892. PubMed
Mizukawa Y, Yamazaki Y, Teraki Y, et al. Direct evidence for interferon-gamma production by effector-memory-type intraepidermal T cells residing at an effector site of immunopathology in fixed drug eruption. Am J Pathol. 2002;161(4):1337–47. doi:10.1016/s0002-9440(10)64410-0. Journal
Özkaya E. Oral mucosal fixed drug eruption: characteristics and differential diagnosis. J Am Acad Dermatol. 2013;69(2):e51–8. doi:10.1016/j.jaad.2012.08.019. PubMed
Patel S, John AM, Handler MZ, Schwartz RA. Fixed drug eruptions: an update, emphasizing the potentially lethal generalized bullous fixed drug eruption. Am J Clin Dermatol. 2020;21(3):393-9. doi:10.1007/s40257-020-00505-3. PubMed
Tan C, Zhu WY. Chinese herbal medicine: a neglected offender for fixed drug eruptions. Eur J Dermatol. 2010;20(3):397–9. doi:10.1684/ejd.2010.0947. PubMed