Drug reaction fixe L27.1

Author: Prof. Dr. med. Peter Altmeyer

All authors of this article

Last updated on: 03.08.2022

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Synonym(s)

Drug exanthema fixed toxic; Drug reaction fixed generalized bullous; FDE; Fixed drug eruption; Fixed drug exanthema; Fixed drug reaction; Fixed toxic drug exanthema; Fixed toxic drug reaction; GBFDE; Generalized bullous fixed drug eruption; Generalized bullous fixed drug exanthema

History
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Bourns in 1899; Brocq in 1894;

Definition
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Localized, spotty or plaque shaped, also bullous or erosive drug reaction,

  • which occurs in a temporal connection with the intake of drugs (triggering drugs see table) in therapeutic doses
  • is limited to a solitary stove or a few stoves
  • and
  • tends to recur in situ (recurrence in loco).

Etiopathogenesis
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The immunopathogenetic mechanism of the fixed drug response has not yet been elucidated (see also under erythema exsudativum multiforme). The central role is played by CD8+ T cells, which have a phenotype similar to the effector memory T cell and are mainly responsible for the epidermal damage. CD8+ positive cells persist for years in old already clinically healed lesions(tissue-resident memory-t-cells) and can be expressed and activated on keratinocytes after re-exposure to the agent via a probably TNF-alpha induced upregulation of ICAM-1 (see below adhesion molecules) (see also UV reactivation reaction). The release of interferon gamma leads to an inflammatory reaction.

The apoptosis of keratinocytes (which is histologically distinct) seems to be induced by a FAS-FAS ligand interaction (see below CD classification - CD95, or CD95L).

Of note is the role of viral infections (e.g., herpes simplex infections) as cofactors for the "recurrence" of the fixed drug response. For the recurrent "in-loco occurrence" a so-called recall reactivation reaction can be assumed, although the immunological processes for this are also still unclear (see also under UV reactivation reaction).

Manifestation
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Occurrence 1-2 weeks after (first) use of the drug. With repeated ingestion, occurrence within 30 min. up to 24 hours possible. The relationship between drug intake and the appearance of the lesions is not always clear.

Occurrence possible in all age groups. Predominance between 20-60 years (average in larger studies at 36-53J). No gender predilection.

Localization
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Ubiquitous occurrence is possible.

Preference is given to the upper extremity (about 50%), followed by the lower extremity, lips, face, penis, vulva; involvement of the oral mucosa can occur very incisively (cheek mucosa, gingiva, hard and soft palate). The mucosa of the glans penis and vulva are also typical (often unrecognized) sites of manifestation.

Clinical features
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Solitary or limited to a few foci, 2.0-5.0 cm in size (rarely up to 10 cm in size), round or oval (rarely also anular), initially saturated red, later blue- to brown-red, after healing brown (postinflammatory hyperpigmentation), sharply demarcated, succulent, itchy or also slightly painful spots or plaques. Vesicular transformation in the center is possible. Diagnosis may be complicated in intertriginous involvement because the characteristic clinical morphology there is obscured by acting local factors. Clinically, (large-) area erosion may be apparent at these sites.

The maximum variant described is the generalized and possibly multilocular bullous fixed drug reaction (GBFDE), which can occur in adults as well as in children.

An extreme intertriginous variant is the so-called " baboon syndrome".

Upon re-exposure, the lesions reappear in exactly the same location within 24 hr. However, a refractory period may occur immediately after healing of the lesion.

To be distinguished are:

  • Classic fixed drug reaction: Most common form, which heals via a long-term persistent postinflammatory hyperpigmentation.
  • Non-pigmented variant of fixed drug reaction: Rarer form; usually occurring over a larger area (up to 10 cm in size) and healing without postinflammatory hyperpigmentation.
  • Urticarial fixed drug reaction: Rare variant, again urticarial and recurring in loco on provocation.
  • Neutrophilic fixed drug reaction: Extremely rare variant that presents histologically as neutrophilic dermatitis. Only a few case reports have been published.

Histology
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Interface dermatitis with numerous apoptotic keratinocytes; lichenoid and perivascular inflammatory reaction of the upper and middle dermis; few eosinophil and neutrophil granulocytes. Indicated or pronounced papilledema up to subepidermal cleft or blister formation. Initially slight, later pronounced pigment incontinence.

Diagnosis
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Clinical picture with recurrence in loco.

Note: Eye drops should also be considered during medical history!

The results of prick-scratch tests are evaluated differently. They are performed in loco in healed lesions. In individual studies (e.g. for non-steroidal anti-inflammatory drugs), reliable positive results of 40% are reported (Andrade 2011).

Oral provocation with the drug in question is the proof.

Therapy
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Withdrawal of the suspected substance, depending on clinical presentation and extent, either wait-and-see or local glucocorticoids.

Internal therapy
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In case of corresponding severity of the clinical picture: systemic glucocorticoids in medium dosages, e.g. 60-80 mg prednisolone equivalent per day p.o. (e.g. Decortin ®).

Later gradual dose reduction, stomach protection. For severe pruritus antihistamines such as Dimetinden, e.g. Fenistil® 2 times/day 1 amp. i.v. or Desloratadin (Aerius®) 1 time / day 1 tbl. p.o.

Progression/forecast
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In larger collectives an average of 2.6 recurrences (1-10 recurrences) were anamnestized.

Tables
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Medication Group

Active ingredients

Classical form

Analgesics/NSAIDs

Acetaminophen, acetylsalicylic acid, ibuprofen, indometacin, naproxen, phenazone derivatives, paracetamol, sulindac

antidepressants/antipsychotics

carbamazepine, lorazepam, lormetazepam (noctamide), oxazepam, temazepam

Antihistamines (H1 blockers)

Cetirizine, dimenhydrinate, hydroxyzin hydrochloride (Atarax), loratadine

Antimicrobially active substances

amoxycillin, ciprofloxacin, clarithromycin, erythromycin, fluconazole, ketoconazole, metronidazole, minocycline, norfloxacin, ofloxacin, penicillin, rifampicin, terbinafine, tetracyclines, trimethoprim-sulfamethoxazole, vancomycin

COX-2 inhibitors

Celecoxib, parecoxib, valdecoxib

Local anaesthetics

Articaine, lidocaine, mepivacaine

Further

Aciclovir, allopurinol, atenolol, barbiturates, BCG vaccine, benzodiazepines, chloroquine, clioquinol, dapsone, foscarnet, dextromethorphan, diflunisal, dimenhydrinate (Volon A), docetaxel, influenza vaccine, heparin, interferon-ribavirin combinations, interleukin-2, iopamidol (contrast medium), Kakkon-To (Japanese medicinal plant), lactose (z.B. in botulinum preparations), magnesium, omeprazole, oral contraceptives, melatonin, metamizole, ondansetron (Zofran), paclitaxel, pyrimethamine sulfadoxins (fansidar), quinolones, sulfasalazine, sulfaguanidine, ticlopidine, tolmetin, tosufloxacintosilate, triamcinolone, tropisetron, tropotecan (hydrogenzamtin)

Non-pigmented variant

betahistine (antiemetic), cimetidine, ephedra heba ("ma huang"), ephedrine, paracetamol, piroxicam, pseudoephedrine, tetrahydrozoline, triamcinolone acetonide

Case report(s)
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Medical history: A 67-year-old patient reported a treatment with Terbinafine because of a therapy-resistant onychomycosis. 2 hours after taking the 1st tablet he had noticed strongly itchy wheals on the inner side of the right upper arm. The treatment was then discontinued. The symptoms had receded.

Diagnosis: Epicutaneous and prick tests with Terbinafine o.B. When provoking the drug orally (125 mg Terbinafine) the patient developed an itchy wheal field of 6x6 cm on the inner side of the right upper arm within 3 hours. Testing was discontinued; the patient received symptomatic therapy with prednisolone and clemastine. Below this the symptoms improved within a few hours.

Diagnosis: Fixed (urticarial) drug reaction.

Literature
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  1. Agnew KL, Oliver GF (2001) Neutrophilic fixed drug eruption. Australas J Dermatol 42: 200-202
  2. Al Aboud K et al (2003) Fixed drug eruption to ibuprofen in daughter and father. J Drugs Dermatol 2: 658-659
  3. Andrade P et al (2011) Patch testing in fixed drug eruptions--a20-year review. Contact Dermatitis 65:195-201.
  4. Bourns DCG (1889) Unusual effects of antipyrine. Br Med J 2: 218-220
  5. Brocq L (1894) Eruption érythémateuse fixe a l`antipyrine. Ann Dermatol Vénéréol 5: 308-313
  6. Flowers H et al (2014) Fixed drug eruptions: presentation, diagnosis, and management. South Med J 107:724-727.
  7. Gilmore E et al (2004) Extensive fixed drug eruption secondary to vancomycin. Pediatric Dermatology 21: 600-602
  8. Hayashi H et al (2003) Multiple fixed drug eruption caused by acetaminophen. Clin Exp Dermatol 28: 455-456
  9. Handisuraya A et al (2011) Fixed drug eruption to mefenamic acid: a case series and diagnostic algorithms. JDDG 9: 374 - 378
  10. Hoetzenecker W et al.m(2016) Adverse cutaneous drug eruptions: current understanding. Semin Immunopathol 38:75-86.
  11. Jung JW et al (2014) Clinical features of fixed drug eruption at a tertiary hospital in Korea. Allergy Asthma Immunol Res 6:415-420.
  12. Kleinhans M et al (2004) Fixed drug eruption caused by articain. Allergy 59: 117
  13. Kornmehl H et al (2018) Generalized fixed drug eruption to piperacillin/tazobactam and review ofliterature
    .Dermatol Online J 24. pii: 13030/qt8cr714g5.
  14. Lee SS et al (2011) Maximal points of head's zone in fixed drug eruption. Ann Dermatol 23(Suppl 3):S383-386.

  15. Pionetti CH et al (2003) Fixed drug eruption due to loratadine. Allergol Immunopathol (Madr) 31: 291-293.
  16. Rödiger C et al. (2011) Fixed urticarial drug eruption? Abstract CD 46 DDG Conference: P02/07
  17. Sehgal VN et al (2003) Bullous fixed drug eruption (BFDE) following per-oral metronidazole. J Eur Acad Dermatol Venereol 17: 607-609
  18. Shiohara T et al.(2015) Crucial Role of Viral Reactivation in the Development of Severe Drug Eruptions: a Comprehensive Review. Clin Rev Allergy Immunol 49:192-202.
  19. Sidhu-Malik NK et al (2003) Multiple fixed drug eruption with interferon/ribavirin combination therapy for hepatitis C virus infection. J Drugs Dermatol 2: 570-573
  20. Tan C et al (2010) Anular fixed drug reaction. JDDG 8: 823-825
  21. Vester K et al (2011) Fixed drug exanthema due to flupirtine. Abstract CD 46th DDG meeting:P02/21.

Disclaimer

Please ask your physician for a reliable diagnosis. This website is only meant as a reference.

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Last updated on: 03.08.2022