Drug reaction fixe L27.1

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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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 reaction is still unknown (see also erythema exsudativum multiforme). The central role is played by CD8+ T cells, which have a phenotype similar to that of effector memory T cells and are mainly responsible for 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 (see also UV reactivation reaction) on keratinocytes after renewed exposure to the agent via a probably TNF-alpha-induced upregulation of ICAM-1 (see below adhesion molecules). The release of interferon gamma leads to an inflammatory reaction.

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

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

Manifestation
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Occurrence 1-2 weeks after (initial) use of the medicine. Repeated use within 30 minutes up to 24 hours is possible. The connection between drug intake and occurrence of the lesions is not always clear.

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

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 restricted to a few foci, 2.0-5.0 cm large (more rarely up to 10 cm large plaques), round or oval (rarely also anular), initially deep red, later blue to brown-red, after healing brown (post-inflammatory hyperpigmentation), sharply defined, succulent, itchy or even slightly painful spots or plaques. Blistery transformation in the centre is possible. In the case of intertriginous infestation, diagnosis can be made more difficult because the characteristic clinical morphology is overlaid by local factors. Clinically impressive is then a (large) area erosion.

The generalised, possibly multilocular, bullous fixed drug reaction (GBFDE) is described as themaximum variant , 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 within 24 hours at exactly the same site. However, a refractory period can occur immediately after healing of the lesion.

A distinction must be made:

  • Classical fixed drug response: Most common form which heals by long-term persistent post-inflammatory hyperpigmentation.
  • Non-pigmented variant of the fixed drug reaction: Rarer form; generally occurs over a larger area (up to 10 cm in size) and heals without post-inflammatory hyperpigmentation.
  • Urticarial fixed drug reaction: Rare variant which recurs urticarially and in loco when provoked.
  • Neutrophilic fixed drug reaction: Extremely rare variant which histologically presents as neutrophilic dermatitis. Only few case reports have been published so far.

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 exanthema on 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 articaine. 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. Pionetti CH et al (2003) Fixed drug eruption due to loratadine. Allergol Immunopathol (Madr) 31: 291-293
  15. Rödiger C et al (2011) Fixed urticarial drug exanthema? Abstract CD 46 DDG-Conference: P02/07
  16. Sehgal VN et al (2003) Bullous fixed drug eruption (BFDE) following per-oral metronidazole. J Eur Acad Dermatol Venereol 17: 607-609
  17. 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.
  18. 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
  19. Tan C et al (2010) Anular fixed drug reaction. JDDG 8: 823-825
  20. Vester K et al (2011) Fixed drug exanthema caused by 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: 29.10.2020