Dermatology

Allergic Contact Dermatitis to Medicines (Medicaments) including active ingredients and vehicles (Contact Dermatitis, Medication)

Allergic Contact Dermatitis to Medicines (Medicaments) including active ingredients and vehicles. ICD - 10 L23.3 Allergic contact dermatitis due to drugs in contact with skin

Are You Confident of the Diagnosis?

  • What you should be alert for in the history

Be alert for itchy rash that does not heal as expected, or with allergy to corticosteroids that transiently improves and then recurs. Inform the patient that you need to know about topicals applied even as infrequently as once per month. Inquire about use of over-the-counter topical medications, emphasizing that it is also important to report those topicals used to treat an initial rash. Inquire about use of borrowed prescription topicals from friends and family. Always ask contact history at least twice, just as systemic drug history. Patients often think of additional contactants on further questioning.

  • Characteristic findings on physical examination

Characteristic findings include red, itchy crusted confluent papules that can affect any area; the face and hands and anogenital area are among the most common sites. The contour is usually poorly defined, except in patients who meticulously apply topical medicament in perfect circles. Ask the patient to pantomime application of their medications. There is often ectopic involvement of the eyelid, neck, or fingers. Ask the patient if they apply medicament with their hands or with an applicator.

  • Expected results of diagnostic studies

Histology will show spongiotic dermatitis or psoriasiform dermatitis if chronic. In cases that mimic cellulitis, there will be no fever and a normal white blood cell count. Bacterial superinfection is common.

  • Diagnosis confirmation

Patch testing or repeat open application testing confirms the diagnosis, but failure to consider the diagnosis is the most common diagnostic error. Failure to perform appropriate comprehensive patch testing with a late (day 5-7 reading) is another common cause of diagnostic error. Another common diagnostic error is attribution of rash to 'atopic eczema'. Many patients with a history of childhood eczema, in fact have allergic contact dermatitis to medicament, and should be evaluated with patch testing.

The most common causes of allergic contact dermatitis to medicaments depend upon prescribing habits in the population studies. In the US, the most common are: the topical antibiotics neomycin and bacitracin; corticosteroids (often screened by patch tests to tixocortal pivalate and budesonide); propylene glycol; clioquinol; lanolin; sorbitan sesquioleate, and the preservatives benzalkonium chloride, quaternium 15; ethylchloroisothiazolinone, chlorocresol, and benzyl alcohol. Tar is a less common cause in recent years, reflecting decreased usage.

In Europe, topical nonsteroidal anti-inflammatory drugs (NSAIDs) are more commonly used and are a common cause of allergic contact dermatitis.

Allergic contact dermatitis to topical antibiotics applied to a cutaneous injury is often mistaken for cellulitis. The predominance of itch over pain, lack of fever, and normal white blood cell count support the diagnosis of allergic contact dermatitis.

Allergic contact dermatitis to topical corticosteroids or the vehicle of topical immunomodulators is often mistaken for intractable atopic dermatitis or psoriasis. Patients allergic to topical anti-inflammatories will see initial improvement in the first few days after application, but will then have worsening itch as the delayed hypersensitivity becomes apparent for as long as 4 weeks after last contact.

Allergic contact dermatitis to emollients or anti-itch preparations or to inactive components of widely applied topicals will cause generalized patchy dermatitis that may mimic dermatomyositis, scabies, or systemic drug eruption. Allergic contact dermatitis may also complicate a known or previously undiagnosed primary skin disease, such as stasis dermatitis.

Who is at Risk for Developing this Disease?

Any combination of preexisting skin inflammation and contact with a sensitizer can result in allergic contact dermatitis. Stasis dermatitis is a very common risk factor for contact allergy to medicaments applied to the lower leg (and often resulting in generalized dermatitis). Workers at risk for irritant hand dermatitis often become allergic to medicaments used to control irritancy or primary contact allergy to an occupational contactant. These include machinists, hairdressers, health care workers, and food handlers.

What is the Cause of the Disease?

  • Etiology

This is a type IV (cell-mediated) hypersensitivity. Poison ivy is a prototype and excellent analogy to explain the delayed onset and delayed resolution to patients. This also explains the need for delayed interpretation of confirmatory diagnostic patch tests.

  • Pathophysiology

Dermal dendritic cells in the presence of danger signals from existing inflammation present a sensitizer to T cells which are then educated in the draining lymph node to recognize that antigen and initiate an inflammatory cascade. Because this is NOT a type 1 (immediate hypersensitivity) reaction, skin prick tests and antigen specific IgE blood tests cannot confirm this diagnosis.

Systemic Implications and Complications

Systemic exposure to a cross-reacting medication can cause systemic contact dermatitis. This may present as flexural redness, erythroderma, morbilliform rash, and/or recall of dermatitis at previous sites of allergic contact dermatitis (including the patch test site!) and/or as systemic malaise and nausea. An example is systemic drug reaction to tobramycin in patients sensitized to topical neomycin. Patch testing is diagnostic, but could trigger systemic symptoms and this should be discussed with the patient before testing in this scenario.

Systemic contact dermatitis to propylene glycol in foods and oral medications is common in patients sensitized to propylene glycol from topical medications. Systemic contact dermatitis occurs more quickly (within hours to 2 days of exposure) than allergic contact dermatitis which may not develop until several days after exposure. Systemic contact dermatitis to corticosteroids is rarely recognized, possibly because the symptoms occur, and therefore are masked, during the therapeutic window of the anti-inflammatory effect.

Treatment Options

Substitution of an alternative based on precise allergen identification by patch testing is the preferred treatment. In the absence of diagnostic patch testing, medicaments that are unlikely sensitizers may be substituted for those suspected of causing dermatitis. Examples of substitutions are given in Table I.

Table I.

Examples of substitutions for common medicament allergies
neomycin/bacitracin systemic antibiotics such as cephalosporins
corticosteroids classes A (e.g. hydrocortisone) and B (e.g. fluocinonide) corticosteroids class C (e.g. desoximetasone)
propylene glycol (e.g. in pimecrolus or in corticosteroid foams) tacrolimusdesoximetasone gel or cream
preservatives in creams (e.g. quaternium 15, methylchloroisothiazolinone) ointments less likely to contain preservatives
'caine' topical anesthetics menthol
other sensitizers in emollients (e.g. fragrance, lanolin, clioquinol) plain petroleum jelly

The best treatment diagnostic test is precise identification of the allergen by patch testing and detailed patient education on avoidance strategies. Software such as the Contact Allergen Management Program (CAMP) can be used to generate a list of alternatives. A follow-up visit after 1 month of avoidance is critical to assess relevance of identified allergens and to evaluate for underlying primary skin disease.

Optimal Therapeutic Approach for this Disease

For mild dermatitis that is incidental (not the reason for outpatient visit or hospitalization), suggest empiric avoidance of common sensitizers, such as neomycin. Four weeks of complete avoidance is required to see approximately 80% improvement in dermatitis, and several months of complete avoidance may be necessary for complete cure.

For severe dermatitis, refer to a dermatologist specializing in allergic contact dermatitis. Consultation should include detailed occupational and prior contact history for possible contact allergens in addition to medicament, comprehensive patch testing, and patient education.

If the skin is too inflamed to patch test, a short course (2 weeks) of systemic corticosteroids may be required prior to testing. In diabetic or severely osteoporotic patients, cyclosporine may be use for short intervals for this purpose. Testing should then commence within 1 week before rash can again become generalized.

Long-term medical management of this curable condition is not justifiable. Specifically, long-term use of corticosteroids or any systemic immunosuppressive places the patient at risk of preventable morbidities. To avoid missing the diagnosis of allergic contact dermatitis to medicament, physicians should consider this diagnostic possibility whenever prescribing or refilling topical or systemic immunosuppressives.

Patient Management

Patients need to know that even a single exposure to a topical allergen will induce return of symptoms for several weeks. Complete avoidance is mandatory. Written information on medicament allergens and possible alternatives should be shared with the patient's other health care providers.

In patients who fail to improve at least 80% after 1 month of complete avoidance, consider:

  1. Failure of patient education.

  2. Retention of topical medicament in clothing or gloves. Medicaments in an ointment base are particularly difficult to launder out of two-ply or mesh fabrics such as elastic in socks, bras, or the interior of gloves.

  3. Cross reactions. For example, a patient sensitized to neomycin may react to tobramycin. A patient sensitized to chloroxylenol in antibacterial soaps may cross react to the preservative chlorocresol in corticosteroids.

Unusual Clinical Scenarios to Consider in Patient Management

Allergic contact dermatitis as the only factor causing dermatitis in a given patient occurs occasionally in the setting of occupational exposure to a strong sensitizer, such as epoxy resin, and then is often compounded by allergic contact dermatitis to medicament used to treat the initial dermatitis.

However, allergic contact dermatitis to medicament is more common in patients with pre-existing inflammatory skin disease, such as irritant hand dermatitis or atopic dermatitis. These patients need education on skin care (which differs with climate changes) and must not be expected to clear completely with avoidance of identified medicament allergies.

Secondary infection is very common in atopic dermatitis patients due to defects in their innate immune response, and must be treated as well. Atopic patients are also predisposed to weaker allergens that are not screened by small standard series designed for the general population. Examples include compositae allergy, probably from aeroallergen exposure to weeds, that may mandate a need to avoid related botanicals such as feverfew in topical preparations, or vitamin E which is a component of many medicaments and personal care products marketed for children.

Fair-skinned patients who blush easily may develop steroid rosacea from use of corticosteroids on the face. Some patients develop 'steroid addiction syndrome' when corticosteroids are applied to the face, eyelid, or scrotum. These patients experience painful rebound, often disproportionate to objective findings of redness, when they discontinue topical corticosteroids for a few days. This is often misinterpreted as allergic contact dermatitis to a number of topicals that are substituted for the corticosteroid. Such patients should be treated with systemic anti-inflammatories such as doxycycline, and advised to expect prolonged waxing and waning of symptoms.

What is the Evidence?

Warshaw, EM, Maibach, HI, Taylor, JS, Sasseville, D, DeKoven, JG, Zirwas, MJ, Fransway, AF, Mathias, CG, Zug, KA, DeLeo, VA, Fowler, JF, Marks, JG, Pratt, MD, Storrs, FJ, Belsito, DV. "North American contact dermatitis group patch test results: 2011-2012". Dermatitis. vol. 26. 2015 Jan-Feb. pp. 49-59.

(Gives prevalence of contact allergy to various allergens from pooled data obtained by US and Canadian expert patch testers.)

Scheman, A, Jacob, S, Zirwas, M, Warshaw, E, Nedorost, S, Katta, R, Cook, J, Castanedo-Tardan, MP. "Contact Allergy: alternatives for the 2007 North American contact dermatitis group (NACDG) Standard Screening Tray". Dis Mon. vol. 54. 2008 Jan-Feb. pp. 7-156.

(Review. Extensive listing of alternatives for patients with identified contact allergens.)

Tamagawa-Mineoka, R, Masuda, K, Ueda, S, Nakamura, N, Hotta, E, Hattori, J, Minamiyama, R, Yamazaki, A, Katoh, N. "Contact sensitivity in patients with recalcitrant atopic dermatitis". J Dermatol. 2015. vol. 42. Jul. pp. 720-2.

(Documents value of patch testing in atopic dermatitis.)

Davis, MD. "Unusual patterns in contact dermatitis: medicaments". Dermatol Clin. vol. 27. 2009 Jul. pp. vi-97.

(Review. Excellent review of this topic.)

Baeck, M, Goossens, A. "Immediate and delayed allergic hypersensitivity to corticosteroids: practical guidelines". Contact Dermatitis. vol. 66. 2012 Jan. pp. 38-45.

(Discusses the difficulty in predicting cross reactions based on structural classification and revises prior classification of cross-reactors from four groups to three.)

Rapaport, MJ, Rapaport, V. "Eyelid dermatitis to red face syndrome to cure: clinical experience in 100 cases". J Am Acad Dermatol. vol. 41. 1999 Sep. pp. 435-42.

(Outstanding case series describing course of steroid addiction syndrome in the eyelids, but applicable to other sites as well.)

Nijhawan, RI, Molenda, M, Zirwas, MJ, Jacob, SE. "Systemic contact dermatitis". Dermatol Clin. vol. 27. 2009 Jul. pp. vii-64.

(Review. Summary of knowledge to date about this poorly understood disease.)

Kulberg, A, Schliemann, S, Elsner, P. "Contact dermatitis as a systemic disease". Clin Dermatol. vol. 32. 2014 May-Jun. pp. 414-9.

(Review. Summary of knowledge to date about this poorly understood disease.)

Nedorost, S, Kessler, M, McCormick, T. "Allergens retained in clothing". Dermatitis. vol. 18. 2007 Dec. pp. 212-4.

(Case series of reactions to medicaments retained in fabrics.)

Morris, SD, Rycroft, RJ, White, IR, Wakelin, SH, McFadden, JP. "Comparative frequency of patch test reactions to topical antibiotics". Br J Dermatol.. vol. 146. 2002 Jun. pp. 1047-51.

(Contrasting prevalence in a European population.)

Killoran, CE, Crawford, GH, Pedvis-Leftick, A. "Two cases of compositae dermatitis exacerbated by moisturizer containing feverfew". Dermatitis. vol. 18. 2007 Dec. pp. 225-9.

(Example of a botanical allergen often overlooked in topical emollients.)

Saap, L, Fahim, S, Arsenault, E, Pratt, M, Pierscianowski, T, Falanga, V, Pedvis-Leftick, A. "Contact sensitivity in patients with leg ulcerations: a North American study". Arch Dermatol. vol. 140. 2004 Oct. pp. 1241-6.

(Gives prevalence of medicament allergies in a high risk population.)
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