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Cutaneous Adverse Drug Reaction to Oral Acetazolamide and Skin TestsJachiet M.a · Bellon N.b · Assier H.b · Amsler E.a · Gaouar H.a · Pecquet C.a · Bourrain J.L.c · Bégon E.d · Chosidow O.b, e · Francès C.a · Ingen-Housz-Oro S.b · Soria A.a
aDepartment of Dermatology and Allergology, AP-HP, Hôpital Tenon, Paris, bDepartment of Dermatology, AP-HP, Hôpital Henri Mondor, Créteil, cDepartment of Dermatology, Hôpital A. Michallon, Grenoble, dDepartment of Dermatology, Hôpital René Dubos, Pontoise, and eUniversité Paris-Est Créteil Val de Marne, Créteil, France Corresponding Author
Dr. Angèle Soria
Department of Dermatology and Allergology, Hôpital Tenon - AP-HP
4 rue de la Chine
FR-75020 Paris (France)
Background: Few cases of cutaneous adverse drug reactions (CADR) to oral acetazolamide, a non-antimicrobial sulfonamide, have been previously reported, and the interest of acetazolamide skin tests has never been studied. Objectives: We report a series of ten patients with oral acetazolamide CADR and skin tests. Patients and Methods: The files of ten patients with CADR secondary to oral acetazolamide prescribed for cataract surgery in most cases referred between 2001 and 2011 in four French dermatology and allergy departments were retrospectively reviewed. Skin tests with acetazolamide were performed in nine patients and twelve controls. Other sulfonamides were tested in five of ten patients. Results: Seven patients developed maculopapular exanthema and four had acute generalized exanthematous pustulosis. Patch tests were positive for 8/9 patients, prick tests for 2/4 and intradermal tests for 3/3. Patch and prick or intradermal test results were concordant in 2/3 positive subjects. Patch tests for other sulfonamides were negative, as were patch tests in controls. Conclusions: We report the largest series of CADR to oral acetazolamide (maculopapular exanthema or acute generalized exanthematous pustulosis). A drug eruption after cataract surgery should be investigated for accountability of acetazolamide. In view of this retrospective study, skin tests and particularly intradermal tests appear to be an important contribution to demonstrate accountability.
© 2013 S. Karger AG, Basel
Acetazolamide is a carbonic anhydrase inhibitor that belongs to the sulfonamide class. Its chemical name is N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)-acetamide. Indications for oral acetazolamide are treatment of idiopathic intracranial hypertension, hypercapnia due to chronic obstructive pulmonary disease, prevention or treatment of postoperative intraocular pressure after cataract surgery and prophylaxis of acute mountain sickness.
Whereas antimicrobial sulfonamides, especially sulfamethoxazole-trimethoprim, are strongly associated with Stevens-Johnson syndrome and toxic epidermal necrolysis, cutaneous adverse drug reactions (CADR) due to acetazolamide are rare . We report a series of 10 patients with CADR with oral acetazolamide and insist on the value of skin tests.
The files of patients referred for suspected CADR secondary to oral acetazolamide between 2001 and 2011 in four French dermatology and allergy departments (Tenon, Mondor, Grenoble and Pontoise Hospital) were retrospectively reviewed. All patients were recruited in dermatology and/or allergology departments (n = 7) or were referred by dermatologists belonging to the multicenter Dermato-Allergology Franco-Belgian Group (REVIDAL-GERDA) (n = 3). For each patient, the following clinical data were collected: age, sex, past history of CADR, concomitant medications, delay between acetazolamide intake and onset of eruption, clinical aspect of the CADR, treatment and evolution. All patients were contacted by phone 1-10 years after the CADR to investigate whether other sulfonamides had been taken since acetazolamide eruption.
All skin tests were performed at least 2 months after skin adverse events. Acetazolamide patch tests were freshly prepared, with commercial acetazolamide (Diamox®, Sanofi, France), diluted at 30% in petrolatum. Test materials used were IQ Ultra Chambers or Finn Chambers (Destaing, France) covered on the upper back with Mefix® (Molnlycke Health Care, Sweden). The patches were removed on day 1 (D1) or day 2 (D2). Readings were performed between D1 and D4 according to clinical practice of each center and to the ICDRG criteria . In comparison, 12 controls, i.e. 10 patients who had never received acetazolamide and 2 controls who had previously received acetazolamide without developing any reaction, were tested with acetazolamide patch tests.
Commercial preparations with acetazolamide were freshly prepared ‘as is' (10 mg/ml) for prick test, and diluted at 1 mg/ml in 0.9% sterile serum saline for intradermal tests. 0.04 ml was injected on the forearm with a negative (serum saline) and positive control (10 mg/ml histamine chlorhydrate). Prick and intradermal tests were read after 20 min, 2 and 4 days.
According to European guidelines on delayed readings, intradermal tests were considered positive when there was an infiltrated and erythematous reaction. To determine the absence of irritancy of positive patch tests, results from 12 controls tested with the same methods were performed with acetazolamide [3,4]. All other drugs used concomitantly by the patients were also tested.
This study received local institutional review board agreement.
The main clinical characteristics of the patients are summarized in table 1. Seven patients developed maculopapular exanthema (MPE) and four patients had acute generalized exanthematous pustulosis (AGEP) (fig. 1). Patient 4 experienced first MPE 24 h after right eye cataract surgery with oral acetazolamide administration and AGEP 6 h after rechallenge of the drug, 10 days after, for left eye cataract surgery. Two patients had mucosal involvement, with oral (2/2) and nasal (1/2) ulcerations. In all cases except one, the time lag of appearance of the drug reaction was short, ranging from 6 to 48 h; for one patient it was 5 days. Two patients had a previous clinical history of skin adverse events with other drugs: patient 1 with venlafaxine, and patient 4 with sulfamethoxazole-trimethoprim and sulfadoxine-pyrimethamine. For the others, data about previous sensitization were missing. Six patients were treated with topical steroids and three patients with oral antihistamines. Three patients required systemic steroids due to severe mucosal or skin involvement. Time lag to recovery ranged between 5 days and 1 month. None of the patients contacted by phone had been rechallenged with sulfonamide after the CADR.
Nine patients were tested with acetazolamide skin tests and were all positive (summarized in table 2).
All skin tests were performed with a delay ranging from 8 weeks to 3 years after the CADR. Patch tests were read on D1 (1/9), D2 (6/9), D3 (1/9) or D5 (1/9). Other sulfonamides were tested in five of ten patients. Patch tests were performed in nine cases and were positive in eight cases: on D2 for six patients with an early reading on D1 for one of them, and on D3 and D5 for two patients.
Four patients also had prick test (10 mg/ml) and three patients had intradermal tests (0.01, 0.1 and 1 mg/ml). Prick tests were positive at late reading (D2) for two patients. Acetazolamide intradermal tests were positive on D1 in one case and on D2 and D4 in all three patients tested (fig. 2). Both the patch test and intradermal tests were positive in 2/3 patients. Patient 4 had a negative patch test with positive pustulosis prick and intradermal tests on D2 and D4.
No side effects or reactivation of the CADR were observed with skin tests. Patch tests for other sulfonamides were negative (patient 5, 6, 8 and 10). Furosemide prick and intradermal tests were negative (patient 2) on D2 and D4. Details concerning tests with other putative drugs and other sulfonamides are summarized in table 2.
A histological analysis of acetazolamide patch test on D2 (patient 2) showed an eczematous pattern characterized by dissociated epidermis with extensive spongiosis, keratinocytes necrosis and dermal perivascular inflammatory infiltrate (lymphocytes, eosinophils and neutrophils).
All other drugs concomitantly administrated with acetazolamide and other sulfonamides were tested and remained negative. All twelve control patients had negative acetazolamide patch tests.
Only a few cases of CADR with oral acetazolamide have been previously reported [5,6,7](table 3). All these cases were severe CADR (AGEP, Stevens-Johnson syndrome). Furthermore, some cases of contact dermatitis, either eczema or MPE, have been reported with topical acetazolamide . We report herein a series of ten cases of CADR to oral acetazolamide, prescribed for cataract surgery in most cases (7/10), as a prevention of peri- and postoperative ocular hypertension. With the aging of the population, cataract surgery is more and more common. Consequently, even if not systematically recommended for that surgery, the use of systemic acetazolamide is expected to increase, and ophthalmologists should be aware of the risk of some severe CADR with this drug.
Most of the patients developed the CADR within a short time after acetazolamide intake, while there were no data about previous exposure, and four patients had a clinical presentation of typical AGEP.
Eight patients had positive patch tests for the putative drug. As previously reported, patch tests are frequently positive in AGEP, especially with numerous causative drugs as antibiotics, immunosuppressive therapies and analgesics [9,10]. To our knowledge no positive patch test has been reported with acetazolamide.
Even though the sensitivity of patch tests in AGEP seems to be high, up to 50% in the study by Wolkenstein et al. , the sensitivity of skin tests and especially prick and intradermal tests with delayed reading is unknown. Moreover the diagnostic value of acetazolamide skin tests is unknown. In our series, the patient who experienced two episodes of CADR due to acetazolamide had positive delayed prick and intradermal test results with local pustulosis. According to our results, we could hypothesize that delayed reading intradermal tests are sensitive to diagnose delayed hypersensitivity to acetazolamide as already reported for others drugs . None of our patients experienced a relapse of the cutaneous eruption secondary to the skin tests. Positive patch tests seem to be specific regarding the negative results observed in the control group.
Cross-reactivity between antimicrobial and non-antimicrobial sulfonamides has already been discussed; some studies conclude to a predisposition to allergic reactions rather than to a cross-reactivity between sulfonamide-based drugs [13,14,15]. In our cases, one patient (patient 4) had a history of CADR with two sulfonamide family drugs, sulfamethoxazole-trimethoprim and sulfadoxine-pyrimethamine, but no test has been performed with these drugs in this patient. As regards this case, we should remain cautious, especially for drugs that may be responsible for severe CADR such as AGEP or Stevens-Johnson/Lyell syndrome.
Although no immune-mediated mechanism has been shown for this hypersensitivity, it has been hypothesized that the arylamine group, present in antimicrobial sulfonamide, is critical in producing hypersensitivity reactions . Only few cases have been documented with cross-reactivity between sulfonamide medications .
However, for all other patients who were tested with a wide spectrum of other sulfonamides and who had never previously received those drugs, results were negative. We did not contraindicate sulfonamides other than acetazolamide to these patients. In contrast, all forms of acetazolamide (oral and eye drops) were definitively contraindicated.
We report the largest series of CADR, MPE and AGEP, to oral acetazolamide. Skin tests and particularly intradermal tests with acetazolamide were useful to confirm the diagnosis either by patch test and if negative by intradermal test with delayed readings. A drug eruption after cataract surgery should be investigated for the accountability of acetazolamide. In view of this retrospective study, skin tests appeared to be an important contribution to demonstrate accountability. Cross-reactivity between acetazolamide and other sulfonamide drugs remains to be evaluated.
The authors declare no conflicts of interest.
Dr. Angèle Soria
Department of Dermatology and Allergology, Hôpital Tenon - AP-HP
4 rue de la Chine
FR-75020 Paris (France)
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