Although antihistamines are the cornerstones for symptomatic treatment of urticaria,1,2 sensitivity reactions to antihistamines in systemic administration have been rarely reported. In this sense, antihistamines may cause fixed drug eruptions, urticaria and other hypersensitivity reactions. Other than these reactions, in a limited number of cases with chronic urticaria, antihistamines may exacerbate the underlying disease, which eventually lead to a difficulty in treatment. Here, we report two cases of chronic urticaria exacerbated with antihistamines and discuss the way of finding therapeutic options for these cases.
In both cases, patients first had skin prick and intradermal tests with antihistamines. If the skin prick tests (SPT) and intradermal tests (IDT) are negative, drug provocation tests were performed. All tests were performed under strict medical surveillance and written signed consents were obtained prior to tests.
Briefly, SPT were performed with dilutions of 1/100, 1/10, undiluted and IDT with dilutions of 1/1000 and 1/100 of the tested drugs. A wheal diameter of 3mm greater than negative control and accompanied by erythema after 20minutes was considered positive. Histamine and saline served as positive and negative controls, respectively. The drug provocation tests were performed in a single-blinded, placebo-controlled design in which the patient was blinded. The doses of the drugs used for DPTs were ¼ and ¾ of the therapeutic doses. Tests were considered positive if any sign of hypersensitivity reactions such as urticaria; angio-oedema; laryngeal oedema; hypotension; dyspnoea; nasal symptoms; 20% fall in FEV1 value; anaphylaxis; or other rashes were observed during or after the test. The tests were considered negative if no adverse reaction occurred within 24hours.
Case 1The first patient was a 42-year-old woman who had chronic recurrent urticaria for three years. She experienced generalised urticarial lesions especially exacerbating with antihistamines like pheniramine maleate on several occasions. As she developed urticaria with the use of several other antihistamines of which she did not remember the names, there was a difficulty in treating the urticaria. On physical examination, she had generalised urticaria all around the trunk, arms and legs. No other pathological findings existed. Her routine blood and urine analysis were in normal range. Allergic work up with SPT with common aeroallergens and foods were negative. Other diagnostic work up such as thyroid autoantibodies, and immunological studies were in normal limits.
She was first skin tested with cetirizine. Prick and intradermal tests showed no reaction. However, she developed urticaria in oral challenge with a cumulative dose of 10mg cetirizine. Therefore, she was tested with hydroxyzine, acrivastine, fexofenadine and desloratadine on consequent days in order to find safe alternatives. Although skin tests with these drugs were negative, oral challenges all resulted in urticarial reactions 3-4hours after the administration of each drug. Finally, she tolerated levocetirizine and loratadine both in skin tests and oral challenges. Therefore, she was recommended to use these antihistamines. In the follow-up period, urticarial lesions showed good response to these antihistamines.
Case 2The second patient was a 28-year-old-man suffering from chronic urticaria for seven years. His urticarial lesions were exacerbated by alcohol intake and use of some analgesic drugs. The patient also described generalised urticarial lesions one hour after intramuscular injection of pheniramine maleate. He was evaluated by a dermatologist and advised to take desloratadine tablets. However, he again had an urticarial reaction 3-4hours after taking desloratadine tablets. He was also prescribed for ebastine and fexofenadine which also resulted with urticaria. SPT and IDT with the culprit drugs resulted negative. He developed urticarial lesions in oral challenge with cumulative dose of 10mg tablet of ebastine 7hours after taking the last dose and with cumulative dose of 180mg tablet of fexofenadine 6hours after taking the last dose. The patient refused to be submitted to oral challenge tests with alternative antihistamines.
In this report, we presented two cases in which chronic urticaria was triggered by several antihistamines. Regardless of underlying disease, chlorpheniramine maleate, and diphenhydramine were the most common antihistamines which cause hypersensitivity reactions. However, cetirizine is the most common antihistamine, reported to lead to hypersensitivity reactions in patients with chronic urticaria and allergic rhinitis.6,7 Both of our cases had hypersensitivity reactions to pheniramine maleate. But they also had challenge proven hypersensitivities to new generation antihistamines such as cetirizine, fexofenadine, ebastine, and desloratadine. So, one should be aware that even new generation antihistamines are capable of exacerbating urticaria in particular patients.
A relationship between certain drugs and exacerbation of urticarial lesions has been well documented for medications such as analgesics).9 However, such a relationship with drugs other than analgesics and urticaria is less defined. As the first line treatment of the underlying urticaria, antihistamines have been assumed as the drugs which least trigger urticaria. However, together with the literature data, although it is very rare, our cases suggested such a relationship for some patients. The underlying mechanism of such a relationship is not well understood. Metabolite haptenisation, enzyme deficiency resulting in antibody production, and complement activation are some examples.8 Although the majority of the reactions are of an immediate nature, type I hypersensitivity is unlikely in the majority of the cases based on negative SPT but positive DPT results.7,8 Suggesting this, hypersensitivity reactions to chemically different antihistamines in the same patient bring the possibility of a non-immune mediated reaction. Rarely, a possible type 1 IgE mediated hypersensitivity to some antihistamines such as diphenhydramine was reported.3 Anaphylactic shock due to antihistamines has been rarely reported.4,5 In terms of non-immediate reactions, a type IV hypersensitivity was diagnosed by a positive patch test in one case who had non-immediate reaction to antihistamines.10
The long term management of these cases carry some difficulties in drug selection as these patients might develop urticaria with use of chemically different antihistamines. However, these cases need some safe alternative antihistamines for the treatment of urticaria. Assuming the uncertainty of underlying mechanisms for immediate reactions, skin tests usually provide limited data about the tolerability of the antihistamines. Drug challenge tests are recommended as the best way to see whether the patient can tolerate a drug or not in such cases.1,2,7 Supporting this data, negative predictive value of SPT was poor and DPT provided safe alternatives in the first patient, however, such an option was not available for the second case as he refused further testing.
Interestingly, Case 1 had hypersensitivity reaction to desloratadine but loratadine and cetirizine but levocetirizine. This is somewhat unexpected as desloratadine and loratadine as well as levocetirizine and cetirizine share similar chemical structures. However, as these groups (ie: loratadine, desloratadine) revealed different drug challenge test results, drug challenge test is still worthy for trying to seek the tolerability of the other one in case of positive reaction to sister drugs, as these drugs are highly effective in treating urticaria.
In conclusion, although antihistamines rarely trigger urticaria, this possibility should be kept in mind where an exacerbation in symptoms after taking an antihistamine occurs. If such a relationship is demonstrated, drug challenge tests are the best way to find a safe alternative to these cases.
