The patient had no previous history of side effects related to ophthalmic antihistamine agents. When the patient first applied alcaftadine 0.25%, there was no cutaneous reaction. One day later, after the second application of alcaftadine 0.25%, bilateral eyelid swelling with erythematous changes was noted. To evaluate the cause of ACD, a patch test was performed. The result was checked 48 h later; Among 3 ophthalmic agents applied, only alcaftadine 0.25% showed a positive result. Although we did not test all components individually, other ingredients such as benzalkonium chloride, monobasic sodium phosphate, dibasic sodium phosphate, sodium chloride, and sodium hydroxide are also included in other two eyedrops we tested. We could exclude a possibility of irritation because skin lesion remained for more than 1 week, while skin lesions induced by irritant typically disappear within 96 h after patch is removed (ref). Therefore, based on the results of the patch test, the patient was diagnosed with ACD caused by alcaftadine 0.25%.
Drug allergy is a type B reaction that is mediated by the adaptive immune system. Type B reactions are uncommon and unpredictable and occur only in people with a certain predisposition. However, recent reports show that previous contact with the causative drug is not a prerequisite for immune-mediated drug hypersensitivity . Sensitization is possible either when are drugs applied to the skin or administered orally. Patients may become more sensitized to antihistamine agents when they are applied to the skin rather than taken orally . In the present case, the patient used alcaftadine 0.25%, which is an antihistamine agents for the treatment of allergic conjunctivitis. Presumably, the eyelid skin was exposed when the drug overflowed and erythematous changes developed by allergic response.
Currently, alcaftadine 0.25% is one of the most prescribed antihistamine agents for allergic conjunctivitis, and is used worldwide [10, 11, 16, 17]. Alcaftadine 0.25% is an H1- and H2-receptor antagonist . There are some reports of side effects related to alcaftadine 0.25% usage [10, 11, 17], and previous studies reported fewer than 4% of subjects had side effects [12, 13]. Its side effects are usually related to ocular problems such as ocular itching, conjunctival redness, chemosis, lid swelling, and tearing [10, 11, 17]. An atypical symptom of bronchitis was also reported . However, there have been no reports to date that alcaftadine 0.25% induces ACD.
There have been some reports of ACD induced by antihistamine agents . Histamine can have direct effects on T lymphocytes, as H1, H2, and H4 receptors are all expressed on CD4+ and CD8+ T cells. Histamine has been shown to inhibit T-cell proliferation through H2 receptors . Therefore, ACD induced by antihistamine agents can be explained by T-cell proliferation caused by inhibiting histamine to H2 receptors [19,20,21]. However, not all antihistamine agents can induce ACD. This is because the effect of histamine on T-cell proliferation seems to vary. Histamine also can increase T-cell proliferation through H1 receptors. In this case, antihistamine agents reduce allergic symptoms by inhibiting T-cell proliferation mediated through H1 receptors. Therefore, histamine has a key role in inflammatory processes, and drugs that target H1 receptors have usually been successful for the treatment of allergy . However, it is important to note that when using antihistamine agents with strong affinity to H1 and H2 receptors, such as alcaftadine 0.25%, ACD may occur .
Ophthalmic agents can cause various side effects and there are many explanations including drug-related allergies, toxic or inflammatory reaction of the drugs, and toxicity of preservatives such as benzalkonium chloride [17, 22]. However, the concentration of benzalkonium chloride in alcaftadine 0.25% is 0.005%, which is very low, and other ophthalmic agents also have approximately the same concentration . Considering that the other ophthalmic agents she used, which also contained benzalkonium chloride, did not induce any allergic reaction, we could attribute alcaftadine 0.25% itself as the causative factor of allergic reaction.
In the present case report, we report a patient with ACD after using alcaftadine 0.25%, which was so severe that the patient required treatment for 9 days until it resolved completely. There is a possibility that more cases of ACD have occurred after using alcaftadine 0.25%, even though no previous reports have been published.
From now on, ophthalmologists should inform patients of the possibility of ACD when prescribing alcaftadine 0.25%. We suggest that wiping off run-over may be useful to prevent this side effect. This case report suggests when cutaneous reactions near the orbit are found after alcaftadine 0.25% use, ophthalmologists should consider ACD.