Chlorhexidine anaphylaxis in three children secondary to oral exposure without evidence of mucosal breach

To the Editor, Chlorhexidine is a synthetic antiseptic of the biguanide family, with a broad spectrum of antibacterial action. It has been used exponentially in perioperative settings, for preoperative skin preparation, antisepsis of surgical or traumatic wounds. Besides skin application, chlorhexidine is used on oral mucosa (mouthwash, toothpaste), eyes (eye drops, contact lens solutions), lubrication of urethral, vaginal, rectal catheters, and central catheters. Moreover, chlorhexidine is among the authorized preservatives and is found covertly in some cosmetic products and systemically administered medicines (e.g., gastric dressings, antiseptic, and analgesic tablets). A Danish study found that 3.6% of 2000 cosmetic products contained chlorhexidine.1 We report for the firsttime anaphylactic reactions in three French children due to oral contact (mouthwash or antiseptic tablets). The clinical manifestations and investigations are described in Table 1. The reactions occurred in absence of evidence of oral mucosa breach that could promote a severe reaction. Two children had presented anaphylactic reactions requiring epinephrine during the initial reaction and one of them during the allergy workup as well (intradermal test). Chlorhexidine allergy was confirmed with at least two confirmatory tests: positive prick or intradermal test and positive chlorhexidine serumspecific IgE (ImmunoCap ThermoFischer Scientific, Uppsala, Sweden: positive chlorhexidine threshold was defined as equal or above 0.1 kUA/L). The prevalence of chlorhexidine allergy is still unknown with little published data outside the perioperative hypersensitivity reactions (POH) where it has been estimated that chlorhexidine was responsible of virtually one in 10 patients with confirmed POH (between 7.7% and 9% in the United Kingdom,2 9% in Belgium,3 and 9.7% in Denmark4). It seems to be less frequent in France.5 More recently, the perioperative anaphylactic shocks survey in all hospitals from the United Kingdom in 2018 listed 18 patients with grade 3– 5 anaphylactic reactions linked to chlorhexidine (i.e., an incidence of 0.78/100,000 anesthesias, whereas the incidence of perioperative anaphylaxis from all causes was 1/10,000 anesthesias).2 In this last study, chlorhexidine was the third most common cause of anaphylaxis after antibiotics and neuromuscular blocking agents (NMBA), respectively. In Egner's cohort, 27% of patients had another drug allergy, the most common being muscle relaxants (16% of the patients).6 As previously seen, allergic symptoms can vary from localized urticaria to anaphylactic shock leading to death. Although reactions following oral exposure are rare and often mild, in Egner's study one patient with confirmed chlorhexidine POH previously exposed orally (mouthwash) developed a grade 4 anaphylaxis during anesthesia.6 Pediatric data describing chlorhexidine allergy are scarce and with an unknown prevalence. Two pediatric clinical cases published in 2017 reported IgEmediated hypersensitivity causing anaphylaxis in a 3yearold child during surgery for hypospadias, and in a 12yearold child following disinfection of a knee wound in Spain.7 The former presented with hypotension, but contrary to descriptions in adults, both presented with respiratory discomfort associated to generalized urticaria. A French case reported an extensive pruritic erythema with edema of the fingers and lowers limbs in a 6yearold child within minutes after application of aqueous chlorhexidine to a hip wound.8 The reaction was rapidly regressive after antihistamine intake. He had already experienced three urticaria episodes following chlorhexidine application on wounds over the previous months. Chlorhexidine allergy diagnosis was confirmed by prick testing and positive chlorhexidinespecific serum IgE. All our patients developed their reactions while using overthecounter products. At present, a search (key word: “chlorhexidine”) in the French pharmacopeia resulted in 65 listed pharmaceutical specialties containing chlorhexidine (gluconate, digluconate, and acetate), in variable forms and quantities, all being overthecounter products. Chlorhexidine is also used in medical devices, such as impregnated compresses or patches used for catheter fixation, but in this context, there is no regulatory frame to limit the quantity of allergen used. The order or magnitude varies greatly between products (e.g., 2– 3 mg chlorhexidine gluconate for a tablet, about 50– 100 mg for a patch, about 1 mg/ml for mouth bath products). There is less visibility on the use of this drug in other products such as toothpaste (e.g., 0.5– 2 mg/ml) or lens products. Systemic reactions to skin tests are rare and are the prerogative of IgEmediated (especially anaphylaxis) reactions to betalactams, one of our patients reacted with anaphylaxis during intradermal test.9 This was the patient with the highest serumspecific chlorhexidine IgE level in our series (and a doubtful SPT, see Table 1). All our patients had serumspecific chlorhexidine IgE levels above 0.1 kUA/l. This cutoff has an estimated sensitivity and specificity of