A retrospective study on titanium sensitivity: Patch test materials and manifestations

Background Titanium is being increasingly used. Although it is considered to be a non‐allergenic material, allergic reactions to it have been reported. Titanium dioxide has been found to be an unreliable patch test material. Few studies to date have profiled titanium allergy, and it therefore remains difficult to distinguish its manifestations. Objectives To evaluate alternatives for titanium dioxide as a patch test preparation, and to profile titanium reactions and manifestations. Methods A retrospective chart review was conducted with 458 patients who underwent patch testing with at least 1 of 5 different titanium salts. Results At least 1 positive result was noted in 5.7% of the patients. The frequency of positive results for the tested salts ranged from 0.9% to 7.9%. Titanium(IV) oxalate hydrate had the highest yield and titanium dioxide the lowest. Erythema, dermatitis and local swelling were the most common objective complaints. In 16 (61.5%) patients, the test result had partial or full clinical relevance. Conclusions No titanium‐specific risk factors and clinical picture could be identified. Titanium dioxide is not adequately sensitive for identifying titanium allergy. The titanium salts seem to be possible superior patch test preparations, but appear to be unsuitable if used singly. The patient's medical history and clinical picture remain crucial in the diagnostic work‐up.


| INTRODUCTION
Titanium (Ti) is a lustrous transition metal that is widely used as an implant material in medicine and dentistry, and, in its oxide form, as a white pigment in personal care products and food. It is often chosen as an implant material, owing to its corrosion resistance and good biocompatibility. 1,2 Many new Ti implant applications are being developed, and, because the age of the western population is increasing, human exposure to Ti is also increasing. 3,4 Although Ti is generally believed to be "hypo-allergenic", numerous articles have been published describing allergic reactions to Ti. [5][6][7] The prevalence of Ti allergy is not known, but is estimated to be very low. Reports on Ti allergy have been summarized by Wood et al and Fage et al. 8,9 They describe adverse effects of Ti, namely, local and systemic symptoms such as local eczema in areas over an implant, pruritus, pain, chronic fatigue syndrome, and neurological symptoms.
Clinical experience with dental and orthopaedic implant patients suggests that Ti allergy occurs more often than patch tests indicate. [10][11][12] The most widely used patch test preparation is Ti dioxide (TiO 2 ), but it rarely confirms clinical suspicion. This might be explained by its poor solubility, resulting in inadequate skin penetration. 6,7 Other Ti salts, such as Ti(IV) chloride, Ti(II) sulfate, Ti(IV) diethanedioate, Ti salicylate, Ti(IV) tetrahydroxide, calcium titanate, Ti(III) nitride, and Ti(IV) oxalate hydrate, have been suggested, but only a few studies have actually examined the use of these salts. 9,13 In our clinic, during the past 10 years, different Ti test salts have been applied to evaluate possible sensitization to Ti. In this study, our objective was to report the frequency of positive patch test reactions to Ti dioxide and its alternatives applied in our clinic. In addition, this article describes the clinical presentation of Ti-allergic patients in our clinic. were removed from the backs of the patients after 48 hours of exposure, and readings were performed on day (D) 2, D3, and D7. Positive reactions rated as +, ++ or +++ in accordance with the ICDRG/ESCD reading criteria were regarded as allergic, 14 whereas doubtful reactions (?+) were not. The relevance of the positive reactions was assessed. An allergen was considered to be clinically relevant if:

| MATERIALS AND METHODS
(1) the existence of exposure could be established, and (2) the patient's complaints could be explained (completely or partially) with regard to that exposure. The relevance was categorized as complete, partial, past, no and unknown relevance. 15 Evaluations were performed by an experienced dermatologist. The significance level for all analyses was P < .05.

| RESULTS
A total of 458 patients were tested with ≥1 Ti salts (see Table S1 for combinations and numbers). At least 1 positive result was noted in 5.7% of patients (n = 26). The results of patch testing with the Ti salts are shown in Table 2 Patients could be divided into three groups: group 1 (n = 248) comprised patients suspected of having Ti allergy; group 2 (n = 163) comprised patients suspected of having a metal allergy other than to Ti; and group 3 (n = 47) comprised patients who were not exposed to Ti-containing medical devices and did not have a specific history of Ti allergy, henceforth called the control group. In group 1, 22 patients showed positive test reactions (8.9%). In groups 2 and 3, 2 patients showed positive reactions (1.2% and 4.3%, respectively) ( Table 3). The

| DISCUSSION
We performed a retrospective study on all patients patch tested with Ti salts in our hospital. A key finding is that the frequency of Ti sensitivity in this large group of patients was 5.7%. This frequency was higher than the sensitivity found in a study by Sicilia et al, which was 0.6%, and that found in a study by Lhotka et al, which was 2%. 7,16 However, in these studies, only TiO 2 was used, which might account for the difference in sensitization occurrence from that in our study. A study in Lithuania reported no positive patch test reaction to any of the 5 Ti salts present in their metal series. 17 However, only a relatively small number of patients were tested. There are currently no reports in which a panel of Ti salts has been used on a large patch test population.
We tested a highly selected population; therefore, the high frequency of Ti sensitization that we found cannot be extrapolated to the general population. In the group of patients suspected of having Ti allergy, an even higher frequency of 8.9% was observed. Interestingly, this frequency was not statistically different from the frequency found in the control group (P = .39). This may be explained by the small sample size of the control group and the relatively low numbers of positive reactions within both groups. Also, the possible referral bias resulting from the selection of patients on the basis of their clinical history has to be taken into account. The potential differences in accuracy of the Ti salts should also be considered. The retrospective nature of this study makes it difficult to address these problems. This is similar to our experience, in which 8 patients who reacted positively to Ti oxalate were also tested with TiO 2 ; none of the tests gave a positive result. However, the difference in frequency of positive Ti oxalate reactions between patients suspected of having Ti allergy and the control group was non-significant (P = .74). As outlined above, this lack of significance may be attributable to unequal group sizes