D3.03 - Titanium allergy – from anamnesis to diagnosis

Wide usage of Titanium (Ti) and its oxide (TiO₂) especially in medical devices has risen concern about allergic reactions caused by them. Existing Ti allergy diagnostic methods require improvement. There is a need for a comprehensive algorithm for Ti allergy diagnosing to determine the actions of specialist at each medical care level.

A medical examination of Ti allergy clinical signs and a survey with a scoring questionnaire enrolled 124 patients. All underwent a sublingual-oral provocative test with TiO₂ (SBL test) with analysis of the oral fluid peroxidase activity (OFPA) changes. A patch test with 0.1% TiO₂ suspension, 1% chromium (III) chloride, 1% cobalt (II) chloride, 0.5% ammonium molybdate (V), 10% aluminum (III) hydroxide, 2.5% nickel (II) sulfate was made to 33 patients. Elemental analysis of Ti in serum before and after SBL test was made to 56 patients (22 - with positive SBL test (group 1); 18 - with well-functioning Ti-containing prosthesis and negative SBL test (group 2); 16 - controls with negative SBL test (group 3).

Based on the questionnaire results, 68 patients (56%) were assigned to the high, 12 (10%) - moderate, 42 (32%) - low-probability of Ti allergy. The total score in patients with Ti allergy clinical suspicion was 6.0 (4.5; 7.0), in controls - 1.0 (0.5; 2.0) (p<0.0001). The Cronbach's alpha coefficient of questionnaire validation was 0.81, indicating a good level of reliability and a sufficient level of internal questions consistency with 62% sensitivity (Se) and 81% specificity (Sp).

SBL test showed a significant increase of OFPA in high-probability Ti allergy group +27.1 (+19.1;+35.0)%, compared to the controls +2.2 (-1.9;+6.2)% (p<0.001). The threshold for OFPA increasing was +14.5% (ROC analysis, AUC=0.770, p<0.001) with Se 70%, Sp 86%.

The patch test revealed 62% at least one positive result in patients reported reactions to metals and none from controls (Se 62%, Sp 90%). In 86% patients sensitization to several metals was detected.

The initial serum Ti content in groups did not differ. After SBL test, in group 1 Ti median level increased from 0.17 (0.12; 0.21) to 0.23 (0.22; 0.24) μg/ml (p=0.01) and exceeded values ​​​​in both others: 0.21 (0.10; 0.23) (group 2) (p=0.03) and 0.11 (0.11; 0.22) (group 3) (p=0.001) (Pic.1). The serum Ti level greater than 0.21 μg/ml after a positive SBL test indicated Ti allergy (Se 77%, Sp 75%).

A step-by-step algorithm for Ti allergy diagnosing has been developed. Firstly - the scoring questionnaire for assessing Ti allergy probability and the need for provocative test. Secondly - SBL test in Ti allergy moderate/high probability and/or patch test - in contact reactions to different metals. The metal allergy can be approved in patients with positive results of provocation and high probability according the questionnaire. Finally the additional high-tech methods (elemental analysis etc.) should be used in case of positive SBL test and Ti allergy moderate probability.

The algorithm application will increase the efficiency of Ti allergy diagnostics to 70-89% at various medical care levels.