Prevalence of Titanium Hypersensitivity in Patients with Titanium Implants: A Systematic Review and Meta-analysis.

BACKGROUND: With increase in exposure to titanium in daily life and its use in medical procedures, there is a greater chance for developing titanium hypersensitivity. Our aim and objective is to examine whether patient patients with titanium implants had a greater incidence of titanium hypersensitivity or not. Titanium is widely considered to have good biocompatibility. A passivating surface layer of TiO2 is formed when exposed to air which gives it good corrosion resistance. These properties along with its high strength, lightweight, and improvements in smelting technologies have led to its widespread use as an intraosseous and periosteal implant in dentistry and orthopedics.
MATERIALS AND METHODS: Only case-control studies were used for the meta-analysis. Studies with a sample size of <5 were excluded. Cutaneous and epicutaneous tests were used in the study.
RESULTS: Three studies met the inclusion criteria. Titanium hypersensitivity is more prevalent in patients with titanium implants.
CONCLUSIONS: It is also used in a variety of medical devices such as pacemakers and insulin pumps. Moreover, our external exposure to titanium is increasing. It is used in aerospace, chemical, and automobile industries. It is also used in jewelry, home furnishings, and in making sports and marine equipment. Titanium implants increase the possibility of developing titanium hypersensitivity, and thus, it should be considered as a major factor in unexplained implant failure where other causes have been excluded. Copyright:

INTRODUCTION

Titanium is mostly used as titanium dioxide. It is used as a whitening agent in paints, sunscreens, and as a filler in pharmaceutical and food industries. This widespread can cause an increased number of patients to be sensitized to titanium. Hypersensitivity is an exaggerated immune response to a known antigen. Metal ions act as haptens and combine with proteins to trigger a cell-mediated immune response. They can also cause the degranulation of mast cells and basophils. They can thus cause Type I and Type IV hypersensitization reactions.[1] Titanium ions accumulate in the peri-implant area, regional lymph nodes, and the lungs.[234] Titanium particles can be found in macrophage lysosomes[56] and can cause Type IV hypersensitivity reactions. Cases of titanium allergy where the main signs and symptoms are urticaria, edema, eczema, and pruritus which may be localized or generalized[789] have been reported in the literature. In some cases, more serious problems such as eczema,[9] slow healing of fractures,[10] pain, necrosis, and weakening of orthopedic implants also happens.[11] Clinical findings and the results from epicutaneous tests[121314] are used to diagnose metal allergy. Susceptibility to metal allergy has been shown to have a genetic link,[10] and many patients can have multiple allergies. A history of reaction to metals or jewelry is a risk factor for developing hypersensitization to metal implants.[15] TTherefore, even if the incidence of titanium allergy in the general population is low, patients with a previous history of allergic reactions to metals/jewelry or other significant allergies (e.g., penicillin allergy), a metal allergy assessment and specific allergy tests before placing implants16 must be done in regular practice.. Epicutaneous tests are the standard procedure to assess Type IV hypersensitivity reactions.[16171819202122] The relation between failure of titanium implants and allergy to titanium is complex. Jacobs et al., 1991,[23] and Witt and Swann 1991[24] found that the levels of titanium in the blood of patients having loose titanium hip implants were increased. Subsequently, Frisken et al., 2002,[25] demonstrated a higher concentration of titanium ions in the regional lymph nodes and lungs of animal subjects with failed titanium implants. Elves et al., 1975,[26] found that orthopedic implants which failed without any plausible explanation had a greater incidence of sensitization to metals than the control group which consisted of implants which failed due to known causes. Most of these studies have been done on orthopedic implants. To what extent can these be extrapolated to dental implants is debatable. Dental implants have a limited area of contact between bone and implant. Furthermore, the oral mucosa has less number of antigen-presenting cells (Langerhans cells) than skin. In addition, dental implants in the oral cavity are covered by a pellicle of glycoproteins which decreases their immunologic potential.[16] The prevalence of titanium allergy, though low, has been largely overlooked by profession. Due to its excellent biocompatibility and mechanical properties, the use of titanium, or a material of choice for numerous medical devices, dental and orthopedic rehabilitation is increasing.[27] Therefore, it is important to evaluate the prevalence of titanium hypersensitivity in these patients and to look for alternatives in patients susceptible to titanium allergy. Various materials have been suggested as alternatives. These include zirconia, hydroxyapatite, tantalum, and polyetheretherketone (PEEK).

MATERIALS AND METHODS

The research question for this study was to assess whether titanium implants increase the risk for developing titanium hypersensitivity as compared to the general population or not. The electronic search was conducted using the PubMed library of United States National Library of Medicine, Cochrane Central Register of Controlled Trials (CENTRAL) of the Cochrane Collaboration, Ovid, ResearchGate, ScienceDirect, EBSCO, Web of Science, and Google Scholar as online search engines. The keywords used in the search were “Titanium” AND “IMPLANT” AND “HYPERSENSITIVITY” or “ALLERGY.” The references given by the selected articles were also used to find relevant publications. The Contemporary Clinical Dentistry (1997–2015), Journal of Maxillofacial Surgery (1997–2015), and Journal of the American Dental Association (2000–2020) were hand searched for relevant articles. For conducting the meta-analysis, the Review Manager (RevMan) [Computer program]. Version 5.4, The Cochrane Collaboration, 2020. was used.

Criteria for selection of studies

The abstracts of all the publications in our search were screened independently by two reviewers. The articles were shortlisted on the basis of the following inclusion and exclusion criteria. Only case–control studies were selected. Studies with a heterogeneous sample consisting of implant materials other than titanium in the same groups were excluded. Studies with a sample size of <5 were excluded. Studies on both dental and orthopedic implants were selected. Cutaneous and epicutaneous tests for titanium hypersensitivity were used. The relevant data from the selected studies (e.g., study design, methods, and outcome measures) were extracted in duplicate independently by two reviewers.

Statistical analysis

The data from the three studies were divided into two groups. Group I was the test group with patients having titanium implants and thus suspected of having titanium allergy. Group II was the control group and included patients without implants. In each group, the incidence of titanium allergies was recorded. Since the cutaneous and epicutaneous tests used in the three studies were slightly different, the random-effects model was used in the study. The individual effect sizes and odds ratios of the three studies were calculated. The Z-score for the overall effect was calculated. For testing the heterogeneity of the studies, the tau-squared and I-squared tests were conducted. The pooled odds ratios from the studies, with 95% confidence intervals, were obtained through the meta-analysis. Begg and Mazumdar test for publication bias was done. The funnel plot for detecting any publication bias was made with the standard error as the y-axis and the log of the odds ratio as the x-axis.

RESULTS

Study selection and organization of the data

Through online search engines, 188 titles and abstracts of studies (both case–control and prospective), case reports, and literature reviews on titanium allergy were found [Figure 1]. Out of these, only three case–control studies were found which exclusively studied titanium allergy and could be thus clubbed together in a meta-analysis [Table 1].

Figure 1

Boolean diagram showing the process of selection of the included studies

Table 1

Outcomes and main features of the selected studies

Included studies	Type of titanium implant	Group 1*		Group 2#		Additional information
		Events	Total	Events	Total
de Graaf et al., 2018[27]	Neurostimulator, insulin pump, orthopedic, dental, surgical	22	248	4	210	Patch testing was done with TiO2, titanium oxalate hydrate, titanium isopropoxide, titanium lactate, and titanium citrate
Hosoki et al., 2018[28]	Dental	4	16	13	254	Patch testing was done for multiple metals, but the data for titanium were grouped separately and hence were extracted for use in the study
Sicilia et al., 2008[29]	Dental	9	35	0	35	Both cutaneous and epicutaneous tests were done using TiO2

*Patients with titanium implants, #Patients without titanium implants

Results of publication bias

Begg and Mazumdar's rank correlation test showed a slight publication bias. The funnel plot for the three studies is shown in Figure 2.

Figure 2

The funnel plot for the three studies

Meta-analysis

The weighted mean of the odds ratios with 95% confidence intervals showed a strong tendency for patients with titanium implants to have a greater incidence of titanium allergy. However, due to the limited number of studies and the slight publication bias, more research needs to be done on titanium allergy [Figure 3].

Figure 3

Forest plot showing the relative effect sizes and the pooled effect of the studies

DISCUSSION

The massive rise in the use of titanium in various fields has led to an increase in the chance sensitization to titanium through percutaneous and permucosal routes in the general population.[27] To detect titanium hypersensitivity, the patch test has not yet been standardized. A standardized patch test will go a long way in giving a better idea about the prevalence of titanium hypersensitivity in the general population.[2829] The exact nature of sensitization to titanium is unknown. Even if titanium is a true sensitizer, it is albeit a weak one. Thomas P et al.[6] showed that the tissue retrieved from a failed titanium hip implant had T-cells and macrophages in the absence of B-cells which suggests Ti allergy. However, Park et al.[30] showed that titanium was not a true dermal sensitizer after local lymph node assay failed to show the signs of titanium allergy. Hosoki et al.[31] described a case of titanium allergy to dental implants where the symptoms (dermatitis and pruritus) were resolved on retrieval of the implants. The prevalence of titanium allergy is probably quite low. It could, however, be the cause of isolated cases of implant failure which cannot be ascribed to any other causes.

CONCLUSIONS

It is, therefore, advisable to test for titanium allergy in patients with a history of multiple and/or severe allergies. These include allergy to artificial jewelry, nickel, cobalt, and penicillin. Furthermore, patients with a previous heavy exposure to titanium (extensive orthopedic, dental rehabilitation with Ti) and those with unexplained implant failure should be tested. Once titanium allergy has been demonstrated in a patient, it is preferable to use alternative treatment modalities or to use alternative materials such as tantalum, PEEK, or zirconia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.