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									Alberto Sicilia                                            Titanium allergy in dental implant
Susana Cuesta
Gerardo Coma
                                                           patients: a clinical study on 1500
Ignacio Arregui                                            consecutive patients
Cristina Guisasola
Eduardo Ruiz
Antonio Maestro

Authors’ affiliations:                                      Key words: cutaneous tests, dental implants, epicutaneous tests, titanium allergy
Alberto Sicilia, Cristina Guisasola, Eduardo Ruiz,
Clinica Sicilia, Oviedo, Spain
Alberto Sicilia, Susana Cuesta, Eduardo Ruiz,              Abstract
Section of Periodontology, Department of Surgery,          Background: In dentistry, allergic reactions to Ti implants have not been studied, nor
University of Oviedo, Oviedo, Spain
Gerardo Coma, Allergologic Center, Oviedo, Spain
                                                           considered by professionals. Placing permanent metal dental implants in allergic patients
Ignacio Arregui, Private practice, Leon, Spain             can provoke type IV or I reactions. Several symptoms have been described, from skin rashes
Antonio Maestro, FREMAP, Gijon, Spain                      and implant failure, to non-specific immune suppression.
Correspondence to:                                         Objective: Our objective was to evaluate the presence of titanium allergy by the anamnesis
Prof. Dr Alberto Sicilia                                   and examination of patients, together with the selective use of cutaneous and
Clınica Sicilia
Urıa 5                                                     epicutaneous testing, in patients treated with or intending to receive dental implants of
Oviedo 33003                                               such material.
                                                           Material and methods: Thirty-five subjects out of 1500 implant patients treated and/or
Tel.: þ 34 985253622
Fax: þ 34 985270532                                        examined (2002–2004) were selected for Ti allergy analysis. Sixteen presented allergic
e-mail: asicilia@clinicasicilia.com                        symptoms after implant placement or unexplained implant failures [allergy compatible
                                                           response group (ACRG)], while 19 had a history of other allergies, or were heavily Ti
                                                           exposed during implant surgeries or had explained implant failures [predisposing factors
                                                           group (PFG)]. Thirty-five controls were randomly selected (CG) in the Allergy Centre.
                                                           Cutaneous and epicutaneous tests were carried out.
                                                           Results: Nine out of the 1500 patients displayed positive ( þ ) reactions to Ti allergy tests
                                                           (0.6%): eight in the ACRG (50%), one in the PFG (5.3%)(P ¼ 0.009) and zero in the control
                                                           group. Five positives were unexplained implant failures (five out of eight).
                                                           Conclusions: Ti allergy can be detected in dental implant patients, even though its
                                                           estimated prevalence is low (0.6%). A significantly higher risk of positive allergic reaction
                                                           was found in patients showing post-op allergy compatible response (ACRG), in which cases
                                                           allergy tests could be recommended.

                                                           Given its high resistance to corrosion in a      biologically inexplicable, yet still shown in
                                                           physiological environment and the excel-         some publications (Hensten-Pettersen
                                                           lent biocompatibility that gives it a passive,   1992; Basketter et al. 2000; El Salam El
                                                           stable oxide film, titanium is considered         Askary 2003), that it cannot cause allergic
                                                           the material of choice for intraosseous use      reactions.
Date:                                                      in the medical field (Smith et al. 1997;             An allergic reaction, or hypersensitiza-
Accepted 19 November 2007
                                                           Sykaras et al. 2000; Frisken et al. 2002;        tion, is defined as an excessive immune
To cite this article:                                      Akagawa & Abe 2003). This metal has              reaction that occurs when coming into
Sicilia A, Cuesta S, Coma G, Arregui I, Guisasola C,
Ruiz E, Maestro A. Titanium allergy in dental implant      been somewhat surrounded by mysticism            contact with a known antigen (Roitt &
patients: a clinical study on 1500 consecutive patients.   in the world of dentistry (Parr et al. 1985),    Delves 2001). According to this, in order
Clin. Oral Impl. Res. 19, 2008; 823–835
doi: 10.1111/j.1600-0501.2008.01544.x                      to the extent that there is a general belief,    for titanium to provoke an allergic reaction

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 2008 The Authors. Journal compilation  2008 Blackwell Munksgaard                                                                                 823
Sicilia et al . Titanium allergy in dental implant patients

it must have antigenic properties and must               made from titanium – have shown an               suppression or overaggressive immune re-
be in contact with the organism. First of                increase in friction-induced corrosion,          sponses cannot be disregarded in particu-
all, we know that in their ionic form,                   with a consequent rise in the internal           larly sensitive patients (Hallab et al. 2001).
metals can be bonded with native proteins                release of particles, which can lead to cell     In the field of dental implants, the appear-
to form haptenic antigens, or can trigger                sensitization, granulomatous infiltration         ance of facial erythaema (Matthew &
the degranulation of mastocytes and baso-                and osteolysis (Elves et al. 1975; Lalor et      Frame 1998; Bircher & Stern 2001) and
philes, being capable of developing type I or            al. 1991; Witt & Swann 1991; Case et al.         non-keratinized, oedematous, proliferative
type IV hypersensitive reactions (Schramm                1994; Revell & Lalor 1995). There are even       hyperplastic tissue (Mitchell et al. 1990)
& Pitto 2000; Hallab et al. 2001). Sec-                  authors who consider this type of prosthe-       have been described.
ondly, our external exposure, in this case               sis (metal-on-metal) a non-indicated device         Many of these investigations have been
to titanium, is massive. Its excellent prop-             (Merritt & Brown 1996), and it is nowa-          carried out with titanium orthopaedic im-
erties and resistance to corrosion have ex-              days used with little frequency. Animal          plants; therefore it is not certain as to what
tended its use into aerospace, chemical and              studies show an increased presence of tita-      extent the discoveries can be extrapolated
nuclear industries, desalination plants,                 nium ions after placing dental implants,         to the oral cavity and dental implants. On
marine equipment, car manufacturing,                     not only in peri-implant tissues (Brune          the one hand, the intraosseus contact sur-
sports, jewellery, home furnishings and                  1986; Wennerberg et al. 2004), but also in       face is smaller in dental implants than in
the medical industry, used particularly in               the regional lymph nodes (by lymphatic           orthopaedic ones (Brunski et al. 2000;
the field of orthopaedic and dental im-                   transport) and in the lungs (the first capil-     Akagawa & Abe 2003), which may be
plants. However, 95% (Weighed 2002) of                   lary filter of blood passing through the          particularly important considering that
the global use of titanium is not in its metal           venae cavae) (Brune 1986; Schliephake            bone has a very low reactivity potential
form, but as titanium dioxide, for its                   et al. 1993; Weingart et al. 1994; Frisken       (Schramm & Pitto 2000). On the other
whitening effect (in all kinds of paints and             et al. 2002). In one of the studies, two         hand, oral mucosa and the skin behave
whitening agents), sunscreen properties                  implants failed, coming loose but with no        very differently from an immunological
and use as a safe excipient in the cosmetic,             infection, and in these particular patients a    point of view, partially because of the
pharmaceutical and food industries. This                 presence of titanium in the lungs was            influence of specific immune systems for
exposure means our body usually has a                    observed to be 2.2–3.8 times higher, and         each organ, such as skin-associated lym-
titanium content of around 50 ppm (Parr                  7–9.4 times higher in the lymph nodes,           phoid tissue and mucosa-associated lym-
et al. 1985).                                            which were enlarged (Frisken et al. 2002).       phoid tissue. A practical application is that,
   Additionally, the insertion of titanium                  Hypersensitivity reaction to a metal          in mucosa, the number of Langerhans’
implants and their permanence in the hu-                 comes from the presence of ions following        cells, which act as antigen-presenting cells,
man body can also cause internal exposure.               ingestion, skin or mucosal contact, or from      is much smaller (Bass et al. 1993;
It has been proven that titanium ions con-               implant corrosion processes (Ahnlide et al.      Schramm & Pitto 2000; Thomas 2000).
centrate in tissues surrounding dental and               2000; Hallab et al. 2001). These ions,           It is because of this, and perhaps also
orthopaedic implants, as well as in regional             although not sensitizers, form complexes         because of its reduced permeability, that
lymph nodes and pulmonary tissue. Con-                   with native proteins and act as allergens        oral mucosa must be exposed to allergen
centrations of between 100 and 300 ppm                   causing       hypersensitivity      reactions    concentrations 5–12 times greater than the
have been discovered in peri-implant tis-                (Schramm & Pitto 2000; Hallab et al.             skin in order to cause tissular microscopic
sues, often accompanied by discolorations,               2001). Their clinical effects are difficult       reactions. Moreover, contact between the
which can be well tolerated (Parr et al.                 to assess due to their infrequent appearance     metal and the host is hampered, as the
1985; Abdallah et al. 1994; Torgersen                    and subtle symptoms (Hallab et al. 2001).        implant and prosthetic structures in the
et al. 1995, 1995b; Haug 1996; Matthew                   In the case of titanium allergy, medical         oral cavity are coated with a layer of sali-
& Frame 1998b), or by type IV hypersensi-                literature has described cases where it has      vary glycoproteins, which act as a protec-
tivity reactions, with titanium particles                mainly appeared as the fundamental cause         tive barrier (Bass et al. 1993).
inside the macrophage lysosomes (Mitchell                of urticaria, eczema, oedema, redness and           The diagnosis of metal allergy is typi-
et al. 1990; Lalor et al. 1991; Revell &                 pruritus of the skin or mucosa, either           cally based on the patient’s medical record,
Lalor 1995; Katou et al. 1996; Matthew &                 localized, at distant sites, or generalized      clinical findings and the results from epi-
Frame 1998; Frisken et al. 2002).                        (Hensten-Pettersen 1992; Haug 1996;              cutaneous tests (Bass et al. 1993; Kusy
   In blood, given its poor solubility (Lalor            Lhotka et al. 1998; Thomas 2000; Tamai           2004). It has been described that people
et al. 1991; Bianco et al. 1996), no signifi-             et al. 2001; Valentine-Thon & Schiwara           have a susceptibility to suffer from metal
cant rise of titanium levels was detected                2003; Thomas et al. 2006). In special cases,     allergy – possibly genetically based (Tho-
after placing three dental implants in hu-               allergic reactions have been associated with     mas 2000) – as it has been observed that
mans (Smith et al. 1997); however, a sig-                more serious problems such as atopic der-        many patients can suffer from multiple
nificant rise has been show in patients with              matitis (Tamai et al. 2001), impaired heal-      allergies and that individuals with previous
a failed, loose titanium hip prosthesis com-             ing of fractures (Thomas et al. 2006), pain,     reactions to metals or jewellery have a
pared with controls (Jacobs et al. 1991). In             necrosis and weakening of orthopaedic im-        greater risk of developing a hypersensitivity
this area, patients with a metal-on-metal                plants (Haug 1996) and tolerance phenom-         reaction to a metal implant (Hallab et al.
total joint replacement – both joint surfaces            ena (Thomas 2000). Non-specific immune            2001). In light of this, although the tita-

824 |    Clin. Oral Impl. Res. 19, 2008 / 823–835                                    c                                       c
                                                                                      2008 The Authors. Journal compilation  2008 Blackwell Munksgaard
                                                                                             Sicilia et al . Titanium allergy in dental implant patients

nium allergy has a low prevalence rate, for       1991). Studies performed with epicuta-            been observed that the percentage of sensi-
patients with a history of previous signifi-       neous tests show a percentage of Ti-sensi-        tizations to metals used in orthopaedic
cant allergies, it may be particularly advi-      tive individuals between 1% and 3%                prostheses that failed without explanation
sable to carry out a metal allergy                (Lhotka et al. 1998; Okamura et al.               (not including fractures and infections) was
assessment and specific allergy tests before       1999); one study with the LMI test reached        74%, against 17% in the control group,
placing permanent implants of such mate-          4% (Merritt & Rodrigo 1996b), while               made up of failed prostheses with explana-
rial (Cook et al. 1991; Tamai et al. 2001).       those performed with the MELISA test              tion (Elves et al. 1975). The fact that
   Results from epicutaneous tests are ac-        fluctuated between 1.5% and 28%, with              hypersensitization can take months or
ceptable as proof of sensitivity to a specific     authors indicating that the most recent           even years to develop (Haug 1996), along
allergen (Bass et al. 1993). This is consid-      studies have shown an increase in sensiti-        with its infrequency and the uncertainty of
ered a standard procedure (Thomas 2000)           zations (Valentine-Thon & Schiwara                its symptomatic expression (Hallab et al.
and is widely used to assess type IV hyper-       2003). Titanium allergy has been described        2001), makes it difficult to perform deeper
sensitivity reactions to titanium (Lalor          in deodorant and cosmetics users (Basket-         studies in this field. In the area of dental
et al. 1991; Lhotka et al. 1998; Okamura          ter et al. 2000; Tamai et al. 2001), after        implantology, the failure of implants has
et al. 1999; Ahnlide et al. 2000; Schramm         local reactions to pacemakers (Peters et al.      been widely studied (Esposito et al. 1999,
& Pitto 2000; Yamauchi et al. 2000;               1984; Verbov 1985; Buchet et al. 1992;            1999b, 1999c), as has their use in compro-
Bircher & Stern 2001; Suhonen & Kanerva           Abdallah et al. 1994; Yamauchi et al.             mised patients (van Steenberghe 2003; van
2001; Kusy 2004; Thomas et al. 2006).             2000; Akaki & Dekio 2002), in patients            Steenberghe et al. 2003b), with the main
These tests can also be used in combina-          with       bronchopulmonary        pathology      causes for failure being infection, impaired
tion with the intradermal inoculation of          through exposure to titanium powder (Red-         healing and overload (Esposito et al. 1999).
the antigen (Yamauchi et al. 2000) to assess      line et al. 1986; Shirakawa et al. 1989;          However, not all failures can be explained
type I hypersensitivity reaction. Tests           Nemery 1990; Breton et al. 1992; Bircher          by these three factors; some are more
based on the use of patient blood samples         & Stern 2001), in monitored hip prosthesis        difficult to explain, such as implant spon-
have also been used, the most common              patients (Merritt & Rodrigo 1996b), in            taneous rapid exfoliation (Deas et al. 2002)
being the lymphocyte transformation test          failed hip and knee prostheses (Cook              and other situations in which the effect of a
(Carando et al. 1985; Cook et al. 1991;           et al. 1991; Lalor et al. 1991) and in            possible hypersensitivity reaction to tita-
Torgersen et al. 1993; Yamauchi et al.            patients with titanium plate osteosynthesis       nium may be taken into consideration.
2000; Hallab et al. 2001; Valentine-Thon          (Matthew & Frame 1998; Thomas et al.                 Taking all these points into account, it
& Schiwara 2003; Thomas et al. 2006), the         2006). In the maxillofacial area, titanium        seems there is a problem – somewhat
memory lymphocyte immunostimulation               allergy has been described in patients with       infrequent – but nevertheless one that has
assay (MELISA) (Valentine-Thon & Schi-            miniplates to treat mandibular fractures          been systematically overlooked by the pro-
wara 2003) and the lymphocyte migration           (Katou et al. 1996), with few and inaccu-         fession. Nowadays, the great biocompat-
inhibition test (LMI or LIF) (Cook et al.         rate references to titanium-allergenic pro-       ibility of titanium has caused the
1991; Merritt & Rodrigo 1996b; Hallab             cesses in patients with dental implants           emergence of techniques, which, in various
et al. 2001). Finally, histological studies       (Mitchell et al. 1990; Matthew & Frame            fields of medicine, imply the permanent
have also been carried out on peri-implant        1998; Bircher & Stern 2001).                      retention (Haug 1996) of implants in the
tissues (Mitchell et al. 1990; Torgersen             There is a complex relation between the        body. This requires the assessment not
et al. 1995b; Thewes et al. 2001), the use        failure of a metal implant and allergy to its     only of the general biological suitability of
of which is restricted to cases in which an       components. A greater concentration of            the implant material (biocompatibility) but
implant is surgically removed, simulta-           titanium ions in the regional nodes and in        also of the individual, seeking out methods
neously taking a sample of the surrounding        pulmonary tissue in specimens with failed         to identify any patients sensitized to its
tissue, or soft tissue biopsy. Anecdotally,       implants has been described in an animal          components, as well as alternative materi-
alternative assessments have also been car-       study (Frisken et al. 2002), and a greater        als in allergic patients (Schramm & Pitto
ried out, such as the Bi-Digital O-ring test      blood concentration of titanium has been          2000), such as tantalum (Johansson et al.
(Tamai et al. 2001).                              described in patients with failed loose hip       1990; Matsuno et al. 2001), hydroxyapatite
   Scientific evidence on the clinical fea-        prostheses (Jacobs et al. 1991; Witt &            (Schwartz-Arad et al. 2005; Simunek et al.
tures of a metal allergy is based on cohort       Swann 1991). Several studies show a               2005; Artzi et al. 2006) or zirconium
studies, case series and isolated clinical        greater sensitization to titanium in patients     (Kohal et al. 2004; Sennerby et al. 2005).
cases. It is estimated that cutaneous hyper-      with a failed titanium orthopaedic prosthe-          Once the gaps in this field have been
sensitivity to metals fluctuates between           sis than in those with successful prostheses      taken into account, this study aims at
10% and 15% (Hallab et al. 2001). There           (Cook et al. 1991; Lalor et al. 1991), which      evaluating the presence of titanium allergy
are no epidemiological studies on the pre-        coincides with findings from classic cohort        by the anamnesis and medical examina-
valence rate of titanium allergy in the           studies in patients with metal implants: a        tion, as regards to selective use of cuta-
general population, although the fact that        prevalence of metal allergy six times             neous and epicutaneous testing, in
external exposure to titanium is so impor-        greater in patients with failed orthopaedic       consecutive patients that have consulted
tant, and that related pathology is scarce,       implants than in the general population           or that have been treated with titanium
makes one suspect it to be low (Lalor et al.      (Hallab et al. 2001). Furthermore, it has         dental implants at a centre specialized in

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 2008 The Authors. Journal compilation  2008 Blackwell Munksgaard                                 825 |    Clin. Oral Impl. Res. 19, 2008 / 823–835
Sicilia et al . Titanium allergy in dental implant patients

periodontal surgery and implantology. The                       allergic reactions such as glottis oedema                 titis de Contacto (Vilaplana et al. 1999;
study also aims at analysing eventual posi-                     or anaphylactic shock).                                                      ´
                                                                                                                          Conde-Salazar-Gomez 2000) and the Mod-
tive results that may occur regarding the                       Extensive surgical internal exposure to                   ified European Standard Series (Suhonen &
possible clinical indicators evoked in the                      titanium (having undergone at least                       Kanerva 2001).
bibliography.                                                   three implant surgeries, including inter-                    Cutaneous tests were performed using
                                                                ventions for treating implants with peri-                 the Prick technique, with immediate read-
                                                                implantitis or removing failed implants                   ings at 10, 20 and 30 min, to assess type I
Material and methods                                            with a clear aetiology).                                  hypersensitivity. Oxide titanium was used
                                                                                                                          in 0.1% and 5% vaseline (Laboratorios
Between December 2001 and December                                                                                        C.B.F. Leti, S.A. Madrid, Spain), titanium
2004, 1500 patients in need of dental im-                                                                                 oxide in 5% vaseline (Laboratorio Martı     ´
plant treatment, or surgery for peri-implant               Composition of test and control groups
                                                           At this clinical stage, 35 patients were                       Tor, Barcelona, Spain) and metallic tita-
pathology, were examined at a centre spe-                                                                                 nium in a 0.1% and 5% aqueous solution.
                                                           selected for the test group. All patients
cialized in periodontal surgery and implan-                                                                                  A drop of the allergen or test substance
                                                           showing at least one of the previous clinical
tology (Clinica Sicilia, Oviedo, Spain). To                                                                               was placed on the forearm skin surface
                                                           indicators of titanium allergy (inclusion
detect the presence of Ti allergy, a two-                                                                                 (if the allergen was in vaseline, an amount
                                                           criteria) were included in this group. The
stage assessment was carried out (Bass et                                                                                 the size of a grain of rice was used). The
                                                           remaining examined patients were ex-
al. 1993; Kusy 2004): an initial clinical                                                                                 allergen was introduced into the epidermis
                                                           cluded. Once the selection of patients was
evaluation and assessment of the patient’s                                                                                by means of a lancet puncture. The lancet
                                                           completed, they were referred to the allergy
medical history and clinical findings, and a                                                                               used in this technique has a 1 mm tip with
                                                           centre for cutaneous and epicutaneous test-
further study with an allergy test on pre-                                                                                side stops so that only the tip penetrates
                                                           ing. At the same time, a further 800 con-
selected patients (Fig. 1).                                                                                               the skin. A test is carried out each time
                                                           trol patients were examined, of which 35
   Clinical assessment: The presence of the                                                                               with a 0.1% histamine solution, which
                                                           were randomly selected to form the control
following clinical indicators of titanium                                                                                 serves as a positive control and helps, by
                                                           group for the second phase of our study.
allergy (inclusion criteria) was evaluated:                                                                               comparison, to interpret the results.
                                                              Thirty-five people were selected for the
   Allergy-compatible reactions group:                                                                                       Epicutaneous tests were carried out with
                                                           test group of which 10 were male (28.57%)
    Presence of allergic symptoms after                    and 25 female (71.4%), aged between 21                         delayed readings at 24, 48 and 72 h to
    implant surgery (intra- or extra-oral                  and 68, with an average age of 50.2 (38.9–                     evaluate type IV hypersensitivity. The
    and local or general redness, urticaria,               61.5). The control group included 16 males                     study involved the use of titanium oxide
    pruritus, rash, dermatitis and eczema-                 (45.7%) and 18 females (51.4%), aged                           in 0.1% and 5% vaseline (Laboratorios
    tous skin reactions).                                  between 21 and 70, with an average age                         C.B.F. Leti S.A.), titanium oxide in 5%
    De-keratinized hyperplastic lesions of                 of 47.69 (36.31–59.07).                                                                     ´
                                                                                                                          vaseline (Laboratorio Martı Tor) and me-
    peri-implant soft tissues.                                                                                            tallic titanium in a 0.1% and 5% aqueous
    Unexplained implant failures (includ-                                                                                 solution. The test substance was deposited
                                                           Clinical allergy study
    ing spontaneous rapid exfoliation).                                                                                   on an area of the skin, normally on the
                                                           Patients were subjected to cutaneous and
                                                                                                                          back, and covered with a waterproof dres-
                                                           epicutaneous tests, following criteria of the
  Predisposing factors group:                                                                                             sing. The results were read at 24, 48 and
                                                           International Contact Dermatitis Research
                                                                                                                          72 h. Vaseline was used as a control.
    History of multiple allergies (allergy to              Group, the Deutsche Kontakt Dermititis
                                                                                                                             The test substance was applied using
    more than two elements or serious                      Gruppe and the Grupo Espanol de Derma-
                                                                                                                          patches or test units. These patches have a
                                                                                                                          marked area (of at least 0.8 cm2) in which
                                                                                                                          the antigen is placed. These specific areas
                                                                                                                          can be cellulose, aluminium or plastic. Two
                                                  1.   Allergy symptoms after implant placement
                                                  2.   Soft tissue hyperplasic lesions                                    types of patches were used: one with a
                  CLINICAL SCREENING              3.   Unexplained implant failures                                       cellulose area with polypropylene insulation
                                                  4.   History of several allergies                                                  s
                  (Clinical indicators)                                                                                   (Curatest , Lohman & Rauscher Interna-
                                                  5.   Heavily Ti-exposed during implant surgeries
                                                  6.   Multiple explained implant failures                                tional GMBH & CO. KG, Neuwied, Ger-
                                                                                                                          many) and another with an aluminium area
                                                                                                                          (Finn Chambers on Scanpor , Epitest Ltd,
                                                                                                                          Tuusula, Finland). The titanium aqueous
                                                                                                                          solution was prepared using metallic tita-
                                                                                                                          nium powder, and its concentration was
                                                                                                                          determined by means of atomic absorption
                                                  CUTANEOUS &
                                                                                                                          spectrophotometry techniques (Alfa Aesar
                                                  EPICUTANEOUS TESTS                                                      GMBH & CO. KG, Karslruhe, Germany).
                                                                                                                             All tests were carried out by the same
Fig. 1. Study diagram.                                                                                                    examiner (G. C.), who was uninformed of

826 |    Clin. Oral Impl. Res. 19, 2008 / 823–835                                                    c                                       c
                                                                                                      2008 The Authors. Journal compilation  2008 Blackwell Munksgaard
                                                                                               Sicilia et al . Titanium allergy in dental implant patients

the group to which the patient belonged.          Statistical analysis                                subjects selected at random (P ¼ 0.002)
                                                  The statistical analysis was performed
The first cases also included the use of                                                               (Table 1).
                                                  using the SPSS 14.0 (SPSS Inc., Chicago,
titanium chloride, titanium sulphate and                                                                 Within the test group, 16 patients were
                                                  IL, USA) program. The estimated preva-
serum with titanium oxide, although this                                                              selected, having displayed a clinical indica-
                                                  lence of the ‘titanium allergy’ variable was
was not continued due to the little benefit                                                            tor from the allergy compatible response
                                                  expressed as a percentage, with the corre-
of chloride and sulphate and the absolute                                                             group (ACRG), while the remaining 19
                                                  sponding 95% confidence range (CR) to
equivalence of the serum with titanium                                                                were selected for showing an indicator
                                                  facilitate the interpretation of the general-
oxide and the titanium in aqueous solu-                                                               from the predisposing factor group (PFG).
                                                  ization of the results. Given the low in-
tion.                                                                                                 After analysing the data from this angle,
                                                  cidence of titanium allergy             and,
   The results were shown in the form of                                                              we noticed that the appearance of subjects
                                                  consequently, the low number of cases
type I or type IV hypersensitivity and by                                                             with titanium allergy in the ACRG group
                                                  observed, the association between the di-
the level of intensity, according to the                                                              was almost 10 times greater than in the
                                                  chotomic qualitative variable ‘titanium al-
following scale:                                                                                      PFG group (eight cases, 50%/one case,
                                                  lergy’ and the remaining variables was
   n                                                                                                  5.3%, P ¼ 0.009). From an exploratory
    mild                                          made with the chi square test with Yates
   nn                                                                                                 point of view, if we analyse the relation
     moderate                                     correction, when the applicable conditions
   nnn                                                                                                between the three possible groups (ACRG,
      significant to strong                        were ideal, or with the Fisher exact test.
   nnnn                                                                                               PFG and control) head to head, we find the
       intense                                    The relative risk of the appearance of tita-
                                                                                                      proportion of patients with a positive re-
                                                  nium allergy was calculated in the groups
   At the same time, a control study was                                                              sponse to titanium allergy to be much
                                                  of interest.
carried out on 800 patients without sus-                                                              higher in the ACRG group than in both
pected titanium allergy to check the ab-                                                              the PFG and control groups (P ¼ 0.005 and
sence of irritative reactions to the              Results                                             Po0.009); however, there were no signifi-
substances used in the titanium allergy                                                               cant differences found between the predis-
study. With these participants, selected          After the clinical diagnostic process and           posing factors group (one case, 5.3%) and
among the guests of voluntary patients,           allergy tests, nine out of the 1500 patients        the control group (zero case) (Table 2).
the same protocol as in the case of sus-          assessed showed a positive reaction to tita-           The analysis of the results obtained for
pected titanium allergy was used, using           nium, representing a prevalence of 0.6%,            the different clinical indicators, despite the
four groups: 200 non-allergic subjects,           which the 95% confidence interval would              groups being progressively smaller, showed
200 subjects with respiratory allergy (type       fluctuate between 0.2% and 1%. All pa-               interesting data when compared with the
I reaction), 200 subjects with cutaneous          tients that tested positive to the Ti con-          control group. Six patients were selected for
allergy (type IV reaction) and 200 subjects       centration at 5% also tested positive at            having shown signs of allergy after dental
allergic to other metals.                         0.1% even though, logically, on a smaller           implant surgery, with three positive cases in
   Simultaneously, as well as the results         scale.                                              this subgroup (50%) (P ¼ 0.002). Eight cases
from additional tests deriving from specific          Cutaneous and epicutaneous tests were            were included for unexplained failed im-
patient needs (e.g. allergy to aspirin and its    performed on 35 cases and on 800 volun-             plants, five of which were positive (62.5%,
derivatives, or to penicillin), patients from     tary control patients at the allergology            Po0.001). Just one of the patients with a
the test group were subjected to supplemen-       centre. The cutaneous and epicutaneous              previous record of multiple allergies proved
tary tests using alternative implant materi-      tests were negative in all control subjects,        positive (10%) (NS, P ¼ 0.222), while none
als such as tantalum (Ta) or zirconium (Zi)       and no irritative reactions were observed.          of the subgroups selected for all other in-
and hydroxyapatite, as well as frequently         Positive reactions to titanium allergy were         dicators (de-keratinized soft tissue hyperpla-
used dental materials (FUDM), which may           only discovered in the test group (nine             sic lesions, high exposure to titanium from
mask our results: chrome, nickel, palla-          individuals), which make up 25.7% of                surgery, or explained failures) turned out
dium, copper, mercury, zinc, barium, gal-         the pre-selected individuals, with at least         positive, the results coinciding with those
lium, indium, gold, silver, platinum, acrylic     a positive clinical indicator (95% CR:              of the control group (Table 3).
monomers (methyl-methacrylate, BIS-               11.2–40.2); obviously, no positive cases               Tables 4a and b show the most signifi-
GMA, BIS-M, EGDMA, TEGMA), acrylic                were discovered among the 35 control                cant characteristics of the medical and
polymers (methacrylate, dimethacrylate),
silicon, thermoplastic nylon resin (Flexite       Table 1. Positive reaction to titanium allergy tests in the group with clinical indicators (test
New York, USA; Valplast New York,                 group) vs. control group
USA), epoxy resin, rubber components                                            Patients          þ                   À                    þ 95% CR
(mercapto and thiuram M rubber mixtures),           Test group (TG)             35                9 (25.7%)          26 (74.3%)            11.2–40.2
formaldehyde,      para-tertiary-butylphenol-       Control group (CG)          35                0 (0%)             35 (100%)
formaldehyde resin (p-tert-butylphenol-
                                                    A significantly higher prevalence is observed in the test group.
formaldehyde resin) and paraphenylenedi-            w2 (Yates correction) ¼ 8.160, df ¼ 2, P ¼ 0.004.
amine (PPD). All patients were subjected to         Fisher exact test: TG vs. CG, P ¼ 0.002.
a negative (glycerol saline solution) and a         þ , cutaneous and/or epicutaneous positive result; À , cutaneous and/or epicutaneous negative
positive control (0.1% histamine).                  result; þ 95% CR, 95% confidence range.

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Sicilia et al . Titanium allergy in dental implant patients

Table 2. Positive reaction to titanium allergy tests in the ‘allergy compatible reactions’,                flammatories, barbiturates, PPD, mites
‘predisposing factors’ and control groups
                                                                                                           and anisakis. In the two males from our
                                                         Total        þ          À        þ 95% CR
                                                                                                           study, neither showed multiple allergies.
  Allergy compatible response group (ACRG)               16           8 (50%)     8      25.5–75.5            The three patients who at the first visit
  Predisposing factors group (PFG)                       19           1 (5.3%)   18         0–15.3
  Control group (CG)                                     35           0 (0%)     35                        showed suspected titanium allergy, which
                                                                                                           was confirmed before the start of any
  A significantly higher prevalence is observed in the ‘allergy compatible reactions’ group with            treatment, did not accept treatment with
  regard to the ‘predisposing factors’ and control groups.
                                                                                                           alternative implants made of zirconium or
  w2(Yates correction) (ACRG vs. PFG) ¼ 25.843, df ¼ 2, Po0.009.
  Fisher exact test: ACRG vs. PFG P ¼ 0.005; ACRG vs. CG Po0.009; PFG vs. CG P ¼ 0.352 NS. Relative        coated with hydroxyapatite or tantallum.
  risk of a positive result ACRG/PFG: 9.45.                                                                One of these patients, after requesting a
  þ , cutaneous and/or epicutaneous positive result; À , cutaneous and/or epicutaneous negative            second opinion, opted for titanium im-
  result; þ 95% CR, 95% confidence range.                                                                   plants at a different centre. We have no
                                                                                                           data on the subsequent progress of this
                                                                                                           patient (4B4).
Table 3. Positive reaction to titanium allergy test in selected subgroups with different                      The remaining six patients were diag-
clinical indicators vs. control group                                                                      nosed due to the occurrence of complica-
  Clinical Indicators                                         Total    þ         À        þ 95%CR
                                                                                                           tions during treatment. In one patient
  Allergy symptoms after implant placement                     6       3          3       (10–90)          (4B1), no additional treatments could be
                                                                                                           carried out given the patient’s complicated
  Soft tissue hyperplasic lesions                              2       0          2
                                                                       (0%)                                medical condition, and the patient passed
  Unexplained implant failures                                 8       5n         3       (29–96)          away in 2006. Two patients suffered loss of
                                                                       (62.5%)                             implants, and replacements were at-
  History of several allergies                                10       1          9       (0–7.2)
                                                                                                           tempted using alternative implants. The
  Heavily Ti-exposed during implant surgeries                  6       0          6                        first (4B2) had undergone multiple success-
                                                                       (0%)                                ful implant procedures since 1998. After
  Explained implant failures                                   3       0          3                        suffering spontaneous rapid exfoliation of
                                                                                                           implant in position 42 (Fig. 2a and b), this
  Control group                                               35       0         35
                                                                                                           was successfully replaced in 2002 with a
  A higher significant prevalence was observed in subgroups associated to the clinical indicators           hydroxyapatite-coated implant (Calcitek,
  ‘allergy symptoms after implant placement’ and ‘unexplained implant failures’ with respect to
                                                                                                           Zimmer Dental, Carlsbad, CA, USA)
  control group.
  Statistically significant differences with respect to control group.
                                                                                                           with gold-plated tailored components (Fig.
  Fisher exact test                                                                                        2c–f). Later on, a root fracture of tooth 33
   Po0.001,                                                                                                forced the insertion of a new zirconium
    P ¼ 0.002.                                                                                             implant, which also proved successful (Fig.
   þ , cutaneous and/or epicutaneous positive result; À , cutaneous and/or epicutaneous negative
                                                                                                           3a–d). The second patient (4A3) suffered
  result; 95% CR, 95% confidence range.
                                                                                                           the only serious medical emergency in this
                                                                                                           patient category, which led to admission to
dental records of patients with positive                 ment 4A3), two of which were discovered           the Emergencies Department with glottis
results. The identity of the patients is                 after showing spontaneous rapid implant           oedema. The treatment plan included the
protected by alphanumeric code, made up                  exfoliation (4B1 and 4B2) and the other two       placement of eight implants in the upper
of the table number, 4a or 4b, and their                 after receiving several interventions in im-      jaw with a one-stage surgical approach,
number in sequence. This code should be                  plants with mobility and for implant com-         which were occlusally protected with a
quoted when making reference to a specific                plications in external centres.                   conventional fixed prosthesis, using teeth
case in the text. Medically, seven patients                 In seven cases, patients showed type I         of bad prognosis as abutments. Those teeth
displayed a good general condition, and two              and IV positive reactions simultaneously,         would be later extracted to place an addi-
showed considerable pathologies (epilepsy                the most prevalent being type I, with the         tional implant in position 23 and to prepare
4A4, and liver cancer and type II diabetes               great majority (six out of seven or 85.7%).       a complete, fixed implant-supported pros-
4B1). Three of the patients showed pre-                  Only in two cases was a pure type IV              thesis, designed with three different sec-
vious allergies (one case of multiple aller-             reaction discovered, in the two male pa-          tions. The implant in position 24 was
gies) and three were heavy smokers. Two                  tients, one of which was of an advanced age       extracted 4 months after the surgery, dur-
were male (22%) and seven female (78%).                  and with an immune condition affected by          ing the prosthesis elaboration phase, due to
  Medical records showed four cases of                   successive and complex oncology treat-            asymptomatic implant mobility. A new
patients suffering from clear allergic symp-             ments (4B1). Of the seven female patients,        provisional acrylic-reinforced implant-sup-
toms (redness, pruritus, oedema and ec-                  further multiple allergies were found which       ported prosthesis was elaborated after ex-
zema of the face, mouth, chest and limbs,                involved other compounds: Cr and Ni in            tracting the remaining teeth, and a few
and in one case glottis oedema, which led                all cases, and in other isolated cases peni-      months later an additional Zi implant
to admission in the Emergency Depart-                    cillin (two), spiramycin, propionic anti-in-      was placed in position 23, which, like the

828 |    Clin. Oral Impl. Res. 19, 2008 / 823–835                                     c                                       c
                                                                                       2008 The Authors. Journal compilation  2008 Blackwell Munksgaard
                                                                      Table 4. Medical and dental history summary and test results of patients with hypersensitization to titanium
                                                                        Patient           Relevant medical       Group/clinical       Previous treatments                    Tests’ date   Tests’ results                              Subsequent treatments
                                                                                          and dental history     indicator
                                                                        4A1               Good general health    PFG                  No                                     03/11/2004    ( þ ) Ti, type I (nn) and IV (nnnn), Cr,    No
                                                                        47-year-old       Allergy to metals      History of several                                                        Ni and Anisakis simples                     Zi implant not accepted
                                                                        woman             and shellfish           allergies                                                                 ( À ) Ta, Zi, HA and FUDM
                                                                                          Allergic rhinitis
                                                                        4A2               Good general health    ACRG                 10-03, IS 7 implants, 3 flaps: 11–21,   16/01/2004    ( þ ) Ti, type I (nnn) and IV (n). Type     Implant-supported prosthesis
                                                                        35-year-old       Severe periodontal     Allergy symptoms     37–38, and 46–48                                     IV Cr, Ni.                                  SPT
                                                                        woman             disease                after implant        ACR: facial erythema, irritation,                    ( À ) Other metals and FUDM                 Follow up during 3 years

                                                                                          50 cigarettes/day      placement            redness and eczema on cheeks and                                                                 No implant complications
                                                                                          Anovulatory drugs                           on space between the eyebrows at                                                                 Keeps smoking
                                                                                                                                      1 month post-surgery
                                                                                                                                      Reappearing at 4 months
                                                                        4A3               Good general health    ACRG                 09-03, IS 8 implants in the upper      30/09/2003    ( þ ) Ti, type I (nnnn) and IV (nn), Cr,    02-06 implant surgery: Zi impl 23
                                                                        49-year-old       Frequent               Allergy symptoms     jaw                                    16/01/2004    Ni, penicillin and spiramycin.              ZSI
                                                                        woman             cephalalgia, allergy   after implant        Teeth-supported fixed provisional       09/03/2006    ( À )Ta Zi and FUDM                         2nd ACR: at 24 h, pruritus, dorsal
                                                                                          to penicillin          placement            1st ACR: at 1 week, redness and                      ( þ ) Ti, type I(nn) and(nn) Cr, Ni.        hands, extremities and chest
                                                                                          Benign                                      glottis oedema, led to admission                     ( þ ) Ti, type I (nnnn) and IV (n) Cr, Ni   eczema

 2008 The Authors. Journal compilation  2008 Blackwell Munksgaard
                                                                                          cementoblastoma                             in emergencies                                                                                   Final full upper jaw prostheses
                                                                                                                                      01-04, implant 24 removed                                                                        supported by 7 implants
                                                                                                                                      (unstable)                                                                                       SPT
                                                                                                                                      New set of implant-supported                                                                     Follow-up during 3 years
                                                                                                                                      fixed provisionals                                                                                No further complications in the
                                                                                                                                      MKIII and MKIV                                                                                   remaining implants
                                                                        4A4               Epileptic              ACRG                 04-98, IS 6 implants in lower jaw      21/11/2002    ( þ ) Ti, type I (                          SPT
                                                                        Mujer 54a.        Depression             Allergy symptoms     with HP                                                ) and IV (nn) Cr, Ni, & penicillin.       Follow-up during 5 years
                                                                                          Neosidantoina and      after implant        Patient developed mucositis and                      ( À ) Other metals and FUDM                 No follow-up after 2003
                                                                                          ASA daily              placement            hyperplasia
                                                                                                                                      11-02, hyperplasia reduction
                                                                                                                                      Amoxicillin, metamizol and CHX
                                                                                                                                      Recurring rush and oral burning

829 |
                                                                                                                                      symptoms after suspending
                                                                        4B1               Hepatitis C, Liver     ACRG                 05-00, IS 6 implants in the lower      04/12/2001    ( þ ) Ti, type IV (nnn).                    Nor further procedures were
                                                                        68-year-old man   cancer, Type II        Unexplained          jaw                                                  ( À ) HA other metals and FUDM              scheduled due to his medical
                                                                                          diabetes, Mod          implant failures     Immediate relining of a full lower                                                               condition
                                                                                          Chronic                                     denture                                                                                          In 2006, patient dies of heart
                                                                                          Periodontitis                               SR exfoliation in 2 implants, in 3–4                                                             failure and liver cancer
                                                                                          PST þ                                       weeks                                                                                            complications
                                                                                                                                      Remaining 4 implants removed in

Clin. Oral Impl. Res. 19, 2008 / 823–835
                                                                                                                                                                                                                                                                            Sicilia et al . Titanium allergy in dental implant patients
830 |
                                                                      Table 4. (Continued)
                                                                        Patient              Relevant medical         Group/clinical           Previous treatments                     Tests’ date       Tests’ results                              Subsequent treatments
                                                                                             and dental history       indicator
                                                                        4B2                  Good general health      ACRG                     09-98/03-99, IS 6 implants in upper      17/01/2002       ( þ ) Ti, type I (nnnn) and IV (nn), Cr,    10-02 IS: Impl 42 HA cylinder
                                                                        43-year-old          Hypercholesterole-       Unexplained              jaw                                      04/11/2002       Ni, and p-phenylenediamine                  (platinated gold cover screw and
                                                                        woman                mia                      implant failures         10-98/11-98, IS Implants 34-36, 44-                       (PPD). ( À ) Ta and FUDM                    healing abutment)
                                                                        (Figs 2 and 3)       Fenofibrate                                        46                                                        Absence of changes                          HAC
                                                                                                                                               12-00, PIS in upper jaw                                                                               04-03 implant prosthesis 32-42
                                                                                                                                               11-01, IS Immediate implant 32, 42                                                                    10-05 Fracture 33, Zi impl.
                                                                                                                                               Non-loaded                                                                                            ZSI.vImplant-supported prosthesis
                                                                                                                                               Implant 42 SR exfoliation in 3                                                                        SPT

Clin. Oral Impl. Res. 19, 2008 / 823–835
                                                                                                                                               weeks                                                                                                 Follow-up during 8 years
                                                                                                                                               BIS, MKIII                                                                                            No further implant complications
                                                                        4B3                  Good general health      ACRG                     1986 Traumatism #11                      08/01/2003       ( þ ) Ti, type IV (nnn).                    No
                                                                                                                                                                                                                                                                                             Sicilia et al . Titanium allergy in dental implant patients

                                                                        29-year-old man      20 cigarettes/day        Unexplained              Fracture and tooth loss                                   ( À ) Other metals and FUDM                 Patient did not accept treatment
                                                                                                                      implant failures         1995, IS implant 11 (EXT)                                                                             with a Zi implant
                                                                                                                                               2002 the implant was extracted
                                                                                                                                               Implant brand unknown
                                                                        4B4                  Good general health      ACRG                     02-96, IS Implant 11 (EXT)               05/12/2002       ( þ ) Ti, type I (nnnn) and IV (n) Cr, Ni   No
                                                                        41-year-old          Moderate C               Unexplained              05-96, the implant was extracted                          and Zn. ( À ) Ta, other metals and          Patient did not accept treatment
                                                                        woman                periodontitis            implant failures         (EXT)                                                     FUDM                                        with a Zi implants
                                                                                                                                               BIS                                                                                                   Ti implants were placed (EXT)
                                                                                                                                                                                                                                                     No follow-up

                                                                        4B5                  Good general health      ACRG                     Childhood: endo treatment and            17/03/2004       ( þ ) Ti, type I (nn) and IV (nn) Cr, Ni,   Patient does not allow extraction
                                                                        45-year-old          Varicose vein            Unexplained              Cyst surgery #21                                          mites, barbiturates and propionic           of implant #21 for aesthetic
                                                                        woman                surgery                  implant failures         06-02, tooth extraction                                   acid derivatives.                           reasons
                                                                                             Allergy to                                        06-03, IS implant flapless 21 (ISQ                         ( À ) Ta, Zi, other metals and FUDM         Keeps smoking
                                                                                             barbiturates                                      59)                                                                                                   Progressive peri-implant bone loss
                                                                                             20 cigarettes/day                                 09-03, provisional prosthesis (EXT)                                                                   and secondary complications
                                                                                                                                               03-04, implant infection and                                                                          (fistula)
                                                                                                                                               allergic reaction, implant with
                                                                                                                                               clinical mobility (ISQ 47)

                                                                        ACR, allergy compatible reaction; ACRG, allergy compatible reactions Group; ASA, acetyl salicylic acid; PFG, predisposing factors group; BIS, Branemark System Standard Implants; CHX, clorhexidine rinses;
                                                                        FUDM, frequently used dental materials; HA, hydroxyapatite; HP, hybrid prosthesis; IS, implant surgery; MKIII–MKIV, MKIII and MKIV Implants (NobelBiocare); SPT, supportive periodontal treatment; ZSI, Z
                                                                        Systems Implants (Constance); 4A1–4A4, patient identification code; EXT, medical–dental treatments performed in external clinics, incomplete information; HAC, Calcitek Implants (Zimmer Dental); ISQ, Ostell
                                                                        Implant Stability Quotient; O3I, Osseotite NT implant (3I); PIS, peri-implant surgery; PST þ, tested positive for the IL-1 genotype; SR exfoliation, spontaneous rapid exfoliation; 4B1–4B4, patient identification

                                                                        code; ( þ ), cutaneous and/or epicutaneous positive result; ( À ), cutaneous and/or epicutaneous negative result. Reactions to cutaneous and epicutaneous tests:

 2008 The Authors. Journal compilation  2008 Blackwell Munksgaard
                                                                                                            Sicilia et al . Titanium allergy in dental implant patients

                                                                                                                   peri-implant soft tissues, presumably asso-
                                                                                                                   ciated with taking antiepileptic medication
                                                                                                                   (4A4). None of them suffered additional
                                                                                                                   implant failures, nor further complications
                                                                                                                   or peri-implant bone loss.
                                                                                                                      No relation could be established between
                                                                                                                   the type of implant and the appearance of
                                                                                                                   cutaneous allergic reactions, implant fail-
                                                                                                                   ures or complications. In patients with
                                                                                                                   positive tests, implants with machined
                                                                                                                   surfaces (Branemark System Standard ,
                                                                                                                   NobelBiocare, Goteborg, Sweden), oxi-
                                                                                                                                          s            s
                                                                                                                   dized titanium (MKIII and MKIV , Nobel-
                                                                                                                   Biocare) and SLA (Osseotite Nt , 3I, Palm
                                                                                                                   Beach, FL, USA) have been placed, before
                                                                                                                   the described allergic episodes. Addition-
                                                                                                                   ally, no discoveries of allergic reactions to
                                                                                                                   zirconium, tantalum or hydroxyapatite
                                                                                                                   were found in the test group.


                                                                                                                   Performing a metal allergy assessment in a
                                                                                                                   high number of patients, expecting a low
                                                                                                                   prevalence of subjects showing positive
                                                                                                                   results, does not justify carrying out allergy
                                                                                                                   tests on all individuals, whereas a two-
                                                                                                                   stage assessment would be more reasonable
                                                                                                                   (Bass et al. 1993; Kusy 2004). The first
                                                                                                                   phase was aimed at identifying potentially
                                                                                                                   allergic patients based on medical records
Fig. 2. A female patient (patient 4B2, Table 4b) who had undergone multiple successful implant surgeries           (predisposing factors) (Brune 1986; Cook et
during the last 4 years had two immediate implants placed after dental extraction of lower incisors in
                                                                                                                   al. 1991; Bass et al. 1993; Schliephake et
November 2001 (a). Implant in position 42 showed spontaneous rapid exfoliation at 3 weeks after placement
(b) and tested positive to Ti allergy. In October 2002, a cylindrical hydroxyapatite-coated implant was placed     al. 1993; Weingart et al. 1994; Thomas
(Calcitek Implants, Zimmer Dental) (c), for which a specific cover screw (d) and gold-plated healing abutment       2000; Hallab et al. 2001; Tamai et al.
(e) were produced. The case was finally restored without further complications.                                     2001; Frisken et al. 2002), on the examina-
                                                                                                                   tion of signs and symptoms associated with
previous Ti implant, was not integrated                  good clinical stability (ISQ 59), a few                   titanium allergy (Hensten-Pettersen 1992;
and was later removed. Following the Zi                  months later suffered a mixed infectious                  Haug 1996; Lhotka et al. 1998; Matthew
implant procedure, in which a small flap                  and allergic flare-up, with the allergic re-               & Frame 1998; Thomas 2000; Bircher &
was raised that did not come to affect the               sponse recurring a few weeks after stopping               Stern 2001; Tamai et al. 2001; Valentine-
neighboring asymptomatic titanium im-                    all medication. The implant displayed a                   Thon & Schiwara 2003; Thomas et al.
plants in positions 21 and 25, the patient               peri-implant bone lesion, which affected a                2006) and on clinical events such as un-
suffered another allergic flare-up, with oe-              significant part of its perimeter, as shown                explained failures (Elves et al. 1975; Cook
dema, pruritus and urticaria of the feet,                by the periapical radiography, and an ISQ of              et al. 1991; Jacobs et al. 1991; Lalor et al.
wrists and chest. The new allergy tests                  41. The implant was declared failed and the               1991; Hallab et al. 2001; Frisken et al.
showed an increased intensity of type I                  patient informed of her allergy, although                 2002) and de-keratinized hyperplasic reac-
hypersensitivity ( þ þ þ þ ), but a nega-                she decided not to have it removed. Its                   tions of the peri-implant mucosa (Mitchell
tive reaction to Zi. During the years of                 development to date has consisted of pro-                 et al. 1990), associated with titanium al-
follow-up for these two cases (3 and 8                   gressive bone loss and the appearance of a                lergy in the literature (titanium allergy
years), no abnormal behaviour was de-                    secondary fistula, but it has remained                     compatible reactions). The second phase
tected in peri-implant tissues around all                clinically stable. Finally, two additional                was used to perform specific allergy tests,
other fixtures.                                           patients displayed an allergic flare-up: one               in this case cutaneous and epicutaneous,
   One of the patients (4B5) who received a              of them after the placement of seven im-                  because these are the tests of choice in
flapless implant in position 21 with an                   plants (4A2) and the other after the surgical             assessing type I and IV reactions in clinical
immediate provisional prosthesis, showing                treatment of a fibrous hyperplasia of the                  allergology (Thomas 2000; Yamauchi et al.

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 2008 The Authors. Journal compilation  2008 Blackwell Munksgaard                                                831 |    Clin. Oral Impl. Res. 19, 2008 / 823–835
Sicilia et al . Titanium allergy in dental implant patients

                                                                                                                     (Kusy 2004) and clinical examination pro-
                                                                                                                     tocols to improve the orientation of pre-
                                                                                                                     and post-operative assessments on these
                                                                                                                     patients. Taking these restrictions into ac-
                                                                                                                     count, it seems more worthwhile to give
                                                                                                                     priority to the assessment of allergy com-
                                                                                                                     patible reactions (ACRG) after fitting den-
                                                                                                                     tal implants, rather than to the possible
                                                                                                                     predisposing factors (PFG) assessed in our
                                                                                                                     study (Table 2).
                                                                                                                        Analysing the results from the PFG
                                                                                                                     group, literature revision suggests that we
                                                                                                                     could expect patients having experienced
                                                                                                                     extensive surgical exposure to titanium and
                                                                                                                     therefore further internal exposure to the
                                                                                                                     metal (Jacobs et al. 1991; Schliephake et al.
                                                                                                                     1993; Weingart et al. 1994; Frisken et al.
                                                                                                                     2002) to show a greater frequency of tita-
                                                                                                                     nium allergy reactions. However, this was
                                                                                                                     not the case, and none of the nine patients
                                                                                                                     from this group proved positive. Likewise,
Fig. 3. In October 2005, the same patient (4B2) had a root fracture of tooth 33 (a). After extraction and adequate   and within the same predisposing factors
healing, the tooth could be replaced by a Zi implant (Z Systems Implants, Constance, Germany) (b), and a
                                                                                                                     group, patients with an allergy profile
single unit implant-supported cemented prosthesis was made (Dr Jose Sua  ´   ´rez Feito) (c and d).
                                                                                                                     (Cook et al. 1991; Thomas 2000; Hallab
                                                                                                                     et al. 2001; Tamai et al. 2001) could repre-
2000; Kusy 2004; Thomas et al. 2006).                      yet unlikely appearance of immunological                  sent a collective sensitive to these types
With this protocol we have discovered a                    tolerance or non-specific immunosuppres-                   of complications. It is eventually paradox-
prevalence of titanium allergy that fluctu-                 sion caused by implant degradation pro-                   ical to find just a single positive case in
ates from 0.2% to 1% of patients either                    ducts (Hallab et al. 2001), may also                      the group of patients having shown a pre-
participating or treated with implants in a                contribute to reducing our study’s preva-                 vious allergy to more than two elements
specialized clinic. Studies carried out with               lence rate.                                               (Table 3).
the patch test on small subpopulations,                       Nonetheless, our results are similar to                   On the other hand, in the titanium
such as 185 consecutive patients from an                   the data obtained in a study carried out                  allergy compatible response group we
orthopaedic clinic (Lhotka et al. 1998), or                with immunologic techniques performed                     found eight positive cases. The symptoms
145 patients with suspected metal allergy                  in blood samples, such as the LMI (Merritt                compatible with an allergic reaction have
(Okamura et al. 1999) and 50 healthy                       & Rodrigo 1996b), where a prevalence of                   been widely described (Hensten-Pettersen
control subjects, show prevalence rates of                 4% was reached. Another alternative for                   1992; Haug 1996; Lhotka et al. 1998;
between 1% and 3% in test cases and 0%                     comparison would be data obtained                         Thomas 2000; Tamai et al. 2001; Valen-
in control subjects, found to be in-line with              through the MELISA test, carried out on                   tine-Thon & Schiwara 2003; Thomas et al.
our results. Our two-phase diagnostic sys-                 blood samples from patient data banks, but                2006), and although the symptoms are not
tem could underestimate the prevalence of                  this shows highly variable results (Valen-                allergen specific, their appearance after a
allergy, should we neglect to analyse the                  tine-Thon & Schiwara 2003), fluctuating                    titanium dental implant procedure could be
1465 patients not preselected in the first                  from 1.5% to 28%, possibly overestimat-                   very useful to detect potential allergy pa-
phase with specific tests. However, the fact                ing the actual prevalence.                                tients (Matthew & Frame 1998; Bircher &
that there were no positive results found in                  From a clinical point of view, it seems                Stern 2001). In our study, 50% of the
the 800 healthy control subjects examined                  interesting to select patients based on clin-             patients with these characteristics proved
at the allergy centre, as with the 50 Oka-                 ical criteria and to carry out specific tests in           positive after performing the specific tests
mura control patients, justifies our deci-                  preselected cases (Kusy 2004) in order to                 (Table 3). Another interesting subgroup
sion not to test all 1500 assessed patients.               determine the suitability of a material that              were the patients who had failed implants
Possible restrictions deriving from the use                will be used in a permanent implant (Haug                 with no clear explanation, also referred to
of cutaneous and epicutaneous tests                        1996; Schramm & Pitto 2000). It proves                    as unexplained failures, in accordance with
(Valentine-Thon & Schiwara 2003), the                      complicated, given the low number of                      the current accepted criteria (Esposito et al.
fact that some hypersensitive reactions ap-                positive reactions – in just nine individuals             1999, 1999b, 1999c). Previous discoveries,
pear over the long-term and the differences                – to establish an association between the                 such as increased internal exposure in con-
between cutaneous reactivity and that                      existence of positive cases and some clin-                trol animals with failed metallic implants
of other organs (Schramm & Pitto 2000;                     ical indicators. However, this would per-                 and in humans with loose hip prosthesis
Thomas 2000), as well as the potential                     haps be useful to prepare questionnaires                  (Frisken et al. 2002; Jacobs et al. 1991;

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                                                                                               2008 The Authors. Journal compilation  2008 Blackwell Munksgaard
                                                                                                      Sicilia et al . Titanium allergy in dental implant patients

Witt & Swann 1991), as well as a greater              (Thomas 2000; Yamauchi et al. 2000),                   (Brunski et al. 2000; Akagawa & Abe
sensitization of patients with a failed ortho-        with the majority of studies performed on              2003), the prosthetic structures and im-
paedic prosthesis (Cook et al. 1991; Lalor            works aimed at detecting type IV hyper-                plants are partially isolated by a layer of
et al. 1991), which is particularly elevated          sensitivity (Lalor et al. 1991; Lhotka et al.          glycoproteins (Bass et al. 1993) and the
when the failure is unexplained (Elves et al.         1998; Okamura et al. 1999; Ahnlide et al.              bone and oral mucosa have a low reactivity
1975), together with data obtained from               2000; Schramm & Pitto 2000; Yamauchi                   (Bass et al. 1993; Schramm & Pitto 2000;
longitudinal studies, which show a percen-            et al. 2000; Bircher & Stern 2001; Suhonen             Thomas 2000).
tage of metal sensitizations six times                & Kanerva 2001; Kusy 2004; Thomas et                      With data from a non-experimental re-
greater in patients with failed metallic              al. 2006). However, we have systemati-                 search study such as this, cause–effect
orthopaedic implants (Hallab et al. 2001),            cally assessed both type I and type IV                 relations cannot be established, and so the
let us establish the hypothesis of a possible         outcomes, which has helped us to identify              conclusions must be interpreted as hypoth-
connection between the inexplicable failed            an elevated number of cases (seven) with               eses to be confirmed later on. Nonetheless,
dental implant and sensitivity to titanium.           type I reactions (Tables 3 and 4). Disregard-          it appears reasonable to conclude that tita-
We found in this group that five out of eight          ing the fact that two of them were cases not           nium allergy can be detected, albeit with a
patients (62.5%) showed a positive reac-              treated at our centre (4A1 and 4B4), the               low prevalence (0.6%), in dental implant
tion to titanium (Table 3). Finally, there are        remaining five proved to have suffered                  patients. Bearing this in mind, perhaps it
reports (Mitchell et al. 1990) of two cases           some form of acute reaction, post-implant              should be considered as a clinical diagnos-
of de-keratinized hyperplasic reactions of            surgery allergic reaction or short-term com-           tic process for suspected titanium allergy in
the peri-implant tissues, whose histologi-            plications, or spontaneous rapid exfoliation           patients intending to receive implants
cal characteristics could be compatible               of an implant (Tables 3 and 4), which seem             made from such material, with allergy tests
with a type IV titanium allergy; after prov-          to support the type I hypersensitivity reac-           performed on those patients at risk. There
ing resistant to treatment, these began to            tion component in these patients.                      is scarce information on the frequency of
disappear after the titanium abutments                   Finally, it is perhaps contradictory that           substantiable clinical complications in pa-
were replaced with others made of gold.               patients sensitive to titanium – having                tients with metallic implants and cuta-
In our study we found two patients with               already lost implants – should retain                  neous reactivity to the same material.
similar characteristics, although none of             others, presumable integrated, without                 Nevertheless, once the allergy has been
them proved positive to the tests performed           further evidence of bone loss, looseness or            diagnosed, the professional must then de-
(Table 3).                                            complications. Of five patients still retain-           termine whether it is suitable to place a
   Although we know that titanium allergy             ing titanium implants, with a follow-up                titanium implant in patients with a posi-
is uncommon (Tamai et al. 2001) and that              between 3 and 8 years, four progressed                 tive reaction to it, given the potential
not all patients sensitized to a metal display        without bone loss or complications in the              medical and legal complications that could
complications following an endosseous im-             peri-implant tissues, with just one case               derive from such a procedure. From the
plant (Thomas 2000), the appearance of                showing a progressive bone loss (Tables 3              authors’ point of view, and following a
significant complications in particularly              and 4). Particularly interesting is a case             basic principle of deontological prudence,
sensitive patients cannot be disregarded              showing a reactivated allergy flare-up after            until research shows otherwise, it would be
(Hallab et al. 2001). In our study, one               surgery to place an additional implant,                convenient to use implants of alternative
patient suffered from glottis oedema, and             which involved none of the surviving im-               materials in patients proving allergic to
this led to admission in the Emergency                plants, to remove the provisional prosthesis           titanium.
Department, while two other patients                  and to place titanium abutments during the
showed cases of spontaneous rapid exfolia-            surgery; all the same, it has progressed for 3
tion of the implants (Tables 4a and b),               years without showing complications in                 Acknowledgements:       The authors
complications that may be considered im-              the original implants (4A3). Today, we                                         ´     ´    ´
                                                                                                             would like to thank Jose Marıa Suarez
portant and that can cause repercussions to           know that just a small percentage of sensi-                               ´            ´
                                                                                                             Feito, Lorena Hernandez, Luis Vazquez,
the health of the patient as well as medical/         tized patients show complications with                         ´                ´
                                                                                                             Angel Alvarez (Prodesmedica), Pepita
legal implications for the professionals.             orthopaedic implants (Thomas 2000), and                 ´
                                                                                                             Perez (Zimmer Dental), and Marıa ´
   It is traditionally believed that a hyper-         dental implants have special conditions                    ˜                      ´
                                                                                                             Muniz and Manuel Gonzalez (Socinser)
sensitive reaction to a metal is essentially          that could prevent them from being af-                 for their generous collaboration, and
type IV or, more rarely, type I (Haug 1996).          fected by an allergic reaction despite devel-               ´
                                                                                                             Marıa de la Fuente (www.visverbi.com)
From our revision, there were very few                oping a cutaneous reaction: the implant–               for the translation and review of the
authors who assessed the type I reaction              host contact surface is very limited                   English manuscript.


Abdallah, H.I., Balsara, R.K. & O’Riordan, A.C.       Ahnlide, I., Bjorkner, B., Bruze, M. & Moller, H.      Akagawa, Y. & Abe, Y. (2003) Titanium: the
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 cognition and management. Annals of Thoracic          contact allergy to gold sodium thiosulfate. Con-       national Journal of Prosthodontics 16 (Suppl.):
 Surgery 57: 1017–1018.                                tact Dermatitis 43: 344–350.                           28–29; discussion 47–51.

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