Assessment for Metal Allergy: Patch Testing

Abstract

The method of choice and gold standard in the diagnosis of delayed-type hypersensitivity is patch testing; therefore, patch testing for metal allergy has become routine. Most national and international baseline series for patch testing contain nickel, chromium and cobalt. There are numerous metals of increasing medical importance that are not on routine patch test programmes. With advances of metallurgy and biotechnology, such metals become increasingly widely present in medical devices, e.g. artificial joints, dental implants, vascular stents, clips and pacemakers. These metals are not routinely tested, as some are not yet commercially available as preparations for patch testing, while others may not be well known to many dermatologists and allergists. This chapter outlines current recommendations and common pitfalls when patch testing to metals. Assessing the clinical relevance of a positive patch test reaction is as important as the execution of patch testing. Several illustrative cases will be provided.

1 Fundamentals of Patch Testing

The patch test is an in vivo test to detect delayed-type hypersensitivity to haptens, including metals. In principle, it is the controlled exposure of a patient’s skin to the suspected hapten in a defined amount for a predetermined time (the widely accepted standard is 2 days). After removal of the test units, repeated evaluations follow for the development of an inflammatory reaction in the skin, which typically take place after 2 days, 4–5 days and 7 days from mounting [1]. Patch test substances are applied on the patient’s skin in commercially available patch test chambers. For obvious reasons, chambers made of metal should be avoided, especially when testing for contact allergy to metals. Chambers are filled with hapten preparations, which typically come in a vehicle of petrolatum (Fig. 11.1) or water (Fig. 11.2). The dosing should be as precise as possible, because too low of an amount of hapten may result in a false-negative reading, whereas too high of an amount may lead to irritant, false-positive reactions. The recommended amount is 20 μg for petrolatum-based preparations and 20 μl for aqueous solutions. Petrolatum is difficult to measure given its viscosity; thus, some training with laboratory scales is required. Water-based solutions can be aliquoted using a laboratory micropipette; however, measuring by drops (equal ca 50 μl) is a common practice. Preparations of metals in petrolatum are relatively stable and may be preloaded and stored overnight in test units that are resealable (e.g. IQ Ultra or IQ Ultimate chambers). In contrast, after loading liquid hapten preparations, chambers should be placed immediately on the patient’s back, as they must not dry before placement. The typical arrangement of patch test units is shown in Fig. 11.3 (adults); in small children, transverse placement may prove more practical (Fig. 11.4). After attaching the test units on the patient’s back, each individual chamber should be firmly pressed in order to ensure good contact and hence penetration into the skin with an even distribution of the hapten in the whole exposure area. The test units are removed after 2 days. Appropriate skin markings allow for proper assignment of emerging reactions to responsible haptens (Fig. 11.5). According to recent guidelines, the recommended observation time is 7 days; however, positive reactions may emerge later than this in some patients.

Fig. 11.1

Loading petrolatum-based hapten preparation into chambers of a patch test unit

Fig. 11.2

Loading water-based hapten preparation into chambers of a patch test unit

Fig. 11.3

A typical arrangement of patch test units in adults

Fig. 11.4

Transverse placement of test units may prove more practical in small children

Fig. 11.5

Marking positions of patch test units of the patient’s back immediately after their removal

The widely accepted system for recording reaction intensity is the International Contact Dermatitis Research Group (ICDRG) scale, described in Table 11.1 and shown in Fig. 11.6. It must be stressed that the intensity of reaction does not necessarily reflect the relevance of a given hapten for the present disease. The intensity of patch test reaction as expressed in the ICDRG score is dependent on the concentration of hapten in the test substance, area of the test chamber used, dose per surface unit and bioavailability from a chosen vehicle. Clinical disease, aside from the concentration and dose of hapten per exposed surface, also depends on the size of the exposed area, frequency and duration of repeated exposures, skin thickness and physiological status of the skin, among other factors. In the case of dental implants and endoprostheses, the route of exposure and bioavailability of the hapten is completely different. Therefore, assessing for the clinical relevance of a positive patch test reaction is as important as the execution of patch testing itself. Several systems for grading the clinical relevance of varying degrees of complexity have been proposed, but none are generally accepted like the ICDRG score. In practice, good results can be achieved by combining two relatively simple and mutually complementary systems: the modified CODEX grading system and the North American Contact Dermatitis Group (NACDG) system. The CODEX system, presented in Table 11.2, is a modification of the original COADEX system ([3], modified by [4]). In the present modification, the letter ‘A’, which originally stood for ‘active sensitization’, has been omitted in the mnemonics for better usability and less confusion. Active sensitization during patch testing, though not impossible, is very difficult to judge in individual cases and extremely rare even among late patch test reactions [5]. Most importantly, it also does not provide information regarding the question of relevance of a positive reaction. Whenever feasible, current relevance (CODEX: C) can be further graded as definite (positive use test with the suspected item or a positive patch test to the object or product), probable (the presence of the hapten in patient’s skin products could be verified, and clinical presentation is consistent with the exposure) or possible (patient was exposed to circumstances in which skin contact with materials known to contain the hapten was likely to occur), in line with the North American Contact Dermatitis Group relevance scoring system [6].

Table 11.1 Notation of patch test results according to the ICDRG

Fig. 11.6

The spectrum of patch test reactions. Explanations for the symbols are given in Table 11.1. Irritant reactions depicted on the right-hand side of the composite picture are a ‘common irritant reaction’ manifesting as homogeneous erythema without infiltration (top) and a ‘poral reaction’ with punctate erythema (bottom). (Reproduced with permission from [2])

Table 11.2 The practical CODEX system for assigning relevance to positive allergic reactions

2 Problems and Pitfalls When Patch Testing with Metals

Common problems with patch tests to metals include limited accessibility of test material and difficulties with reading and interpreting the results due to intrinsic irritant properties of many metals. In an adult population heavily exposed to metals (metal workers), non-allergic irritant reactions constituted 6.5% of all patch test reactions seen to nickel sulphate 5% pet., 13% of reactions to potassium dichromate 0.5% pet. and 18.3% of reactions to cobalt chloride 1% pet. [7]. The authors divided non-allergic reactions to metals into three distinct types: (1) the ‘common irritant reaction’ manifesting as homogeneous redness without infiltration; (2) the ‘poral reaction’ with punctate erythema, sometimes slightly papular or haemorrhagic, presenting as small dots distributed within the test area; and (3) the ‘pustular reaction’ with one or numerous pustules in the exposed area. Examples of these reactions are shown in Fig. 11.6 (common irritant reaction in the upper right corner, poral reaction in the lower right corner) and Fig. 11.7a, b (pustular reaction). Fischer and Rystedt observed that poral reactions were more reproducible than the other irritant reactions, which they ascribed to a constitutional, non-allergic susceptibility to metals in such individuals. Storrs and White [8] studied clinical and microscopic features of irritant reactions to cobalt and found that, regardless of the ‘petechial’ appearance and regular spacing suggesting involvement of hair follicles, epidermal inflammation and necrosis in such reactions actually surround the acrosyringium, i.e. the intraepidermal spiral duct of the eccrine sweat gland; over time, individual reactions may become confluent to form a purpuric-appearing plaque. The authors stressed that such reactions are neither follicular nor petechial, nor allergic. This problem seems more frequent in children. Marcussen [9] observed that patch test reactions to nickel presenting as clusters of small erythematous dots at regular spaces were predominantly seen in children with no convincing history of nickel allergy; moreover, such reactions could not be confirmed in intradermal testing or patch testing repeated after a longer time interval. He suggested, therefore, that these were primary irritant reactions due to peculiarities of the epidermal barrier that disappear around 8 years of age, which may correspond to the individual susceptibility mentioned by Fischer and Rystedt [7]. Not all physicians seem aware of these phenomena, which may in part explain higher patch test positivity rates reported among younger children. In a multicentre study based on the work of paediatric or general allergists, rather than dermatologists [10], patch tests to nickel sulphate 5% pet. were reported positive in 35.9% of 7–8-year-olds versus 19.4% of 16–17-year-olds; similar trends also were seen for cobalt chloride 1% pet. (9.7% versus 6.5%) and potassium dichromate 0.5% pet. (6.8% versus 3.2%).

Fig. 11.7

(a) Irritant reaction of pustular type to zinc chloride 2% pet. immediately after removal of the patch test (after 2 days of occlusion). (b) The same test site 1 day later. Note the apparent ‘decrescendo’ pattern indicating that healing processes had begun immediately after removal of the irritant

In summary, one must be aware of the risk of irritant patch test reactions to metals that may occur in any age group, especially younger ages. Nevertheless, true allergic reactions to metals do occur in infants and children: rates of ascribed clinical relevance out of all positive patch tests to nickel sulphate (200 μg/cm²) varied from 4.8% (just 1 out of 26) in Danish infants at 3–18 months of age [11] to 69.4% in Danish children 12–16 years old [12]. Among Brazilian children 0–12 years old, the relevance rate was 82.8% of all positive reactions to nickel sulphate 5% pet. [13]. Of all reactions to potassium dichromate 54 μg/cm² and cobalt chloride 20 μg/cm² seen among Danish teenagers (12–16 years old), 16.7% and 58.5%, respectively, were assessed as clinically relevant [12].

Aside from nickel, cobalt and chromium which are present in most baseline series, as well as a few other metals like palladium or gold, there are scarce epidemiological data or clinical experience on most remaining metals, partly due to the limited availability of patch test substances. The situation has partly improved after a commercial metal series for patch testing was introduced. Table 11.3 collates presently available patch test preparations of metals, while Table 11.4 summarizes our experience with commercial preparations. Despite continuous development in the field, some metals frequently found in implanted medical devices, or other metal alloys, are still not available commercially (e.g. barium, hafnium, yttrium), although they seem to have at least some sensitizing potential based on their chemical properties and casuistic clinical observations. Moreover, new metals may be put into use in medical devices, e.g. a recent inclusion of cerium (Ce) in dental implant alloys. In such cases, custom-made preparations seem the only option for diagnostic work-up. A few examples of custom-made patch test preparations used in our clinic are given in Table 11.5; since their initial creation, some of these have become available as commercial preparations.

Table 11.3 A summary of commercially available patch test preparations for metals as of 2016

Table 11.4 An overview of patch test results to metals in patients referred to our clinic for the diagnosis or prediction of allergy to implanted metal devices—results with commercially available test substances

Table 11.5 An overview of patch test results to metals in patients referred to our clinic for possible allergy to implanted metal devices—results with custom-made test substances

When selecting the formula and vehicle for patch test substances, de Groot’s excellent reference book [14] and an extensive literature search are obligatory. Irritant properties of metals are a well-known problem that may bias patch test outcome. Concentrations of metals in patch test preparations should not be so high as to cause irritant reactions; on the other hand, too low of a concentration of the hapten bears the risk of doubtful or false-negative reactions. With scarce evidence, the chosen concentration is not always optimal for diagnosis. In 2010, the author had the opportunity to patch test a group of healthy soldiers with newly available commercial preparations of metals. One of the outcomes was a series of inflammatory reactions with pustules, rather than vesicles, to zinc chloride pet. 2%, with no traceable relevance (Fig. 11.7a, b). Irritancy due to too high of a concentration seemed a possible explanation. After the concentration was reduced to 1%, this problem never occurred again; however, irritant reactions still have occurred (compare Table 11.4). Nevertheless, further decreasing the concentration might result in an increased risk of false-negative reactions. In routine testing, the proven way around the present risk of false-positive reactions is a repeated, careful reading of patch test reactions by an experienced dermatologist or allergist, with photodocumentation of the reaction and reanalysis of the photographs in chronological order in case of any doubt. Such time series may reveal various patterns. A clear decrease in the intensity of inflammation on subsequent readings (the so-called ‘decrescendo’ pattern in analogy to a decrease in volume of a musical passage) reflects a rapidly healing process and speaks in favour of an irritant reaction or a false-positive patch test result (Fig. 11.7a, b). Sharply demarcated reactions reflecting the shape of the test chamber or reactions that occur only in a part of the occluded area also suggest an irritant reaction. On the other hand, an inflammatory reaction covering entirely, or even expanding beyond the area of occlusion, blurry edges and increasing intensity on subsequent readings (the so-called ‘crescendo’ pattern) are suggestive of a true allergic reaction (Fig. 11.8a, b). However, mixed patterns may also emerge. In case of any doubt, when the result of patch testing has a potentially significant impact (such as deciding whether to use or remove an implant or artificial joint), patch testing with a dilution series of the hapten in question should be undertaken in the patient, along with a group of healthy controls whenever feasible.

Fig. 11.8

(a) True allergic reactions may not yet be seen after 2 days: at the moment of removing patch tests units, only slight erythema can be seen, insufficient for recognizing any definite reaction. (b) One day later, a + reaction to cobalt (II) chloride hexahydrate 1% pet. (position 5) and a ++ reaction to nickel sulphate hexahydrate 5% pet. are clearly visible, consistent with the ‘crescendo’ pattern reflecting the progression of allergic processes triggered by the haptens

3 Diagnostic Work-Up and Assessment of Relevance: Examples from Practice

The cases below illustrate the practice of patch testing to metals with a focus on the discussion of clinical relevance of positive patch tests. Unfortunately, unlike fashion jewellery, implants and prostheses are in most cases difficult to remove in order to see if the patient’s problems would improve. The readers are kindly asked to bear in mind the risk of misinterpreting the facts in each individual case and to use their own critical judgement.

3.1 Patient 1: Nickel and Cobalt Allergy in a Child

A 10-year-old patient had suffered from hand eczema for the preceding 3 years. Initially, only the dominant right hand was involved, but eczema of the left hand appeared 2 years later. She had been a compulsive finger sucker, nail biter and hand washer, washing her hands around 20 times daily with hot water and abundant soap. The parents noted that the eczema had started under and next to the costume jewellery rings that the child had been wearing since the age of 4 years old (Fig. 11.9a, b). Patch testing with a commercial baseline series (Chemotechnique) revealed positive reactions to nickel sulphate hexahydrate 5% pet. (N-002A, ICDRG: +, CODEX: C) and cobalt chloride hexahydrate 1% pet. (C-017A, ICDRG: +, CODEX: C), deemed as clinically relevant based on the pronounced eczema around the rings and the presence of both nickel and cobalt in both of these (positive Chemo Nickel Test and Chemo Cobalt Test). Ultimately, allergic contact dermatitis to nickel and cobalt with irritant contact dermatitis of the hands due to the child’s compulsive behaviour was diagnosed.

Fig. 11.9

(a) Palmar aspect of the right hand of Patient 1 with dermatitis most pronounced on the proximal phalanx of her middle finger, where she typically wore the cobalt- and nickel-containing ring. The ring was moved to the adjacent finger only for the picture. (b) Dorsal aspect of the left hand of Patient 1. The ring was moved from the middle finger onto the adjacent finger just before taking the picture

3.2 Patient 2: Hand Dermatitis to Aluminium

A 49-year-old patient complained of hand eczema that had started 3 months earlier and was gradually worsening. He had a history of past episodes of foot dermatitis or eczema dispersed over the trunk, which were transient and never motivated him to seek a doctor. The present hand eczema, however, became aggravating to the extent that his work was made impossible. For the last 8 years, he had been working as a sales representative delivering men’s suits and trousers to garment stores. His work involved handling clothes hangers, which were made of aluminium or (less frequently) stainless steel. Patch testing with a commercial baseline series, textile finishes and dyes and a metal series (Chemotechnique), along with samples of garment textiles and plastic protective bags for the cargo, revealed allergy to aluminium powder (Chemotechnique, A-021, ICDRG: +, CODEX: C) and aluminium chloride hexahydrate 2% pet. (A-022, ICDRG: +, CODEX: C). The patient was advised to always handle his cargo using protective gloves, which resulted in considerable improvement within 2 weeks, thus confirming the clinical relevance of aluminium allergy for his hand eczema. He also reacted to textile dyes Disperse Blue 3 and Disperse Blue 106 (both ICDRG: + and CODEX: O), which in light of the distribution pattern could be causative of his past episodes of dispersed dermatitis. He did not, however, react to any of the textile samples taken from the suits he was handling at his present job.

3.3 Patient 3: Allergic Contact Dermatitis to Gold

A 52-year-old office clerk complained of a 4-month history of eczema of her right hand and both eyelids. Her past history did not give any clues as to a possible provoking agent, except that she had noticed a slight irritation around her gold wedding ring when washing dishes without gloves. She assumed that the problem was caused by detergent collecting under the ring and removed it 2 days before the first visit. She had not noticed any symptoms of metal intolerance in the past. On patch testing, she developed positive reaction to gold sodium thiosulphate 2% pet. (Chemotechnique, G-005B, ICDRG: +, CODEX: C), with no other relevant positive reactions. She was instructed not to wear any gold jewellery, and her dermatitis both on the hand and eyelids cleared within 2 weeks without a need for further treatment. Current clinically relevant positive patch tests to gold seem relatively rare; however, these relevance rates are not much different from other common metals. Those who notice intolerance of gold tend to remove their gold jewellery, so it is more probable to find past relevance rather than current relevance for positive patch tests to gold [15].

3.4 Patient 4: Persistent Patch Test Reaction to Gold

A 5-year-old boy had suffered since the age of 1 from exfoliative dermatitis of the palms and soles with periodic spread of eczema to other body sites. The parents did not suspect any provoking or aggravating factors other than ‘running on all fours on the carpet floor’. Patch tests with the baseline series were carried out as allergic contact dermatitis was part of the differential diagnosis. No history of metal intolerance was given by the parents; however, gold was added to the test programme as the child was from a community in which the abundance of gold in daily objects was used for showing social status. Patch tests revealed a clinically relevant allergy to Dermatophagoides mix 30% pet. (Chemotechnique Mx-21C, ICDRG: +, CODEX: C) and propolis 10% pet. (P-022, ICDRG: +, CODEX: C). There was also a positive patch test reaction to gold sodium thiosulphate 2% pet. (G-005B, ICDRG: +, CODEX: E). This reaction was deemed an immunological remnant from previous exposure, as the parents described a custom in their community of each newborn being given a gold necklace with a pendant. The boy had received a golden teddy bear pendant, which he used to suck on ‘very eagerly’. As a precaution, the parents were instructed to isolate the child from direct contact with gold objects. A month later, they reappeared stating that, after patch testing, all positive reactions on the boy’s back cleared up within 2 weeks, and the skin greatly improved with appropriate treatment and removal of the carpet and propolis-containing products from the household. However, the patch test reaction to gold re-emerged a month later with a parallel recurrence of eczema of the hands and feet. In the patch test site to gold, a dermal-type infiltrate was present (Fig. 11.10). The reaction was still present during a last check-up 7 months after the test, although the eczema gradually resolved by this time. It is unclear whether the child got ahold of some gold objects to provoke the relapse or if it was a kind of late recall phenomenon due to exposure from patch testing. The temporary clearance after patch testing seemed to speak against the latter possibility, but both alternatives would suggest a current relevance (CODEX: C). Long-lasting reactions to gold after patch testing are a known phenomenon [16] that may distress patients and parents.

Fig. 11.10

Persistent reaction to gold in Patient 4 still present 7 months after the patch test

3.5 Patient 5: Photoallergic Dermatitis to Copper

A 34-year-old hairdresser complained of ‘sun allergy’ manifesting as dermatitis of the face and dorsal aspects of her hands that appeared on the second day of her summer vacation at the seaside and persisted over the rest of her stay. This problem had appeared on vacation for the second year in a row. In the past, she had also experienced a few episodes of skin rash provoked by cosmetics. The patient was patch tested to the baseline series, cosmetic series, hairdressing series (Chemotechnique) and her own cosmetics, which resulted in a confirmation of contact allergy to 4-phenylenediamine (P-006, ICDRG: +, CODEX: C) and 2-bromo-2-nitropropane-1,3-diol (Bronopol) 0.5% pet. (B-015B, ICDRG: +, CODEX: C). Both haptens were present in products used in her hair salon. It seemed, however, that these sensitizations could not explain her dermatitis while on holiday. She went on to undergo photopatch testing, during which she developed some flagellate erythema with a few wheals on the irradiated area, while no definite photoallergy to any of the agents from the photopatch series could be confirmed. Upon repeat questioning, the only conspicuous event that took place shortly before the first episode of her ‘sun allergy’ was the implantation of a copper-based IUD (Multiload Cu 375), which she still had in place. In order to clarify this, a second photopatch test was undertaken that revealed photoallergic reactions to copper (I) oxide 5% pet. (C-021, ICDRG: +, CODEX: C) and copper (II) sulphate 2% pet. (C-022, ICDRG: +, CODEX: C). The confirmation of clinical relevance came after she had the IUD removed: she did not experience any skin problems during the following summer.

3.6 Patient 6: Allergy to Titanium

A 62-year-old office clerk needing a hip replacement was referred for patch testing with a metal series because of a history of jewellery and wristwatch intolerance. Patch tests revealed no reaction to ‘common metals’ (Ni, Co, Cr); however, she developed a positive reaction to titanium oxalate 5% pet. (Chemotechnique T-041, ICDRG: +, CODEX: C) and a weak, macular, slightly infiltrated response to titanium nitride 5% pet. (T-039, ICDRG: ?+, CODEX: C). No visible reaction was present to titanium dioxide 10% pet. (T-040), calcium titanate 10% pet. (C-049) or titanium 10% pet. (T-042). Only after hearing about the results, the patient mentioned that 7 years earlier she had had a partial gastrectomy for a perforating stomach ulcer. After the surgery, she suffered from persistent nausea and vomiting. Because the symptoms continued, surgical revision was undertaken a few weeks later, after which she quickly recovered. The patch test result reminded her that titanium staples were used during the gastrotomy, and they were removed at the revision because the stomach wall had already healed and they were no longer needed. This seems to speak in favour of past clinical relevance of allergy to titanium in this patient. On patch testing, she also reacted to zinc chloride 1% pet. (Z-007, ICDRG: +, CODEX: D), stannous chloride 1% pet. (S-013, ICDRG: ++, CODEX: D) and a preparation of niobium (V) chloride 2% pet. (ICDRG: +, CODEX: D), with which no causal relationship with her symptoms could be found.

3.7 Patient 7: An Abscess with Fistula in a Protracted Spine Stabilization of Scoliosis

An 18-year-old student had undergone an orthopaedic stabilization 2 years earlier for his pronounced scoliosis and chronic severe back pain. The implanted device consisted of two longitudinal rods connected to the vertebrae by 22 screws, with two transverse bars for stabilization. Delayed healing of the covering skin was noted over one of the transverse bars; thus, it was subsequently removed to lessen pressure on the skin, which was assumed as the reason for incomplete healing. The local wound included a putrid cyst in the mid spinal area with a periodically opening fistula (Fig. 11.11a). Despite removal of the bar, the cyst had never healed, and every 2–3 weeks, the fistula reopened with putrid discharge. Regardless of the problem, the patient delayed device removal for more than a year, citing the fear of a relapse of his back pain. As the pus was sterile on several occasions, a hypothesis of allergic reaction to the stabilizing device was put forward, and the patient was referred for assessment of the possible role of metal allergy in his problem. The device was made of an alloy-containing niobium (Nb), aluminium (Al), iron (Fe) and tantalum (Ta). The patient was patch tested to the entire metal series (Chemotechnique). As two metals (Nb and Ta) of the device were not available commercially for testing at that time, test preparations of niobium chloride 2% pet. and tantalum chloride 1% pet. were custom-made and checked in five volunteers (staff members) with negative results. The patient reacted to both niobium from day 2 (Fig. 11.11b) and tantalum from day 3 (Fig. 11.11c), in both cases ICDRG: + and CODEX: C. During patch testing, the putrid discharge from the fistula reappeared, as seen in Fig. 11.11b.

Fig. 11.11

(a) Patient 7 before patch testing. A scar along the spine with a closed fistula can be seen. (b) Positive patch test reaction to custom-made niobium (V) chloride 2% pet. (position 3) on the third day of the test. The ‘dermal’-type reaction is characterized by a dominating infiltrate and lack of eczema. Note the putrid discharge from the fistula. (c) Positive reaction to custom-made tantalum (VI) chloride 2% pet. (position 4) on the fourth day of the test. ‘Dermal’ patch test reactions are difficult to capture on camera; low-angle, tangential illumination may help with this regard

3.8 Patient 8: Dental Implant Intolerance

A 55-year-old patient self-reported long-standing recurrences of metal and cosmetic allergy. She had a history of severe intolerance reaction after the fitting of a dental crown: the next day after the procedure, she developed dyspnoea and nausea with recurrent vomiting. She had to be hospitalized, and oral corticosteroids were required to control the symptoms. Two weeks later, the tooth with the newly fit crown was removed, and the patient became symptom-free within a couple of days. Subsequent attempts at mounting dental crowns made of various alloys all caused problems described by her dentists as inflammatory periodontitis, accompanied with periodic fever, throat swelling and erythema with oedema accompanied by a burning sensation of the hands and neck. The patient stated that ‘every metal in the mouth caused swelling, nausea and also other problems’. Because of the repeated tooth extractions following crown intolerance, tooth implants were advised. The patient had an array of allergy consultations. She was tested to a sample of the alloy used for the crowns as well as samples of seven various acrylate-based filling materials provided by the dentist, with ‘an early reaction after 24 h’ to potassium dichromate 0.5% pet. and a ‘late reaction after 48 h’ to the crown’s alloy sample supplied by her dentist described only as a ‘Ni-Cr crown’. The readings were performed only after 1 and 2 days. On the basis of the results, the patient was instructed that her problems were caused by chromium which she ought to avoid, and no other contraindications for dental restoration were given. Subsequently, she received three dental implants (Osstem Germany; metals in the alloy: Al, V, Fe, Y, Ti). Within a few days, she developed the same array of symptoms as described above and required steroids to control the symptoms. Following this, the patient was patch tested to the European Baseline Series with negative results to all haptens, including Co, Cr and Ni; she could not recall if the steroids were withdrawn before the tests. At this point, the author had the opportunity to assess the patient. The diagnostic work-up included patch testing to a metal series and dental material series (Chemotechnique), which revealed allergy to cobalt (II) chloride 1% pet. (C-017A, ICDRG: ++, CODEX: C), gold sodium thiosulphate 0.5% pet. (G-005A, ICDRG: ++, CODEX: C—she had reported episodes of eczema underneath her wedding ring that forced her to stop wearing the jewellery), as well as clearly irritant reactions to zinc chloride 1% pet. (Z-007, ICDRG: IR, CODEX: -) and potassium dichromate 0.5% pet. (P-014A, ICDRG: IR, CODEX: -), which might possibly have corresponded with the ‘early reaction’ to Cr described by a previous allergist. There was also a positive reaction to iron (III) chloride 2% pet. (I-016, ICDRG: ++), which was difficult to assess with regard to clinical relevance. As there was no literature on iron allergy except for contact allergy to iron oxide-based cosmetic pigments and immediate reactions to intravenous iron, the relevance of iron in the patient’s implants seemed impossible to credibly assess at this stage (CODEX: D). The only metal of the implant alloy not tested yet was yttrium, which would provoke suspicion as a transition metal; however, yttrium was not commercially available for testing. Therefore, a test preparation of yttrium chloride 2% pet. was produced in our laboratory. Five volunteers (staff members) did not show any reaction to the preparation (except slight erythema in one), while the patient tested positive, thus confirming her hypersensitivity to yttrium (ICDRG: +, CODEX: C). Based on this finding, the decision to remove the implants was made, which resulted in a rapid resolution of the patient’s symptoms. Subsequently, titanium implants were offered to her as the best option available for her dental restoration. The sole metal components in the alloy were Ti (99.66%) and Fe (0.03%). On previous patch tests, she did not react to titanium; thus, the proposed implants seemed a reasonable option. However, given the ++ patch test reaction to iron chloride and her long history of metal intolerance, the recommendation was made to initially fit just one implant in her jaw and wait for a month or two for any possible reactions to emerge. The oral surgeon, however, instead fitted altogether six Ti-Fe implants in one session. The typical symptoms recurred within 10 days, eventually leading to a second implant removal procedure shortly thereafter. This reaction demonstrated that iron allergy was, in fact, also clinically relevant in this patient, changing the final CODEX score into C. The patient received a metal-free, methacrylate-based, removable dental prosthesis, which she has tolerated. In Table 11.4, she is among the six patients with patch test reactions to iron assessed as relevant. In all remaining patients, the relevance could be tracked back to iron oxide dyes in cosmetics, rather than to implanted devices.

3.9 Patient 9: Allergy to Niobium in Dental Crowns

A 43-year-old office clerk reported a self-suspected intolerance to dental crowns. Approximately half a year after receiving her first dental crowns, she started having skin problems that she described as ‘a rash with breaking and oozing of the skin’. A few months later, she also developed hyperhidrosis, ‘breaking blisters’ and ‘bruises that were coming and going all over the body’. She was then patch tested by an allergist and diagnosed with allergy to nickel. As nickel was present in her dental crowns, they were removed, and all her symptoms ceased within a month’s time. Subsequently, her dentist told her that she needed another dental crown; thus, she opted for extensive patch testing to metals before selecting the crowns to be used. She was patch tested to a commercial metal series (Chemotechnique), as well as to hafnium (Hf), niobium (Nb), tantalum (Ta) and yttrium (Y), all of which are used in dental alloys. Within 15 min after patch test application, the patient reported an intense burning sensation at the location of niobium chloride 2% pet. (Fig. 11.12a). This custom-made test substance was previously tested in volunteers and three dozens of patients with only one rather mild irritant reaction recorded; thus, acute toxicity could be ruled out. The test substance was immediately removed from the patient’s skin surface with a paper towel, and she was given 20 mg of loratadine to prevent possible contact urticaria syndrome. After another 20 min, the pruritus resolved, and erythema became less pronounced; thus, the patch test unit was mounted again on the patient’s back after removal of the chamber with niobium chloride, and after 1 hour of further observation, the patient was sent home symptom-free. Two days later, in the area of the terminated test to Nb, a distinct erythematous macule was present with a tallow-coloured, slightly depressed centre (Fig. 11.12b). Over the course of observation, the lesion gradually took on a more necrotic appearance (Fig. 11.12c). The lesion appeared somewhat vasculitic; however, the patient refused a skin biopsy to verify this suspicion. In the following week, she developed bruises that were ‘exactly the same kind as 2 years ago’ (Fig. 11.12d). Her dentist confirmed that niobium was indeed present in the alloy used for the crowns fitted in the patient 4 years earlier. Overall, allergic vasculitis to niobium was favoured as the cause of this rare clinical picture. The patient also had typical eczematous patch test reactions to nickel sulphate hexahydrate 5% pet. (N-002A, ICDRG: +, CODEX: O), cobalt chloride hexahydrate 1% pet. (C-017A, ICDRG: +, CODEX: O) and gold sodium thiosulphate 0.5% pet. (G-005B, ICDRG: +, CODEX: D) of no apparent relevance to her present problems. This atypical case illustrates the importance of patch testing broadly and remaining open-minded.

Fig. 11.12

(a) Immediate reaction to niobium chloride 2% pet. in Patient 9. (b) Erythematous macule with a tallow-coloured, slightly depressed centre in the site of patch test to niobium chloride 2% pet. after 2 days. (c) The reaction to niobium with necrotic appearance as seen after 7 days from the start of patch testing. (d) A ‘bruise’ on the patient’s earlobe appeared on the seventh day of testing which, according to the patient, was identical with the lesions that appeared when she was first exposed to niobium from her dental crowns