Flare-up reactions after oral challenge with nickel in relation to challenge dose and intensity and time of previous patch test reactions

BACKGROUND: In this study we have taken an interest in systemic exposure to nickel in patients with delayed hypersensitivity to nickel. OBJECTIVE: The aim of the study was to more closely investigate the importance of factors such as ingested nickel dose, time interval between nickel patch testing and oral nickel challenge as well as degree of nickel hypersensitivity in relation to flare-up reactions. METHODS: Thirty nickel-sensitive female subjects were patch tested with a serial dilution of nickel sulfate in water on 4 different test occasions during a period of 7 months. One month after the last patch test the patients were randomly divided into 3 different groups. The patients in the groups were challenged orally with a placebo capsule, 1.0 mg nickel, or 3.0 mg nickel. RESULTS: None of the patients challenged with placebo had flare-up reactions of earlier patch test sites, but 2 of the patients challenged with 1.0 mg nickel and all of the patients challenged with 3.0 mg nickel had flare-up reactions. There were significantly more flare-up reactions of the most recent patch test sites (1 month) compared with the most distant (8 months) test sites. There was also a statistically significant positive correlation between the intensity of previous positive patch tests and the flare-up reactions. CONCLUSION: In the assessment of the possibility of systemic allergic contact dermatitis from nickel, the dose as well as the intensity and time since previous nickel eczema have to be considered.     

Patch test results with serial dilutions of nickel sulfate (with and without detergent), palladium chloride, and nickel and palladium metal plates

Clinical experience suggests the existence of different degrees of sensitivity in nickel-allergic patients. For quantification of this phenomenon, 462 consecutive patients with previously diagnosed or strongly suspected nickel allergy were tested with serial dilution patch tests with 5 ppm to 5% nickel sulfate in pet. (Ni), and 5 ppm to 1% nickel sulfate in pet. with 1% detergent (Ni/D). Additionally, nickel and palladium metal plates were tested in 103, and cobalt salts, dichromate and palladium chloride (PdCl₂) in most patients. 332 patients reacted positively to Ni or Ni/D. The influence of a concomitantly administered detergent was not significant. A significant correlation was found between positive reactions to low concentrations of Ni (or Ni/D), i.e., 0.1% or less ( N =166), and concomitant reactions to nickel metal plates, cobalt salts and PdCl₂ and a history of ear piercing with metal intolerance. The clinical relevance of reactions to PdCl₂ is at present not clear. A subgroup of nickel-allergic patients with "high sensitivity" can be defined. In future studies further addressing the clinical relevance of high versus low sensitivity, patch testing with 0.01, 0.1, 1.0 and 5% nickel sulfate in pet is recommended instead of routine tests with 5% only.     

Peroral nickel provocation in nondyshidrosiform and dyshidrosiform nickel eczema

The flare-up of pompholyx-type nickel eczema induced by oral nickel challenge has been dealt with in several publications. To compare the reactivity of non-pompholyx and pompholyx-type nickel eczema, we challenged three groups of female volunteers (7 with non-pompholyx-type and 12 with pompholyx-type nickel eczema plus 10 control subjects without nickel allergy) with an oral dose of 2.5 mg nickel. By patch testing we additionally determined the degree of cutaneous nickel sensitivity using a series of nickel sulfate dilutions (5.0-0.00001%) and an possible cobalt allergy using 1% cobalt chloride. In 8 of the 19 patients with nickel allergy, the oral nickel challenge was positive (rash, flare-up at sites of healed eczema and former nickel patch tests, and worsening of preexisting eczema; acute pompholyx lesions only in patients with pompholyx-type eczema). The positive results showed the same frequency in non-pompholyx eczema (43%) as in the pompholyx type (42%). Moreover, no substantial difference was found in the degree of cutaneous nickel sensitivity between the two groups of eczema, and there was no correlation between these results and the outcome of the oral nickel challenge. An additional cobalt allergy was recorded significantly more often in pompholyx-type eczema (P = 0.048), yet there was no influence on the oral nickel challenge. The laboratory parameters examined (differential white cell count and total IgE) did not differ in either of the two eczema groups and did not change substantially during nickel challenge reactions.     

Isolated and concurrent prevalence of sensitization to transition metals in a Spanish population

Background Positive patch test results to transition metals (nickel sulphate, palladium chloride, cobalt chloride and potassium dichromate) alone and in combinations with one another are well known. Numerous factors may play a role in isolated and concurrent sensitization to these allergens. Objetive This study aims to describe the isolated and concurrent prevalence of sensitization to transition metals in a Spanish Dermatology Department, between 2000 and 2005, and to determine the prevalence of concomitant positive patch test reactions to different transitional metals. Patients/methods Patients (N= 1092) were tested with the standard series of our Allergic Contact Unity, using a standardized technique. Data from these patients were recorded on a computer entry form and analysed. Statistical analyses to evaluated associations of metal contact allergy were performed, and we evaluated the concordance among these associations of transition metals. Results Three hundred twenty (29.3%) patients reacted positively to nickel, 128 (11.7%) to palladium, 118 (10.8%) to cobalt and 82 (7.5%) to chromium. The prevalence of positive reactions to metals was 32.4%. The association of palladium–nickel was the most frequent, with an acceptable concordance (k= 0.46). Conclusion This study illustrates that concomitant positive patch test reactions to different transitional metals are frequently seen in patients with allergic contact dermatitis. Our results reflect the high prevalence of sensitization to nickel in Spain.     

Pathogenesis of orally induced flare-up reactions at old patch sites in nickel allergy

The flare-up reaction of old patch test sites following oral intake of antigen have been shown to be site and antigen specific reactions. Using enzyme and immunohistochemistry, the morphology of 6- to 8-week-old patch test sites, before and after oral challenge with nickel, was investigated. Before oral challenge, small scattered perivascular cell infiltrates consisting of macrophages, mast cells, T-lymphocytes, and OKT6+ dendritic cells were found in old patch test sites. In early and strong flare-up reactions combined with systemic toxicoderma-like reactions, polymorphonuclear leukocytes and lysed granular fragments from these cells were prominent. In slower flare-up reactions with little systemic involvement, T-lymphocytes predominated. We conclude that cells, probably macrophages, which are able to secrete inflammatory mediators promoting chemotaxis for polymorphonuclear leukocytes and/or T-lymphocyte proliferation, may play an important role in initiation of the flare-up reaction.     

Multiple sensitivities to transition metals: the nickel palladium reactions

Patch test data of 1000 consecutive patients sensitive to at least 1 substance of our standard series showed that transition metals gave associated reactions amongst themselves more frequently than they did with the remaining substances. The responses to transition metals were largely variable and seemed dependent not only upon the associated exposure to different metals or the concomitant responses of the T cell clones, as reported by others, but also upon the chemical properties of the metals and the consequent interactions inside the skin. Concomitant reactions to nickel sulfate and palladium chloride were the most frequently found associated positivities and occurred in a minority of nickel-sulfate-sensitive subjects. In 43 out of 45 of these subjects, patch tests to mixed solutions containing nickel sulfate, plus sulfates of magnesium, zinc, and manganese at higher doses, were not able to reduce the nickel sulfate reactions. This behaviour contracted with that found in the majority of subjects sensitive only to nickel sulfate. These findings seem to demonstrate that, whilst in subjects with positive reactions to nickel sulfate alone antigen formation involves biomolecules containing ions, in those with concomitant reactions to palladium chloride, other structures are involved.     

Allergic patch test reactions to palladium chloride in schoolchildren

A study of the prevalence of allergic patch test reactions to palladium chloride compared to nickel sulfate was performed in a group of Finnish schoolchildren. All adolescents 14–18 years of age in a Finnish town with 40 000 inhabitants, who had received orthodontic treatment with metallic appliances at a municipal dental clinic, were included in the study. The selection of patients was based on patient records. A non-treatment control group was randomly selected from the same age groups of the town population. A total of 700 subjects (77% of those invited), 417 (60%) girls and 283 (40%) boys, participated. The majority (91%) of the girls had pieced ears. Orthodontic treatment was equally common (67–70%) in the boys and the girls. The girls had a much higher frequency of allergic patch test reactions to both nickel sulfate and palladium chloride. Of the 700 adolescents tested 48 (7%) had an allergic patch test reaction to palladium chloride. Of the 417 girls, 44 (11%) were palladium-chloride-positive, whereas only 4 of the 283 boys tested (1%) had an allergic patch test reaction to palladium chloride 3 patients reacted to palladium chloride only, whereas all other patients with allergic patch test reactions to palladium chloride also had an allergic patch test reaction to nickel sulfate. The results support the concept of cross-reactivity between nickel sulfate and palladium chloride. The clinical significance of the allergic patch test reactions caused by palladium chloride remains unclear.     

Contact dermatitis to palladium: A study of 2,300 patients

In the last few years, several investigators have detected a high prevalence of positive patch test reactions to palladium chloride in nickel-sensitized patients. In the majority of these patients, the positive patch tests to palladium chloride had no clinical relavance. The purpose of this study was to evaluate the prevalence and the clinical relevance of the patch test reactions to palladium in patients undergoing patch tests. Two thousand three hundred consecutive patients with allergic contact dermatitis were patch tested with PdCl₂ (1% petrolatum) between January 1991 and September 1992. A positive reaction to palladium chloride was detected in 171 of the 2,300 patients (7.4%). One hundred sixty-nine of these 171 patients had a concomitant positive reaction to nickel sulfate. In our opinion, the similarity of the external electronic structure of these two elements is not sufficient by itself to justify a wrong immunologic recognition, whereas a stereochemical analysis of the compound of these two metals could better explain the possible mechanism of this cross-reaction.     

Patch testing with pure palladium metal in patients with sensitivity to palladium chloride

During a 15-month period, 536 patients being investigated for suspected contact dermatitis were patch tested with the European standard series and palladium chloride 1% pet. 13 patients (2.4%) had a positive allergic response to palladium chloride and all 13 were also allergic to nickel. 12 of these 13 patients consented to further patch testing with discs of pure palladium metal foil, and none reacted. We have shown previously that palladium chloride patch test material contains traces of nickel, and propose an explanation for these results in terms of the additive effect of allergens when tested in combination.     

Single doses of local betamethasone do not suppress allergic patch test reactions to nickel sulfate

Topical corticosteroids are usually banned on test areas prior to patch testing. The previous literature on the effect of topical corticosteroids is conflicting. Patients allergic to nickel sulfate were patch tested on 4 sites with nickel on day (D) 0. Intracutaneous betamethasone was injected to test sites on D-1, D0 and D1. NaCl injection on D-1 was control. The patch test reactions were evaluated clinically and with laser Doppler. There were no differences in patch test reaction intensities on sites treated with intracutaneous betamethasone as compared to control. A single local dose of potent corticosteroid does not suppress allergic patch reactions to nickel. The current practice of avoiding topical corticosteroid use prior to patch testing should be re-evaluated.     

Cross-reactivity to palladium and nickel studied in the guinea pig.

In recent years there have been several reports on concomitant patch test reactions to palladium and nickel, which belong to the same group in the periodic table. Exposure to palladium mainly takes place via dental alloys and jewelry. However, the clinical relevance of simultaneous reactivity to these metals is unknown. To elucidate the question of cross-reactivity, guinea pigs were induced with palladium or nickel and simultaneously challenged with palladium and nickel. Animals sensitized to palladium according to the guinea pig maximization test method (GPMT) or to a new method by van Hoogstraten & Scheper (H&S) reacted to palladium as well as to nickel. On the other hand, animals sensitized to nickel according to H&S reacted to nickel but not to palladium. The GPMT shows that palladium is a more potent sensitizer than nickel: could palladium be the primary sensitizer in humans?     

Oral prednisone suppresses allergic but not irritant patch test reactions in individuals hypersensitive to nickel

A multicentre, randomized, double-blind, crossover study was designed to investigate the effects of prednisone on allergic and irritant patch test reactions. 24 subjects with known allergy to nickel were recruited and patch tested with a nickel sulfate dilution series in aqueous solution, 5% nickel sulfate in petrolatum and 2 dilution series of the irritants nonanoic acid and sodium lauryl sulfate. The subjects were tested x2, both during treatment with prednisone 20 mg oral daily and during placebo treatment. The total number of positive nickel patch test reactions decreased significantly in patients during prednisone treatment. The threshold concentration to elicit a patch test reaction increased and the overall degree of reactivity to nickel sulfate shifted towards weaker reactions. The effect of prednisone treatment on the response to irritants was divergent with both increased and decreased numbers of reactions, although there were no statistically significant differences compared with placebo. It is concluded that oral treatment with prednisone suppresses patch test reactivity to nickel, but not to the irritants tested.     

Metal allergen of the 21st century--a review on exposure, epidemiology and clinical manifestations of palladium allergy

Consumers are mainly exposed to palladium from jewellery and dental restorations. Palladium contact allergy is nearly always seen together with nickel allergy, as palladium and nickel tend to cross-react. We aimed to analyse the available palladium patch test data and case reports to determine whether the prevalence of palladium mono-sensitization has increased. Based on available patch test data from the period 1986-2008, a total of 10 778 patients were patch tested with palladium chloride. The median prevalence of palladium allergy was 7.8% (range <1.0-19.0%) in dermatitis patients and 7.4% (range 1.3-13.9%) in dental patients. The median prevalence of palladium mono-sensitization (defined as the presence of palladium allergy and the absence of nickel allergy) was 0.2% (range 0-1.6%) in dermatitis patients and 0.5% (range 0-7.2%) in dental patients. A slight increase in the prevalence of palladium mono-sensitization was observed over the study period. We conclude that clinically relevant palladium allergy should mainly be suspected in patients who present with allergic contact granulomas at sites of piercing, but also in patients who have clinical disease and palladium patch test reactivity without concomitant nickel reactivity. Palladium salts should be included in dental screening patch test series. Palladium use in jewellery should be limited until we know more about the risk of sensitization.     

Nickel chloride/chlorides of divalent metal interactions in nickel-sensitive subjects

Abstract To verify if the counter-ion Cl^? permits the same interactions between nickel and divalent metals with physicochemical similarities as the counter-ion SO₄^? does, 50 sensitive subjects to nickel sulfate 5% pet. who previously gave positive patch test reactions either to 8 μl of aq. nickel sulfate 0.1 M or to 8 μl of aq. nickel chloride 0.1 M, or to both, were patch retested simultaneously to 8 μl of respectively, aq. nickel sulfate 0.1 M and aq. nickel chloride 0.1 M, and to 8 (il of aq. mixed solutions containing, respectively, nickel chloride 0.1 M +magnesium chloride 0.3 M, nickel chloride 0.1 M+ zinc chloride 0.3 M, nickel chloride 0.1 M+zinc chloride 0.5 M, nickel chloride 0.1 M + manganese chloride 0.3 M, and nickel chloride 0.1 M + manganese chloride O.5 M. Whilst 4 subjects gave a positive patch test response to only nickel sulphate. 8 gave a positive response to nickel chloride alone and the remaining 38 gave a concomitant positive response to both. In all subjects who gave positive responses to nickel chloride, the chlorides of divalent metals were not able to inhibit or reduce the positive reaction. 25 healthy subjects patch tested to both single salts and mixed solutions, and all gave negative responses. 9 of the 50 subjects, 4 who previously gave positive reactions to only nickel chloride 0.1 M, and 5 with concomitant reactions of equal intensity to both nickel chloride and nickel sulfate 0.1 M, were patch retested simultaneously to 8 μ1 of, respectively, aq. nickel sulfate 0.1 M, aq. nickel chloride 0.1 M and aq. mixed solutions containing nickel sulfate (0.1 M) mixed with sulfates (0.3 M) and nickel chloride (0.1 M) mixed with chlorides of Mg, Zn, Mn (0.3 M). Whilst the mixed sulfate solutions were able to reduce nickel sulfale, 0.1 M patch test positive reactions, those containing chlorides, at all concentrations tested, did not inhibit the nickel chloride reactions in any of the subjects. The results of the tests to chlorides, compared to those reached on testing to sulfates of the same metals, lead us to hypothesize that the anion probably affects the uptake and local tissue distribution of the metal, modulating in this way, together with the individual cutaneous ligands, its effects.     

Cross-reactivity patterns of cobalt and nickel studied with repeated open applications (ROATS) to the skin of guinea pigs.

BACKGROUND:The relevance of patch-test reactivity to chemicals on cross-challenge is hard to state, but it is generally assumed that the patient might risk a relapse of contact dermatitis when exposed to the cross-reacting compound(s). OBJECTIVE: To study relevance by using the repeated open application test (ROAT) and applying the inducing allergen cobalt chloride (CoCl(2)) or nickel sulfate (NiSO(4)) as well as the possibly cross-reacting compound (NiSO(4) or CoCl(2)) topically to guinea pigs. Method:Animals were induced according to the guinea pig maximization test (GPMT) method, patch tested and then treated for 10 days using ROATs. Sensitivity thresholds were determined with serial dilution tests. RESULTS: Guinea pigs induced with CoCl(2) reacted in patch testing (100%) and in ROATs to CoCl(2) (93%) but not to NiSO(4). Animals induced with NiSO(4) reacted in patch testing to NiSO(4) (100%) but not to CoCl(2), and in the ROATs to NiSO(4) (41%) and less to CoCl(2). CONCLUSIONS: Our results support the assumption that the concomitant patch test reactivity is due to multiple sensitizations rather than cross-reactivity. We previously found that animals induced with palladium chloride (PdCl(2)) also reacted to NiSO(4) on patch testing but not in the ROATs, indicating that the results from patch testing might overestimate the risk of a relapse. ROATs in patients with solitary and/or concomitant sensitivity to CoCl(2), NiSO(4) or PdCl(2) are desirable.     

Cobalt allergy in hard metal workers

Hard metal contains about 10% cobalt. 853 hard metal workers were examined and patch tested with substances from their environment. Initial patch tests with 1% cobalt chloride showed 62 positive reactions. By means of secondary serial dilution tests, allergic reactions to cobalt were reproduced in 9 men and 30 women. Weak reactions could not normally be reproduced. A history of hand eczema was found in 36 of the 39 individuals with reproducible positive test reactions to cobalt, while 21 of 23 with a positive initial patch test but negative serial dilution test had never had any skin problems. Hand etching and hand grinding, mainly female activities and traumatic to the hands, were found to involve the greatest risk of cobalt sensitization. 24 individuals had an isolated cobalt allergy. They had probably been sensitized by hard metal work, while the individuals, all women, who had simultaneous nickel allergy had probably been sensitized to nickel before their employment and then became sensitized to cobalt by hard metal work. A traumatic occupation, which causes irritant contact dermatitis and/or a previous contact allergy or atopy is probably a prerequisite for the development of cobalt allergy.     

False-positive, follicular and irritant patch teat reactions to metal salts

853 hard metal workers were patch tested with nickel sulphate 5%, potassium dichromate 0.5% and cobalt chloride 1%, each in petrolatum. Non-allergic reactions appeared in 6.5% of the nickel tests, 13% of the chromium tests and 18.3% of the cobalt tests. Most of the individuals with positive, poral or pustular reactions were retested with serial dilutions of metal salts in pet. and in water. The accuracy of a positive initial nickel reaction was 83%, a chromium reaction 40% and a cobalt reaction 62%. The nonallergic reactions were partly reproducible and correlated with both the type of patch test material and with individual factors. Weak and moderately strong positive patch test reactions to metal salts may be irritant and should be checked with serial dilution tests or at least be retested. A reduction of the cobalt chloride concentration from 1% to 0.5% in the standard test material is discussed.     

Concomitant positive reactions to allergens in a patch testing standard series from 1988-1997.

BACKGROUND: Patch testing is a useful diagnostic technique in patients with suspected allergic contact dermatitis (ACD). Concomitant reactions may reflect associations between tested allergens. OBJECTIVE: This study was performed to identify positive correlations between reactions to test substances in a standard screening series. The results of patch testing in patients seen from 1988 to 1997 are described. METHODS: Data were collected from chart review for patients who underwent patch testing to the full standard screening series at the Massachusetts General Hospital Contact Dermatitis Clinic. The Fisher exact test was used to evaluate associations between allergens. RESULTS: A total of 927 patients were patch tested to 22 allergens included in a screening tray. The mean age was 43.9 years, and 68.6% were women. Two or more positive reactions occurred in 36.5% of patients. Reactions to 13 pairs of allergens were found to be significantly correlated: balsam of Peru/fragrance mix, carba mix/thiuram mix, carba mix/paraben mix, cobalt chloride/potassium dichromate, cobalt chloride/nickel sulfate, ethylenediamine/neomycin sulfate, formaldehyde/imidazolidinyl urea, formaldehyde/paraben mix, formaldehyde/quaternium-15, imidazolidinyl urea/quaternium-15, neomycin sulfate/potassium dichromate, paraben mix/quaternium-15, and potassium dichromate/thimerosal. CONCLUSION: Concomitant reactions to 13 pairs of allergens in a standard series occurred at a rate greater than would be predicted by chance. Such associations may reflect cross-sensitization or cosensitization.     

Contact allergy to metals in adolescents. Nickel release from metal accessories 7 years after the implementation of the EU Nickel Directive in Poland

Background. Contact allergy among adolescents is an important issue. Objectives. To assess the prevalence of contact allergy to metals in adolescents aged 15 years and nickel release from metal accessories that are in direct contact with the skin. Methods. Three hundred and nine females and 219 males, all 15 years old, from randomly selected secondary schools were examined and patch tested with nickel sulfate, cobalt chloride, palladium chloride, and potassium dichromate. Three hundred and ninety-nine metal accessories were tested with the dimethylglyoxime (DMG) test. Results.'Metal dermatitis' was reported by 19.4% of females and 0.5% of males. Positive patch test reactions were found in 8.5% of the adolescents (12.9% in females; 2.3% in males), namely to: nickel (12.3% of females; 1.4% of males); palladium (5.2% of females; 0.5% of males); cobalt (3.2% of females; 1.4% of males); and chromium (1.3% of females; 0.9% of males). Allergic contact dermatitis caused by metals was diagnosed in 9.7% of females and in 0.5% of males. Of the metal items, 26.1% gave positive DMG test results: 10.0% of earrings, 11.4% of snaps, and 56.2% of belt buckles. Conclusions. Despite the implementation of the Nickel Directive in Poland, nickel still remains an important causal factor for allergic contact dermatitis. Numerous metal accessories do not comply with the Directive.     

Investigation of contact allergy to dental metals in 206 patients

Background:  Contact allergy to dental materials is poorly understood; clinical manifestations are heterogeneous.
Objective:  To analyse positive patch test reactions to metals (as their alloys or salts) used in dentistry together with clinical symptoms and possible relevance to dental fillings.
Methods:  We retrospectively analysed 206 patients who underwent patch testing with metals used in dentistry because of suspected contact allergy to them.
Results:  Twenty-eight of 206 patients had positive patch test reactions to metals used in dentistry. The number of positive patch test reactions was highest for gold sodium thiosulfate, palladium chloride, and nickel sulfate ( n  = 10, respectively), followed by amalgam, ammoniated mercury, and cobalt chloride ( n  = 4, respectively) and amalgam-mixed metals (including copper, tin, zinc, and silicon), and ammonium tetrachloroplatinate ( n  = 1). Only 14 (7%) of 206 patients had a clinically relevant contact allergy with conditions of the oral mucosa ( n  = 7 with lichen planus and n  = 7 with stomatitis) and positive patch test reactions to dental metals containing the suspected allergen. Improvement of symptoms was assessed in one patient with amalgam contact allergy 2 weeks after removal of dental fillings.
Conclusions:  Clinically relevant contact allergies to dental metals are infrequent. Gold sodium thiosulfate and palladium chloride presented the most frequent contact allergens.