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.     

Interaction of metals in nickel-sensitive patients

Nickel (Ni) dermatitis is, thought to involve the formation of complexes between Ni ions and suitable proteins. 4 groups of 30 subjects who gave positive patch test responses to NiSO₄ 2.9% aq. were each retested to 1 of 4 different solutions containing equimolar (0.1 M) amounts of NiSO₄ plus MgSO₄. NiSO₄ plus CuSO₄, NiSO₄plus ZnSO₄. and NiSO₄ plus Li₂SO₄, respectively. The results, evaluated at 2 days by visual scoring only, demonstrated that the 4 metals exerted a different influence on the nickel reactions, perhaps interfering with one or more factors affecting the formation of Ni++ complexes.     

Prevention of nickel-induced allergic contact reactions with pentoxifylline

In this study, we investigated the effect of pentoxifylline, an inhibitor of TNF-α, on the contact sensitivity response induced by nickel. For induction, open epicutaneous sensitization by NiSO₄. 6H₂O (25% aq.) solution was applied on the backs of 38 albino guinea pigs 5 days a week for 4 weeks. NaCl (0.9%) solution was applied epicutaneously to 10 albino guinea pigs as a control group. 19 were sensitized by nickel and developed positive patch test reactions. Patch tests were repeated after 10 of the sensitized pigs were given pentoxifylline 20 mg/kg/day orally. At the end of this study, only 2 positive patch test reactions were observed in the pentoxifylline-treated group, while 7/9 of the untreated guinea pigs developed positive reactions. These results suggest that pentoxifylline inhibits the contact sensitivity response induced by nickel only during drug administration.     

Pretreatment of the test area with 1-day occlusion improves the response rate to NiSO4 5% pet. Patch tests in subjects with a positive history of nickel allergy

A group of 58 women, aged 18 to 51 years, with a clinical history of nickel allergy, who exhibited equivocal or negative reactions to nickel sulfate 5% pet, patch tests performed on the skin of the back, were recruited consecutively from the patch test clinic from September 1993 to June 19944. In order to improve the response rate to NiSO₄ 5% pet, patch tests, a testing procedure utilizing pretreatment of the test area by 1-day (24-h) occlusion was introduced. Patients underwent 2 patch tests on adjacent sites of the volar surface of both forearms. 3 of the patch tests were performed with 40 mg nickel sulfate 5% pet., whereas a control test was carried out by occluding with an empty chamber. 2 of the nickel sulfate test sites were pretreated with 1-day occlusion performed with an empty chamber. A visual grading system and echographic measurement were used to quantify the responses 30–40 min after patch test removal. Echographic evaluations were carried out using a 20 MHz B-scanner. Measurement of skin thickness and determination of the hypoechogenic dermal area, both considered to be parameters of inflammation, were used to evaluate the intensity of the allergic reaction. At the 3-day (72-h) evaluation. 19 subjects out of 58 clearly showed positive reactions to nickel sulfate 5% pet, at pre-occluded skin sites. Moreover, values of skin thickness and of 0–30 areas at positive pre-occluded nickel test areas were higher in respect to control test areas, confirming clinical evidence of increased response to NiSO₄, after occlusion.     

Pre-treatment of nickel test areas with sodium lauryl sulfate detects nickel sensitivity in subjects reacting negatively to routinely performed patch tests

A fair % of patients with a clinical history of nickel allergy show negative patch test results. To improve the response rate to NiSO₄ 5% pet, patch tests, a testing procedure utilizing pre-treatment of I he lest area by a 24-h application of sodium lauryl sulfate (SLS) was introduced 46 women with a clinical history of nickel sensitivity who exhibited negative reactions to nickel sulfate 5% pet, patch tests. were studied, Patients underwent d patch tests on adjacent sites on the volar surface of the forcarms. 4 patch tests were performed with a 72-h application of 40 mg nickel sulfate 5% pet. While I of these patch tests served as control. 3 test areas underwent 24-h pretreatment with 40 μl SLS. 1 with 0.1% and 2 with 0.5% solution. To evaluate differences in the reactivity to SLS plus nickel sulfate related to the site on the forearm, 0.5% SLS pre-treatment was performed both on a proximal and on a distal lest site. At the 72-h evaluation. 19 subjects out of 46 showed positive reaction to nickel sulfate 5%. At skin sites pre-t railed with SLS. Whereas 23 patients reacted positively at 0.5% SLS pre-treated ureas. Echographic values of skin thickness and of hypo-echogeme dermal areas al positive pre-treated nickel lest. Next higher than al control Jest areas, confirming the clinical evidence of an increased response to NiSO₄ after SLS pre-treatment. The inflammatory reaction, is evaluated clinically and echographically, was much higher al distal skin areas (0.l% SLS and distal (0.5%.) SLS than at proximal 0.5% SLS ones.     

Recommendation to include fragrance mix 2 and hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral) in the European baseline patch test series

Background:  The currently used fragrance mix in the European baseline patch test series (baseline series) fails to detect a substantial number of clinically relevant fragrance allergies.
Objective:  To investigate whether it is justified to include hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral^®) and fragrance mix 2 containing hydroxyisohexyl 3-cyclohexene carboxaldehyde, citral, farnesol, coumarin, citronellol, and α-hexyl cinnamal in the European baseline patch test series.
Methods:  Survey of the literature on reported frequencies of contact allergy and allergic contact dermatitis from fragrance mix 2 and hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral) as well as reported results of experimental provocation test.
Results:  Fragrance mix 2 has been demonstrated to be a useful additional marker of fragrance allergy with contact allergy rates up to 5% when included in various national baseline patch test series. Of the fragrance substances present in fragrance mix 2, hydroxyisohexyl 3-cyclohexene carboxaldehyde is the most common sensitizer. Contact allergy rates between 1.5% and 3% have been reported for hydroxyisohexyl 3-cyclohexene carboxaldehyde in petrolatum (pet.) at 5% from various European centres when tested in consecutive dermatitis patients.
Conclusions:  From 2008, pet. preparations of fragrance mix 2 at 14% w/w (5.6 mg/cm²) and hydroxyisohexyl 3-cyclohexene carboxaldehyde at 5% w/w (2.0 mg/cm²) are recommended for inclusion in the baseline series. With the Finn Chamber^® technique, a dose of 20 mg pet. preparation is recommended. Whenever there is a positive reaction to fragrance mix 2, additional patch testing with the 6 ingredients, 5 if there are simultaneous positive reactions to hydroxyisohexyl 3-cyclohexene carboxaldehyde and fragrance mix 2, is recommended.     

Linalool – a significant contact sensitizer after air exposure

Background: Linalool is a widely used fragrance terpene. Pure linalool is not allergenic or a very weak allergen, but autoxidizes on air exposure and the oxidation products can cause contact allergy. Oxidized (ox.) linalool has previously been patch tested at a concentration of 2.0% in petrolatum (pet.) in 1511 patients, and 1.3% positive patch test reactions were observed.
Objective: To investigate the optimal patch test concentration for detection of contact allergy to ox. linalool.
Methods: Four concentrations of ox. linalool (2.0%, 4.0%, 6.0%, 11.0% pet.) were tested in 3418 consecutive dermatitis patients.
Results: Ox. linalool 2.0%, 4.0%, 6.0%, and 11.0% pet. detected positive patch test reactions in 0.83%, 3.2%, 5.3%, and 7.2% of the tested patients, respectively. The doubtful reactions increased with rising concentrations but relatively less, giving 5.1%, 6.4%, and 7.3% doubtful reactions, respectively, for ox. linalool 4.0%, 6.0%, and 11.0% pet. Few irritative reactions were seen.
Conclusions: Raising the patch test concentration for ox. linalool gave a better detection of contact allergy, as many as 5–7% positive patch test reactions were detected. We suggest a patch test concentration of ox. linalool 6.0% pet. for future patch testing, giving a dose per unit area of 2.4 mg/cm² when 20 mg test substance is tested in small Finn Chambers^®.     

Interaction of palladium ions with the skin

Abstract 87 subjects sensitive to both nickel sulfate and palladium-chloride pet., were contemporaneously patch retested to nickel sulfate 5% pet., metallic palladium chloride 1% pet. and to palladium chloride 1% aq. Whilst all subjects reacted to nickel sulfate and palladium chloride pel., only 3 reacted to palladium chloride aq. No positive reactions were found to metallic palladium. The negative results to palladium chloride aq. are probably due to the formation of a new palladium ion (PdC₄)^2?, achieved on adding an amount of hydrocloric acid to the aqueous solution of PdCl2. The findings seem to demonstrate that the allergic reaction to palladium depends on the arrangement of the metal electrons. The sensit-ization to palladium does not seem to be dependent on the element itself but on the complexes formed by the different compounds. The concomitant reactions to nickel and palladium ions could be dependent on the generation of similar complexes between the ions and the skin proteins.     

Contact stomatitis due to palladium and platinum in dental alloys

We report a patient with contact stomatitis due to combined sensitization to palladium and platinum. Patch testing showed strong and persistent allergic patch test reactions to palladium chloride (1% pet.) ammonium tetrachloroplatinate (0.25% pet), and a palladium metal plate. A platinum metal plate showed a weaker reaction. Histological examination of a biopsy from the test site of palladium chloride (1% pet.) at D3 showed both eczematous and lichenoid changes.     

Is the variability of nickel patch test reactivity over time associated with fluctuations in the systemic T‐cell reactivity to nickel?

Background  Patch test reactivity to nickel varies over time. To what extent this variation is associated with fluctuations in the T-cell reactivity to nickel is not known.
Objectives  Our aim was to investigate the relationship between variation over time in the patch test and the systemic T-cell reactivity to nickel.
Methods  Patients ( n  =   15) with a history of contact allergy to nickel were subjected to three consecutive patch tests at 3-month intervals, utilizing NiSO₄ at 10 concentrations ranging from 0·0032% to 12·5%. Prior to each patch test, blood mononuclear cells were analysed for T-cell reactivity to nickel by interleukin (IL)-4 and IL-13 enzyme-linked immunospot assay.
Results  Eleven patients reacted positively in all three patch tests, two patients reacted in one or two tests and two remained negative. All 13 positive patients displayed variability over time, in terms of the lowest dose of nickel to which they responded. Also the cytokine response to nickel varied over time but the patients' mean cytokine response was positively correlated with their mean patch test reactivity ( r _s = 0·70, P  <   0·01 for IL-4; r _s = 0·78, P  <   0·001 for IL-13). However, although the changes over time in patch test reactivity and the cytokine responses to nickel displayed a similar pattern in many patients, there was no significant correlation between the individuals' variation over time in vivo and in vitro .
Conclusions  The overall magnitude of the T-cell reactivity to nickel and the patch test reactivity are closely associated but fluctuations in the systemic T-cell reactivity cannot be singled out as the major cause of longitudinal variability in nickel patch test reactivity.     

Allergy to phosphorus sesquisulfide: 0.5% pet. is a more appropriate concentration for patch testing

Patch testing was performed with phosphorus sesquisulfide P₄S₃ in 2 groups containing equal numbers of patients using different concentrations (0.5% P₄S₃ in pet. and 1% P₄S₃ in pet., the usual suggested test concentration as recommended by the International Contact Dermatitis Research Group). We found that there was a statistically significant increase in the number of clinically irrelevant irritant reactions in the group tested with the concentration (χ²= 16, P < 0.0004). We recommend that patch testing with phosphorous sesquisulfide should he at a reduced concentration of 0.5% pet.     

Open, closed and intradermal testing in nickel allergy

Open, closed and intradermal testing with NiCl₂ was performed in 15 subjects with patch-test-proven allergy to 5% NiSO₄ in pet. Intradermal testing proved to be a reliable method in confirming nickel sensitivity within 24 h. Open testing with non-toxic concentrations of NiCl₂ in alcohol resulted in 73% and 93% positive reactions at 24 h and 48 h readings, respectively. This test method can be used as a reliable screening method in nickel allergy. Open testing often resulted in positive reactions within a few hours. This makes it possible to investigate pathogenetic events of acquired allergic contact dermatitis at a much earlier stage than with the usual 48-h occlusion. 24-h occlusion with Finn Chambers is not sufficient if one is to avoid false negative reactions in nickel allergy. Occlusion with Finn Chambers seems to delay the reaction.     

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.     

Frequency of sensitization to methyl aminolaevulinate after photodynamic therapy

Background:  Allergic contact dermatitis to methyl aminolaevulinate (Metvix™) after topical application in photodynamic therapy (PDT) has previously been described in case reports.
Objective:  To compare the frequency of sensitization to Metvix^® cream in a group of patients previously treated at least five times with Metvix-PDT with the frequency observed in an unexposed control group.
Methods:  Twenty patients treated five times or more with Metvix-PDT and 60 controls with no prior exposure to Metvix^® were patch tested with Metvix^® cream and Metvix^® placebo cream. Subsequently, the patients were interviewed to determine the relevance of a positive patch test reaction to Metvix^®.
Results:  Of 20 patients treated with Metvix-PDT, 7 were sensitized to Metvix^® cream, giving a sensation risk of 35%. In the control group, 1 of 60 became sensitized after a single exposure to Metvix^® cream (1.7%). There was no reaction to the placebo cream. The positive patch tests to Metvix^® were considered relevant in four of seven patients (57%).
Conclusions:  This study demonstrates a considerable risk of sensitization after Metvix-PDT. We suggest that the patients are interviewed to detect late or persistent local reactions after PDT. These reactions are often considered to be local infections but may represent allergic contact dermatitis, and therefore, patients should be offered patch testing with Metvix^® cream.     

Effect of hand dermatitis on the total body burden of chromium after ferrous sulfate application in cement among cement workers

Background:  Ferrous sulfate (FeSO₄) added to cement has been used to reduce the prevalence of dermatitis in workers. However, the effect of dermatitis on the total uptake of chromium in cement with or without FeSO₄ has not been previously explored.
Objective:  The objective of this study was to compare the urinary chromium levels before and after FeSO₄ addition among cement workers with or without hand dermatitis.
Methods:  Thirty-five male workers were recruited in this study for two consecutive years: 2003 without using FeSO₄ and 2004 after adding FeSO₄. Urinary chromium was used as a biomarker to estimate the total body burden of chromium.
Results:  Urinary chromium concentration showed significant decreases after FeSO₄ was used, and a larger decrease of urinary chromium was observed in workers with hand dermatitis than for those without hand dermatitis. Moreover, a significant decrease of urinary chromium was observed in workers with hand dermatitis in both 2003 and 2004.
Conclusion:  FeSO₄ decreases the total body burden of chromium, especially in workers with severe and continuous hand dermatitis.     

p-Phenylenediamine sensitization is more prevalent in central and southern European patch test centres than in Scandinavian: results from a multicentre study

Background:  Positive patch test reactions to p -phenylenediamine (PPD) are common. PPD is used in oxidative hair dyes and is also present in dark henna temporary 'tattoos'. Cross-sensitization to other contact allergens may occur. Because subjects sensitized to PPD are at risk of clinically severe reactions upon hair dyeing, there is a need for 'current' prevalence data on PPD sensitization.
Objectives:  To compare PPD patch test results from dermatitis patients tested between 2003 and 2007 in 10 European patch test centres and to analyse the causes and determine relevance of positive PPD patch test reactions.
Materials:  Patch testing was performed using PPD (1% free base in petrolatum from Trolab (Almirall Hermal GmbH, Reinbeck, Germany) or Chemotechnique (Malmö, Sweden), equivalent to 0.090 mg/cm² in the TRUE^® test from MEKOS Laboratories AS). Statistical analysis was performed using the chi-squared test.
Results:  The weighted average prevalence was 4.6% among 21 515 patients. PPD sensitization occurred more often in centres located in Central and Southern Europe than in Scandinavian centres (odds ratio = 2.40; 95% confidence interval = 2.07–2.78). The overall proportion of positive patch test reactions to PPD that were registered as being of either current or 'past' relevance was high (weighted average 53.6% and 20.3%, respectively). Consumer hair dyeing was the most prominent cause of PPD sensitization (weighted average 41.8%). Furthermore, occupational hair dye exposure (10.6%) and cross-sensitization to textile dyes (12.6%) were frequently reported.
Conclusions:  PPD sensitization caused by exposure to hair dyes is frequent and remains a present problem for patients visiting contact dermatitis clinics, especially in patch test centres located in Central and Southern Europe.     

Contact dermatitis from metallic palladium in patients reacting to palladium chloride

1307 consecutive patients were patch tested with PdCl2 1% pet. 32 patients were positive; 29 also showed a reaction to NiSO4. 470 patients were additionally tested with a metallic palladium disc. 3 had a positive reaction, and none of them reacted to PdCl2 or NiSO4 pet. A positive patch test to PdCl2 pet. is in most cases probably due to a cross-reaction with nickel in nickel-sensitive subjects. Patients positive to PdCl2 tolerate skin contact with metallic palladium.     

Is the irritant benzalkonium chloride a contact allergen? A contribution to the ongoing debate from a clinical perspective

Background:  Benzalkonium chloride (BAC) is a well-recognized irritant. However, doubts exist that it is also a contact allergen.
Objective:  Analysis of clinical patch test data addressing the reaction profile and synchronous reproducibility of BAC 0.1% in petrolatum (pet.) and possible increases in risk of BAC contact allergy in certain (occupationally exposed) subgroups.
Patients /Methods:  Data of 42 898 patients tested with BAC 0.1% in pet. in 3 different series (topical drugs, ophthalmics, and disinfectants) in the departments of the Information Network of Departments of Dermatology ( http://www.ivdk.org ) between 1996 and 2006 was analysed.
Results:  Overall, morphologically 'positive' reactions were rare, 0.6–1.5%, with a total of 41 stronger positive reactions. Concordance, assessed in 3322 patients tested in duplicate, was low (kappa coefficient 0.15, 95% CI: 0–0.31). Positive test reactions were observed significantly more often in the disinfectants series compared with the 2 other series, indicating that suspected exposure to disinfectants may be associated with sensitization. However, variation of stronger BAC test positivity across potentially relevant (occupational) groups was non-significant.
Conclusion:  This analysis of routine clinical data and a number of previous reports add further, if weak, evidence to the notion that BAC is a contact allergen, albeit a very rare one.     

Correlation between laser Doppler perfusion imaging and visual scoring of patch test sites in subjects with experimentally induced allergic and irritant contact reactions

Purpose: To compare laser Doppler perfusion imaging (LDPI) measurements in experimentally induced allergic contact reactions and irritant contact reactions. The degree of correlation between visual scores and LDPI measurements was also studied.
Methods: Fifteen patients with known contact allergy to nickel or fragrance were patch tested with nickel sulfate 5% pet., fragrance mix 8% pet., sodium lauryl sulfate (SLS) 0.5% pet., SLS 1.0% pet. and two empty control chambers. Visual readings and LDPI measurements were taken at 0, 48 and 96 h.
Results: There was a positive correlation between visual scores and LDPI measurement in the nickel sulfate and fragrance mix patch test sites. However, no correlation between visual scores and LDPI measurements was seen in the SLS 0.5% and SLS 1.0% patch test sites. There was no significant difference ( P =0.125) in LDPI measurements between contact-allergic reactions and contact-irritant reactions.
Conclusion: LDPI correlates with visual scoring in contact-allergic reactions, but not in irritant reactions. LDPI is not useful in distinguishing between allergic and irritant reactions.     

Effective photodynamic therapy of actinic keratoses on the head and face with a novel, self-adhesive 5-aminolaevulinic acid patch

Background:  Photodynamic therapy (PDT) is increasingly used for the treatment of actinic keratosis (AK).
Objectives:  To investigate both the efficacy of different application times and the safety of a novel patch (PD P 506 A) containing aminolaevulinic acid in the PDT of mild to moderate AK.
Methods:  Applications of PD P 506 A for 0.5, 1, 2 and 4 h were compared in a multicentre, randomized, blinded-observer, parallel-group study. After patch removal, study lesions were illuminated with red light ( λ _em ≈ 630 nm; 37 J/cm²). Study lesions were not pretreated (e.g. by curettage) prior to PDT. Efficacy was evaluated 4 and 8 weeks after treatment. Safety and tolerability were determined through laboratory analyses and documentation of both local reactions and adverse events.
Results:  A total of 149 patients were initially enrolled. Of these, 140 patients (520 lesions) completed the study according to protocol. Eight weeks after treatment, 86% of the AK lesions (74% of the patients) treated with 4-h patch application showed complete clearance. The complete clearance rates of lesions (patients) for the 2-, 1- and 0.5-h treatment arms were 73% (47%), 72% (50%) and 51% (24%), respectively. Statistically, the 4-h application was identified as the 'best treatment'. Patients with clearance seemed to experience local reactions to a greater extent than patients without clearance. Local reactions to study treatments did not exceed the expected range.
Conclusions:  The results of this first clinical efficacy study suggest excellent therapeutic outcomes with a single PD P 506 A PDT with a 4-h application.