Allergic reactions in oral and perioral diseases—what do allergy skin test results show?
D1X XJ Budimir,D2X XDMD, PhD,aD3X XM Mravak-Stipetic,D4X XDMD, prof. PhD,bD5X XV Bulat,D6X XMD,aD7X XI Fercek,D8X XMD,a D9X XI Japundzic, DMD,D10X XaandD11X XL Lugovic-Mihic,D12X XMD, prof. PhDa,c
Objective. The aim of this study was to examine potential allergic reactions to different materials in oral and perioral diseases.
Study Design. The study included 230 consenting subjects in total—180 patients with oral and perioral diseases (30 patients each in the following groups: angioedema, oral lichenoid reactions [OLRs], burning mouth syndrome [BMS], gingivostomatitis, cheili- tis, and perioral dermatitis) and 50 healthy controls. Comprehensive diagnostic workups were performed prior to patch testing with standard series allergens and with specific dental materials and skin prick testing (SPT) for food, preservatives and additives, and inhalants.
Results. Positive allergy test results were more common in patients with oral diseases than in controls, with significantly greater frequency of contact allergies in the cheilitis group (P = .048). The most common allergens in the majority patients were cobalt chloride (13.3% in BMS vs 10% in controls) and nickel sulfate (10% in gingivostomatitis and 6.7% in cheilitis vs 3.3% in controls), and preservatives (23.3% in angioedema and BMS).
Conclusions. Allergy skin tests are reliable and justified for diagnosing allergies in cases of persistent or recurrent oral diseases.
This is the only way to confirm allergies and is the basis for consequent allergen avoidance for the benefit of the patient. (Oral Surg Oral Med Oral Pathol Oral Radiol 2019;127:40 48)
When treating patients who suffer from persistent oral and perioral diseases, one often encounters the issue of potential allergies, especially those connected to dental materials and dental procedures.1-4Although this topic has been researched extensively, the results are still ambiguous. The role of allergies in oral dis- eases has not been completely clarified, but there is sig- nificant evidence that various substances can cause both immediate-type (type I) and, more commonly, delayed-type (type IV) reactions.1,2,5In terms of clini- cal presentation, they can manifest as oral lichenoid reactions (OLRs), cheilitis, stomatitis, gingivitis, perio- ral dermatitis, burning mouth sensations, and swelling of the lips and face.5-10 Other possible symptoms include paresthetic and burning sensations in the oral cavity, which could point to oral allergy syndrome (OAS), or pollen-food allergy syndrome, a hypersensi- tivity reaction (type I) to plant-based foods, manifest- ing most commonly with pruritus of the lips, tongue, and mouth.11,12
In previous studies, where tests for immediate-type allergies (type I) were not included, results were con- tradictory (Table I)4,6-8,10,13,14Because the frequency of allergic reactions in oral conditions has not been
sufficiently established and the data are contradictory, it remains unclear how justified the use of allergy skin tests is and which allergens are most commonly involved in oral allergic reactions. This is of particular interest in persistent/recurrent oral conditions of unknown etiology in relation to dental alloys and mate- rials for dental appliances and restorations as well as for preparations for the oral cavity. The aim of our study was to examine potential allergens and allergic reactions in frequent oral and perioral diseases by con- ducting allergy skin tests.
SUBJECTS AND METHODS
This prospective research was conducted from Septem- ber 2011 to January 2016 at the Department of Derma- tovenereology, University Hospital Center Sestre milosrdnice, and the Department of Oral Medicine, School of Dental Medicine, University of Zagreb, Cro- atia. The study was approved by the Ethics Committee of the University Hospital Center Sestre milosrdnice (No. EP-7999/11-18). After the participants provided their informed consent, they were incorporated into the study. The study was conducted according to the guide- lines of the Helsinki Declaration.
Statement of Clinical Relevance
In cases of persistent or recurrent oral and perioral diseases, allergy skin tests are reliable and justified for diagnosing allergies because it is the only way to confirm allergies to ensure a good outcome for the patient.
aDepartment of Dermatovenereology, University Hospital Center Sestre milosrdnice, Zagreb, Croatia.
bDepartment of Oral Medicine, School of Dental Medicine, Univer- sity of Zagreb, Zagreb, Croatia.
cSchool of Dental Medicine, University of Zagreb, Zagreb, Croatia.
Received for publication May 25, 2018; returned for revision Jul 29, 2018; accepted for publication Aug 3, 2018.
Ó 2018 Elsevier Inc. All rights reserved.
2212-4403/$-see front matter
http://doi.org/10.1016/j.oooo.2018.08.001
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Vol. 127 No. 1 January 2019
Ref. No. Year Author/country Respondents Methods Results Common allergens
[7] 2006 Khamaysi et al./
Israel
121 patients (cheilitis and perioral dermatitis; burning mouth; oral lichen planus; orofacial granulo- matosis; glossodynia; recurrent aphthae; hand dermatitis)
Patch test with the dental screening and bakery series
Positive with regard to diagnosis: cheili- tis and perioral dermatitis (41.9%);
burning mouth (42.1%); oral lichen planus (35.3%); orofacial granuloma- tosis (46.2%); glossodynia (12.5%);
recurrent aphthae (16.7%); hand eczema (38.9%)
Gold sodium thiosulfate (14.0%) Nickel sulfate (13.2%) Mercury (9.9%) Palladium chloride (7.4%) Cobalt chloride (5.0%)
2-Hydroxyethyl methacrylate (5.8%)
[10] 2007 Torgerson et al./USA 331 patients (BMS, lichenoid tissue reaction, cheilitis, stomatitis, gin- givitis, orofacial granulomatosis, perioral dermatitis, recurrent aph- thous stomatitis)
Patch test with an 85-item oral anti- gen screening series to flavorings, preservatives, dental acrylates, medications, and metals
Positive patch test (after 96 hours) in 44.7% patients with oral diseases (27.2% patients had 2 or more positive reactions)
Positive with regard to diagnosis: BMS (42.1%); lichenoid tissue reaction (55.9%); cheilitis (25.9%); stomatitis (55.6%); gingivitis (64.0%); orofacial granulomatosis (30.8%); perioral der- matitis (80%); recurrent aphthous sto- matitis (33.3%)
Potassium dicyanoaurate (19.6%) Nickel sulfate hexahydrate (12.5%) Gold sodium thiosulfate (11.6%) Fragrance mix (9.8%)
Palladium chloride (9.7%) Balsam of Peru (7.2%)
Beryllium sulfate tetrahydrate (5.4%) Cobalt chloride (5.2%)
2-Hydroxyethyl methacrylate (5.2%) Gold chloride (4.3%)
[13] 2009 Raap et al./
Germany
206 patients who underwent patch testing because of suspected con- tact allergy to dental metals
Patch test with the European base- line series
Patch test was positive in 13.6% patients Positive with regard to diagnosis: oral lichen planus (18.4%); stomatitis (20%); periodontitis (22.2%); cheilitis (16.7%); recurrent aphthosis (5.6%);
glossodynia (33.3%); burning mouth/
tongue (21.4%)
Gold sodium thiosulfate (4.9%) palladium chloride (4.9%) Nickel sulfate (4.9%) Amalgam (2%)
Ammoniated mercury (2%) Cobalt chloride (2%) Amalgam-mixed metals (0.5%) Ammonium tetrachloroplatinate (0.5%)
[6] 2014 Ahlgren et al./Sweden 83 patients with biopsy-verified OLL
Patch test with a recently developed lichen series, consisting of 66 rele- vant substances from the dental series and the cheilitis series of the Department of Occupational and Environmental Dermatology in Malm€o
Total of 129 contact allergies were found 20.2 % of the allergic reactions in 23 patients were seen on day 7 only 25.2 % increase in positive test reac- tions with an additional reading on day 7 (statistically significant)
Mercury, nickel, gold, and cobalt (the highest frequency of late positive aller- gic reactions)
[4] 2014 Rai et al./India 20 patients who had undergone den-
tal procedures with symptoms of oral lichen planus, oral stomatitis, burning mouth, and recurrent aph- thosis; including dental personnel with history of hand dermatitis
Patch test with Chemotechnique dental series
6 patients with stomatitis, lichenoid lesions, and oral ulcers showed posi- tive patch tests to a variety of dental materials;
7 dental personnel with hand dermatitis showed multiple allergies to various dental materials; 7 patients with ulcers had negative patch tests
Nickel sulfate and potassium chromate
(continued on next page)
ORIGINALARTICLE
127,Number1Budimiretal.41
Subjects
The study included 230 consenting subjects in total—
180 patients with oral and perioral diseases and 50 healthy controls (HCs). We had 6 patient groups according to clinical presentation: angioedema, OLRs, burning mouth syndrome (BMS), gingivosto- matitis, cheilitis, and perioral dermatitis. Each disease category comprised 30 patients. The angioedema group comprised patients with recurrent or persistent marked swelling of the lips, tongue, and perioral skin, not affecting the throat or other parts of the body. Hereditary angioedema was excluded. The OLRs group included patients with solitary, unilateral lesions in direct contact of affected mucosa with offending agents or amalgam restorations.15 A diag- nosis of OLR was confirmed on the basis of clinical presentation and histopathologic findings. Patients who fulfilled clinical criteria for idiopathic BMS and complained of oral mucosal burning without visible oral diseases or oral lesions were included in the BMS group; the majority had intermittent symptoms of burning with unknown and unidentified local and systemic causes (as confirmed by diagnostic workup before allergy tests).16The cheilitis category included patients with various clinical cheilitis forms (angular cheilitis, cheilitis simplex, exfoliative cheilitis, con- tact cheilitis, and granulomatous cheilitis). Diagnoses were established on the basis of clinical criteria.17-19 The category of gingivostomatitis comprised patients with affected gingiva and adjacent oral mucosa, including those with plasma cell gingivitis, exfolia- tive gingivitis, and ulcerative stomatitis, as well as those with aphthous stomatitis.17 Diagnostic criteria for ulcerative stomatitis were those established by Chorzelski et al.20 The diagnosis of perioral dermati- tis was based on a clinical picture of clusters of tiny 1- to 2-mm erythematous papules or papulopustules on perioral skin around the mouth not involving ver- milion and accompanied by burning and itching sensations.17
Prior to allergy skin tests, all patients underwent a comprehensive diagnostic workup, which included detailed patient history, comprehensive clinical exami- nation of the patient’s oral cavity and skin, total blood count test, microbiological examination of oral swabs for gram-positive cocci and Candida species, and biopsy and direct and indirect immunofluorescence studies to exclude other diseases. The workup also checked blood glucose levels, autoimmune markers, C1 esterase inhibitor (C1-INH) levels, and total/spe- cific immunoglobulin E. Mucosal biopsy was manda- tory in patients with a clinical diagnosis of granulomatous cheilitis, plasma cell gingivitis, desqua- mative gingivitis, and ulcerative stomatitis to confirm the clinical diagnosis.
Table?I.Continued Ref.No.YearAuthor/countryRespondentsMethodsResultsCommonallergens [8]2015Kimetal./Korea44patients(orallichenplanus,chei- litis,BMS,andothers)PatchtestwithChemotechnique dentalscreeningseries70.5%positivereactionstooneormore allergens Positivewithregardtodiagnosis:oral lichenplanus(75%),cheilitis(75%); BMS(25%),andothers(75%)
Goldsodiumthiosulfate(25.0%) Nickelsulfate(25.0%) Potassiumdichromate(22.7%) Cobalt(15.9%) Palladium(6.8%) Mercury(4.5%) Copper(4.5%) Methylhydroquinone(4.5%) [14]2016Yoshimuraetal./Brazil54patientsusingdentalprostheses (totalorpartial)PatchtestwithBrazilianstandard seriesandcomplementarydental series
63%patientswerepositivetoatleastone substance 35.2%hadoralcomplaints(oralburn- ing,labialitchingorgingival erythema)
Thimerosal(14.49%) Nickelsulfate(14.49%) Benzoylperoxide(24.63%) Vanillin(alcoholicextract)(8.69%) Cobaltchloride(5.79%) Perfume(mix)(4.34%) Eugenol(4.34%) BMS,burningmouthsyndrome;OLL,orallichenoidlesions.
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42 Budimir et al. January 2019
When choosing diseases of interest for this study, we considered that the above-mentioned diseases are very common in the general population among all age groups and may also be associated with allergy-causing substances (allergens) and allergic reactions. The com- plete inclusion criteria were age (18 years and older);
clinically significant oral and perioral disease diag- nosed by an experienced dermatologist and oral medi- cine specialist; signed informed consent and subject willingness to undergo all recommended diagnostic and allergy tests; and absence of known or verified local or systemic factors of the underlying disease.
Exclusion criteria were specific nonallergic subtypes of oral and perioral diseases with known etiology; posi- tive microbiologic test results for fungal and bacterial infection (swabs taken from labial and oral mucosa and perioral skin); positive direct and/or indirect immuno- fluorescence test results for an autoimmune disease; a history of hereditary angioedema or decreased C1-INH levels; verified drug-induced angioedema and herpetic gingivostomatitis/cheilitis; and use of particular drugs (corticosteroids, antihypertensives, antihistamines, tri- cyclic antidepressants, asthma medications, proton pump inhibitors, and nonsteroidal anti-inflammatory drugs).
Allergy skin tests were performed, and allergic reac- tions were interpreted by a dermatovenerologist. Patch tests were performed with relevant contact allergens (standard series allergens in Croatia and specific dental materials, based on medical history), and skin prick tests (SPTs) were performed with preservatives and additives, foods, and inhalants. Subjects who tested positive were given instructions on how to avoid aller- gens and were referred to their primary physician or dentist for further monitoring and care.
Patch testing
Patch testing was performed on all subjects, and the European Society of Contact Dermatitis guidelines were followed.21 Allergens were applied to the patients’ upper backs (Patch Test Strips Curatest, Loh- man & Rauscher International, Rangsdorf, Germany), and the results were read after 48 and 72 hours. Reac- tions were recorded as weak (+), strong (++), and very strong (+++). Standard allergen kits were used, sup- plied by the Institute of Immunology, Zagreb, Croatia:
potassium dichromate (0.5% pet.), cobalt chloride (1%
pet.), nickel sulfate (5% pet.), fragrance mix (8% pet.), epoxy resin (1% pet.), p-phenylenediamine (0.5%
pet.), N-Isopropyl-N-phenyl-4-phenylenediamine (0.1% pet.), mercapto mix (2% pet.), thiuram mix (1%
pet), carba mix (3% pet.), paraben mix (15% pet.), bal- sam of Peru (25% pet.), neomycin sulfate (20% pet.), colophony (20% pet.), formaldehyde (1% water), thi- merosal (0.1% pet.), quaternium-15 (1% pet.), lanolin
(30% pet.), ammoniated mercury (10% pet.), phenyl- mercuric acetate (0.01% water), ichthammol (10%
pet.), and sulfur precipitated (10% pet.).
Also, each subject was asked about potential dental allergens. When an allergy to another dental material not included in the standard allergy kit was suspected, in coordination with the supervision of dentists, patch tests to additional dental substances created in our lab- oratory were conducted: the gold silver casting alloy Auropal (2% pet.), methyl methacrylate (2% pet.), 2- hydroxyethyl methacrylate (2-HEMA) (2% pet.), the cobalt-chrome alloy Wironit (2% pet.), Ivocron poly- mer (2% pet.), hexachlorophene (1% pet.), and resor- cinol (2% pet.). Other substances were not tested.
Prick tests
SPTs were conducted by the application of allergen drops (supplied by the Institute of Immunology, Zagreb, Croatia) to the forearm (with 1% histamine as positive controls and saline solutions as negative con- trols). Results were read after 15 minutes, a wheal diameter of at least 3 mm being considered a positive result.22 SPTs were performed for inhalants (house dust, mites, feathers, pollens [grass, trees, weeds], ani- mal hair, fungi, mold, bacteria, herbal fibers, wool fab- rics, silk, synthetics and flours), for food (eggs, milk, meat [groups 1 and 2], vegetables [groups 1 and 2], fruits [groups 1, 2, and 3], fungi, coffee, tea, cocoa, freshwater fish and sea fish, and flour), and for preser- vatives and additives (acetylsalicylic acid, sodium ben- zoate, tartazine, potassium metabisulfite, sodium glutamate, glutaraldehyde, and citric acid).
Statistical analysis
Our statistical analysis considered (1) prevalence of allergic reactions detected by each type of test (contact, inhalants, nutritive, additives) as a dichotomous vari- able (0 = absent; 1 = present) and (2) severity as the number of allergens detected in each test type (scalar value). The presence of allergens was analyzed also as a group by all tests together (0 = no detected allergens;
1 = at least one allergen detected by one of the tests).
To compare differences between patient groups, the x2 test was used, and to compare each patient group with controls, Fisher’s exact test was used. Effect size was assessed by the ’ coefficient. Kruskal-Wallis and Mann-Whitney tests with Bonferroni correction were used to compare age groups and number of allergens between groups. Bivariate and multiple logistic regres- sion models determined which tests could be used as disease predictors. Age was grouped by decade and included in the model as a continuous predictor, and gender was a dichotomous variable (0 = female;
1 = male). Presence of at least 1 allergen was used as a dichotomous variable (0 = absent; 1 = present). Odds
ratios (ORs) with 95% confidence intervals (95% CI) served as a measure of association between presence of each allergen group and disease manifestation in com- parison to controls (0 = diseased; 1 = healthy). Multiple linear regression analysis assessed whether diagnosis of a particular disease is able to predict total number of allergens. We used the commercial statistical software SPSS version 22.0 (SPSS Inc., Chicago, IL), and statis- tical significance was set at P< .05.
RESULTS
Demographics and medical history
Of the 230 subjects included in the study, 78.3% were females and 21.7% were males. Women were predomi- nant in every group, but the differences between groups in gender distribution were not significant.
The patients’ ages ranged from 18 to 90 years (median 50), patients with BMS being the oldest (median 60 years) and those with perioral dermatitis the youngest (median 30 years).
All disease groups, except the gingivostomatitis group (93.3%), comprised fewer females compared with the HC group (84%), but the differences were not significant. Those with angioedema, gingivostomatitis, and BMS were significantly older (median age range 50 60 years) compared with controls (median 40 years; P< .05).
Gender differences were not significant between the tested groups (x2test), and neither were there any dif- ferences between any of the disease groups and the HCs (individual Fisher’s exact tests). According to patients’ medical histories, self-reported causes of oral diseases were, in order of prevalence, as follows:
unknown etiological factors, foods, and prosthetic appliances (Figure 1).
Prevalence of allergens in individual oral diseases Allergic reactions were most commonly found in chei- litis (60%) and BMS (56.7%) and least frequently in gingivostomatitis (43.3%) and in HCs (34%). The pres- ence of an allergen was a significant predictor only for BMS and the risk of BMS was 6 times higher in per- sons with 1 or greater detected allergen than in those without any established allergen (95% CI 1.7 20.8;
P = .005).
The number of allergens ranged from 1 to 11; the highest number of allergens was found in angioedema and OLRs and the least in gingivostomatitis (up to 4).
The mean number was between 0 and 1 and did not dif- fer significantly between types of diseases and controls.
Diagnosis of a particular disease failed to predict total number of allergens in multiple linear regression.
Patch test results
Delayed-type allergic reactions determined by patch testing were mostly established in cheilitis (26.7%) and BMS (20%) (Table II). Such reactions were least com- mon in angioedema (6.7%) and in HCs (8%).
The most common allergens in the majority of groups were cobalt chloride, especially prominent in BMS (13.3% vs HCs 10%) and nickel sulfate (gingi- vostomatitis 10% and cheilitis 6.7% vs HCs 3.3%)
Positive reactions to cobalt were commonly observed in cheilitis, gingivostomatitis, perioral derma- titis, BMS, OLR, and angioedema. Also, nickel sulfate was frequently positive in cheilitis, gingivostomatitis, and angioedema.
The largest number of contact allergens was found in patients with cheilitis.
Fig. 1. Self-reported etiologic factors in patient groups.
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44 Budimir et al. January 2019
SPT results
Immediate-type allergic reactions occurred most often in OLRs (53.3%) and least often in gingivostomatitis, perioral dermatitis and controls (33.3%) but with no significant differences between groups (Figure 2).
Allergies to inhalants were most common in OLRs (46.7%); nutritive allergies were most common in BMS (16.7%); and allergies to preservatives and addi- tives were mostly found in BMS and angioedema (both 23.3%). Grass pollen was the most common inhalant in most of the diseases; in OLRs, it was dust and tree pol- len. In subjects with OLRs, inhalants were statistically
more frequent, with a low effect size of 5.5%
(P = .049). The most common additive allergen was glutaraldehyde, followed by citric acid. The most com- mon nutritive allergen was fruit; in BMS, it was mush- rooms, fruits, and vegetables. In SPTs, the highest number of allergens was in angioedema and BMS. Pos- itive SPT results in patients did not significantly differ from those in HCs.
Disease associations
Disease prediction from allergy tests was successful only for BMS. Persons with a positive SPT were 3.5 Table II. Numbers and percentages of subjects with positive tests and most common allergens
Disease Numbers and percentages of
subjects with positive tests
Most common allergens Subjects with positive reactions (%)
Cheilitis 8/30
26.7%
Cobalt chloride Nickel sulfate Mercury precipitate
10 6.7 6.7
Gingivostomatitis 5/30
16.7%
Nickel sulfate Cobalt chloride Mercury precipitate
10 6.7 3.3
Perioral dermatitis 5/30
16.7%
Fragrance mix Cobalt chloride Nickel sulfate
6.7 6.7 3.3
Burning mouth syndrome 6/30
20%
Cobalt chloride P-phenylenediamine
colophony
13.3 3.3 3.3 Oral lichenoid reactions 3/30
10%
Cobalt chloride Gold Thimerosal
6.7 3.3 3.3
Angioedema 2/30
6.7%
Cobalt chloride Nickel sulfate
3.3 3.3
Controls 4/30
8%
Cobalt chloride Nickel sulfate
10 3.3
Fig. 2. Distribution of subject groups to positive prick test results (early hypersensitivity to inhalants and nutritive allergens, preservatives, and additives).
times more likely to have BMS (95% CI 1.0 11.8;
P = .045). Increased age also increased the probability of BMS. The probability of BMS was 8.9 times higher in subjects allergic to foods (95% CI 1.3 63.4;
P = .029); 7.7 times higher with a contact allergen (95% CI 1.2 50.4; P = .033) and 5.8 times higher with an additive allergen (95% CI 1.1 31.0; P = .038).
The risk of angioedema was 3 times higher in subjects with at least any one allergen detected (95% CI 1.1 8.9; P = .032).
DISCUSSION
Various dental materials and oral preparations, such as alloys, prosthetic material, antiseptics, toothpastes, lip cosmetics, acids, and so on, may cause both allergic and nonallergic (irritative) contact reactions.5Among the materials used in dentistry, alloys are the most fre- quent allergens, followed by rubber, polymers, and acrylates, whereas reactions to local anesthetics are quite uncommon1,9,23 Both noble dental alloys (com- prising more than 40% gold, palladium, and/or plati- num) and semiprecious and nonprecious alloys are of base metals, which contain a large percentage of nickel, cobalt, chromium or beryllium, and stainless steel or titanium.8,9
Patch test results in other studies of oral and perioral diseases show various frequencies of allergens, reveal- ing particular allergens found in dental metals (e.g., nickel and gold).13,24 According to Khamaysi et al.,7 contact allergic reactions were most frequently found in cheilitis (41.9%), perioral dermatitis (41.9%), and OLRs (35.3%), the most commonest allergens being gold sodium thiosulfate, nickel sulfate, mercury, palla- dium, chloride, cobalt chloride, and 2-hydroxyethyl methacrylate. Torgerson et al.10 discovered positive contact allergies in 44.7% of patients with oral dis- eases, and possible multiple positive reactions caused by cross-reactions which we also observed. Analyzing patch test results for patients with metals in their oral cavities, Raap et al. found 13.6% positive reactions, particularly to gold sodium thiosulfate and palladium chloride.13 According to Kim et al.,8 positive patch tests for dental materials were found in 70.5% of patients, mostly in oral lichen planus (75%), cheilitis (75%), and BMS (25%); the most common allergens were gold sodium thiosulfate and nickel sulfate, potas- sium dichromate, cobalt, palladium, mercury, copper, and methylhydroquinone.
Cheilitis can be a consequence of contact with vari- ous substances, such as medications, toothpaste ingre- dients (e.g., sodium lauryl sulfate), cleaning agents for braces (potassium-persulfate), dental floss (colo- phony), nail polish, cosmetics (e.g., lipstick, lip gloss), musical wind instruments (nickel, wood), etc.25 A study of cheilitis patients who had undergone patch
testing confirmed irritant contact dermatitis in 36%, allergic contact dermatitis (25%), atopic eczema (19%), and unknown causes of disease (9%).25Torger- son et al. observed a similar frequency (25.9%).10Kim et al. observed a higher frequency (75%), particularly to metals used in dentistry.8In our study, allergies to mercury were uncommon (cheilitis 6.7%, gingivosto- matitis 3.3%), similar to results from Khamaysi et al.
(4.1% of patients).7
Perioral dermatitis is occasionally associated with allergic reactions, as supported by our study, too.
Although Torgerson et al. reported positive patch tests for perioral dermatitis in 80% of patients,10and Kha- maysi et al. showed them in 41.9%,7 positive test results were less frequent (16.7%) in our study, with fragrances, cobalt chloride, and nickel sulfate being the most common contact allergens. Although some stud- ies have suggested a connection between perioral der- matitis and dental alloys as causative or aggravating factors, some others have reported no adverse reactions in patients allergic to nickel upon application of dental crowns or bridges.26,27
OLRs are often associated with contact allergies and positive patch test results.28-31 Torgerson et al.
observed positive patch test results in 55.9% of patients with OLRs.10 Using patch tests on patients with OLRs, Laine et al. found allergies to metals in 67.7%, particularly mercury, gold, and cobalt.29Stud- ies28,29 often mention allergic reactions to mercury, but we observed no positive reactions and neither did Kim et al. (who explained it as being caused by reduced use of amalgams).8 When patch tests yield negative results, irritative contact reactions to mer- cury are possible; thus, removal of an adjacent amal- gam can initiate improvement.5,28 Because these patients often complain of oral sensitivities and unpleasant oral burning sensations, the immediate- type hypersensitivity test is also useful.5,32
Gingivostomatitis may also be associated with con- tact allergies after exposure to dental materials (e.g., metals or plastics in braces).5Torgerson et al. observed statistically more frequent contact allergies in 55.6%
of tested patients with stomatitis and in 64% of those with gingivitis.10In our patients with gingivostomati- tis, positive patch test results were less frequent (16.7%), mostly to nickel sulfate, cobalt chloride, and mercury precipitate. Cobalt chloride was the most commonly recorded contact allergen in the majority of our disease groups, whereas in the gingivostomatitis group, it was nickel sulfate. In dentistry, nickel is used for fabrication of space maintainers, brackets, fillings, and crowns.9,33,34 Allergic reactions to nickel from alloys may manifest as burning sensation, gingival hyperplasia and severely inflamed hyperplastic gingi- val tissue, numbness on the sides of the tongue,
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46 Budimir et al. January 2019
alveolar bone loss, and edema of the gums, palate, and throat.9,33 Also, allergies to nickel sulfate are fre- quently associated with chromium and cobalt reactiv- ity. Thus, according to the patient’s medical history, a possible allergy to nickel sulfate should be explored by a dermatologist who would conduct a patch test.9
BMS is a disease of unknown etiology; however, vari- ous substances, such as foodstuffs, additives, metals, and plastics, have been cited as potential causes.5It is, there- fore, necessary to rule out all possible etiologic factors, including allergies. Torgerson et al. reported positive patch test results in 42.1% of subjects with BMS,10 whereas in our study, they were less frequent (20%); the most frequent contact allergens were cobalt chloride, p- phenylenediamine, and colophony. Also indicated were allergies to nutritive allergens (16.7%).10 As indicated by our results, the risk of this disease is higher in patients with atopia, although with no statistical significance. In certain cases, BMS may manifest similarly to OAS, which appears in those with atopia manifesting an allergy to food as a result of cross-reactions with inha- lants (and commonly is determined with SPTs). How- ever, positive allergy test results do not necessarily indicate a connection to oral symptoms because BMS has multifactorial etiology and other causes must be excluded. Skin test results are influenced by many varia- bles, including a patient’s skin response, the specific technique used, and tester consistency. Also, potential interference from particular medications should be taken into account before testing. Steele et al. showed that patch testing can identify patients with BMS who are allergic to dental metals or dietary additives and may benefit from the removal or avoidance of these.35 According to Lynde et al., contact allergies may be an etiologic factor in some patients with BMS, making patch testing useful in this disease.36
Angioedema can be induced by various factors and allergens (predominantly immediate-type, but also delayed type), such as drugs, foodstuffs, preservatives, and cosmetics. Such reactions can occur as a result of a latex allergy, dental products, food ingredients, and so on.1,25 We found additive allergens in 23.3% of patients with angioedema, and we then advised them to avoid additives so that we could monitor their condi- tion after elimination. Our results indicate the risk of angioedema is 3 times higher in subjects with con- firmed allergens, and this risk increases with age.
The importance and usefulness of patch testing is in revealing allergies, along with long-term patient moni- toring during avoidance of the offending allergen for a mandatory period to establish clinical relevance. Clini- cal relevance is defined by specific morphologic symp- toms in the oral cavity, together with a positive patch test reaction to dental materials containing the sus- pected contact allergen.4Previous research has shown
that positive patch test results predominantly correlate with clinical oral symptoms.4 However, according to other study results, only some patients (those with lichen planus and stomatitis) had a clinically relevant contact allergy and positive patch test reactions to den- tal metals containing the suspected allergen.13
Our research presents the results of allergy tests in common oral and perioral diseases. Given the varying results of individual studies on the usefulness of allergy tests in oral and perioral diseases with nonspecific sen- sations, in cases of persistent or recurrent diseases, car- rying out allergy tests is justified. Therefore, in cases of nonspecific oral problems, it is important to examine patients’ medical histories and, in consultation with their dentists, carry out allergy tests on the specific dental substances/allergens that have been or will be used in treatments.37 The choice of allergens to be tested is also important; it varies by studies, countries, and number of allergens.14
One should also keep in mind that patch tests have a few limitations and pitfalls with regard to oral dis- eases.3These are caused by different allergen concen- trations in the oral mucosa and in the standard patch preparations and by the differences in the pH of the skin and oral mucosa, which may result in either false- positive/false-negative reactions or nonspecific irrita- tive reactions. Also, sometimes positive allergy test results just reflect sensitivity of the general population.
When carrying out patch tests and recording reactions, a standard reading may be insufficient, so subsequent tests should be read after 7 and 10 days or more, such as in patients allergic to mercury.6One should always keep in mind that the same substances to which a patient tested negative might still induce an irritative (nonallergic) reaction.
As this study did not include patient follow-up, future long-term studies would enhance the under- standing the relevance of allergy in these diseases. The most important measures include giving patients advice on how to avoid allergens and monitoring their conditions and clinical pictures. Likewise, allergy tests can be conducted before complex and expensive proce- dures are performed, both for the patient’s benefit and for the doctor’s satisfaction.
CONCLUSIONS
To our knowledge, this is the first research involving patients with different oral and perioral diseases in which patch and prick tests were performed in the same patients and the results compared with healthy subjects as controls. However, our study did not include monitoring for final outcomes, so long-term studies in future are necessary to supplement our cur- rent findings. It remains to be seen whether future anal- yses of the effects of elimination of certain substances
will prove efficient. at the end of DISCUSSION, and
“Allergy skin tests are reliable and justified for diag- nosing allergies in cases of persistent or recurrent oral diseases. This is the only way to confirm allergies and is the basis for consequent allergen avoidance for the benefit of the patient.”
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Reprint requests:
Iva Japundzic, Clinical Department of Dermatovenereology, Univer- sity Hospital Center Sestre milosrdnice, Vinogradska cesta 29, HR- 10000 Zagreb, Croatia.
iva.japundzic@gmail.com
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48 Budimir et al. January 2019
