Standard Patch Test Results and Clinical Relevance: A Cross-Sectional Study of 10-year Retrospective Experience

Abstract

Background:

Allergic contact dermatitis (ACD) is a type IV hypersensitivity reaction, and The European Standard Series (ESS) Patch Test (PT) is widely used in determining the possible responsible allergens causing ACD. The dynamic nature of the industrial products, socioeconomic and environmental factors cause the frequency of common allergens to change over the years and among different regions.

Aims and Objectives:

This study aimed to retrospectively evaluate the results of ESS PT of our centre in the last decade, and determine the current spectrum of allergens and their clinical relevance.

Materials and Methods:

The data of patients who underwent ESS PT in our clinic between January 2010 and March 2020 were included in the study. The patient files were examined retrospectively. The clinical relevance was evaluated according to the COADEX system. Statistical analysis used: SPSS for Windows version 23.0 software program.

Results:

The data of 1037 patients [623 (60.1%) female, 414 (39.9%) male] were analysed. The mean age was 38.34 ± 14.55 years. The five most common allergens were nickel sulphate (23.1%), cobalt chloride (12%), potassium dichromate (9.5%), Fragrance mix II (7.3%) and balsam of Peru (5.7%). According to the COADEX coding system, current relevance was detected in 319 (49.3%) of 646 patients who had a positive reaction to any substance in the patch test.

Conclusion:

Our study showed that with increasing awareness in society, the tendency to avoid some well-known allergenic substances and consumer products causes changes in common allergens. These results prove the value of long-term surveillance of contact allergy.

Introduction

Allergic contact dermatitis (ACD) is a delayed type hypersensitivity reaction and accounts for about 20% of all contact dermatitis. The cutaneous responses of ACD depend on the duration and nature of contact with a particular chemical and individual host susceptibility.[1] The prevalence of contact allergy in the general population is estimated to be between 12.5% and 40.6%.[2,3] The detection of the noxious environmental factor that causes contact allergy helps eliminate allergens and thus alleviates dermatitis.[1,4]

Patch testing is the application of allergens at certain concentrations to the back skin of patients who are suspected of having ACD with a history and clinical examination. It is the gold standard for the diagnosis of ACD. The ideal is to do a patch test with all allergens but considering that there are more than 3000 allergens in nature, it is not possible to test all allergens in clinical practice. However, because 15-20 allergens are responsible for 80% of all ACDs, the patch test application is very useful. The test items, which consist of substances with the highest potential in the development of ACD, are used as the European Standard Series Patch Test (ESS PT).[1,4,5]

The dynamic nature of industrial products and substances causes the frequency of allergens to change over the years. Besides, the frequency of allergens might vary considerably according to geographical regions and socioeconomic factors. For these reasons, it is essential to report ESS PT results from different centres periodically.

This study aimed to retrospectively evaluate the results of ESS PT of our centre in the last decade and determine the current spectrum of allergens and their clinical relevance.

Materials and Methods

The patients who underwent ESS PT between January 2010 and March 2020 were included in our study. Ethics approval was obtained from the local ethics committee (Ethics approval: 566/22.07.2020). The forms routinely used in our allergy unit were retrospectively reviewed, and the sociodemographic characteristics of patients, possible triggering factors, previous treatments, and the clinical relevance of PT results according to the COADEX coding system were analysed.[5,6,7]

Application of patch test was performed according to practice guides.[1,4] The ESS PT used was imported from Chemo technique Diagnostic (Malmo, Sweden). Due to modifications in ESS PT, there have been 30 materials tested between January 2020 and March 2020. Apart from this period, ESS PT used in our unit consisted of 28 materials [Table 1].

Table 1.

European Standard Serial Patch Test materials used in our allergy unit

Allergens	Transporter (%)	Allergens	Transporter (%)
1. Potassium dichromate	0,5 pet	16. 4-tert-Butylphenol Formaldehyde resin	1 pet
2. P-Phenylenediamine	1 pet	17.2- Mercaptobenzothiazole (MBT)	2 pet
3. Thiuram mix	1 pet	18. Formaldehyde	2 aq
4. Neomycin sulphate	20 pet	19. Fragrance mix 1	8 pet
5. Cobalt chloride	1 pet	20. Sesquiterpene lactone mix	0,1 pet
6. Caine mix 3	10 pet	21. Quaternium 15	1 pet
7. Nickel sulphate hexahydrate	5 pet	22. Propolis	10 pet
8. 2-Hydroxyethyl methacrylate	2 pet	23. Methylchloroisothiazolinone+Methylisothiazolinone	0,02 aq
9. Colophony	20 pet	24. Budesonide	0,01 pet
10. Paraben mix	16 pet	25. Tixocortol-21-pivalate	0,1 pet
11. N-isopropyl-N-phenyl-4-Phenylenediamine	0,1 pet	26. Methyldibromo glutaronitrile (MDGN)	0,5 pet
12. Lanolin alcohol	30 pet	27. Fragrance mix 2	14 pet
13. Mercapto mix	2 pet	28. Lyral	5 pet
14. Epoxy resin, Bisphenol A	1 pet	29. Methylisothiazolinone*	0.2% aq
15. Balsam Peru	25 pet	30. Textile dye mix*	6.6 pet

Pet: petrolatum, aq: water. *These allergens were tested part of ESS PT in our unit only between January and March 2020

When the history of specific allergens was available, the existing suspicious substances were added to the test. Patch tests were evaluated according to the guide and positive and negative reactions were interpreted in line with the criteria of the International Contact Dermatitis Working Group (ICDRG).[1,4,5]

Data were analysed by using SPSS for Windows version 23.0 software program. Measurable variables were presented as mean ± standard deviation, and categorical variables as numbers and percentages. Pearson Chi-Square and Fisher's exact Chi-square test, among other statistical methods, were used. P < 0.05 was considered statistically significant.

Results

The data of 1037 patients [623 (60.1%) females, 414 (39.9%) males] were retrospectively analysed. The mean age was 38.34 ± 14.55 (range: 6-86) years. The average duration of complaints was 182.9 weeks, with a median value of 52 weeks. History of personal atopy was observed in 260 (25.1%) patients, familial atopy in 241 (23.2%), history of known allergy in 317 (30.6%) and the presence of autoimmune diseases in 23 (%2,2) patients [Table 2]. The five most common allergens were nickel sulphate (23.1%), cobalt chloride (12%), potassium dichromate (9.5%), fragrance mix (7.3%) and balsam of Peru (5.7%), respectively [Table 3]. The most common irritant reaction was detected with cobalt chloride, seen in 6.7% of patients. According to the COADEX coding system, current relevance was detected in 319 (49.3%) of 646 patients who had a positive reaction to any substance in the patch test (P < 0.05) [Table 4]. Hands were the most common localisation of ACD (59.6%), followed by foot (24%), forearm (17.1%), chest (15.3%) and face (14%).

Table 2.

Sociodemographic and clinical characteristics of patients

Variable	Results
Sex	Male: 414 (39,9%)
	Female: 623 (60,1%)
Age	Mean: 38,34 years (min: 6, max: 86)
	Median: 37
The duration of symptom onset	Mean: 182,9 weeks
	Median: 52 weeks
History of personal atopy	(+): 260 (%25,1)
	(-): 777 (%74,9)
History of familial atopy	(+): 241 (%23,2)
	(-): 796 (%76,8)
History of known allergy	(+): 317 (%30,6)
	(-): 720 (%69,4)
Autoimmune disorders	(+): 23 (%2,2)
	(-): 1014 (%97,8)
Relation with work environment	(+): 116 (%11,2)
	(-): 920 (%88,8)

Table 3.

The comparison of most common allergens across different series

Our Allergy Unit					Boyvat et al.[10]		Uter et al.[4] (ESSCA study)
Order of allergens	Allergens/2010-2020 Current study	Patients (%)	Allergen/1999-2009	Patients (%)	Allergen/2013-2019	Patients (%)	Allergen/	Patients (%)
1	Nickel sulphate	23,1	Nickel sulphate	16,5	Nickel sulphate	19.6	Nickel sulphate	17.6
2	Cobalt chloride	12	Cobalt chloride	8,1	Potassium dichromate	6.5	Fragrance mix I	6.9
3	Potassium dichromate	9,5	Potassium dichromate	7,6	Cobalt chloride	6	Methylisothiazoline	6.2
4	Fragrance mix II	7,3	Fragrance mix II	5,4	Balsam of Peru	5	Balsam of Peru	5.8
5	Balsam of Peru*	5,7	Paraben mix	5,4	Paraphenylenediamine	3.7	MCI/MI***	5.7
6	Paraphenylenediamine	4,6	Formaldehyde	4,3	Fragrance mix I	3.6	Cobalt chloride	5.3
7	MDBGN**	4,1	Paraphenylenediamine	3,8	Textile dye	3.3	MDBGN	3.8
8	Thiuram mix	3,5	N-isopropyl-N-phenyl-4-Phenylenediamine	3,8	MCI/MI	3.1	Potassium dichromate	3.7
9	Methylisothiazoline	3	Balsam of Peru	3,8	MDBGN	3.1	Fragrance mix II	3.7
10	Neomycin	2	Epoxy resin	3,4	Methylisothiazoline and thiuram mix	Both 2.9	Paraphenylenediamine	3.4

*Balsam of Peru: Also known as Myroxylon pereirae resin. **MDBGN: Methyldibromo glutaronitrile. ***MCI/MI: Methylchloroisothiazolinone + Methylisothiazolinone

Table 4.

Results of clinical relevance according to COADEX coding system

COADEX coding system	Patients, n (%)
Current relevance (the patient has been exposed to allergen prior to the current episode of dermatitis, and improves when the exposure ceases)	319 (49.3)
Doubtful relevance (Relevance difficult to assess, no traceable relationship between the positive test and the disease	91 (8.8)
Exposed (a history of previous exposure but not resulting in dermatitis from that exposure)	140 (13.5)

Furthermore, a positive reaction with nickel sulphate was observed more frequently in female patients (P < 0.001), those with a personal history of atopy (P < 0.001) and a history of known allergy (P < 0.001). On the other hand, a positive reaction to budesonide was observed more frequently in male patients (P = 0.018).

When patch test results are divided into 2-year intervals, and the positivity of patch test materials are compared, potassium dichromate (P < 0.001), cobalt chloride (P = 0.005) and formaldehyde (P = 0.008) positivity were found to be more frequent in 2013-2014 period than in other years. In 2015-2016, paraben mix, and balsam of Peru positivity were more frequent than others (P = 0.001). Apart from these, no allergens reached a statistical difference between these 2-year periods.

Discussion

The current study reports the results of 1037 patients consecutively patch tested with the ESS PT at our department and our results showed 60.1% of the patients who had ESS PT for ACD were women. This finding was similar to our centre's previous results and previous Turkish studies from different geographical regions.[8,9,10,11] Female predominance in patch testing was also found in European and Asian studies.[3,4,12] The fact that women take part in professions and housework with more intense chemical contact might be the reason for exposure to allergens more frequently, which may explain the more frequent diagnosis of ACD and the need for PT in this group.

The most common five allergens were similar to our previous experience. However, fragrance mix II and balsam of Peru were detected more frequently in the last decade, becoming 4^th and 5^th common allergens, respectively, leaving paraben behind.[11] Furthermore, our current 10-year retrospective study was similar to the study of Boyvat et al.,[10] identifying the most common three allergens as the same [Table 3]. However, it was different from the work of the European Surveillance System on Contact Allergies (ESSCA) evaluating results of ESS PT in the ESSCA network between 2015 and 2018.[4] The most frequently reported allergens from Europe are fragrance mix-I (6.9%) and methylisothiazolinone (6.2%), after nickel.[1,4] On the other hand, Asian patients have been reported to be more reactive than Caucasians in some studies, but the data was mostly insignificant statistically.[13,14] Another study found a similar incidence of ACD between black and caucasian patients, but differences were shown in the most frequent contact allergens.[15]

Therefore, these differences emphasise the regional changes in allergens due to different substances used in that region, and these differences should be considered and the patch test series should be updated. Moreover, significantly high positivity in patch test results of potassium dichromate (P < 0.001), cobalt chloride (P = 0.005) and formaldehyde (P = 0.008) in 2013-2014 period and paraben mix and balsam of Peru positivity in 2015-2016 (P = 0.001) than other time periods in our current study support the fact that temporal changes in allergens can also occur. Thus, common allergens should be documented in different time frames, even for the same region. This value of surveillance of contact allergy and of the importance of single allergens and time trends have also been shown in large database studies.[4,16,17,18]

Nickel continues to be the most frequent positive allergen worldwide due to its high usage its resistance to oxidation and corrosion, and its affordable cost.[19] It is a common metal present in various alloys. Nickel sensitivity can also be acquired by occupational exposure (such as hard metal work, and mining, especially a risk factor for males).[20,21] It was the most common allergen in our study, as in other studies including Europeans, Asians and Indians.[3,4,12,13,22,23]

However, the frequency of nickel positivity increased in our centre over the years, while nickel sensitivity decreased with Nickel Directive's adoption in European Union countries.[24] Similar results are also shown in Indian studies. Rates of sensitivities to specific allergens such as Nickel have not changed much as shown in comparison within the same region of India.[23,25]

Implementing a legal regulation in our country similar to Europe might decrease nickel sensitivity. Significantly higher positive PT results with nickel in female patients (P < 0.001), those with a personal history of atopy (P < 0.001) and a history of allergy (P < 0.001) show that females, individuals with atopic diathesis or known allergy are prone to have ACD more than others. It is generally believed that individuals with atopic diathesis may be at higher risk of contact sensitivity to allergens than non-atopic individuals due to the defective skin barrier and frequent use of topical products.[26] Mutations in the filaggrin gene and some cytokines of the Th2 pathway released from the skin due to ACD can also exacerbate nickel sensitisation by turning this environment into a vicious circle.[26,27,28,29,30] In the presence of a multifactorial environment that affects exposure and sensitization, atopy might increase the likelihood of nickel positivity in patch testing. However, a recent retrospective study showed that nickel-induced contact allergy was less common in atopic individuals. It has been suggested that metal products induce sensitisation via Toll-like receptor 4 (TLR-4) unlike other contact agents, but in atopic dermatitis, Th2 pathway cytokines in the environment suppress TLR-4 expression.[31,32] The positive reaction rate against nickel was found to be 8-19% in the literature, and it was more common in women than in men, in our study.[3,33]

Following nickel, cobalt and potassium dichromate were the most common allergens in our series. Cobalt is often found as a siccative in paints and used in various alloys. Cobalt sensitivity usually accompanies nickel sensitivity in women and chromate sensitivity in men.[34] On the other hand, potassium dichromate is a marker for contact allergy to chromium and is used in many areas (cement, textile dyes, alloys, tattoos, etc). The prevalence of chromium sensitization increases with age and may be related to cement or leather exposure.[35,36] Both cobalt and potassium dichromate are found in materials often used in daily life, thus, detected very often in the patch tests in different regions as in ours.[12,13,23]

Fragrance mix, Balsam of Peru (BOP), and paraphenylenediamine (PPD), allergens associated with cosmetic products, take the first three places after metals in our series like the European and Indian series.[4,12] Fragrance mix allergy tends to occur earlier in women due to high usage of cosmetic products, and the prevalence increases at older ages due to age-related poor skin barrier function and increased use of topical medicaments and emollients.[37,38,39] BOP, is a thick fluid with a cinnamon-vanilla-like odour secreted from the tree Myroxylon balsamum pereirae. Chemicals related to BOP are commonly found in spices and flavouring agents and in cosmetic, fragrance, and medicinal products. For some patients allergic to BOP, external avoidance of fragrance is not enough to eliminate their dermatitis. Potential allergens related to BOP are commonly found in citrus fruits, sweets, tomatoes, certain spices, condiments, and some liquors.[40] Thus, continuing sensitivity to BOP commonly seen in ESS PT in different studies including our current study might be attributed to the increased usage of cosmetics and the insufficiency to eliminate BOP not only from external exposure but also insufficient elimination of BOP from oral consumption of its derivates and potential allergens. PPD, a colouring agent often found in hair dyes and body painting (temporary/black-henna tattoos), is a well-known substance causing contact dermatitis and occupational dermatitis, especially in hairdressers and beauticians.

Sensitivity to Methyldibromo glutaronitrile (MDBGN) (4.1%) followed fragrance allergies in our current study. The sensitisation frequency of MDBGN in Europe changes between 2.5% and 3.1%.[4,41] Due to a significant increase in contact allergy to MDBGN, it was banned from leave-on products and rinse-off products by the EU legislation as well as from cosmetics.[41] However, it continues to be a prevalent allergen both in our series and in Europe.

Isothiazolinones are often the most common cause of contact allergy to preservatives. Methylisothiazolinone is a crucial preservative found in personal cosmetic products, which has been found to have a relatively frequent positive reaction throughout Europe in recent years, also been chosen as the “contact allergen of the year” in 2013 by the American Contact Dermatitis Society.[42,43,44] Its frequency is increasing in our country, as also shown in our study.[10,45] This, in turn, shows the need to take precautions against specific allergens within cosmetic content, especially methylisothiazolinone, due to the growing trade between countries and the increasing trend of cosmetic product consumption. As a result, dermatologists' awareness of new or common allergens in their region and populations should be increased. Thus, reducing the use of common allergens in products may improve the quality of life and prevent sick leave and/or economic losses.

Budesonide is a non-halogenated corticosteroid used in topical preparations for the treatment of rhinitis and asthma, and it is a good marker of corticosteroid allergy. For the corticosteroid markers of the baseline series, the highest number of positive reactions was found for budesonide (overall prevalence 1.9%, 95%CI: 1.7–2.1%).[46,47] In our study, a positive reaction to budesonide was observed more frequently in male patients (P = 0.018). However, its prevalence has tended to decrease over the years because it is no longer used as a topical dermatological drug itself, but only used in aerosols.

The most common localization of ACD were hands, followed by foot, and forearm in our current study, as well as our previous experience.[11] However, following hand localization in Boyvat et al.'s[10] study, legs were the second most common side, followed by face involvement. This was also varied in the ESSCA study, face being the second common site followed by legs.[4] Regarding anatomical sites of ACD, a stable common share of hand dermatitis was observed. However, increased face dermatitis might be due to the recent epidemic of sensitizations with many cosmetic-related substances.[4] Leg and foot dermatitis could be decreased further by using less allergenic products to treat foot and leg ulcers and diseases.

The positive reactions in the patch test do not always explain the current clinical findings, thus causing misinterpretations. The COADEX coding system was developed to standardise the evaluation of the clinical significance of positive reactions detected in patch tests. In our study, current relevance was found in most cases. Identifying the actual relationship between the clinical findings and the allergen with a positive reaction will guide the intervention and treatment attempts to be made after the patch test. For this purpose, standardised evaluation methods are critical because it allows more accurate interpretation of patient results, better statistical comparisons as common evaluation criteria in studies, and determination of the true relationship between allergen and clinic.

Our study has shown the value of surveillance of contact allergy as increasing knowledge in the society, and the tendency to avoid some renowned allergenic substances and consumer products results in changes in common allergens. By showing these changes with real world data, allergens with increased frequency or newly added allergens can be determined. These results will also be a guide in updating the patch tests, determining the current substances that cause ACD and changing consumer habits and products when necessary. Furthermore, positive reactions should be evaluated with reliable systems like the COADEX coding system to determine the clinical relevance of specific allergens to guide patients better.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.