Allergens in Hand, Foot, and Hand-Foot Eczema: An Intercomparison by Patch Testing.

BACKGROUND: Hand eczema (HE), foot eczema (FE), and hand-foot eczema (HFE) manifest on exposure to various agents in day-to-day life or in occupations or both.
OBJECTIVES: The objectives of this study were to identify pattern of allergens causing HE, FE, and HFE and to identify multiple and concurrent contact allergies.
MATERIALS AND METHODS: A study was conducted from October 2013 to August 2015 which included 190 patients. Patch test was performed for 78.94% of patients (n = 150). The statistical tests used were descriptive, Cramer's V, and Chi-square tests.
RESULTS: The most commonly affected group was HFE (55.8%) followed by HE (22.1%) and FE (22.1%). Allergens showed positivity either singly 56.3% (n = 67) or in combination 43.69% (n = 52). Nickel (41.79%) was the most common allergen in all the three groups followed by potassium dichromate. Late reactions (after day 7) were observed in 17.64% of patients (n = 21). Nickel was observed in 42.85% (n = 9) and paraphenylenediamine was observed in 28.57% of patients (n = 6) with P values of <0.001 and 0.050, respectively. Multiple contact allergies were seen in 44% of patients (n = 52). Concurrent reactions (55.8% [n = 29]), polysensitization (34.6% [n = 18]), and mixed reactions (9.6% [n = 5]) (P value of <0.001) were observed.
CONCLUSION: Significant multiple contact allergies including concurrent reactions with nickel sulfate, potassium dichromate, cobalt chloride, and polysensitization were observed. No significant differences in allergen pattern were observed in HE, FE, and HFE. RECOMMENDATION: Day 7 reading is recommended in HFE. Copyright:

Introduction

A delayed type of hypersensitivity response to exogenous agents causes hand–foot eczema (HFE). HFE manifests on exposure to various ingredients in day-to-day life[12] or as occupational contact dermatitis or both.[3] HFE affects social, occupational, and psychological performance of an individual and adds to morbidity. Identification and avoidance of responsible external agents is of paramount importance in the effective management of HFE.[4]

Studies with large sample sizes on hand eczema (HE) and foot eczema (FE) have been documented,[45] in literature. However, there are very limited data on the intercomparison of the three groups – HE, FE, and HFE. HFE is very commonly observed in the outpatient department. The present study was designed to identify the allergens, both common and unique, responsible for HE, FE, and HFE and to compare the data across the three sites – hand, foot, and hand–foot.

Aims and objectives

The aim and objectives of this study were to identify and compare the patterns of allergens responsible for HE, FE, and HFE and to identify multiple and concurrent contact allergies.

Materials and Methods

The present study was a cross-sectional, descriptive, hospital-based study comprising of 190 patients with HFE and was conducted from October 2013 to August 2015. Out of the 190 patients, 106 had HFE and 42 each had HE and FE. Suspected allergic contact dermatitis (ACD) or patients with contact dermatitis were included and subdivided into three groups based on the site affected. Patients who were on immune suppressive therapy, systemic allergies such as bronchial asthma, any variant of endogenous dermatitis, dermatological problems other than ACD that manifested over hands and feet, and patients unwilling to undergo patch testing were excluded from the study. An informed consent was taken from all patients involved in the study, and clinical data of each patient were recorded on a standard pro forma. A detailed history including occupation, hobbies, duration of the disease, previous treatment, and other personal history was taken before clinical examination.

Baseline investigations such as absolute eosinophil count, total count, random blood sugar, and potassium hydroxide (KOH) tests were carried out. Other relevant investigations were performed depending on the case. KOH and skin biopsies were performed for doubtful cases and those proven ACD were included in the study. Patients were treated during an acute stage of disease and advised to undergo patch testing after the acute stage subsided. A semi-structured questionnaire was used to collect the data on demographic profile, clinical features, and patterns of allergen profiles observed in HFE.

Patch testing was done for all the patients using the Indian standard series approved by the Contact and Occupational Dermatoses Forum of India. The details of procurement of allergens were as follows:

Manufacturer–Chemotechnique Diagnostics, Sweden

Supplier–Systopic Laboratories, New Delhi, India

Dilution–0.5%–100%

Vehicle –Petrolatum

Chambers–Aluminum

Application period–48 h

Days of reading –Day 3, Day 5, and Day 7.

Ethical committee clearance was taken for the study.

Statistical analysis

In the present study, Cramer's test was applied to find out the association between rows and columns of tabulated results of the study. Quantitative data were statistically presented using mean and standard deviation. For verifying associations, Chi-square test and Cramer's V were used. All tests were done using the software SPSS Version 16 (IBM corporation, Chicago, USA). P ≤ 0.05 was considered statistically significant.

Results

Out of 190 patients, 47.9% (n = 91) were male and 52.1% (n = 99) were female. The age range was between 17 and 71 years. The mean age of the study group was 44.58 ± 14 years for males and 40.18 ± 14 years for females. Majority of the patients, i.e., 84.73% (n = 161) who had HFE belonged to the age range of 21–60 years. Regarding the occupation of the patients, we found 35.3% (n = 67) of them to be homemakers, 24.7% (n = 47) to be farmers, and 17.9% (n = 34) to be masons [Table 1]. The most common affected group was HFE followed by HE and FE [Figures 1 and 2]. Duration of the disease among the patients ranged from 3 days to more than 10 years, where 11.1% (n = 21) of the patients had the disease for >5 years and 83.15% (n = 158) of the patients had taken some form of treatment in the past. History of use of topical steroids was found in 36.3% (n = 69) of the patients and use of unknown topicals was found in 45.3% (n = 86) of the patients, which was statistically significant at P < 0.001 level.

Table 1

Occupation of patients

Occupation×site cross tabulation
Occupation	Site			Total
	H	F	HFE
Farmer
Count	8	9	30	47
Percentage within site	19.0	21.4	28.3	24.7
Homemaker
Count	14	16	37	67
Percentage within site	33.3	38.1	34.9	35.3
Mason
Count	7	5	22	34
Percentage within site	16.7	11.9	20.8	17.9
St/Te/Of/Cl – Student/
Teacher/Officer/Clerk
Count	8	8	11	27
Percentage within site	19.0	19.0	10.4	14.2
Others
Count	4	3	6	13
Percentage within site	9.5	7.1	5.7	6.8
Hospital staff
Count	1	1	0	2
Percentage within site	2.4	2.4	0.0	1.1
Total
Count	42	42	106	190
Percentage within site	100.0	100.0	100.0	100.0

HFE: Hand-feet eczema

Figure 1

Site of involvement

Figure 2

(a) Hand eczema. (b) Foot eczema. (c) Hand–foot eczema

Out of the 150 patients who underwent patch test, 93 showed positive reactions on day 3 and 98 on day 5. Five patients who had a negative reaction on day 3 became positive on day 5. Allergens showed positivity, either singly 56.3% (n = 67) or in combination 43.69% (n = 52). Nickel was the most common allergen in all the three groups (41.79%) [Table 2]. A late reaction (after day 7) to the patch test was seen in 17.64% (n = 21) of the patients [Figure 3]. Nickel was the allergen in 42.85% (n = 9), with the significance level of 0.005 and 28.57% (nf = 6) showed positivity to paraphenylenediamine (PPD) with a significance level of 0.050. Other late reactors observed were potassium dichromate, thiuram mix, and fragrance mix [Table 3]. Nickel (42.85%) showed the maximum number of early negative and late positive reactions followed by PPD (28.57%). In HE, 8 patients were positive for single allergen and 6 for combined allergens. In the case of FE, the corresponding numbers were 8 and 7, respectively. In HFE, the corresponding numbers were 12 and 16, respectively. Nearly 44% (n = 52) of the patients showed multiple contact allergies, which was not statistically significant [Table 4]. Further, it was found that 55.8% (n = 29) of the patients had concurrent reactions with nickel [Figure 4], potassium dichromate, and cobalt and 34.6% (n = 18) had polysensitization [Figure 5], which was statistically significant (P < 0.001). Concurrent reactions were associated with polysensitization in 9.6% (n = 5) of multiple contact allergens.

Table 2

Patterns of allergens in hand, foot, and hand-foot eczema

Allergen × site cross tabulation
Allergen	Site			Total
	Hand	Foot	HFE
0	10 (32.3)	10 (32.3)	11 (35.5)	31 (100.0)
1	2 (12.5)	3 (18.8)	11 (68.8)	16 (100.0)
2	0 (0.0)	2 (66.7)	1 (33.3)	3 (100.0)
3	1 (33.3)	0 (0.0)	2 (66.7)	3 (100.0)
4	2 (40.0)	0 (0.0)	3 (60.0)	5 (100.0)
5	7 (25.0)	4 (14.3)	17 (60.7)	28 (100.0)
6	2 (66.7)	0 (0.0)	1 (33.3)	3 (100.0)
7	0 (0.0)	2 (66.7)	1 (33.3)	3 (100.0)
8	0 (0.0)	1 (50.0)	1 (50.0)	2 (100.0)
9	0 (0.0)	1 (100.0)	0 (0.0)	1 (100.0)
10	0 (0.0)	1 (100.0)	0 (0.0)	1 (100.0)
11	0 (0.0)	1 (50.0)	1 (50.0)	2 (100.0)
12	0 (0.0)	2 (18.2)	9 (81.8)	11 (100.0)
13	0 (0.0)	0 (0.0)	2 (100.0)	2 (100.0)
14	0 (0.0)	0 (0.0)	6 (100.0)	6 (100.0)
15	0 (0.0)	1 (50.0)	1 (50.0)	2 (100.0)
16	0 (0.0)	1 (50.0)	1 (50.0)	2 (100.0)
17	0 (0.0)	0 (0.0)	1 (100.0)	1 (100.0)
18	1 (25.0)	0 (0.0)	3 (75.0)	4 (100.0)
19	0 (0.0)	0 (0.0)	1 (100.0)	1 (100.0)
20	1 (100.0)	0 (0.0)	0 (0.0)	1 (100.0)
21	0 (0.0)	0 (0.0)	1 (100.0)	1 (100.0)
22	0 (0.0)	0 (0.0)	1 (100.0)	1 (100.0)
23	0 (0.0)	1 (100.0)	0 (0.0)	1 (100.0)
24	0 (0.0)	0 (0.0)	1 (100.0)	1 (100.0)
25	0 (0.0)	0 (0.0)	1 (100.0)	1 (100.0)
26	1 (100.0)	0 (0.0)	0 (0.0)	1 (100.0)
27	1 (50.0)	0 (0.0)	1 (50.0)	2 (100.0)
28	0 (0.0)	1 (100.0)	0 (0.0)	1 (100.0)
29	0 (0.0)	1 (100.0)	0 (0.0)	1 (100.0)
30	0 (0.0)	0 (0.0)	1 (100.0)	1 (100.0)
31	2 (50.0)	1 (25.0)	1 (25.0)	4 (100.0)
32	1 (50.0)	0 (0.0)	1 (50.0)	2 (100.0)
33	0 (0.0)	0 (0.0)	1 (100.0)	1 (100.0)
34	0 (0.0)	1 (100.0)	0 (0.0)	1 (100.0)
35	0 (0.0)	0 (0.0)	1 (100.0)	1 (100.0)
36	0 (0.0)	0 (0.0)	1 (100.0)	1 (100.0)
37	1 (100.0)	0 (0.0)	0 (0.0)	1 (100.0)
Total	32 (21.3)	34 (22.7)	84 (56.0)	150 (100.0)

HFE: Hand-foot eczema, 0: Patch test negative, 1: Potassium dichromate, 2: Neomycin sulfate, 3: Cobalt chloride, 4: Paraphenylenediamine, 5: Nickel sulfate, 6: Colophonium, 7: Nitrofurazone, 8: Lanolin alcohol, 9: Myroxylon pereirae resin, 10: Thiuram mix, 11: Formaldehyde, 12: Potassium dichromate, cobalt chloride, 13: Potassium dichromate, paraphenylenediamine, 14: Potassium dichromate, nickel sulfate, 15: Potassium dichromate, Nitrofurazone, 16: Potassium dichromate, thiuram mix, 17: Neomycin sulfate, nitrofurazone, 18: Cobalt chloride, nickel sulfate, 19: Cobalt chloride, nitrofurazone, 20: Paraphenylenediamine, neomycin sulfate, 21: Paraphenylenediamine, nickel sulfate, 22: Paraphenylenediamine, colophonium, 23: Nickel sulfate, lanolin alcohol, 24: Nickel sulfate, thiuram mix, 25: Nickel sulfate, parthenolide, 26: Epoxy resin, Nitrofurazone, 27: Fragrance mix, nitrofurazone, 28: Nitrofurazone, myroxylon pereirae resin, 29: Lanolin alcohol, myroxylonpereirae resin, 30: Potassium dichromate, neomycin, nitrofurazone, 31: Potassium dichromate, cobalt chloride, nickel sulfate, 32: Potassium dichromate, paraphenylenediamine, nickel sulfate, 33: Potassium dichromate, nickel sulfate, fragrance mix, myroxylon pereirae resin, 34: Potassium dichromate, cobalt chloride, paraben mix, nickel sulfate, black rubber mix, 35: Potassium dichromate, 2-mercaptobenzothiazole, p-chloro-m-cresol, parthenolide, 36: Neomycin sulfate, cobalt chloride, nickel sulfate, fragrance mix, 2-mercaptobenzothiazole

Figure 3

Extremely strong reaction to paraphenylene diamine 3+ (International Contact Dermatitis Research Group)

Table 3

Late reactions

Reaction × allergen × site cross tabulation
Site			Day	Allergen							Total
				Neomycin sulfate	Paraphenylenediamine	Nickel sulfate	Nitrofurazoned	Thiuram mix	Potassium dichromate, nickel sulfate	Potassium dichromate, nickel sulfate, fragrance mix, myroxylon pereirae resin
Hand	Reaction	7	Count	-	-	1	-	-	-	-	1
			Percentage of allergen	-	-	50	-	-	-	-	50
		16	Count	-	-	1	-	-	-	-	1
			Percentage of allergen	-	-	50	-	-	-	-	50
		Sub-total	Count	-	-	2	-	-	-	-	2
			Percentage of allergen	-	-	100	-	-	-	-	100
Foot	Reaction	7	Count	1	-	1	-	-	-	-	2
			Percentage of allergen	100	-	100	-	-	-	-	50
		16	Count	-	-	-	1	1	-	-	2
			Percentage of allergen	-	-	-	100	100	-	-	50
		Sub-total	Count	1	-	1	1	1	-	-	4
			Percentage of allergen	100	-	100	100	100	-	-	100
Hand-foot	Reaction	7	Count	1	4	2	-	-	-	-	7
			Percentage of allergen	100	66.7	33.3	-	-	-	-	46.69
		16	Count	-	1	2	-	-	1	-	4
			Percentage of allergen	-	16.7	33.3	-	-	100	-	26.68
		19	Count	-	1	1	-	-	-	1	3
			Percentage of allergen	-	16.7	16.7	-	-	-	100	20.01
		36	Count	-	-	1	-	-	-	-	1
			Percentage of allergen	-	-	16.7	-	-	-	-	6.62
		Sub-total	Count	1	6	6	-	-	1	1	15
			Percentage of allergen	100	100	100	-	-	100	100	100
Grand total count				2	6	9	-	-	1	1	21

Table 4

Multiple contact allergies

Type of reaction	Site
	Hand	Foot	Hand-foot
Concurrent
Count	4	5	20
Percentage within site	50	55.6	57.1
Polysensitization
Count	3	3	12
Percentage within site	37.5	33.3	34.3
Mixed
Count	1	1	3
Percentage within site	12.5	11.1	8.6
Total
Count	8	9	35
Percentage within site	100	100	100

Figure 4

Concurrent reactions

Figure 5

Polysensitization

Discussion

We identified 190 patients with HFE. Among the three groups HFE, HE, and FE, the most common was HFE, followed by HE and FE. A majority of the patients who had HFE and subjected for patch test were in the average age range of 21–60 years. Various authors[678] in the past have observed that this finding may be due to the increased exposure to environmental allergens of the working and earning members.

The point prevalence, 1-year prevalence, and lifetime prevalence of HE investigated by various authors were found to be 4%, 10%, and 15%, respectively.[1] In a study conducted on 1000 patients with ACD, it was found that majority had footwear dermatitis.[9] This was explained to be due to the practice of Indians wearing shoes and sandals on bare feet without socks, making them more susceptible to shoe allergy. Moreover, the quality control of shoe production in India is not satisfactory.[10] Similarly, we found that farmers and masons who had FE had increased exposure to chromates and rubber. Bajaj et al. suggested that wearing thick absorbent socks and using other nonchromate chemicals for tanning and curing leather could minimize this form of exposure.[9]

Most of the patients with HFE (79.3%) who underwent patch test showed at least one or more positive results. This figure is much higher than the rate of positive reactions (32.3%) that was reported recently from Turkey in a very similar study.[11]

Out of the 150 patients who underwent patch test, 93 showed positive reactions on day 3 and 98 on day 5. Five patients who showed a negative reaction on day 3 were positive on day 5. Twenty-one patients showed positive reaction de novo on day 7. A study conducted by Mayo clinic on 36,064 patch test reactions found that the most optimal time to read the test was on day 3 and day 5.[12] Therefore, in our study, the readings were interpreted after 48 h (day 3) and after 96 h (day 5).

Allergens either alone or in combination were studied in the three groups. Among single allergens, nickel was the most common in all the three groups followed by potassium dichromate. Nickel was the most common allergen among females, especially homemakers. Females showed an increased sensitization to nickel due to increased exposure through drinking water, hard water, air, cosmetics, and detergents.[1314] In particular, Indian women, due to their traditional customs and religion, have increased usage of jewellery, which poses a risk of nickel allergy. Female gender has been identified as a risk factor for the development of nickel allergy with a relative risk of 3.74.[15] A study on 567 Danish citizens found that nickel sensitization was higher among patients with ear piercing (14.8%) compared to those without ear piercing (1.8%).[16] Nickel allergy can also be occupational and is found among metal workers, retail clerks, hairdressers, domestic cleaners, and caterers. Exposure to new consumer sources with nickel content, such as gadgets, such as mobile phones and computers, could be an added explanation for nickel allergy.[17] A time series study, investigating 180,390 patients with suspected ACD, showed that the prevalence of nickel allergy had decreased significantly, by at least 10%, in young females with dermatitis in four European countries following nickel regulation.[18]

Various studies from India[19] and abroad showed potassium dichromate to be exclusively affecting males, i.e., 9/9 (100%), where chromate had been frequently encountered as the most common cause for HE. Chromates are present in cements, leather, matches, bleaches, yellow paints, varnishes, certain chromate-containing glues, soap, detergents, cloves, and pepper.[19] In our study, masons were the most commonly affected group. One of the patients had no occupational contact with chromates, but on regular follow-up showed significant improvement in HFE after avoidance of pepper and cloves in diet. Western countries have reported sharp decline in chromate sensitivity since the legislation that was passed to add ferrous sulfate to cement. Adding ferrous sulfate to cement converts the easily absorbable hexavalent chromium into the less-sensitizing trivalent form.[20] In France, the removal of chromium from a popular brand of household bleach resulted in a dramatic decline in chromate sensitivity in women.[21]

Patch test reactions becoming positive de novo on day 7 or later have been described as late reactions. In our study, we found majority of late reactions to nickel and PPD to be statistically significant. Other late reactors observed in our series were potassium dichromate, thiuram mix, and fragrance mix. The allergens showing late reactions in previous studies are PPD, epoxy resin,[22] metals such as nickel, and topical antibiotics such as neomycin.[23] A large series from Mayo clinic observed late reactions to metals and neomycin.[24] Other studies have found late reactions to PPD.[2425] PPD is known for its ability to cause active sensitization during patch test and late reactions as late as day 7 or day 9.[24] The sensitivity of diagnostic patch testing may be reduced by lowering the concentration of allergens in the patch test.[2425] Our series were patch tested with 1% PPD and late reactions were observed. The Mayo clinic study observed that reactions to fragrance mix might dissipate after day 5. However, we found a positive reaction to fragrance mix on day 7, which was negative in readings on day 3 and day 5. Sensitization to repeated patch testing with PPD was noticed by Davis et al.[24] However, the Mayo clinic study and our series have not done repeated patch testing, but have observed late reactions.

In our study, single allergen positivity and combinations were 8, 6; 8, 7, and 12, 16 in the three groups HE, FE, and HFE, respectively. Among single allergens, nickel was the most common in all the three groups. Development of contact allergy is the result of the interplay between environmental exposure and individual susceptibility, as only a fraction of individuals exposed get sensitized. Chemical resemblance occurs between the allergens such as potassium dichromate, cobalt chloride, and nickel sulfate. The nature of the exposure relating to type, potency, dose of allergen,[2627] occlusion extent, and duration,[2829] simultaneous exposure to more than one allergen[3031] or irritants,[3233] and inflamed or damaged skin,[28] all influence the risk of and can increase susceptibility toward the development of contact allergy and multiple contact allergies. There is no generally accepted definition for multiple contact allergies. Some authors use two or more, others three or more, contact allergies as cut point.[34] In our series, we considered two or more allergen positivity as the cutoff for multiple contact allergies. A hypothesis has been put forward that patients with multiple contact allergies have an inherent increased susceptibility.[35] Varying numbers of statistically significant associated duplet allergen combinations have been identified ranging from 13 to 166 combinations.[363839] In a study by Bruynzeel et al.,[40] nickel sulfate, fragrance mix, and balsam of Peru were the three allergens in the European Standard Series, with most associations to other allergens. They are also the most frequent sensitizers.[40] In the general population, 2.4%–5.5% of people are sensitized to nickel and 0.6%–1.5% to potassium dichromate.[41] Almost 13% and 5% of patients engaging in contact dermatitis investigations have been shown to be sensitized to these two metals, respectively, in a study.[42]

Conclusion

HFE was the most commonly affected group. Late positive reactions were mostly shown by nickel and PPD. Multiple contact allergies including concurrent reactions and polysensitization were observed. The most common allergens were nickel and potassium dichromate. No significant difference in the allergen pattern was observed between the three groups. The study is important on the following counts: first, a significant multiple contact allergies including concurrent reactions with nickel sulfate, potassium dichromate, cobalt chloride, and polysensitization were observed. A dermatologist should be aware of concurrent reactions, and patients allergic to one allergen should be evaluated and advised appropriately regarding the avoidance of allergens. Second, day 7 reading is recommended in HFE, as few reactions are negative during the initial readings which turned positive on day 7 reading. To conclude, concurrent reactions, multiple allergies, polysensitization, and identification of late reactors are important in the interpretation of patch test and management of ACD.

Financial support and sponsorship

Partial financial assistance was provided as academic grant given by JSS Medical College, JSS Academy of Higher Education and Research, Mysuru.

Conflicts of interest

There are no conflicts of interest.