Allergens causing contact dermatitis of the feet: Investigation and analysis of allergic reaction causes

Abstract

Introduction

Allergic contact dermatitis of the feet is a significant problem that affects the quality of life and requires attention from the medical community due to the number of studied and still unidentified allergens. The purpose of this review article is to summarize the available scientific data regarding the most common allergens that cause ACD of the feet.

Methods

Nickel sulphate, neomycin sulphate, thiuram mix and colophony occupy a significant place in the prevalence of allergies. The prevalence of sensitization to rubber and leather products can vary depending on the ethno-demographic characteristics of the country, as well as the specifics of a person's professional activity, such as the use of protective waterproof shoes, increased humidity of the microclimate, and atopy in anamnesis.

Results

Patch testing has been shown to be an important method for identifying allergens, however, not all footwear components are tested during patch testing with standard allergen series, requiring the use of patches made from patient shoe samples.

Conclusions

Expanding the scope of patch testing to include other possible allergens is important for the accurate diagnosis of ACD of the feet and a more detailed study of those allergens that were previously considered rare.

Introduction

Contact dermatitis of the feet (or as it is more commonly called “shoe dermatitis” in specific cases) is a type of contact dermatitis caused by compounds that, when in contact with the skin of the feet, cause an irritating and/or allergic reaction [1]. The pathophysiology of contact dermatitis includes keratinocyte necrosis that is associated with irritant contact dermatitis, while the presence of eosinophils and mild vesiculation with exocytosis is characteristic of allergic contact dermatitis (ACD), reflecting its immunological nature described by Johansen et al. [2]. The usual manifestations of this disease are a red and scaly rash, often itchy, located on the toes, interdigital spaces, and the sole surface of the foot. Shoe dermatitis can affect people of any age, gender, or ethnicity. However, according to the Traidl et al. [3] and Atwater et al. [4] analysing data from North American Contact Dermatitis Group and the Information Network of Departments of Dermatology, contact dermatitis when wearing shoes was more common in younger patients (up to 40 years) and men. More than 60% of individuals tested for allergen sensitization by patch testing have been shown to test positive for allergens associated with footwear (e.g., potassium dichromate, colophony, and formaldehyde resins). However, there are allergens that are also common in everyday consumer products, textiles and workplaces, highlighting the prevalence of foot dermatitis triggers. Workers in industries such as medicine, cleaning, food processing and building are particularly vulnerable due to repeated exposure to irritants and allergens in the workplace. At the same time, aerogenous ingress of allergens onto the skin of the feet is not excluded, which significantly complicates the identification of the provoking allergen, according to the data of the American Contact Dermatitis Society [5].

This problem is also widespread among the pediatric population, because children very often suffer from skin rashes of various etiologies, including allergic ones, which is why according to Zafrir et al. [6], all children with foot dermititis should perform patch testing regardless of atopic background. It is worth noting that shoe materials are constantly changing and modifying, and according to an Australia/New Zealand clinical narrative the use of commercial allergen series may be ineffective, and testing on patient shoe samples is time-consuming and questionable [7]. According to Uter et al. [8] testing using patient shoe materials can more than triple the diagnostic efficiency and can compensate for unknown or newly discovered allergens not included in commercial patch series.

Thus, the variety of allergens makes the diagnosis and treatment of contact dermatitis of the feet a difficult task due to their large number, and modern diagnostic methods do not always give accurate results, which can lead to errors in diagnosis and treatment. Individual susceptibility to allergies cannot be ruled out either, it can vary significantly between individuals of different social groups and within the same population. It is also important to consider not only allergens, but also other factors such as irritants, mechanical friction and infections that can lead to foot dermatitis. Typical at first glance symptoms of ACD can be the result of such diseases as “athlete's foot”, psoriasis, lichen planus, juvenile plantar dermatosis and atopic dermatitis. The need for an interdisciplinary approach to solving the problem of contact dermatitis of the feet involves the joint work of dermatologists, allergists, immunologists, epidemiologists and other specialists. Further studies of contact dermatitis of the feet will help to better understand the nature of this disease, develop more effective methods of diagnosis, treatment and prevention, as well as improve the quality of life of patients.

The purpose of this study is to pinpoint the prevalent allergens responsible for ACD of the feet and the factors that contribute to the onset of allergic reactions.

Materials and methods

This literature review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines for transparent and comprehensive reporting of systematic reviews and meta-analyses. Following these principles, research aims to promote equity, reduce bias, and increase the relevance and applicability of findings to diverse communities around the world. A comprehensive strategy was applied to identify relevant studies, involving extensive searches of three key databases: PubMed, Scopus, and Web of Science from January 1, 2019, to May 15, 2024. In addition, to increase the accuracy of the methodology and minimise the possibility of missing relevant materials, the reference lists of the studies included in the review were manually searched.

Eligibility criteria were defined according to the Participants, Interventions, Comparisons, Outcomes and Study Design (PICOS) framework. Filtering of publications obtained during the search was carried out according to the criteria of inclusion and exclusion from the study. The following criteria were selected for inclusion in the review: articles must be published within the specified time frame; articles must be published in academically significant resources; articles should be review, comparative, and experimental studies (like randomised controlled trials, clinical case-type studies, cohort studies, and case series) that address the topic of allergens in contact dermatitis of the feet. Despite the fact that some works did not fit into the previously established deadline, it was still decided to include them in the review, because their data coincided with the data of the initially selected works, met the goals of the study and answered the questions posed. Exclusion criteria from the study were: incompletely published research results; missing parts of the study (e.g., abstract or discussion); studies published by the same author or group of authors (more than 2); studies related to contact dermatitis of various body sites without reference to the skin site of the feet. Comparison groups or conditions were excluded as this review focused on a study of allergens in contact dermatitis of the feet.

In the course of filtering, a total of 44 sources were incorporated into the literature review. The data collection process involved extracting various key details and contextual factors from the selected studies. These included participant characteristics such as age distribution, sex, and any relevant comorbidities. In addition, variables such as publication date, main study objectives, sample size, and country of origin were recorded. For intervention conditions, details regarding study design, duration, training context, and specific aspects of the behavioural intervention were documented.

Results and discussion

Key data about triggers and risk factors for ACD of the feet

ACD develops due to an immune reaction in response to contact with an allergen when the skin is repeatedly exposed to it [9]. The appearance of ACD is observed 8–28 days after the first contact, which often complicates the identification of the allergen, which requires a detailed study of the anamnesis. Clinical manifestations of ACD are characterised by pink, itchy macules, xerosis, and fissures of the skin, sometimes with wet secretions and the formation of long crusts, which indicates the attachment of a secondary bacterial infection (which is not a rare situation in the lower extremities) [10]. ACD can occur on the back or sole of the foot, depending on the site of contact with the allergen, but it usually manifests clinically in the area between the toes or the arch of the foot. This is attributable to the dorsal side of the foot having a thinner stratum corneum compared to other areas, making it more prone to skin barrier defects and allergen sensitization. Skin rashes can sometimes correspond to shoe details such as sandal straps, hardware or stitching (Fig. 1).

Fig. 1.

Potential allergens that can provoke the development of contact dermatitis of the feet

Fonacier et al. [11] describe the following classification of contact allergens: fragrances, preservatives, excipients, resin, textile dyes, drugs for local treatment and metals and biomedical devices. A more detailed list of allergens according to the described groups is presented in Fig. 1. Meanwhile, there is currently no specific classification for allergens of ACD of the feet.

Clinical manifestations of contact dermatitis can vary from minor erythematous changes to a severe course in the form of difficult-to-heal wounds, resembling “trench foot”, which was described in the article by De Leeuw et al. [12], and the authors recommend the routine use of allergic skin tests and trial local and systemic treatment based on the results of the examination. In turn, Dutt and Yilmaz Demirdag [13] in their clinical case hypothesized that allergy tests can be useful only in those cases when the dermatitis is insensitive to the treatment, since there are possible cases of allergic reaction to the components of medicines, which will be discussed in more detail later. Although contact dermatitis of the feet is often a disease associated with non-occupational activities, it can also be associated with work due to insufficient protection from harmful factors in the workplace, such as humidity, or due to inappropriate use of occupational footwear [14, 15]. This can cause not only an allergic or irritating skin reaction, but also skin infections, exacerbation of chronic skin lesions. The most common work-related contact dermatitis is irritant contact dermatitis of the feet caused by increased sweating of the feet, especially in protective waterproof footwear and it is associated with significant absenteeism, diminished quality of life, and severe symptoms such as itching and pain.

Researchers describe that there are many styles of shoes: casual, business, work and sports shoes, which are made all over the world from leather, glue, metals, rubber, dyes, fragrances and other synthetic materials, which makes it impossible to precisely identify all their components [16]. A wide range of potentially sensitizing chemicals are used in the production and finishing of shoes. Thus, in the examination by Lazzarini et al. [17] of 52 patients with symptoms of contact dermatitis of the feet, 56% had positive reactions of patch tests with standard series, as well as an additional 45% with specific series, which was statistically significant, and among which there was polysensitization to substances that vulcanize rubber, metals, and drugs for local treatment. This indicator is impressive in its magnitude, however, the data obtained in other studies vary significantly depending on the ethno-demographic characteristics of the patient (Table 1).

Table 1.

Comparative characteristics of the main clinical observations analysed in the study

Authors and year of publication	N*	Country of research	Detected allergens (%)
Traidl et al. [3]	119	Germany	Potassium dichromate (10.8%), colophony (7.2%) Mercapto mix (4.6%) Mercaptobenzothiazole (4.0%) P-tert-butylphenol formaldehyde resin (1.6%)
	417	Switzerland
Atwater et al. [4]	33	United States	Potassium dichromate (29.8%) P-tert-butylphenol formaldehyde resin (20.1%) Thiuram mix (13.3%) Mixed dialkyl thioureas (12.6%) Carba mix (12%)
	661	Canada
Lazzarini et al. [17]	52	Brazil	Nickel sulfate (41.4%) Cobalt chloride (20.7%) Ppd mix (13.8%) Potassium dichromate (13.8%) Colophony (6.9%) P-ter-butylphenol, thiuram, carba mix, and formaldehyde (3.4%)
Chaiyabutr et al. [18]	247	Thailand	Carba mix (7.7%) Mercapto mix (6.9%) Potassium dichromate (6.9%)
Sánchez-Sáez et al. [19]	3,265	Spain	Potassium dichromate (70.4%) Mercapto mix (4.3%) P-tert-butylphenol formaldehyde resin (1.9%)**
Sahana et al. [20]	190	India	Neomycin sulfate (66.7%) Nickel sulfate (31%) Potassium dichromate (18.8%) Nickel sulfate (14.3%) Potassium dichromate+cobalt chloride (18.2%)
Herro et al. [21]	101	United States	P-tert-butylphenol formaldehyde resin (15%), myroxylon pereirae (12%) Cobalt (11%) Formaldehyde (10%) Fragrance mix 1 (10%) Colophonium (9%) Potassium dichromate (8%) Neomycin sulfate (8%) Tixocortol-21-pivalate (7%)
Mohanty et al. [22]	58	India	Mercaptobenzothiazole (50%) Potassium dichromate (40%) Thiuram mix (20%) Paraphenylenediamine (10%)
Kumar et al. [23]	80	India	Potassium dichromate (35.3%) Nickel (23.5%) Mercapto mix (17.7%) 2 – mercaptobenzothiazole (14.7%) Fragrance mix (14.7%) Colophony (11.8%)
Thyvalappil et al. [24]	389	India	Black rubber (16%) Mercapto benzo thiazole (13.4%) Thiuram mix (9.5%) Potassium dichromate (7.5%) Disperse blue (7%) Colophony (6.5%) Nickel sulphate, neomycin sulphate and disperse orange (6% each)

Note: * – number of patients; ** – a subgroup of patients with isolated lesions of the feet older than 18 years.

From 2004 to 2014, a retrospective observational study was conducted by the core group of GEIDAC (Spanish Research Group on Contact Dermatitis and Skin Allergy) in eight Spanish hospitals to investigate patients with suspected ACD [25]. Among the 450 cases of clinically detected foot dermatitis, 41% were male, and 5.6% were likely related to occupational exposure. The higher incidence in females may be due to the greater variety of materials in women's footwear and the tendency for women to go without socks, increasing sensitization risk. ACD was diagnosed in 47% of cases, with a statistically significant prevalence among patients aged 21 to 60, an age range associated with an active lifestyle and diverse footwear use. The most common allergens identified were potassium dichromate, cobalt chloride, p-tert-butylphenol-formaldehyde resin, mercapto mix, and mercaptobenzothiazole.

The epidemiological data presented by the Indian group of researchers Agrawal et al. [26] revealed that foot dermatitis was more common in men (32%), and hand dermatitis was more common in women (71.1%). Dermatitis of the hands was observed more often among housewives (29.7%), and dermatitis of the feet among physical workers (57.7%). A permanent course was observed in dermatitis of the feet (83%), while a recurrent course of dermatitis of the hands could be assessed in 38.1% of cases. A significant deterioration in the quality of life was noted for symptoms such as burning sensation, peeling, wet discharge, a history of atopy, and seasonal deterioration. As for the difference in patch testing results, Chaiyabutr et al. [18] in their study describe that among the Thai population the chemicals used in the manufacture of rubber appear to be the most common causative allergens. This can be partly attributed to the popularity of rubber footwear in tropical climates and the prevalence of agricultural work in Asian countries. In contrast, leather is the primary allergen in Europe, and rubber chemicals are typically not among the top three allergens in European footwear. These differences likely arise from the varying materials used in shoe manufacturing across regions. For instance, Europe's generally colder climate leads to a higher usage of leather shoes compared to other types.

Among the risk factors, in addition to professional and ethnic-demographic factors, the association of the development of dermatitis of the hands with dermatitis of the feet should be highlighted. From information on 3,265 patients who participated in a study authored by Sánchez-Sáez et al. [19] found that 9.4% of them had eczema of the feet, and 42.1% of this subgroup of patients had combined eczema of the feet and hands. Positive results of patch testing were more often found in patients with isolated lesions of the feet, while sensitization to potassium dichromate was seen in 70.4%, to mercapto mixture in 4.3%, and to p-tert-butylphenol-formaldehyde resin in 1.9% in cases of patients older than 18 years. In the pediatric subgroup, the trend was somewhat different (namely, 68.8%, 18.8% and 6.2%, respectively). Also, a certain percentage of cases was due to an allergic reaction to a mixture of aromatic compounds. In a study authored by Lopez-Castillo et al. [27] the percentage of combined allergic dermatitis of the hands and feet among 2,926 patients was significantly less than in the previous study – 8%, which is related to the initial selection of patients in the study, since the researches specifically focused on eczema of the hands. One way or another, the main allergens for combined allergic dermatitis were potassium dichromate and cobalt chloride, and in cases of polysensitization, the biocide methylisothiazolinone occupied a significant place. Sahana et al. [20] conducted a study among 190 patients with signs of ACD of the skin of the hands, feet and combined lesions and found a completely different ratio given that 55.8% of patients with eczema of the hands and feet, and 22.1% of feet only. Nickel was the predominant allergen across all three groups, accounting for 41.79% of cases, followed by potassium dichromate. Paraphenylenediamine also emerged as significant, affecting 28.57% of patients.

Discussing polymorbidity, according to Herro et al. [21], ACD was detected in 40–65% of patients with atopic dermatitis, leading to exacerbation of skin lesions. Emulsifiers, flavors, preservatives, corticosteroids, and other components found in topical treatments are crucial substances to identify and test in patients with similar pharmacological backgrounds [28]. For children with atopic dermatitis exhibiting persistent moderate to severe dermatitis on their hands or feet, patch testing is strongly recommended. However, conducting these tests can be challenging as Th2 inflammation may suppress the contact allergic response during the control or remission phase of atopic dermatitis. The European Task Force on Atopic Dermatitis (ETFAD) advises maintaining a low threshold for patch testing with standard series and components of topical treatments for patients with atopic dermatitis [29, 30]. Moreover, patch testing is suggested for patients with atopic dermatitis who have persistent symptoms, unusual lesion locations, or unexplained flare-ups, particularly when considering systemic interventions.

Shoe components as the most frequent allergens in ACD of the feet

Leather in textile products that has been treated with tanning substances is usually chrome tanned, namely potassium or sodium bichromates. Allergy to chromium often occurs when using leather products, and its prevalence is about 2–4% according to The Health and Occupation Research network in Great Britain [31]. A safe alternative for those who are allergic to chromate is the use of vegetable tanning products with the use of tanning plant substances – tanninoids from tree bark (most often oak and linden), roots, fruits and leaves [32]. However, in the conditions of mass production, this technology is not economically profitable, which is why it is replaced by a cheaper and more effective chrome tanning process, and there is also a difference in the physical and chemical properties of the treated leather. This forces patients to be very careful when choosing leather goods, to be interested in their composition and to contact manufacturers.

Recent studies have shown that trivalent chromium, which is the main form of chromium in new leather products, can cause allergic reactions in people with an allergy to chromium, and that prolonged use of leather products can change to the form of hexavalent chromium, the content of which is regulated at the legal level in Europe since 2015 [33]. Currently, the only available method of spot testing for chromium release is the diphenylcarbazide test, but it has not yet become widespread due to certain limitations [34]. In cases of contact dermatitis caused by an allergy to chromium, it is enough for the patient to exclude items made of leather from his wardrobe, but such avoidance of products that release chromium does not always result in immediate symptom relief, which makes it difficult to determine the significance of the allergy. It is notable that chromium finds extensive application in electroplating and cement because of its remarkable corrosion resistance. It is also present in various alloys such as stainless steel, cobalt-chromium-molybdenum steel, and vitallium, often in concentrations ranging from 20% to 30%. This element is commonly utilised in the manufacturing of prosthetic implants. Patients, especially those being considered for prosthetic implantation, should be informed about its presence in such implants [35].

Vulcanization catalysts employed in rubber production facilitate the polymerization of base substances like natural latex or nitrile butadiene rubber, which are utilised in the production of gloves and various rubber items. These catalysts fall into five primary categories: thiurams, dithiocarbamate/carba (CM), benzothiazoles, guanides, and thioureas [36, 37]. Carba mix, a rapid accelerator found in over 90% of gloves, is widely used in numerous consumer products and certain fungicides. Cross-reactivity between dithiocarbamates and thiurams is possible, likely due to their similar chemical structures and involvement in redox processes. In a study conducted by S.P. Mohanty et al. involving 58 patients, mercaptobenzothiazole emerged as the most common allergen (50%), followed by potassium dichromate (40%), a mixture of thiurams (20%), and paraphenylenediamine (10%) [22]. Desquamation was observed in nearly 80% of patients, often leading to crust formation. Housewives, students, and cement workers were identified as the most susceptible group due to their frequent use of rubber footwear (Fig. 2).

Fig. 2.

A clinical example of patch testing: A) a solid arrow shows a weakly positive reaction, and a hatched arrow shows a strongly positive one; B) an example of polysensitization

Similar conclusions were obtained by Kumar et al. [23] in a group of 90 patients belonging to the age category of 21–40 years, and most often among them were farmers, housewives and students. The most common allergens were potassium dichromate (35%), nickel sulfate (23.5%) and a mixture of mercapto and mercaptobenzothiazole. The authors also took into account medicinal allergens, and dermatitis was mainly caused by neomycin. Polysensitization was observed when using a mixture of mercapto, mercaptobenzothiazole, potassium dichromate and flavorings. However, Rundle et al. [38] published their clinical case in which a 12-year-old boy developed severe bilateral foot dermatitis. Extensive patch testing was conducted, which showed a significant positive response to dialkylthiourea mixtures. A detailed analysis of his history suggests that he was probably exposed because of neoprene taekwondo shoes. After taking measures to avoid allergens, the dermatitis disappeared. Therefore, despite the prevalence of allergies to a mix of carb and mercapto mix, better not to forget about other rubber components that can be potential allergens. This in turn encourages patch testing with samples of one's own shoes, which is not a common practice.

It is also worth noting that ACD can be accompanied by the development of a secondary bacterial or fungal infection, which should be treated with topical or oral antibiotics/fungicides in combination with topical steroids of intermediate and high potency to reduce inflammation, but these medications can also be a potential allergen. Antifungal drugs can cause ACD, which develops as a result of the action of azole antifungal agents, such as econazole, miconazole, tioconazole, and clotrimazole, which can be found not only in pharmaceutical products, but also in cosmetic products [39, 40]. These patients have often experienced sensitization to more than one antifungal drug, which may significantly limit future treatment choices in patients with fungal infection of feet. Amongst other contact allergens, it is noteworthy to observe an increase in sensitization to biocides – agents employed to hinder microbial growth during transportation, storage, and usage. Currently, there is no legislation regulating the utilization of biocides in footwear, potentially contributing to the rise in contact allergies associated with biocides sourced from non-cosmetic origins like footwear. Isothiazolinone, considered a rare allergen, is associated with various product lines such as detergents, paints, clothing, and leather goods, with approximately 90% of sensitized patients linked to its production [41]. It is likely utilised in clothing and leather goods to decrease microbial growth during transport, particularly in regions with hot and humid climates, akin to the application of dimethyl fumarate in leather goods [42, 43].

ACD of the feet poses a multifaceted challenge in allergology, primarily due to the complexity of differential diagnosis, which in turn complicates the selection of appropriate therapy for patients. Existing studies investigating allergens triggering ACD of the feet have encountered several limitations. These include inadequate follow-up durations for certain patients, hindering the determination of the long-term clinical significance of ceasing contact with the allergen. Furthermore, certain studies lacked specific data regarding the types of shoes worn and the duration of their usage, primarily due to their retrospective nature, leading to incomplete documentation of relevant information. Future research endeavours should prioritise extended follow-up periods and comprehensive data collection methodologies to gain a deeper understanding of the clinical implications associated with discontinuing the use of footwear containing pertinent allergens. This approach will facilitate more informed decision-making regarding therapeutic interventions for patients afflicted with ACD of the feet.

Conclusions

In summary, there is currently no specific classification of allergens tailored to contact allergic dermatitis of the feet. Nonetheless, it is feasible to categorise allergens into shoe-related factors (such as rubber, leather, fragrances, dyes, and biocides) and local treatments (typically antifungal). ACD triggered by chromium is frequently linked to leather items subjected to chrome plating, notably shoes and gloves, particularly those utilizing hexavalent chromium. Likewise, allergic reactions to various rubber components, particularly vulcanization catalysts, are prevalent among the population.

The carba compound, prevalent in most rubber products, stands out as a key allergen, although research indicates that other substances like mercaptobenzothiazole can also elicit allergic responses. Patch testing emerges as a crucial diagnostic tool for identifying allergens, aiding in the identification of specific substances responsible for reactions. Therefore, broadening the range of patch testing to encompass additional potential rubber allergens is essential for pinpointing the underlying cause of allergic reactions. While avoiding contact with leather or rubber products may offer some relief, it does not always provide immediate symptom alleviation. Certain medications, particularly azole antifungals, can also induce ACD, commonly found not only in medical products but also in cosmetics like nail polish. Additionally, sensitization to biocides is worth noting, as they are present not only in shoes but also in textile items, furniture, and various household products. Existing studies examining allergens triggering ACD of the feet have several limitations.

Therefore, future research endeavours should prioritise longer follow-up periods and systematic data collection to gain deeper insights into the clinical repercussions associated with discontinuing the use of footwear containing relevant allergens.