Keywords

Introduction

Chemicals That Trigger Nonimmunological and Immunological Contact Urticaria

Immediate skin contact reactions are characterized by the instantaneous development of itchy flares, wheals, and/or dermatitis on the skin following external contact with a substance. These reactions usually manifest as contact urticaria (CoU), contact urticaria syndrome (CUS), or protein contact dermatitis (PCD) [1]. CoU generally appears within approximately 30 min and clears completely within hours, without residual signs of irritation. An ever-expanding list of causes has been reported, of which most are proteins (molecular weight 10,000 to several hundred thousand daltons), but also chemical compounds of low molecular weight (LMW) (<1,000 Da).

LMW chemical agents can be responsible for immediate contact skin symptoms in the different categories of CoU. According to the underlying mechanisms involved, CoU is classified as nonimmunological or immunological. A third category exists for reactions with mixed features or undetermined pathomechanisms [2]. This third category is much less common and is not covered herein.

Nonimmunological CoU (NICoU) is the most common form of the disease. NICoU occurs without prior exposure to an eliciting substance and without previous sensitization. Chemicals inducing NICoU are frequently encountered in our environment as biocides or preservatives, fragrances, and flavorings in cosmetic products, toiletries, drugs, topical medicaments, and foodstuffs [3, 4], although other miscellaneous chemicals and metals can also be responsible for these reactions. Most individuals react to these substances with local erythema and/or edema within 45 min after application, albeit with widely varying intensities of skin reaction [5]. The pathogenesis is not clearly understood but seems to involve the release of vasogenic mediators without involvement of immunological processes (Fig. 8.1a). Because of the lack of response to antihistamines and positive responses to acetylsalicylic acid and nonsteroidal anti-inflammatory drugs, it has been proposed that the physiopathology involves prostaglandin release from the epidermis rather than histamine release from mast cells [6, 7].

Fig. 8.1
figure 1

General mechanisms of nonimmunological contact urticaria (NICoU) (a) and immunological contact urticaria (ICoU) (b)

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Conversely, immunological CoU (ICoU) is an immediate type I hypersensitivity reaction, mediated by allergen-specific immunoglobulin (Ig) E in previously sensitized individuals [2]. Thus, ICoU requires sensitization and appears after repeated contacts with the trigger substance. It is more frequent in people with previous atopic symptoms. Histamine release is the major mechanism of action observed. This mechanism includes allergen penetration through the epidermis and binding to IgE at the surface of mast cells and basophiles, causing degranulation and release of histamine and other vasoactive substances such as prostaglandins , leukotrienes , and kinins [8] (Fig. 8.1b). In rare cases, IgG or IgM has been also incriminated. The consequences are potentially more serious than for NICoU, as reactions may not remain localized to the area of contact, and generalized urticaria, or even involvement of organs such as the respiratory and gastrointestinal tract, may follow and lead to anaphylactic shock.

A large number of causes have been documented as producing ICoU. The most common agents inducing ICoU are food proteins (animal or vegetal), animal proteins, and natural rubber latex, and these have been largely reviewed [9, 10]. However, LMW chemicals including drugs, biocides, and preservatives, and metals or industrial compounds can also produce ICoU. These chemicals are very often present in drugs, cosmetics [11], and industrial preparations. Extensive lists of proteins and chemicals are reported as causing ICoU, but only some of these being reported as occupational [2, 10, 12]. Most publications about CoU concern case reports or small series, and epidemiological studies are scarce. However, some data indicate that ICoU is not rare, although frequently underestimated. The ultimate evidence corroborating that a compound is responsible for ICoU is the measurement of specific IgE in the serum of the patient by the radioallergosorbent test (RAST) whenever possible. The patient’s serum is incubated with the agent bound to a solid phase, and the amount of specific IgE recognizing and binding to the agent is quantified with radiolabeled anti-IgE [13]. Determination of specific IgE by RAST will confirm type I hypersensitivity, but its ordinary detection is restricted to some compounds, particularly when they are nonproteinaceous.

Table 8.1 summarizes the most often reported LMW chemical agents producing immediate nonimmunological and immunological skin reactions [1, 12]. The most important LMW chemicals responsible for NICoU and ICoU are described in this chapter and classified into the major families of products, fragrances and cosmetic ingredients, biocides and preservatives and drugs, together with other categories.

Table 8.1 Chemical compounds reported as triggering nonimmunological contact urticaria (NICoU) and immunological contact urticaria (ICoU) skin reactions [1, 12]
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Fragrances and Cosmetics Ingredients

NICoU reactions to fragrances and to cosmetics ingredients are well known [14]. They have been often reported to some of the constituents of the Fragrance Mix I (FMI) and to balsam of Peru [15].

The FMI, developed in the late 1970s, and the Fragrance Mix II (FMII) developed in 2005, are the most valuable screening tools for the detection of delayed hypersensitivity to fragrances [16, 17]. Indeed, the components of FMI (α-amyl cinnamaldehyde , cinnamaldehyde , cinnamic alcohol , eugenol , isoeugenol , geraniol , hydroxycitronellal , and the natural extract oak moss) and FMII (hydroxyisohexyl 3-cyclohexene carboxaldehyde , citral, α-hexyl-cinnamaldehyde , citronellol , farnesol , and coumarin ) are the most common skin sensitizers identified as responsible for delayed-type allergic contact dermatitis to fragrances. Consequently, clinical relevance to these chemicals must be carefully examined because individuals may develop simple NICoU or CoU associated with delayed hypersensitivity. Chemical structures of FMI and FMII ingredients are shown in Fig. 8.2.

Fig. 8.2
figure 2

Chemical structures of the components of fragrance mix (FMI) and FMII

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Safford et al. conducted a study on 20 patients positive to the FMI in 48 h and classified the FMI ingredients according to the decreasing ability to induce CoU as follows: cinnamaldehyde , cinnamic alcohol , isoeugenol , hydroxycitronellal , and geraniol [18]. Cinnamaldehyde and cinnamic alcohol were the strongest urticaria inducers for nonallergic patients.

CoU from cinnamaldehyde has been reported by several authors [3], leading even to anaphylaxis [19]. Among the many components of balsam of Peru, cinnamaldehyde is described as well as the strongest agent inducing NICoU, followed by cinnamic acid, benzoic acid, and benzaldehyde [20].

Balsam of Peru is derived from the sap of the tree Myroxylon pereirae (MP) . It is composed of 250 constituents, of which 189 are of known chemical structure [21]. MP has been used in topical medicaments for its antibacterial properties, and in many countries it has been abandoned for that use because of its sensitizing potential. However, it may still occur in natural and herbal products, being used as a flavor or perfume ingredient. Extracts and distillates of MP are still used in perfumes [22]. It is thus possible that these can cause allergic reactions in MP-sensitized individuals.

Cinnamaldehyde is the main component of cassia oil (~90%) and cinnamon bark oil (~75%). It is also the main component of artificial cinnamon oil. Smaller quantities are found in many other essential oils. In nature, the trans-isomer is predominant. It is a yellowish liquid with a characteristic spicy odor, strongly reminiscent of cinnamon. Being an α,β-unsaturated aldehyde , it undergoes many reactions, such as hydrogenation to cinnamic alcohol . Its oxidation occurs readily on exposure to air yielding cinnamic acid. Cinnamic acid has been also used in perfumery, and as a flavoring ingredient in pharmaceutical preparations and in food products. Forsbeck and Skog found CoU from cinnamic acid 5% in petrolatum in three of five patients with immediate skin reactions to balsam of Peru [20].

Geraniol is an olefinic terpene mainly present in palmarosa, geranium, and rose oils. It is a colorless liquid, with a flowery rose-like odor. A case of a patient with CoU from geraniol has been reported to be caused by immunological mechanisms. The patient developed widespread urticaria and flare reactions on the face and neck at the 72-h reading of the patch test [23]. Oxidation processes produce the aldehydes geranial and neral, and in addition, hydroperoxides. Autoxidation greatly influences the sensitizing effect of geraniol , becoming a potent allergen [24].

Eugenol and isoeugenol are phenylpropene compounds. Eugenol is the main component of several essential oils; clove leaf oil and cinnamon leaf oil may contain more than 90%. Eugenol occurs in small amounts in many other essential oils. It is a colorless to slightly yellow liquid with a spicy, clove odor. It is widely used in dental practice to relieve pain arising from various sources, such as pulpitis and dentinal hypersensitivity. It is also used in toothache drops, mouthwash, and antiseptics. Eugenol in dental preparations has been reported to cause CoU, gingivitis, stomatitis venenata, and allergic hand eczema in dental personnel [25, 26]. It is considered to be a less common sensitizer than isoeugenol , cinnamaldehyde , or cinnamic alcohol . Isoeugenol occurs in many essential oils, mostly with eugenol , but not as the main component. Commercial isoeugenol is a mixture of cis- and trans-isomers, in which the thermodynamically more stable trans-isomer dominates. It is a yellowish, viscous liquid with a fine clove odor. Isoeugenol is a strong allergen [27]; it caused contact allergy in 1.7% of 2261 consecutive tested eczema patients in an European multicenter study [28]. It is found in many cosmetic products and may be present in relative highly concentrations.

Coumarin is an aromatic lactone naturally occurring in Tonka beans and other plants, determining, for example, the odor of woodruff. It is widely used in fine fragrances for spicy green notes. Considered for long time a sensitizer, impurities have been blamed for the sensitizing effect [29].

Fragrances and cosmetic products contain also ingredients other than odorant compounds that have been described to produce NICoU and ICoU. Among these are benzophenone, polysorbates, sorbitan sesquioleate, propylene glycol, and wool alcohols.

Benzophenones are photo-screen agents used in sunscreens and cosmetics, such as anti-aging creams, hair sprays and shampoos, and paints and plastics. Benzophenones have been documented to cause numerous adverse cutaneous reactions, including contact and photo-contact dermatitis, contact and photo-contact urticaria, and anaphylaxis. In recent years these chemicals became particularly well known for their ability to provoke allergy and photo-allergy [30]; they were named the American Contact Dermatitis Society’s Allergen of the Year for 2014. CUS at stage IV has been reported in the case of people applying sunscreen and self-tanning products, benzophenone-3 being the major cause [31]. Benzophenone-3 , also named oxybenzone , is often incorporated into sunscreen formulations to offer enhanced UVA protection because its absorption spectrum extends to less than 350 nm. Cases of anaphylaxis from topical application of benzophenone-3 have been published. The cases resulted in a generalized wheal and flare reactions and syncope after widespread application of a sunscreen or sunless tanning product with this filter. CoU developed after more limited exposure [31, 32].

Polysorbates are a class of emulsifiers used in some pharmaceuticals and food preparations, but they are also often used in cosmetics to solubilize essential oils into water-based products. Oily liquids, they derive from esterification of ethoxylated sorbitan with fatty acids. The nomenclature used for polysorbates is characteristic. For example, polysorbate 80, also called polyoxyethylene 20 sorbitan monooleate. The number 20 following the “polyoxyethylene” part refers to the total number of oxyethylene –(CH2CH2O)– groups found in the molecule. The number following the “polysorbate” part is related to the type of fatty acid associated with the polyoxyethylene sorbitan part of the molecule. Monolaurate is indicated by 20, monopalmitate by 40, monostearate by 60, and monooleate by 80. Already in the 1970s, Maibach and Conant reported an urticaria case to polysorbate 60 in a male patient with redness on the forehead when applying hydrocortisone 1% cream [33]. The chemical responsible in the cream was determined to be polysorbate 60, an emulsifying agent mixture of stearate esters of sorbitol and sorbitol anhydrides, consisting mainly on the monoester. It is also known as Tween 60 or polyoxyethylene 20 sorbitan monostearate. Since then, several cases have been reported. More recently, a biologically induced urticaria from polysorbate 80 in a psoriasis treatment in Spain has been reported [34]. Sorbitan sesquioleate , a sorbitol-based emulsifier, is actually added to the FMI ingredients to constitute the mixture. Sorbitol-based emulsifiers are commonly used in topical corticosteroids, topical antibiotics, and antifungals, moisturizing creams, and lotions. Contact dermatitis from sorbitol derivatives appears to be increasingly prevalent [35]. This trend goes hand-in-hand with the ICoU to sorbitan sesquioleate reported in a corticosteroid ointment [36].

Propylene glycol , also called propane-1,2-diol, is a viscous colorless alcohol (chemically classed as a diol), nearly odorless but possessing a weak sweet taste. It is mainly used for the production of unsaturated polyester resins. It is also used as a humectant food additive (E1520), a hygroscopic compound used to keep products moist, as a moisturizer in cosmetics, food, toothpaste, mouthwash, and tobacco products, as the main ingredient in deodorant sticks, as an antifreeze liquid, and as a solvent in many pharmaceuticals and topical formulations. Propylene glycol is one of the major ingredients of the cartridges used in electronic cigarettes where it is aerosolized in the atomizer. It has been associated with irritant and allergic contact dermatitis as well as CoU in humans. These sensitization effects can be manifested at propylene glycol concentrations as low as 2% [37]. Still, the Cosmetic Ingredient Review Panel found that propylene glycol is safe if used in cosmetic products at concentrations not exceeding 50% [38]. The work of Maibach and Conant cited here describing an urticaria case to polysorbate 60 concerned a hydrocortisone cream containing propylene glycol [33]. CoU could not be concluded in experiments with open propylene glycol application. Only one report describes NICoU after topical application [39, 40].

Wool alcohols are the principal component of lanolin, a natural product obtained from the fleece of sheep. Sebum is extracted from the wool, cleaned, and refined to produce anhydrous lanolin, which consists of wool alcohols, fatty alcohols, and fatty acids. Currently, wool alcohols are considered the main sensitizers in lanolin. Wool alcohols, wool fat, anhydrous lanolin, lanolin alcohol, wool wax, and wool grease are just some of the terms used interchangeably with lanolin. Lanolin is a good emulsifier, meaning that it binds well with water and is particularly useful in the manufacture of pharmaceutical and cosmetic formulations. Wool alcohols are found in many pharmaceutical preparations, cosmetics, and toiletries, and also have some industrial uses. The general incidence of lanolin allergy in consecutively tested eczema patients is about 2% to 3% [41].

Biocides and Preservatives

Preservatives are added to water-containing products (e.g., cosmetics) to inhibit the growth of nonpathogenic and pathogenic microorganisms that may cause degradation of the product or be harmful to the consumer. After fragrances, they are the most important cause of allergic contact dermatitis, being this very well documented [42]. CoU is less common. The literature consists essentially of case reports, and studies on actual incidence and prevalence are lacking.

Chemicals with preservative properties that are worth describing in the CoU context are discussed here. It is not always clear, depending on the underlying mechanisms involved, if the reactions are involving the immune system. Chemical structures are shown in Fig. 8.3.

Fig. 8.3
figure 3

Chemical structures of the most important preservatives and biocides

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Sorbic acid , or 2,4-hexadienoic acid , is a colorless solid slightly soluble in water. It is an antimicrobial agent often used as a preservative in food and drinks (E200). In general, the salts (sodium, potassium, and calcium sorbates, E201–E203) are preferred over the acid form because they are more soluble in water, but the active form is the acid. CoU from sorbic acid is thought to be rare, but a few reports can be found in the literature. Some authors have described that creams and shampoos containing sorbic acid caused erythema, slight itching, and sometimes edema [43,44,45]. As is sorbic acid, benzoic acid is a natural preservative, having antibacterial and antifungal properties. It is well recognized to cause NICoU with concentration-dependent reactions [46]. Present also in balsam of Peru, it induced CoU at 5% in patients with immediate contact reactions to balsam of Peru [20]. It is commonly used also as a preservative in acidic food products. Thus, cases have been reported in food additives, and benzoic and sorbic acids elicit NICoU at concentrations in use in salad dressings or other food products [45, 47].

Formaldehyde (HCHO) and its releasers constitute an important class of preservatives in consumer goods. HCHO is the simplest of the aldehydes category of compounds. It is a frequent and potent sensitizer and a strong ubiquitous allergen, including from non-cosmetics sources of contact. Its bactericidal and fungicidal properties confer it a place of choice for preservation of cosmetics, but its use has been reduced because of the bad press it has as an irritant, sensitizer, and carcinogen [48]. Exposure to HCHO in the EU is thus subjected to restrictions. Free HCHO may be used as a preservative in all cosmetic products (maximum authorized concentration 0.2%, but only 0.1% in products for oral hygiene) except aerosol cosmetics. EU regulation 1223/2009 permits the use in nail hardeners up to a maximum concentration of 5%. Annex VI of the Cosmetics Directive 76/768 EC further stipulates that all finished products containing HCHO or substances that release it must be labeled with the warning “contains formaldehyde” wherein the concentration of free HCHO in the finished product exceeds 0.05% [49]. On January 1, 2016, the EU officially adopted its reclassification under the CLP (Classification, Labelling and Packaging) Regulations EC 1272/2008, as a Class 1B carcinogen and Class 2 mutagen. For its continued use in cosmetics, the criteria specified for CMR 1A and 1B must be met, including the Scientific Committee on Consumer Safety (SCCS) to declare it safe for use in cosmetic products. The SCCS has published recently an opinion that states that nail hardeners with a maximum concentration of 2.2% free HCHO can be used. Even if it is a strong sensitizer, reported immediate reactions to HCHO are mainly classified as NICoU because they seem not to be mediated by IgE [49]. However, there is still no consensus in the reports that have appeared as to whether the mechanism is immunological or nonimmunological [50]. Most of the literature on generalized urticaria, respiratory compromise, and anaphylaxis concerns exposure to HCHO-containing disinfectants used for root canals and other dental procedures [51, 52]. There have been few reports on allergy to HCHO associated with IgE, and single cases of HCHO-specific IgE-mediated urticaria exist in the literature [51,52,53]. Thus, probably HCHO should be classified as a substance that shows mixed features of NICoU and ICoU, as the mechanism remains unclear.

As an alternative to the use of HCHO, chemical compounds that slowly release it in the presence of water and under usage conditions, the so-called formaldehyde-releasers, are commonly employed as preservatives in cosmetics (water-based preparations) instead of free HCHO. Examples are bronopol and imidazolidinyl urea . Unfortunately, many formaldehyde releasers used in cosmetics are also skin sensitizers, as caused by released HCHO but also by reactive intermediates other than HCHO that could be involved in the formation of the hapten–protein antigenic complex, a key step of the sensitization process, and thus explaining their sensitizing potential per se [54].

Methylisothiazolinone (MI) and methylchloroisothiazolinone (MCI) are the active ingredients of the biocide Kathon CG (MI/MCI 1:3 combination), used since the 1980s and one of the most common sources of allergic contact dermatitis caused by preservatives [55, 56]. Following the introduction in the EU of a 15 ppm use limit in cosmetics, contact allergy to MI/MCI significantly decreased to a prevalence rate of about 2% after the 1990s. The sensitizing potential of the mixture was mostly attributed to the chlorinated derivative MCI, shown to be the stronger sensitizer, whereas the nonchlorinated MI was reported to be a much weaker allergen. Thus, in the early 2000s, MI alone started to be used as preservative in industrial products and in 2005 in cosmetics, but at higher concentrations than in the MI/MCI mixture because of its lower biocide potential. As a consequence, over recent years there has been an alarming increase in the prevalence of allergic contact dermatitis to MI [57, 58]. Occupational cases of contact dermatitis to MI first were reported from paints [59], followed by nonoccupational cases essentially seen from wet wipes for hygiene and cosmetics [60]. Severe cases of airborne and systemic dermatitis have appeared recently from exposure to MI present particularly in water-based wall paints [61]. At the same time, MI/MCI contact allergy has increased significantly during the past few years [62]. It has been proposed that the rise in MI/MCI contact allergy was likely linked to the higher consumer exposure to MI, and most probably resulted from a previous sensitization of individuals to MI. Because the occurrence of consumer products containing only MI is only in the recent few years, questions were raised about the MI and MCI cross-reaction pattern. Studies of chemical reactivity in situ in a reconstructed human epidermis model showed that reaction mechanisms for MI and MCI were different, making it difficult to explain cross-reactivity [63]. CoU cases caused by isothiazolinones are rare and are generally classified as NICoU [64].

CoU to other biocides such as benzyl alcohol , 2- phenoxyethanol , and polyethylene glycols , used as preservatives in a wide number of cosmetics and topical preparations, has also been reported [65,66,67,68]. CoU from alcohols was reviewed in the 1990s, with cases classified as nonimmunological and some as immunological based on open skin tests [69].

Other important biocides have been correlated to ICoU such as parabens, and many antiseptics such as mercurochrome, chloramine, chlorhexidine, and chlorocresol.

Parabens (methyl, ethyl, propyl, butyl) are a series of parahydroxybenzoates or esters of parahydroxybenzoic acid (also known as 4-hydroxybenzoic acid). Parabens are effective preservatives in many types of formulas, especially in cosmetic products. They are also used as food additives. In individuals with normal skin, parabens are, for the most part, nonirritating and nonsensitizing. Routine testing in the European standard series yields low prevalence rates of sensitization [70, 71]. At the usual concentration of 0.1–0.3% in cosmetics, parabens rarely cause adverse reactions. They have been reported to cause localized CoU when applied to the skin, and an IgE immune-mediated mechanism is suspected.

Mercurochrome is the trade name of merbromin, an organomercuric disodium salt and a fluorescein, used as a topical antiseptic. Because mercury is highly toxic, it is no longer sold in the US from 1998 and in France from 2006. Mercurial compounds are known as causing allergic contact dermatitis, and immediate hypersensitivity is rarely induced. A few cases have been reported in which immediate hypersensitivity to mercuric fluorescein compounds has been proved by skin test and histamine liberation [72, 73].

Chloramines are derivatives of ammonia by substitution of one, two, or three hydrogen atoms with chlorine atoms. Monochloramine (commonly called chloramine ) is an inorganic compound with the formula NH2Cl. Chloramine is commonly used as a sterilizer, disinfectant, and chemical reagent. It has been described as an occupational hazard for pharmaceutical workers, nurses, and cleaners. Goossens et al. reported the first case of immediate positive epicutaneous tests to chloramine powder solutions used by a nurse [74]. All skin tests performed on the patient were suspicious of an immediate-type reaction. The immunological nature of the clinical manifestations was investigated by RAST on serum of the patient. High levels of IgE antibodies to chloramine were found, those previously bound to human serum albumin (HSA) . The clinical manifestation on the patient was confirmed by radioimmunoassay and classified as a stage 3 CUS. Chloramine is often confused with chloramine-T as both are employed as sterilizer, antiseptic, and disinfectant agents. However, they are two different chemicals. Chloramine-T is a N-chlorinated deprotonated sulfonamide, white powder, in contrast to chloramine, a simple monochlorinated amine that is a colorless liquid usually handled as a diluted aqueous solution. Allergic asthma caused by chloramine-T is well known and the reactions are IgE mediated. Kramps et al. were able to demonstrate the presence of specific IgE antibodies in the serum of asthmatic-chloramine T-allergic patients [75]. However, skin symptoms of IgE-dependent CoU have also been reported in the case of a hospital bath attendant in Finland. The performed RAST to chloramine-T showed specific IgE antibodies, with values being defined as positive [76].

Chlorhexidine is a synthetic chlorophenyl-bis-biguanide compound, containing two chloroguanide chains linked by a hexamethylene chain. It is a strong base and a di-cation at physiological pH. Usually insoluble in water, it needs to be formulated with gluconic or acetic acid to form water-soluble digluconate or diacetate esters. Chlorhexidine , especially as digluconate ester, is widely used in many dental topical applications (toothpaste, dental gel, mouthwash solutions) as it binds oral mucosa, inhibiting dental plaque formation. It is also used as disinfectant and antiseptic of minor cuts and wounds. It can cause both type I immediate allergy and type IV delayed allergy. Despite its common usage, the sensitization rate seems low, but this is certainly underestimated. It may induce immediate-type sensitivity reactions either by topical application or by insertion of coated catheters in surgical fields. The mechanism suspected is an IgE-mediated pathomechanism in sensitized individuals [77]. Many healthcare workers are exposed to hand washes containing chlorhexidine. In the United Kingdom, four cases of occupational IgE-mediated allergy to chlorhexidine were identified, the diagnosis being made on an appropriate clinical history with positive serum-specific IgE to chlorhexidine and/or positive skin prick testing [78]. The main aspects of chlorhexidine toxicity have been reviewed elsewhere [79].

Chlorocresol (p-chlorocresol) is a chlorinated phenol used as an antiseptic and preservative. It forms colorless crystals at room temperature and is slightly soluble in water. For medical use it is dissolved in alcohol combined with other phenols. Several case reports involve chlorocresol as a cause of CoU, but whether this occurs through an immunological mechanism is not clear [80, 81].

Drugs

Drugs , small reactive chemicals, can induce both NICoU and ICoU within minutes to 1 h after exposure. These drugs include mainly antibiotics, because of direct contact of nurses and healthcare personnel during their preparation, or employees during their production in the pharmaceutical industry. Penicillins and cephalosporins are the most incriminated (Fig. 8.4). All these seem to have an immunological physiopathology and are discussed following. For most of the other drugs reported, observed immediate contact reactions cannot be definitely classified as nonimmunological or immunological. Often, skin tests do not allow distinguishing between an IgE-dependent reaction and a nonspecific histamine release, and research of specific IgE by using the radioallergosorbent test (RAST) is only available for some drugs. One example is given by lidocaine.

Fig. 8.4
figure 4

Chemical structures of drugs involved in immediate skin contact reactions

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Lidocaine is a common amino amide-type local anesthetic applied topically. It is also an antiarrhythmic drug applied intravenously. An immediate positive patch test and prick test demonstrated its involvement in the simultaneous presence of CoU and allergic contact dermatitis in the same patient [82, 83].

Ketoprofen ((RS)-2-(3-benzoylphenyl)-propionic acid), an important cause of photo-contact dermatitis, has also been described as responsible for CoU [84]. It is one of the propionic acid class of nonsteroidal antiinflammatory drugs (NSAID) with analgesic effects.

Other immediate reactions have been observed in personnel of psychiatry services during the manipulation of phenothiazines , antipsychotic drugs related to the thiazine class of heterocyclic compounds, such as chlorpromazine and promethazine . The latter is a first-generation antihistamine of the phenothiazine family. It is a chiral compound and is found as a mixture of enantiomers. Among the many professional areas where case reports of CoU have been recorded, workers in the pharmaceutical and chemical industries are of considerable concern, as they are in contact with highly reactive substances (some listed in Table 8.1) used for synthesis, for example, that have been also described as inducers of immediate skin reactions. The pathogenesis of NICoU to all these chemicals is not clearly defined. Different urticariogens may act by different mechanisms. For example, dimethyl sulfoxide can both damage blood vessels and cause mast cell degranulation. However, antihistamines do not inhibit reactions to dimethyl sulfoxide and other NICoU triggering agents, although ethylsalicylic acid and nonsteroidal antiinflammatory drugs do, both orally and topically, suggesting a role for prostaglandins [7].

However, the main drugs responsible for occupational CoU are antibiotics and, particularly, penicillin, ampicillin, amoxicillin, and cephalosporins. Antibiotics are very often associated with ICoU [85].

The term penicillin is often used to refer to benzylpenicillin (penicillin G, found in 1928), procaine benzylpenicillin, benzathine benzylpenicillin, and phenoxymethylpenicillin. The core of the molecule has the formula R-C9H11N2O4S, where R is a variable side chain that differentiates the penicillins from one another. The key structural feature is the four-membered β-lactam ring, essential for antibacterial activity. Thus, all penicillin antibiotics contain a common nucleus (6-aminopenicillanic acid ) composed of a β-lactam ring fused with a thiazolidine ring, this complex connected to a side chain. An intact β-lactam ring is necessary for bactericidal activity, and the side chain determines the spectrum of antibacterial activity, the susceptibility to destruction when exposed to acids and β-lactamases, and pharmacokinetics properties. Allergic reactions are estimated to occur in approximately 2% of patients treated with penicillin. Severe reactions to penicillin such as anaphylaxis can occur and are potentially life threatening. Penicillin is a hapten and becomes immunogenic only when it binds to a protein. The β-lactam ring covalently binds to lysine residues of proteins and forms the penicilloyl group, known as the “major determinant” because it is the major penicillin metabolic product. Penicillin metabolites also form disulfide bonds with sulfhydryl groups of cysteine, producing the “minor determinants,” so called because they are formed in smaller quantities. Thus, immediate allergic reactions to penicillin are mediated through IgE antibodies against either the major or minor determinants or both. Based on this, penicillin skin testing techniques have been developed demonstrating the presence or absence of specific IgE antibodies against major and minor determinants. The use of benzylpenicilloyl-poly-l-lysine can test IgE antibodies against major determinants. Histamine is used as a positive control, and saline is used as a negative control. Skin detection of serum IgE specific for major penicillin determinants has a high positive predictive value but fails to identify patients with penicillin allergy. It has been suggested that, ideally, skin testing to major and minor penicillin determinants would improve diagnosis. Methods of preparation of reagents for minor determinants have been published, and penicillin G has been used as a partial source of minor determinants. Alternatives to benzylpenicilloyl-poly-l-lysine and minor determinant mixtures are commercially available for skin testing [86]. Penicillin skin testing is believed to be safe if done properly; although severe reactions such as anaphylaxis have been reported, these were produced because of violation of the test protocols such as doing intracutaneous testing without first doing prick testing.

After penicillins, cephalosporins are the most important β-lactams inducing IgE-mediated reactions [87]. Allergy has been reported with use of a specific cephalosporin, as a cross-reaction between different cephalosporins or as a cross-reaction to other β-lactam antibiotics. Unlike determinants derived from penicillins, cephalosporin allergenic determinants have not been well identified, and thus standardized diagnostic skin testing is not available. Nevertheless, skin testing with diluted solutions of cephalosporins can be valuable in confirming IgE-mediated hypersensitivity reactions [88, 89].

Pyrazolone is a five-membered ring lactam. It is a derivative of pyrazole that has a keto (=O) group. There are three isomers: 3-, 4-, and 5-pyrazolone. Pyrazolones are NSAIDs and the most frequent drugs inducing selective reactions thought to be mediated by specific IgE. Sensitivity of diagnostic tests is poor, probably because knowledge of the structures involved is incomplete. Research is today ongoing on pyrazolone metabolites and its relevance to hypersensitivity reactions [90].

Steroids are organic compounds with four rings arranged in a specific molecular configuration. The core structure is composed of 17 carbon atoms, bonded in four fused rings: three cyclohexane rings (A, B, C) and one cyclopentane ring (D). Steroids vary by the functional group attached to this core and by the oxidation state of the rings. Corticosteroids (i.e., cortisol or hydrocortisone) are potent antiinflammatory and immunomodulator agents used in treatment of various inflammatory diseases, including allergic diseases. They can in some cases induce immediate or delayed hypersensitivity reactions. Topical corticosteroids are well-known contact sensitizers. However, diagnosing an allergic reaction is still a challenge for clinicians. Although knowledge of delayed hypersensitivity as a secondary effect of topical use is improving, little is known about immediate reactions to systemic corticosteroids [91]. Cases of urticaria from hydrocortisone have been reported, in atopic patients after hydrocortisone injection or infusion, and in patients treated with hydrocortisone sodium succinate. All cases are thought to be IgE mediated [92, 93].

Other Chemicals

Chemicals not belonging to the families of compounds already described but necessary to mention are shown in Fig. 8.5.

Fig. 8.5
figure 5

Chemical structures of other low molecular weight (LMW ) compounds involved in immediate skin contact reactions

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Epoxy resins are LMW pre-polymers, which normally contain at least two epoxide groups. The epoxide group is also known as the glycidyl or oxirane group. Cyclic acid anhydrides are synthetic highly reactive LMW compounds widely used as curing agents for epoxy resins and in the production of polyester resins. Commonly used anhydrides are phthalic , tetrahydrophthalic , methyl tetrahydrophthalic , hexahydrophthalic , methyl hexahydrophthalic , and maleic and trimellitic anhydrides. Cyclic acid anhydrides often cause allergic respiratory diseases, and in the literature only single case reports of CoU of a few patients were found. However, occupational CoU has been described by a Finnish study as workers may be exposed in powder or liquid form during manufacturing processes [94]. Data are presented for 21 subjects who had been exposed to organic acid anhydrides and examined during the period 1990–2006. The majority of the patients had been exposed to an epoxy resin containing methyl hexahydrophthalic anhydride. Specific IgE results were in line with the prick tests, and the large reaction was seen for the acid anhydride to which the patient had been exposed. Phthalic anhydride IgE was positive in 19 of 20 patients.

Another important constituent of epoxy resins that has been incriminated as producing immediate reactions is bisphenol A. It is an organic synthetic compound belonging to the diphenylmethane derivatives group and bisphenols, with two hydroxyphenyl groups. It is a colorless solid soluble in organic solvents, but poorly soluble in water. Specific IgE cases have been reported [95, 96].

Acrylates are the salts, esters, and conjugated bases of acrylic acid and its derivatives. They are common monomers (i.e., methyl methacrylate) in polymer plastics. Acrylates easily form acrylate polymers because of the high reactivity of the constituting double bonds. Monomers such as 2-ethylhexyl acrylate, acrylic acid, cyanoacrylates, and methyl methacrylate have been reported to cause immediate skin reactions [97].

Aromatic amines are a broad group of chemicals used in a variety of applications, such as hair dyes, ink for printers, photographic products, and the paper and textile industries. According to their large spectrum of application, skin exposure of the general population to these compounds is high. Safety aspects and toxicity studies have shown that para-amino aromatic compounds and their derivatives are strong skin sensitizers, generally related to dyeing products. One of the best known is para-phenylenediamine (PPD) . PPD is one of the most common primary intermediates of oxidative hair dyes and is usually reported as the main sensitizer in hair dye dermatitis. PPD is therefore included in the European Standard Series for diagnostic patch testing of eczema patients and is generally regarded as the screening agent for contact allergy to para-amino aromatic compounds but also to azo-aromatic compounds used in textile dyes [98,99,100]. It can also induce immediate-type reactions, going from local urticaria to fatal systemic reactions and anaphylactic shock [101,102,103].

Other chemical compounds of LMW reported as inducing ICoU are aliphatic polyamides, methylethyl ketone, widely used as a solvent in plastic manufacturing, and monoamylamine , a vehicle ingredient of topical medicaments. Also reported is benzonitrile , a useful solvent and versatile precursor to many derivatives, carbamate-constituting groups of polyurethanes and diethyl fumarate.

Finally, metals and metallic salts can also cause occupational CoU . Aluminum, chromium, cobalt, iridium salts, nickel, platinum salts, and rhodium have been reported. Among these, platinum salts are important allergens in the catalyst industry, and clinical manifestations may involve both the respiratory system and the skin [104,105,106,107,108,109].