REACTIONS IN THE SKIN

III. REACTIONS IN THE SKIN

The most important skin symptoms are listed in Table 4. In addition to these, exanthe- matous rashes mimicking virus exanthemas are often suspected to be caused by foods and food additives. Such reactions will not be discussed in detail because they can hardly be distinguished from exanthemas due to several other causes.

A. Urticaria and Angioneurotic Edema

Chronic and recurrent urticaria from ingested food additives has gained more attention than other possible side effects from these chemicals ( Table 5 ).

The provocative effect of aspirin in urticaria was realized in the late 1950s (Calnan, 1957; Warin, 1960). It was soon found that this phenomenon was not restricted to aspirin but that other salicylates were also capable of producing exacerbation of urticaria (Moore- Robinson and Warin, 1967). In various investigations on chronic and recurrent urticaria,

Table 4 Symptoms and Signs in the Skin Caused by Food Additives Symptoms and signs

Mechanism(s) underlying the reaction Acute urticaria

Type I allergy (IgE mediated)

Exacerbation of chronic and Type III allergy (immunocomplex disease) recurrent urticaria Angioedema

Intolerance

Contact urticaria Immunologic (ICU)

Type I allergy (IgE mediated)

Nonimmunologic (NICU)

Mechanism(s) unknown

Purpura Thormbocytopenia (type II reaction); allergic vasculities (type III reaction); unknown (nonthrombocytopenic purpura) Fixed and lichenoid

Type IV allergy?

eruptions Primary irritant dermatitis

Irritancy

Allergic contact dermatitis

Contact allergy (type IV)

Photodermatitis

Photoallergy or phototoxicity

Orofacial granulomatosis

Unknown

Table 5 Food Additives Causing or Aggravating Urticaria and Angioneurotic Edema

Benzoic acid, benzoates Sorbic acid, sorbates Azo dyes (tartrazine and others) Canthaxanthine, β-carotene Annatto Quinoline yellow Butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) Nitrites and nitrates Spices (e.g., cinnamon, clove, white pepper) Ethanol

the number of aspirin-sensitive patients has been on average 20% (Juhlin, 1986). Natural salicylates are unlikely to cause any trouble even in aspirin-sensitive people.

Swain et al. (1985) measured the salicylate content of our daily foodstuffs, the high- est concentrations being 218 mg/100 g in curry powder, 203 mg/100 g in paprika hot powder, and 183 mg/100 g in dry thyme leaves. The authors estimated our daily intake of natural salicylates varies between 10 mg and 200 mg in western diets. The amount may be high enough to produce symptoms in some highly sensitive people.

Azo dyes, especially tartrazine, new coccine, and Sunset Yellow, have been known to be precipitating factors in chronic urticaria since 1959 (Lockey, 1959; Juhlin et al., 1972; Desmond and Trautlein, 1981; Freedman, 1977b). Because of frequent harmful reactions, both urticaria and asthma, azo dyes have been removed from most foodstuffs and medicines in many western countries, and U.S. regulations require specific labeling of FD&C Yellow No. 5 and Yellow No. 6.

In alcoholic beverages there are several agents that can cause urticaria and angioneu- rotic edema. Salicylates and flavoring substances (Feingold, 1968; Lockey, 1971) are re- sponsible for such reactions more often than ethanol itself. Clayton and Busse (1980) reported a case of anaphylaxis from red and white wine, but the causative chemical re- mained unknown. A peroral challenge with 20 g of pure ethanol produced urticaria in a female patient who also developed symptoms from acetic acid but not from acetaldehyde or from flavored soft drinks (Karvonen and Hannuksela, 1976). Reports of two other cases of ethanol urticaria were verified with challenge tests (Hicks, 1968; Ormerod and Holt, 1983), and two cases of probable ethanol urticaria have been published (Strean, 1937; Biro and Pecache, 1969). The mechanism of ethanol urticaria is unclear. In the case of Ormerod and Holt (1983), neither H1 nor H1 ⫹ H2 antihistamines prevented whealing, but indomethacin, 25 mg/day; Naloxone infusion, 0.4 mg/min; and sodium chromogly- cate, 100 mg/day, did. It thus seems that the mechanism might well not be type I allergy.

In recent years, butylated hydroxytoluene (BHT), butylated hydroxyanisole, sorbic acid, canthaxanthine, quinoline yellow, nitrites and nitrates, cloves, and cinnamon have been added to the list of inducers of urticaria (Juhlin, 1981; Warin and Smith, 1982; Hannuksela, 1983) (Table 5).

Angioneurotic edema is a common accompanying symptom in chronic and recurrent urticaria, occurring in two-thirds of the patients, most commonly on the face (lips, eyelids, cheeks) and tongue and on the hands and feet (Champion et al., 1969; Juhlin, 1981). Other Angioneurotic edema is a common accompanying symptom in chronic and recurrent urticaria, occurring in two-thirds of the patients, most commonly on the face (lips, eyelids, cheeks) and tongue and on the hands and feet (Champion et al., 1969; Juhlin, 1981). Other

B. Contact Urticaria

Contact urticaria appears as a wheal and flare reaction on normal or eczematous skin within some minutes to an hour after agents capable of producing this type of contact reaction have been in touch with the skin. In mild reactions there are redness and itching but no wheals. The difference between an immediate irritant (toxic) reaction and contact urticaria is far from clear, and therefore there is much confusion in using terms such as contact urticaria, immediate contact reaction, atopic contact dermatitis, and protein contact dermatitis (Table 6). Immediate contact reaction includes both urticarial and other reac- tions, whereas protein contact dermatitis includes allergic and nonallergic eczematous der- matitis caused by proteins or proteinaceous materials. Dermatitis is usually seen in food handlers, veterinarians, and slaughterers (Hjorth and Roed-Petersen, 1976). Atopic contact dermatitis is an immediate type of allergic contact reaction in atopic people (Han- nuksela, 1980). It may be regarded as a special form of immunologic or allergic contact urticaria.

Contact urticaria is also known as contact urticaria syndrome (Maibach and John- son, 1975), which, in addition to localized urticaria and eczematous dermatitis, also in- cludes generalized urticaria or maintenance of status asthmaticus.

According to the mechanism underlying the urticarial reaction, contact urticaria is divided into two main types, namely immunologic (ICU) and nonimmunologic contact urticaria (NICU). There are still some substances that cannot be classified as agents causing either ICU or NICU.

1. Symptoms and Signs Subjective symptoms include itching, tingling, and burning sensations on the contact sites.

Objectively, wheals and redness can often be demonstrated with an open application test or rub test, or with a use test when examining a patient in the office. In ICU the symptoms and signs appear within a few minutes and in NICU usually in 30–45 min (Hannuksela

Table 6 Terminology of Immediate Contact Reactions Term

Remarks

Immediate contact reaction Includes urticarial, eczematous, and other immediate reactions Contact urticaria

Allergic and nonallergic contact urticaria reactions Protein contact dermatitis

Allergic and nonallergic eczematous immediate reactions caused

by proteins or proteinaceous material

Atopic contact dermatitis Immediate urticarial or eczematous IgE-mediated immediate con-

tact reaction

Contact urticaria syndrome Includes both local and systemic immediate reactions precipitated by contact with contact urticaria agents Contact urticaria syndrome Includes both local and systemic immediate reactions precipitated by contact with contact urticaria agents

Eczematous dermatitis with or without tiny vesicles may result from continuously recurring contact urticaria, but it may also appear without any signs of urticaria. This type of dermatitis cannot be distinguished from primary irritant or delayed allergic contact dermatitis, either clinically or histologically. The patient history is usually suggestive of contact urticaria, and the mechanism can be classified in most cases by using the various skin tests mentioned above.

Generalized urticaria is a rare complication of ICU, and only very strong allergens are capable of producing it. In addition to the skin, the lips, tongue, oral mucosa, and throat often react with contact urticaria, but the patient usually notices only a vague itching (Hannuksela and Lahti, 1977; Niinima¨ki and Hannuksela, 1981).

2. Immunologic Contact Urticaria Of the many food additives, spices are the most common causes of immunologic contact

urticaria (ICU) (Table 7). Mustard, cinnamon, and cayenne produce both ICU and NICU reactions, but many other spices, such as cardamom, caraway, and coriander, produce mostly ICU. Persons working in grill bars and pizzerias are exposed to many powdered spices and may get occupational ICU dermatitis on the hands and face. The most common nonoccupational ICU reactions from spices appear as cheilitis, perleche, and eczema around the lips, as well as mucosal edema in the mouth (‘‘lump’’ in the larynx), expecially in children (Niinima¨ki and Hannuksela, 1981). Systemic reactions from ingested spices are to be expected occasionally. Peppers have caused nasobronchial and gastrointestinal symptoms and shock (Rowe and Rowe, 1972), and cinnamon and cloves have caused chronic urticaria (Warin and Smith, 1982; Hannuksela, 1983).

Immediate allergy to various spices is usually connected with birch pollen allergy (Niinima¨ki and Hannuksela, 1981). There are obviously common antigenic determinants in birch pollen, various fruits such as apples and pears, carrots, celery tuber (Halmepuro and Lowenstein, 1985), and spices.

Cremodan SE40, a food consolidator containing mono-, di-, and triglycerides of fatty acids, sodium alginate, polysorbate 80, guar gum, carrageenan (Camarasa, 1981), and BHT (Osmundsen, 1980) have been reported to be causes of contact urticaria in occa- sional cases.

3. Nonimmunologic Contact Urticaria Of the spices, cinnamon, mustard, and cayenne are the most well-known producers of

nonimmunologic contact urticaria ( Table 8 ). Balsam of Peru, benzoic acid and benzoates,

Table 7 Food Additives Causing Immunologic Contact Urticaria Various spices: cinnamon, mustard, cayenne, cardamom, caraway, coriander, etc.

Cremodan SE40 (di- and triglycerides) Polysorbate 80 Sodium alginate Guar gum Carrageen α-Amylase

Table 8 Food Additives Producing Nonimmunologic Contact Urticaria

Benzoic acid and benzoates Sorbic acid and sorbates Cinnamic acid and cinnamates Cinnamaldehyde Various spices: cinnamon, mustard, etc.

sorbic acid and sorbates, cinnamic acid and cinnamates, and cinnamaldehyde readily produce contact urticaria when applied to the skin. The concentration capable of caus- ing NICU depends on the vehicle, the skin region exposed, and the mode of exposition (Lahti, 1980; Lahti and Maibach, 1985). Sorbic acid, for example, causes wheal and flare reactions when tested at 5% in petrolatum, but only a few people react to a 0.2% mixture.

The back skin, the face, and the extensor sides of the upper extremities react to NICU agents more readily than other parts of the body, the soles and palms being the least sensitive areas (Lahti, 1980; Gollhausen and Kligman; 1985). Scratching does not enhance the reactivity; neither does the use of occlusion. On the other hand, stripping the skin weakens the contact urticarial reaction. Topical or systemic antihistamines do not influence the skin response to NICU substances, but local anesthesia and the use of strong topical steroids diminish the reactivity of the skin (Lahti, 1980). Systemic aspirin inhibits NICU reactions to most NICU agents (Lahti et al., 1986).

Nonimmunologic contact urticaria reactions are to be expected on the hands of em- ployees handling food additives in the food industry. Such reactions from benzoic and sorbic acids, benzoates, and sorbates are obviously rare, but they are somewhat more commonly seen from spices.

In a kindergarten, salad dressing containing benzoic acid and sorbic acid raised perioral NICU reactions when the children smeared the dressing around their mouths for fun (Clemmensen and Hjorth, 1982). Flavored food was reported to cause generalized urticaria and gastrointestinal symptoms in six patients with a marked contact urticarial reaction to 25% balsam of Peru in petrolatum (Temesvari et al., 1978).

C. Purpura

Allergic purpura appeared 3 h after peroral provocation with 10 mg of tartrazine in a 51- year-old man suffering from cold urticaria and recurrent episodes of purpura (Parodi et al., 1985). The provocation was repeated four times, resulting in purpura each time. Pur- pura with fever, malaise, and pains in the abdomen and joints in five patients (Michaelsson et al., 1974) and allergic purpura in one patient (Criep. 1971) were apparently caused by tartrazine. A placebo-controlled oral challenge with 50 mg of ponceau red produced cuta- neous leucocytoclastic vasculitis in a 24-year-old woman (Veien and Krogdahl, 1991). The vasculitis faded in two months during an additive-free diet.

Purpuric eruptions from quinine are well documented. The mechanism in thrombo- cytopenic purpura is cytotoxic allergy (type II) (Belkin, 1967). There are also quinine- induced nonthrombocytopenic purpuras (Levantine and Almeyda, 1974).

Table 9 Causes of Primary Irritant Contact Dermatitis (Especially in Bakers)

Emulsifiers Acetic, ascorbic, and lactic acids Potassium bicarbonate Potassium bromate and iodide Calcium acetate and sulfate Bleaching agents

D. Fixed, Bullous, and Lichenoid Eruptions

Quinine frequently produces lichenoid eruptions (Almeyda and Levantine, 1971), and less frequently bullous and fixed eruptions (fixed erythema) (Derbes, 1964). Fixed drug erup- tion from tartrazine was recently published by Orchard and Varigos (1997).

E. Primary Irritant Contact Dermatitis

The usual causes of irritant dermatitis in food handlers are wet work and detergents. How- ever, some food additives are possible irritants and may be partly responsible for hand dermatitis. Table 9 lists some irritants that bakers may encounter (Fisher, 1982).

F. Allergic Contact Dermatitis

Esters of p-hydroxybenzoic acid (parabens), sorbic acid and sorbates, BHA, BHT, gallate esters, vitamin E, propylene glycol, spices, essential oils, and other flavoring agents cause delayed-type contact allergy, which may be of significance to food handlers and consumers (Table 10).

Parabens are important contact allergens in cosmetics and other dermatological prep- arations. They are also used as preservatives in foods and drugs. Although parabens may

Table 10 Food Additives Inducing Contact Allergies Parabens

Sorbic acid Butylated hydroxytoluene and butylated hydroxyanisole Gallates (octyl, lauryl) Vitamin E (tocopherols) Propylene glycol Spices, essential oils, and balsams Azo dyes Karaya gum Benzoyl peroxide Ethanol Metabisulfites and sulfites α-Amylase Foodmuls E3137 Sorbic acid Butylated hydroxytoluene and butylated hydroxyanisole Gallates (octyl, lauryl) Vitamin E (tocopherols) Propylene glycol Spices, essential oils, and balsams Azo dyes Karaya gum Benzoyl peroxide Ethanol Metabisulfites and sulfites α-Amylase Foodmuls E3137

Sorbic acid has become a more and more popular preservative in bakery products in recent years. Contact allergy is fairly infrequent and is most commonly due to the use of creams containing sorbic acid. Ingested sorbic acid has not been reported to produce or worsen eczematous dermatitis.

Contact sensitivity to BHT and BHA is rare. Roed-Petersen and Hjorth (1976) re- ported two female patients with hand dermatitis. One patient was allergic to BHT but not BHA; the other reacted to both BHA and BHT. The two patients got rid of their hand dermatitis by using topical corticosteroids and a diet free of antioxidants. Further, these two patients had itching and vesicular eruption when taking 5–10 mg of BHA daily for

4 days, suggesting that antioxidants in foods were the causative factor or at least an ex- acerbating factor in their hand dermatitis. Butylated hydroxyanisole was the apparent cause of occupational hand dermatitis, circumoral dermatitis, and cheilitis in a cook who had skin trouble after handling and eating mayonnaise containing BHA (Fisher, 1975).

Lauryl gallate in a margarine was the cause of occupational hand dermatitis in five bakers and pastry cooks investigated by Brun (1964, 1970). Burckhardt and Fierz (1964) also reported five cases of occupational contact allergy to gallates in margarine, and van Ketel (1978) reported one case of occupational hand and face dermatitis from peanut butter containing octyl gallate. Ingested gallates appear to be harmless even in hypersensitive individuals.

Vitamin E (tocopherol) is a potent contact sensitizer. The antioxidant in ‘‘E-deodor- ants’’ produced so many cases of allergic contact dermatitis in the early 1970s that these deodorants were withdrawn from the market (Fisher, 1976). Ingested vitamin E, however, has not been reported to produce allergic reactions.

Propylene glycol (PG) is a good solvent and vehicle for many substances, in addition to which it is antimicrobic and hygroscopic (isotonic concentration about 2% in water) (Reynolds and Prasad, 1982). According to the FAO/WHO, its estimated acceptable daily intake is up to 25 mg/kg body weight, or 1.75 g/70 kg. The average daily intake of PG is estimated to be about 0.5 g (Andersen, 1983).

Propylene glycol is widely used in dermatological preparations, up to 70% w/w, mostly because of its hygroscopic and dissolving properties. Under occlusion it irritates the skin easily (Warshaw and Herrmann, 1952; Hannuksela et al., 1975). It is difficult to assess whether patch test reactions are primary irritant or allergic. All patch test reactions caused by PG at 2% in water and most of those elicited by 10% PG seem to be allergic and clinically relevant (Hannuksela and Salo, 1986).

Peroral ingestion of 2–15 mL of PG produced an exanthematous reaction in 8 of

10 persons with a positive patch test result with 2% PG in water. The corresponding number among those reacting to 10–100% PG in patch testing was 7 of 28 cases and none of 20 control subjects (Hannuksela and Fo¨rstro¨m, 1978). In one of the patients, PG in food was the apparent cause of recurrent rashes. In another study, 15 mL of PG produced an exanthematous rash in 2 of 5 patients with a positive patch test reaction to 2–100% PG (Andersen and Storrs, 1982). It thus seems that propylene glycol is a rare but possible cause of exanthematous rash even in amounts ingested in daily food.

Spices and other flavoring agents are numerous and mostly poorly standardized. Many of them are potent contact allergens, but the exact composition of the chemicals Spices and other flavoring agents are numerous and mostly poorly standardized. Many of them are potent contact allergens, but the exact composition of the chemicals

Niinima¨ki (1984) patch tested 2258 eczema patients, 150 of whom (6.6%) were allergic to balsam of Peru. Further patch tests with nine powdered spices were positive in 3–46% of patients allergic to balsam of Peru but only sporadically in patients not allergic to the balsam. Cloves elicited allergic patch test reactions most often (46%), then came Jamaica pepper (21%) and cinnamon (15%). The other spices tested were ginger, curry, cardamon, white pepper, vanillin, and paprika, being positive in 3–6% of patients allergic to balsam of Peru.

Niinima¨ki (1984) also made challenge tests with various spices (300 mg in gelatin capsules) in 71 patients with Peru balsam allergy and in 50 dermatological patients with negative patch test results. Seven of the balsam of Peru allergic patients (10%) had objec- tive symptoms regarded as positive challenge test results. Two patients had urticarial le- sions, one on the back skin at the patch test site of balsam of Peru and the other on the waist. The latter patient also had facial dermatitis and conjunctival irritation. four patients experienced vesiculation (pompholyx) on the palms and fingers, and in one patient the patch test reaction to Jamaica pepper was reactivated, although the reaction had already faded away prior to the challenge test. None of the 50 control patients had symptoms from ingested spices. Flavoring agents in food caused a flare-up of contact dermatitis in an elderly patient allergic to balsam of Peru reported by Bedello et al. (1982).

Rare causes of occupational allergic hand dermatitis in bakers are benzoyl peroxide, Karaya gum, and azo dyes (Fisher, 1982). Ethanol is also capable of producing contact allergy, and allergic patients may have an erythematous rash after drinking alcoholic bev- erages (Drevets and Seebohm, 1961; Cronin, 1980).

Metabisulfites and more rarely also sulfites cause both occupational and nonoccupa- tional allergic contact dermatitis (Fisher, 1989; Vena et al., 1994). They are also capable of producing irritant contact dermatitis. An emulsifying agent, Foodmuls E3137, caused hand dermatitis in a 37-year-old male baker, in whom both patch test and scratch-chamber test were positive, the former after 48 and 72 h and the latter after 24 h (Vincenzi et al., 1995). α-Amylase, a flour additive, causes both delayed and immediate skin contact aller- gies in bakers (Morren et al., 1993).

G. Photodermatitis

Cyclamate is the only food additive that has been reported to cause photodermatitis via an apparently allergic mechanism (Kobori and Araki, 1966; Lamberg, 1967).

H. Orofacial Granulomatosis

Orofacial granulomatosis is a descriptive name for a variety of conditions presenting as chronic or fluctuating swelling of lips and other peroral regions and the oral mucosa. Often there are noncaseating granulomas or at least epithelioid cells in the dermis. These conditions include, for example, Crohn’s disease, Melkerson–Rosenthal syndrome, and sarcoidosis.

The cause of orofacial granulomatosis is unknown. In individual cases, food addi- tives have been found to be at least provocative. Food or food additive intolerance was reported as a causative factor in 14 of 80 patients by Patton et al. (1985). Carmoisine, Sunset Yellow, and monosodium glutamate were attributed to orofacial granulomatosis The cause of orofacial granulomatosis is unknown. In individual cases, food addi- tives have been found to be at least provocative. Food or food additive intolerance was reported as a causative factor in 14 of 80 patients by Patton et al. (1985). Carmoisine, Sunset Yellow, and monosodium glutamate were attributed to orofacial granulomatosis

In another study on Melkersson–Rosenthal syndrome, food additives did not show any influence on the symptoms or signs when they were given in double-blind manner to the patients (Morales et al., 1995).

I. Exacerbation of Atopic Dermatitis

Van Bever et al. (1989) investigated the role of food and food additives in severe atopic dermatitis. They made double-blind placebo-controlled challenge tests with four food ad- ditives (tartrazine, sodium benzoate, sodium glutamate, and sodium metabisulfite), acetyl- salicylic acid, and tyramine through a nasogastric tube in six children. All six children reacted to at least one additive while placebo challenges remained negative. The authors considered the aggravation of atopic dermatitis by food additives to be due to erythemo- genic and urticariogenic properties of the additives rather than to direct effect on atopic dermatitis. In a series of 91 adult atopic dermatitis patients, Hannuksela and Lahti (1986) found one positive reaction in double-blind peroral challenge with 100 mg of β-apocaro- tenal plus 100 mg of β-carotene.