Allergy 1998:53:1074-1077Printed in UK - all rights reserved

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ALLERGY "ISSN 0105-4538

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Role of nonallergic hypersensitivityreactions in children with chronic urticaria

Ehlers I, Niggemann B. Binder C, Zuberbier T Role of nonallergichypersensitivity reactions in children with chronic urticaria.Allergy 1998: 53: 1074-1077. © Munksgaard 1998.

Background IgE-independent (pseudoallergic) reactions to food and foodingredients are common in a subgroup of adult patients with chronicurticaria, who have daily spontaneous occurrence of wheals. However, forchildren with chronic urticaria (duration longer than 6 weeks, no physicalinfluence), no data on the importance of pseudoallergen-induced chronicurticaria are available. Therefore, we investigated the role of nonallergichypersensitivity to food in all children seen with chronic continuous urticariain our two clinics over the last 2 years (n = 16).Methods All patients were given a low-pseudoallergen diet for 3 weeksfollowed by provocation with food rich in pseudoallergens. To identify themain eliciting agents, a subgroup of responders was exposed to food additivesby double-blind, placebo-controlled food challenges.Results Pseudoallergen-induced urticaria was diagnosed in 12 cases (75%).Reactions occurred mainly to coloring agents and preservatives, but also tomonosodium glutamate and a sweetener (saccharin/cyclamate).Conclusions TTiese results confirm that nonallergic hypersensitivity reactionsplay a role in children with chronic urticaria, although the latter disease israre at that age. In children, food additives, especially coloring agents andpreservatives, appear to play a more important role in eliciting nonallergichypersensitivity reactions than in adult patients, where naturally occurringpseudoallergens in fruits and vegetables are mainly responsible.

\. Ehlers\ B, Niggemann ,̂C. Binder̂ , T. Zuberbier̂Departments ot 'Dermatology and 'Pediatrics,Charlte, Humboldt-Universltv Berlin, Germany

Key words: children; chronic urticaria; diet;food intolerance; nonallergic hypersensitivity;pseudoallergy.

Dipl. oec. troph. Imke EhlersDepartment of DermatologyChariteSchumannstr 20/2110117 BerlinGermany

Accepted for publication 7 April 1998

Food- and drug-related reactions mimicking allergicreactions without specific sensitization of theimmune system are well known. Several terms havebeen used lo describe these reactions, such as"idiosyncrasy", "intolerance", "pseudoallergy", and"nonallergic hypersensitivity", among others. Inchronic continuous urticaria, which is characterizedby a duration of more than 6 weeks, daily spon-taneous occurrence of wheals, and exclusion ofacute, intermittent, and physical forms of urticaria,nonallergic hypersensitivity reactions to food andfood additives have been reported repeatedly (1,2), In a prospective study in adult patients hospi-talized for chronic urticaria, it could be confirmedthat 73% of the patients with daily spontaneousoccurrence of wheals benefited from a strict elimi-nation diet avoiding all food additives as well asnatural foods known to cause urticaria, such astomatoes, berries, matured cheese, and alcohol (3).

However, in children, no data on the importanceof pseudoallergen-induced chronic urticaria areavailable, possibly beeause chronic continuous urti-caria is rarely seen at that age. In the literature,only a few studies have investigated the patho-genesis of urticaria in children (4-11). However,because the terminology for the different forms ofurticaria has been used inconsistently and the term"chronic urticaria" - in contrast to the stringentcriteria mentioned above - has been used todenote also physical forms of urticaria, the inter-pretation of the results of these studies regardingthe importance of food- or food additive-inducedurticaria is difficult. In these studies, physical formsof urticaria (mainly urticaria factitia) accountedfor most of the identified eliciting factors (4, 6,10). Apart from one study (9), food and foodadditives played only a minor role (4, 5, 10).Unfortunately, the methods of diagnosis are often

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Nonallergic hypersensitivity in children

poorly documented. In one study, food additivesand acetylsalicylic acid are listed together as acausative factor (6); thus, the relevance of foodadditives on their own is not known.

Therefore, we conducted a prospective study atthe departments of Pediatrics and Dermatology ofthe Charite, Berlin, to assess the role of foodallergy and nonallergic hypersensitivity in chronicurticaria in children.

Material and methodsPatients

All children with moderate to severe chronic con-tinuous urticaria of at least 3 months' duration,seen from 1995 to 1997 (n=16, mean age 12 years,range 3-17 years), were included in the study. Theseverity was documented by a score ranging from0 to 3, as used in a previous study in adult patientswith chronic urticaria (3). Nine children were seenon an outpatient basis, and seven patients werehospitalized.

Diet

All patients were put on a special strict eliminationdiet until remission of symptoms (Table 1). ln viewof the fact that in adult patients remission ofsymptoms usually occurs within 2 weeks, the dietwas followed for 3 weeks.

Laboratory tests

IgE-mediated allergy as a cause of whealing wasexcluded by patient history and skin prick test orinvestigation of specific IgE in serum (PharmaciaCAP System).

Food challenge

Oral provocation tests were performed by reintro-duction of normal food in all patients havingimproved on elimination diet in order to establishthe diagnosis of pseudoallergy/nonallergic hyper-sensitivity, and by double-blind, placebo-controlledexposure to food additives - those known to elicitnonallergic hypersensitivity - in gelatin capsules(Table 2) in a subgroup of patients. Since non-allergic hypersensitivity reactions, in contrast toIgE-mediated allergic reactions, often occur witha latency of only 6-24 h, only one challenge testwas performed per day. After positive reactions,testing was stopped until symptoms ceased. Symp-tomatic treatment (preferably antihistamines) wasgiven only in the case of intolerably severe reactions.

ResultsOf 16 patients, 13 (81%) (six hospitalized, seven onan outpatient basis) went into remission under astringently controlled low-pseudoallergen diet.Nine of them were free of symptoms within 10 daysof diet. Three patients improved considerably butcontinued to show a few wheats for several weeks.Finally, symptoms ceased completely. All of thesechildren continued to react with wheals after acci-dental mistakes or discontinuation of the diet.However, on adherence to the diet, none of themneeded any medication. These cases were diag-nosed as pseudoallergen-induced urticaria. One 17-year-old patient improved on diet but did notrespond to reintroduction of prohibited food. Hersymptoms ceased completely after eradication ofHelicobacter pylori.

One hospitalized patient and two outpatientsfailed to respond to the diet. In order to identify

Table 1. Low-pseudoallergen diet. Strictly forbidden; all food containing preservatives, dyes, or antioxidants, all industrially processed food should be carefully

checked for additives IZuberbier et al. |31)

Allowed Forbidden

Basic food

Fats

Milk products

Food from animals

Vegetables

Fruit

Herbs, spices.

seasoning

Sweets

Beverages

Spreads

Preservative-free bread, potatoes, rice, unprocessed cereals

flour (not self-raising!), rice cakes, durum wheat pasta

{without egg)

Butter, cold-pressed plant oils

Fresh milk, cream without stabilizers, white cheese, fromage

frais, small amount of mild Gouda cheese

Fresh meat without seasoning

All except those listed as forbidden (e.g., lettuce, carrots.

zucchini, cabbage, broccoli, asparagus)

None

Salt, sugar, chives, onions

NoneMilk, mineral water, coffee, black tea

Honey

All others (e.g., pasta with eggs, cake, biscuits, potato chips)

All others (e.g., margarine, mayonnaise)

All others

All others including eggs, seafood, smoked meat

Artichokes, peas, mushrooms, spmach, rhubarb, tomatoes and

tomato products, olives, sweet peppers, spinach

All, including dried fruits or fruit juices

All others including garlic and other herbs

All, including chewing gum

All others including beer, wine, spirits, and herbal teas

All others

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Ehlers et al.

Table 2 Pseudoallergens used for provocation tests (masked in gelatincapsules)

Pseudoallergens

Coloring agentsA20 dyes

Other syntheticdyes

Natural colors

Preservatives

Antioxidants

Taste enhancers

Naturally occurringsubstances

Name

TartrazineSunset yellowAzorubineAmaranthPonceauBrilliant black BNQuinoline yellowErythrosinePatent blueIndigotineIron(lll) oxide, redCochineal

Sorbic acid

Sodium benzoate

p-Hydroxybenzoate

Sodium metabisulfite

Sodium nitrate

Butylhydroxyanisol (BHA)

Butylhydroxytoluol (BHT)

Propylgallate

Tocopherol

Monosodium glutamate

Salicylic acid

E number

E102

E110

E122

E123

E124

E151

E104

E127

E131

E132

E172

El 20

E200

E211

E214-219

E223

E251

E320

E321

E310

E306-309

E621

Dose |mg)

5055555555555

1000

1000

1000

50100

50505050

200

100

the main eliciting agents in children with pseudo-allergen-induced chronic urticaria, double-blind,placebo-controlled food challenges (DBPCFC) withfood additives were performed in six children. Onlyone patient with proven pseudoallergy did notreact after DBPCFC The outcome of the foodchallenges is documented in Table 3. The maineliciting agents were preservatives and coloringagents. In one child, a sweetener (saccharin/cyclamate) was also tested because of an implica-tion in the patient's history, and it proved to causepositive reactions. This child was rechallenged byDBPCFC 1 year later. Reactions to the sweetenerwere still positive, while other food additives whichcaused wheals 1 year before were negative.

DiscussionIn our study, 12 of 16 patients with chronic contin-uous urticaria (75%) were diagnosed as sufferingfrom nonallergic hypersensitivity, a result which isin line with the results in adult patients (73%) (3).The time needed before the patients went intoremission clearly points to a nonallergic mechanismof reaction. In IgE-mediated allergy, whealinggenerally ceases shortly after elimination of the

allergen. In one case, there was an improvement indiet, but remission of all symptoms occurred oniyafter eradication of H. pylori. Since food challengein this patient was negative (in contrast to the otherpatients' improvement on diet), a direct effect ofthe food can be excluded. However, until now, itwas unclear whether H. pylori itself or the inflam-mation caused by the infection was responsible.Therefore, in this patient, the diet might haveinfluenced symptom severity by an indirect effecton gastric inflammation through the elimination offatty, sour, and spicy food.

DBPCFC in six patients revealed that foodadditives caused 83% of nonallergic hypersensitivityreactions. The reactions were mainly to coloringagents and preservatives but also to monosodiumglutamate and a sweetener (saccharin/cyclamate).Coloring agents, especially tartrazine, and preserv-atives such as benzoic acid have previously beenimplieated in provoking urticarial reactions in chil-dren (6, 8-12). Only a few other studies havedocumented reactions to glutamate in children (7,8, 13). In adults, nonallergic hypersensitivity reac-tions to glutamate are well documented, althoughurticaria is rarely mentioned (14,15). Studies inves-tigating the potency of sweeteners to induce non-allergic hypersensitivity reactions are rare. Onestudy asserts that saccharin can provoke urticaria(16), and another study found that aspartamecauses whealing (17). However, Garriga et al. (18)found that hypersensitivity reactions to aspartame

Table 3. Positive reactions to individual pseudoallergens after double-blind,placebo-controlled food challenge in six patients. In 5/6 patients, eliciting foodadditives could be identified. One child was negative

Patient no. Eliciting agents

A20 dyes (see Table 2)Iron(lll) oxide redSorbic acidp-Hydroxybenzoate

ErythrosinePatent blue VIndigotineQuinoline yellowIron(lll) oxide red

Sorbic acidp-HydroxybenzoateMonosodium glutamateSaccharin/sodium cyclamate

Mixture of coloring agents (quinoline yellow, sunsetyellow, azorubine, patent blue)

Sorbic acidBenzoic acid

p-Hydroxybenzoate

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Nonallergic hypersensitivity in children

were not reproducible. A recent study demon-strated that the sweetener aspartame was no morelikely than placebo to cause urticaria (19).

One child did not respond to oral provocationwith encapsulated food additives, but did reactrepeatedly after food rich in pseudoallergens. Thisphenomenon is rarely seen in children but is oftenobserved in adult patients. While 73% of patientswith chronic urticaria improved markedly on a low-pseudoallergen diet and reacted to reintroductionof normal (pseudoallergen-containing) food, only19% of DBPCFC with encapsulated food additiveswere positive (3). The observation that one childwith pseudoallergy did not react to challenges withencapsulated food additives confirms that naturallyoccurring pseudoallergens can cause wheals alsoin children, although to a lesser degree than inadults. Thus, only a diet which avoids both groupsof pseudoallergens, namely, food additives andnaturally occurring pseudoallergens, will identifyall cases of nonallergic hypersensitivity in child-hood. Therefore, the often-used additive-free dietshould be replaced by a strict low-pseudoallergendiet.

Most studies describe chronic urticaria in chil-dren as a self-limited disease (5, 6, 8). ln a follow-up study, Pollock & Warner (7) found that at least26 out of 34 children (76%) did not react torechallenge; in only two children could urticariastill be provoked. However, they did not react tothe whole range of food additives initially found tohe positive. This finding is in line with the obser-vation that one of our patients reacted only tosaccharin/cyclamate on rechallenge after 1 year, butnot to preservatives and monosodium glutamate.

From a nutritional point of view, the low-pseudoallergen diet provides a good basis for abalanced diet without the risk of deficiencies. How-ever, since food aversions in childhood are com-mon and forbidden foods therefore cannot bereplaced easily, the diet may not always be asbalanced as it should be. To avoid deficiencies andmaintain compliance, it is very important to enlargethe list of foods allowed as soon as the diagnosisof pseudoallergy/nonallergic hypersensitivity isconfirmed. Formerly prohibited foods should bereintroduced step by step. ITie order of intro-duction should be determined with regard to theunlikelihood of certain foods to cause reactions andto the preferences of the patient (for further infor-mation, see Ehlers & Zuberbier [20]). The pro-cedure of enlarging the list of food allowed can beperformed on an outpatient basis.

In conclusion, our findings confirm that non-allergic hypersensitivity reactions play a role inchildren with chronic urticaria, although the latterdisease is rare in childhood. The management of

food-induced chronic urticaria by diet requireshighly motivated families. However, our data indi-cate that this method is worth trying.

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