CONTACT DERMATITIS IN CHILDREN WITH AND WITHOUT ATOPIC DERMATITIS WHICH...

CONTACT DERMATITIS IN CHILDREN WITH AND

WITHOUT ATOPIC DERMATITIS; WHICH ARE THE

FREQUENT ALLERGENS?

Stefanie Lubbes

s1924524

Stage wetenschap: 05 augustus 2013 t/m 31 januari 2014

Extern (hoofd)begeleider AMC: Dr. M.A. Middelkamp Hup

Extern begeleider VUmc: Dr. T. Rustemeyer

Facultair begeleider UMCG: Dr. M.L.A. Schuttelaar

Contact dermatitis in children with and without atopic dermatitis; which are the frequent allergens?

1

ABSTRACT

Background. Data on contact dermatitis in children is poor. This study aims to identify the

occurrence of contact dermatitis in children. This will allow better identification of potential

sensitizers and improve patients’ care in children.

Methods. We retrospectively analyzed data of patients aged 0-17 years, that were patch tested

with at least the European baseline series between 1996-2013 in three University Hospitals

across the Netherlands.

Results. 1012 Children (male 37%, mean age 13 years) were included, of which 469 (46%)

developed ≥1 positive reactions. The most frequent reactions were found to nickel (16.4%),

cocamidopropyl betaine (15.9%), fragrance mix I (9.9%), amerchol L-101 (8.8%) and wool

alcohols (6.2%). Children with atopic dermatitis reacted significantly more frequent to wool

alcohols (p<0.04), amerchol L-101 (p<0.04) and fragrances compared to children without

atopic dermatitis. Strikingly, significantly less positive reactions to wool alcohols, fragrances

and caine mix were found testing with the TRUE-test compared to chamber patch test

preparations.

Conclusion. Cocamidopropyl betaine frequently has positive reactions in children. Atopic

dermatitis is a risk factor for developing reactions to wool alcohols and fragrances. Especially

in children with recalcitrant atopic dermatitis, contact dermatitis caused by these allergens

should be considered. The difference in positive reactions to important allergens between

TRUE test and chamber patch test preparations is striking and needs further investigation.

This observation is especially important as the TRUE test is easy to use in children, and these

allergens could therefore be missed in this population.

SAMENVATTING

Achtergrond. Data over contacteczeem bij kinderen is schaars. Het doel van deze studie is

het voorkomen van contacteczeem bij kinderen te analyseren. Dit geeft betere identificatie

van potentiële allergenen en hiermee zal de zorg voor de patiënt verbeteren.

Methoden. We hebben de data van patiënten van 0 tot 17 jaar oud retrospectief geanalyseerd,

deze hebben een plakproef gehad met minimaal de Europese standaard reeks in de periode

van 1996 tot 2013 in drie Universitaire medische centra verspreid over Nederland.

Results. 1012 Kinderen (man 37%, gemiddelde leeftijd 13 jaar) werden geincludeerd, hiervan

hadden 469 (46%) ≥ 1 positieve reacties. De meest frequente reacties waren op nikkel

(16,4%), cocamidopropyl betaïne (15,9%), fragrance mix I (9,9%), amerchol L-101 (8,8%) en

wolalcoholen (6,2%). Kinderen met atopisch eczeem reageerden significant vaker op

wolalcoholen (p<0,04), amerchol L-101 (p<0,04) en fragrances vergeleken met kinderen

zonder atopisch eczeem. Opvallend was dat er significant minder reacties gevonden werden

op wolalcoholen, fragrances en caïne mix bij het gebruik van de TRUE-test.

Conclusion. Cocamidopropyl betaïne had frequent positieve reacties bij kinderen. Atopisch

eczeem is een risicofactor voor reacties op wolalcoholen en fragrances. Zeker bij kinderen

met therapieresistent atopisch eczeem zou contacteczeem ten gevolge van deze allergenen

overwogen moeten worden. Het verschil in reacties op belangrijke allergenen tussen de

TRUE-test en kamer-testmethodes is opvallend en hier is meer onderzoek naar nodig. Deze

observatie is voornamelijk van belang omdat de TRUE-test eenvoudig te gebruiken is bij

kinderen en deze allergenen hierom gemist zouden kunnen worden in deze populatie.


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ACKNOWLEDGEMENT

When I started this internship I was absolutely clueless about how much work research on

contact dermatitis actually is. Just a half year ago, I had never heard of substances like

cocamidopropyl betaine, dimethylaminopropyl amine and sorbitan sesquioleate. When I

started in the Academic Medical Center about 400 clinical charts were waiting for me, so

there was work to do! I really took a dive in the world of contact dermatitis which is a great

area for research. At first it was a little tough but I managed my way through and terms like

cocamidopropyl betaine nowadays sound very familiar and I really learned to appreciate the

value of science.

I would like to thank a few people for giving me this unique opportunity to perform this

research. Dr. Schuttelaar, for guiding me through the data of the UMCG. Dr. Rustemeyer, for

explaining me a lot about contact dermatitis and answering about a thousand of my emails.

And last but not least; dr. Middelkamp Hup, for having endless discussions with me and great

guidance through this research internship.

Thank you!

Stefanie Lubbes


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TABLE OF CONTENTS

CONTACT DERMATITIS IN CHILDREN WITH AND WITHOUT ATOPIC DERMATITIS; WHICH ARE

THE FREQUENT ALLERGENS? ..................................................................................................1

ACKNOWLEDGEMENT .............................................................................................................2 INTRODUCTION .......................................................................................................................4

METHODS ...............................................................................................................................5 RELEVANCE ........................................................................................................................5

RESULTS.................................................................................................................................8

PRIMARY ANALYSIS ............................................................................................................8 SECONDARY ANALYSIS; EMERGING ALLERGENS? ............................................................ 12

TRUE-TEST VERSUS CHAMBER PATCH TEST PREPARATIONS ............................................ 13 DISCUSSION.......................................................................................................................... 14

ATOPIC DERMATITIS AND CONTACT DERMATITIS ............................................................. 15 AGE AND CONTACT DERMATITIS ...................................................................................... 16

SECONDARY ANALYSIS; EMERGING ALLERGENS? ............................................................ 17 TRUE-TEST VERSUS CHAMBER DEVICES .......................................................................... 17

CONCLUSION ........................................................................................................................ 19 REFERENCE LIST .................................................................................................................. 20

APPENDIX............................................................................................................................. 25 TUSSENTIJDSE EVALUATIE WEEK 6 ................................................................................... 25

TUSSENTIJDSE EVALUATIE WEEK 12 ................................................................................. 26 EINDBEOORDELING .......................................................................................................... 27


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INTRODUCTION Allergic contact dermatitis (ACD) in children was considered to be rare in the past. Exposure

to allergens in childhood was thought to be less compared with adults and ACD in children

was therefore unexpected. However, recent data suggests that it might be more common than

previously thought [1-3]. Research in unselected groups of children in the general population

on the prevalence of ACD is scarce, varying numbers ranging from 13.3 up to 23.3% have

been reported [4-7]. In selected populations of children, who were referred for patch testing

because of a suspected ACD, an increase of reported sensitization rates was observed [1;2].

This may indicate that ACD has become more common in childhood. However this is

influenced by patch testing children more frequently and ACD in children might be detected

more often compared to the past.

ACD has a considerable morbidity and can start at a very young age [8]. The exposure to

allergens in the environment differs due to the age of the patients, as for example adolescents

are often exposed to other allergens than pre-school children. The age of the patient also

determines the amount of available skin for patch testing, resulting in patch testing of only a

selection of allergens.

The relation between atopic dermatitis (AD) and ACD is unclear and is a matter of

controversies. Higher, lower and equal positive patch test rates in patients with AD have been

reported in several studies [9-12]. Lower rates are traditionally explained by the activated

immune system in patients with AD resulting in a decreased risk of contact sensitization,

higher rates might be caused by an increased penetration of allergens resulting in contact

dermatitis [13]. In any case, ACD can occur in children with AD and its impact should not be

underestimated.

The golden standard for diagnosing ACD is generally accepted to be the epicutaneous patch

test in which sets of allergens are applied to the upper back. Sensitization to a selection of the

most common allergens is tested with the European baseline series (EBS). The EBS is tested

routinely in all patients regardless of their clinical history. Previous reviews have identified

multiple allergens in several populations of children with presumable ACD [1-3]. The most

common allergens reported in children are metals (nickel, cobalt and chromate), fragrances,

preservatives, wool alcohols, topical antibiotics and chemicals used in rubber [3].

Data from the Netherlands reporting causative allergens in children is limited. A prospective

study by de Waard-van der Spek et al. [14] gathered the results of the patch test data of 79

children. The most common allergen was nickel (n=17) which was followed by a sensitization

for the patients’ own shoes (n=6). Children are being exposed to a number of different

allergens. In today’s modern life potential allergens are present in cosmetics, toiletries, skin

care products, materials used in clothing and shoes, shin guards, hair dyes, body piercings and

temporary tattoos. Changes in exposure also depend on prevalent fashion trends and may

change in time, contributing to a shift in allergen exposure in children. Exposure to these

agents varies according to the age group. The location of the dermatitis also reflects

differences in allergen exposure. And finally, children with atopic dermatitis are exposed to

different allergens compared to non-atopic children due to their frequent use of topical

medicaments and emollients.

The primary aim of the study is to determine frequent allergens in children suspected of

having allergic contact dermatitis, especially in children with atopic dermatitis. The secondary

aim of the study was to detect emerging allergens in this study population. With these aims

we try to evaluate the occurrence of contact dermatitis in children which will improve the

identification of potential allergens.


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METHODS

A retrospective analysis of 1083 cases of patients aged up to 17 years was performed. These

patients were referred for patch testing in three University Hospitals (AMC, VUmc and

UMCG) in the period 1996 to 2013 because of a suspected contact dermatitis. Inclusion

criteria in this study was that, at least a selection of allergens, of the European Baseline series

(EBS) had to be patch tested at minimum. In 21 children a shortened version of the EBS was

patch tested, these patients were included as well. A number of patients were excluded due to

an invalid test or because the inclusion criterion could not be met, this is demonstrated in

diagram 1. The EBS was patch tested on a routine basis in all children regardless of their

clinical history. A set of extra allergens (outside of the EBS), as listed below in table 1, were

used in two University Hospitals (VUmc and UMCG) and were patched tested on a routine

basis in all children.

Optionally additional patch test series were performed on indication and this was dependent

of the patients’ clinical history. This includes for example cosmetic series, hairdresser series,

metal series and others. In patients that were patch tested twice all substances to which the

patients reacted were included in this research with no regards to reproducibility of the

reactions.

We performed the primary analysis only on the data from the allergens that were tested on a

routine basis in all patients to prevent a selection bias. The secondary analysis was performed

on the data from allergens that were tested routinely and on indication outside the EBS. The

aim of this analysis was to detect emerging allergens that are not tested in the EBS. In this

analysis a cut-off value of 200 times a substance was patch tested was used as a baseline to

prevent a selection bias as much as possible. A value of 200 was chosen to reach a

comparable number of patients that were tested at minimum for substances in the EBS.

Epicutaneous patch testing was performed in a standard manner. The patch test was applied

on intact skin on the patients’ upper back for 48 hours minimum and was subsequently

removed and an evaluation of the reactions was performed. The results were evaluated after

72 hours (day 3) as well and in some cases also at day 7 depending on the allergens that were

tested. The reactions were scored according to the guidelines from the ICDRG [15]. Different

materials were used (table 2). Van der Bend square chambers ® (van der Bend BV, Brielle,

The Netherlands) were used in the University Hospitals. One of the University Hospitals used

the TRUE-test for routine testing consisting of 24 allergens, the additional substances from

the European baseline series were supplemented with allergens from Almirall.

The patch test reactions were systematically collected in databases at each University

Hospital. Clinical charts were studied where required. Additional data was collected from the

clinical charts in all cases of the AMC because of differences in the collected data between

the University Hospitals. The following information was collected; gender, age, patch test

date, patch-test series, allergens with positive reactions, the course of the reaction, sites of

eczema, atopic status (atopic dermatitis, allergic rhinoconjunctivitis, allergic asthma) and a

score for the clinical relevance. Atopic dermatitis was evaluated on basis of the expert’s

opinion at the time of consultation and was scored positive, negative, unclear or unknown.

Retrospectively atopic dermatitis was scored positive when it was noted to be positive in the

clinical chart.

RELEVANCE

The clinical relevance was determined for each allergen that was tested positive to evaluate

the relation between the reaction and the clinical symptoms. A positive reaction could be of

past, current or unknown relevance. A reaction was of current relevance when it was related


6

to the current clinical symptoms and of past relevance when it was related to a past clinical

episode.

The reactions could be of "certain", "probable", "possible" or "unlikely-not" relevance which

was evaluated at the time of consultation and retrospectively. “Certain” was given when the

clinician was 100% convinced that the allergen was causative for the dermatitis. The patient

had to be exposed to the allergen, the allergen was present in the environment of the patient.

The sites of the dermatitis had a clear relation with the allergen containing product. Preferably

there was data after elimination but this was only available in a few cases. The relevance was

found “probable” when there was a strong relation between allergen and exposure but the

above criteria couldn’t be met. A “possible” relevance was given when the relation between

exposure and dermatitis was less clear but suspect for contact dermatitis. The relevance score

“unlikely-not” was given when contact dermatitis wasn’t suspected or was due to a cross

reaction.

Excel software (Microsoft Office 2007) was used to store and manage the data. Statistical

analysis was performed using SPSS software (2011, IBM SPSS Statistics, Version 20.0.

Armonk, NY). A chi square test was used to evaluate differences between groups. The

Fisher’s exact test was used in cases of low cell counts. A value of p<0,05 was considered

statistically significant.

1083 Patients referred

for patch testing

AMC

n=384

VUmc

n=463

UMCG

n=237

Excluded

n=53

Excluded

n=5

Excluded

n=13

n=5 no show on

reading day

n=48 only tested

with additional

series

n=5 only tested with

additional series

n=13 only tested

with additional

series

Diagram 1. Excluded patients


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Table 1. Overview of allergens tested in the European Baseline series and routinely tested extra allergens.

Allergens were tested in petrolate (pet) or aqua (aq) in all University hospitals unless noted otherwise. 1Tested in

AMC. 2Tested in VUmc. 3Tested in UMCG. 4TRUE-test allergens.

Table 2. Overview of the materials used in the University Hospitals

EUROPEAN BASELINE SERIES ROUTINELY TESTED EXTRA ALLERGENS

Substance Concentration Substance Concentration Potassium dichromate

0.5% pet Disperse blue 106

2,3 0.3% pet

Neomycine sulfate 20% pet Diazolidinyl urea2,3 2% pet Thiuram mix 1% pet Imidazolidinyl urea2,3 2% pet p-Phenylenediamine (PPD) 1% pet Turpentine peroxide2 0.3% Fragrance mix II 14% pet 2-Bromo-2nitropropane-1,3-diol2,3 0.25% pet Clioquinol 5% pet Amerchol L-1012 50% pet Mercapto mix 2% pet p-Tolueensulfonamide2,3 10% pet Formaldehyde 1% aq Cocamidopropyl betaine (CAPB)2 1% aq Caine mix 10% pet 2-n-Octyl-4-isothiazolin-3-on2 0.1% pet Colophonium 20% pet Iodopropyl butylcarbamate (IPBD)2 0.2% pet N-isopropyl-N-phenyl-4-phenylenediamine (IPPD) 0.1% pet Sorbitan sesquioleate (SSQ)2 20% pet Lanolin (wool alcohols) 30% pet Methylisothiazolinone2 0.05% aq Myroxylon pereirae (Balsam of Peru) 25% pet Benzophenone 42 10% pet Epoxy hars 1% pet Propyl gallate2 0.5% pet Paraben mix 16% pet 3-dimethylamino-1-propylamine

(DMAPA)2 1% pet

p-tertButylfenolformaldehyderesin 1% pet p-Toluenediamine2,3 1% pet Fragrance mix I 8% pet 4-aminoazobenzene3 0,25% pet Budesonide 0.01% pet Disperse orange 3

3 1% pet

Nickel 5% pet Disperse yellow 33 1% pet Quaternium-15 1% pet Hydroxymethylpentylcyclohexenecarboxaldehyde (Lyral)

5% pet

Cl/Me-isothiazolinone (Kathon CG) 0.01% aq Mercaptobenzothiazole (MBT) 2% pet Tixocortol-21-pivalate 0.1% pet Sesquiterpene lactone mix 0.1% pet Methyldibromoglutaronitril (Euxyl K-400) 0.3% pet Cobalt chloride 1% pet Primine1,2 0.01% pet Benzocain1 5% pet 1,2-Benzisothiazolin-3-one (BIT) 0,05% pet Wood tar mix1 5% pet 4,4-diaminodiphenylmethane1,3 0,50% pet Quinolone mix2,3,4 0,19 mg/cm2 Black rubber mix2,3,4 0,075 mg/cm2 Thimerosal2,3,4 0,0080 mg/cm2 Carba mix

2,3,4 0,25 mg/cm2

Ethylene diamine dihydrochloride2,3,4 0,050 mg/cm2

University Hospital Period Allergens AMC 1996-2012 Allergens from Chemotechnique Diagnostics®

VUmc 2004-2013 Primarily allergens from Trolab® Almirall, additionaly TRUE-test

UMCG 2002-2013 Primarily TRUE-test, additional allergens from Trolab® Almirall


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RESULTS

PRIMARY ANALYSIS

A total of 1012 patients were included in this research, 37% was male and 63% female. In

total 469 children had at least one positive reaction giving a sensitization rate of 46%

(469/1012). The percentage of children with a monosensitization was 47%, 27% had a

polysensitization (≥ 3 reactions). There were 954 reactions to multiple allergens in total.

These reactions were in 12% of past relevance and of current relevance in 87%, it was

unknown in 1%. The current relevance score was “certain”, “probable” or “possible” in 73%.

The relevance of the reactions was scored as “certain” in 26%, “probable” in 19%, “possible”

in 28%, “unlikely-not” in 21% and was unknown in 6%.

The mean age in this population was 13.3 years [0-17]. We divided the patients in three age

groups. The representation of patients from different age-groups 0-4 years, 5-11 years and 12-

18,0 years old was respectively 7%, 24% and 70%. There were 322 children patch tested with

the TRUE-test, 691 children were tested with chamber test methods combined with allergens

from Chemotechnique or Almirall. One patient was patch tested with both systems. In total

525 children (52%) were affected by atopic dermatitis, 397 children (39%) had no atopic

dermatitis. In 9% the atopic status was unknown or unclear. The sensitization rate of children

with and without atopic dermatitis was respectively 48% and 47%.

The primary aim of this study was to determine the most common allergens in children with a

suspected contact dermatitis. A ranking of the most frequent reactions is listed in table 3. The

most common allergens were metals, detergents, wool alcohols, fragrances and rubbers.

Nickel was the most common sensitizer with 16.4%. It had a current “certain-probable”

relevance of 25% and was in 29% associated to a past clinical episode. Surprisingly

cocamidopropyl betaine (CAPB), a substance that isn't tested in the EBS was the second most

common after nickel with positive reactions in 15,9%. Of the reactions to CAPB 56% had a

"certain-probable" current relevance. The next most common allergen was fragrance mix I

with 9.9% and had an associated "certain-probable" current relevance of 54%. The wool

alcohols (wool alcohols 30% pet and amerchol L-101) were also among the most frequent

reactions in this population with 8.8 and 6%. These were clinically relevant in about the half

of the cases with a relevance of respectively 50 and 54%. From the reactions to amerchol L-

101 there was in nine cases a simultaneous reaction to wool alcohols. The next most common

sensitizers were cobalt (6.0%), wood tar mix (5.4%) and dimethylaminopropylamine

(DMAPA) with 5.0%. DMAPA had a positive patch test together with CAPB in six cases

(60%). Budesonide and tixocortol-21 pivalate, indicators of a corticosteroid allergy, were

among the lesser frequent reactions with 0.2 and 0.8%. Not one positive reaction to clioquinol

or the quinolone mix was found, it was tested in 996 children. When comparing the patch test

reactions between genders some differences were observed. The metals nickel and cobalt

were significantly more common in females. Nickel had more reactions in females with 22%

versus 7.6% (p<0.01). In cobalt the difference was less prominent with 7.3 versus 3.8%

(p<0.05). p-Phenylenediamine PPD was a significantly more common allergen in females

(p<0.01). CAPB had more frequent positive patch test reactions in the male population

(p<0.05). Also reactions to 2-n-octyl-4-isothiazolinon-3-on (p<0,05) and neomycine (p<0,02)

were significantly more common in boys.


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Substance Percentage positive female

Percentage positive

male

p-value male vs female

Percentage positive AD+

Percentage positive AD-

p-value AD+ vs AD- Certain- probable- current relevance

16,4% (164/998) Nickel 22% 7,6% p<0,01 (0,000) 15,8% 17,5% 0,481 25%

15,9% (54/339) Cocamidopropyl betaine 13,0% 21,6% p<0,05 (0,041) 19,0% 12,1% 0,106 56% 9,9% (100/1008) Fragrance mix I 9,7% 10,4% 0,711 12,1% 8,1% p<0,05 (0,048) 54%

8,8% (30/339) Amerchol L-101 9.0% 8,6% 0,915 12,6% 5,3% p<0,04 (0,030) 50% 6,2% (63/1009) Wool alcohols 5,7% 7,1% 0,352 7,8% 4,3% p<0,04 (0,030) 54%

6,0% (60/997) Cobalt chloride 7,3% 3,8% p<0,05 (0,023) 4,5% 8,1% p<0,03 (0,023) 23%

5,4% (12/221) Wood tar mix 7,3% 3,1% 0,175 5,2% 6,7% 0,635 25%

5% (10/201) Dimethylaminopropylamine 4,1% 6,3% 0,499 5,3% 4,0% 1,00 70%

4,9% (28/574) Fragrance mix II 5,1% 4,5% 0,773 5,3% 4,3% 0,572 61%

4,4% (30/675) N-isopropyl-N-phenyl-4-phenylenediamine

5,1% 3,4% 0,296 4,7% 4,4% 0,858 20%

3,8% (38/1004) Myroxylon pereirae 3,3% 4,6% 0,324 5,6% 2,0% p<0,01 (0,005) 55%

3,4% (11/322) Black rubber mix 3,7% 2,9% 0,717 0,6% 6,5% p<0,01 (0,005) 18%

3,3% (33/999) Potassium dichromate 2,5% 4,6% 0,082 3,1% 3,8% 0,573 49%

2,8% (13/460) Diaminodiphenylmethane 3,7% 1,2% 0,154 2,6% 3,8% 0,484 46%

2,7% (4/146) Aminoazobenzene 3,4% 0 1,0 1,5% 5,2% 0,336 75%

2,7% (4/146) Disperse orange 3 3,4% 0 1,0 1,5% 5,2% 0,336 25%

2,7% (4/146) Disperse yellow 3 3,4% 0 1,0 1,5% 5,2% 0,336 50%

2,7% (6/313) p-Toluenediamine

2,6% 0 0,342 0,6% 3,9% 0,095 83%

2,7% (9/339) Sorbitan Sesquioleate 1,3% 5,2% 0,068 4,0% 1,5% 0,309 11%

2,6% (6/231) Benzophenone 4 1,4% 4,5% 0,205 3,8% 1,2% 0,407 0%

2,4% (24/997) p-Phenylenediamine 3,5% 0,5% p<0,01 (0,003) 2,1% 3,0% 0,392 75%

2,3% (18/773) Caine-Mix III 2,6% 1,8% 0,505 2,5% 2,0% 0,617 0%

2,1% (21/1001) Colophonium 2,1% 2,2% 0,913 1,4% 2,8% 0,125 43%

1,8% (4/221) Compositae mix 1,7% 2,1% 1,00 3,2% 1,1% 0,356 25%

1,7% (17/1000) Cl/Me-isothiazolinone 1,7% 1,6% 0,876 2,5% 0,8% 0,072 53%

1,7% (4/231) Propyl gallate 0,7% 3,4% 0,156 1,5% 2,3% 0,651 25%

1,7% (9/545) Hydroxymethylpentylcyclohexenecarboxaldehyde

2,3% 0,5% 0,269 2,5% 0,9% 0,312 100%

1,5% (15/998) p-tertButylfenolformaldehyderesin 1,4% 1,6% 0,972 1,6% 1,5% 0,968 13%

1,5% (15/996) Neomycine sulfate 0,8% 2,7% p<0,02 (0,017) 1,0% 1,5% 0,647 13%

1,5% (15/1002) Mercapto mix 1,0% 2,4% 0,066 1,2% 2,0% 0,297 33%


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Table 3. Ranking of the routinely tested allergens.

1,4% (14/1002) Thiuram mix 1,6% 1,1% 0,500 1,2% 1,8% 0,445 29%

1,4% (4/290) Methylisothiazolinone

1,6% 1,0 % 1,0 1,9% 0,9% 0,638 100%

1,3% (4/310) Benzocain 1,7% 0,8% 0,644 1,9% 0,8% 0,634 0%

1,2% (8/661) Carba mix 0,9% 1,8% 0,451 1,7% 0,4% 0,248 38%

1,1% (11/998) Methyldibromoglutaronitrile 0,8% 1,6% 0,225 1,4% 0,8% 0,527 36%

1,1% (7/661) Thiomersal 1,1% 0,9% 1,00 0,6% 1,6% 0,248 0%

1,0% (10/995) Sesquiterpene lactone mix 0,8% 1,4% 0,388 1,2% 0,3% 0,146 30%

1,0% (10/1000) Mercaptobenzothiazole 0,6% 1,6% 0,187 1,0% 1,0% 1,0 40%

1,0% (3/290) 2-n-Octyl-4-isothiazolin-3-on 0 2,9% p<0,05 (0,047) 1,3% 0,9% 1,00 33%

0,9% (6/661) Ethylene diamine dihydrochloride

0,5% 1,8% 0,099 0,6% 1,3% 0,426 0%

0,9% (9/995) Quaternium 15 1,1% 0,5% 0,498 1,4% 0,5% 0,313 33%

0,9% (9/1001) Parabenen mix 1,0% 0,8% 1,00 0,8% 1,3% 0,512 33%

0,9% (3/339) Iodopropynyl butyl carbamate 0,4% 1,7% 0,271 1,1% 0,8% 1,00 67%

0,8% (8/996) Epoxy resin 0,8% 0,8% 1,00 0,8% 1,0% 0,734 0%

0,8% (8/1003) Tixocortol-21-pivalate 1,1% 0,3% 0,270 1,3% 0,3% 0,148 38%

0,7% (3/438) Imidazolidinyl Urea 1% 0 0,554 0 1,8% 0,077 67%

0,6% (6/1000) Formaldehyde 0,8% 0,3% 0,421 1,0% 0,3% 0,242 50%

0,6% (4/670) Primine 0,7% 0,4% 1,000 1,2% 0 0,132 25%

0,6% (2/339) Turpentine peroxide 0 1,7% 0,116 0 0,8% 0,431 0%

0,5% (2/438) 2-Bromo-2-nitropropane-1,3-diol

0,3% 0,7% 0,551 0,4% 0,6% 1,00 100%

0,3% (1/389) 1,2-Benzisothiazolin-3-one 0 0,7% 0,344 0 0 - 100%

0,2% (2/1003) Budesonide 0 0,5% 0,138 0,4% 0 0,509 50%

0,2% (1/438) Diazolidinyl urea 0,3% 0 1,00 0 0,6% 0,422 100%

0,2% (1/438) Disperse blue 106 0,3% 0 1,00 0,4% 0 1,00 0%

0,0% (tested:322) Quinolone mix

0.0% (tested:674) Clioquinol


11

Looking at the differences between children with and without atopic dermatitis it comes to

notice that there are some prominent differences between these groups. Amerchol L-101,

which was routinely tested in VUmc, and wool alcohols, tested routinely in the European

baseline series, were significantly more common in the group of children with atopic

dermatitis (13% versus 5% and 8% versus 4% respectively) Wool alcohols had a "certain,

probable" current relevance of 66% in the group of children with atopic dermatitis versus 29%

in children without atopic dermatitis. This difference in relevance was also observed for

Amerchol L-101 with 59% versus 14% in the group of children without atopic dermatitis.

Also fragrances were more common in the group of children with atopic dermatitis. Fragrance

mix I shows a significant difference with respect to the group of children with atopic

dermatitis (12.1% versus 8.1%, p<0.05). Myroxylon pereirae also had frequently positive

reactions in this group (5.6% versus 2.0% p<0.01). Finally another interesting observation in

this group of children was that reactions to chloormethylisothiazolinone were more common

however no significance was reached (2,5% vs 0,8%).

There were some allergens that had frequently more reactions in the group without atopic

dermatitis. Cobalt chloride had a sensitization rate of 8% in children without atopic dermatitis

versus 5% in atopic dermatitis (p<0.03). The relevance rates for both groups were about equal

with 26% and 28%. Black rubber mix was more common in children without atopic dermatitis

with 7% versus 1% (p<0.01).

Differences between age-groups were observed. The percentage of positive reactions was

higher in the age group of 0-4 years old with 54% which was 42% in children of 5-11 years

and 48% in children of 12-17 years. Reactions to nickel and wool alcohols were more

common in the younger age group. The reactions to wool alcohols 30% pet seem to decrease

with age and reactions were significantly more common in the age group of 0-4 years

compared with children older than 12 years (p<0.05). Also fragrances often had reactions in

the age group of 0-4 years. In the age group of 12-18 years nickel was the most common

allergen with 17.0%.

These age-groups were also divided over children with and without atopic dermatitis. Wool

alcohols were more common in children of 0-4 years with atopic dermatitis (15.6%)

compared with the age group of 12 years and older (6.4%) but no significance was reached.

Nickel and CAPB were the most common in children older than 12 years regardless of the

atopic status. Fragrances were among the most common allergens in all age-groups.

Table 4. Reactions divided over age-groups.

0-4 YRS (n=70) Substance 5-11 YRS (n=240)

Substance 12+ YRS (n=702)

Substance

25,0% (1/4) Amerchol L-101 13,5% (7/52) Amerchol L-101 17,0% (119/701)

Nickel

25,0% (1/4) SSQ 13,5% (7/52) CAPB 16,6% (47/283)

CAPB

22,4% (15/67) Nickel 13,4% (32/238) Fragrance mix I 8,8% (62/701) Fragrance mix I

12,9% (9/70) Wool alcohols 13,0% (30/230) Nickel 7,8% (22/283) Amerchol L-101

8,7% (6/69) Fragrance mix I 7,6% (18/238) Wool alcohols 6,4% (45/701) Cobalt chloride

8,0% (2/25) 4,4 diaminodiphenylmethane

5,8% (3/52) SSQ 5,7% (9/158) DMAPA

7,1% (1/14) Fragrance mix II 5,6% (13/231) Potassium dichromate

5,5% (8/145) Wood tar mix

6,1% (4/66) Cobalt chloride 5,5% (3/55) Wood tar mix 5,3% (24/449) Fragrance mix II

6,1% (2/33) IPPD 5,0% (7/141) IPPD 5,1% (36/701) Wool alcohols

6,1% (2/33) Black rubber mix 4,8% (11/230) Cobalt chloride 4,2% (21/501) IPPD

% children ≥1 reaction

54,3% % children ≥1 reaction

42,1% % children ≥1 reaction

47,7%


12

0-4 yr ATOPIC DERMATITIS NO ATOPIC DERMATITIS 50,0% (1/2) Amerchol L-101 20,0% (1/5) Black rubber mix 50,0% (1/2) Sorbitan Sesquioleate 16,7% (1/6) Ethylene diamine dihydrochloride

26,2% (11/42) Nickel 15,4% (2/13) Nickel 15,6% (7/45) Wool alcohols 12,5% (1/8) Diaminodiphenylmethane

11,1% (1/9) Fragrance mix II 7,7% (1/13) Multiple substances1

5-11 yr 25,0% (6/24) Amerchol L-101 11,9% (12/101) Fragrance mix I 20,8% (5/24) Cocamidopropyl betaïne 11,1% (4/36) Black rubber mix

15,4% (18/117) Fragrance mix I 11,1% (11/99) Nickel 15,3% (17/111) Nickel 9,1% (2/22) Wood tar mix

8,5% (10/118) Wool alcohols 8,0% (8/100) Potassium dichromate, wool alcohols

12+ yr 18,9% (28/148) Cocamidopropyl betaïne 19,9% (56/282) Nickel 14,7% (53/361) Nickel 13,8% (15/109) Cocamidopropyl betaïne 11,6% (42/361) Fragrance mix I 8,5% (24/282) Cobalt chloride 10,1% (15/148) Amerchol L-101 6,7% (19/282) Fragrance mix I

6,4% (23/361) Wool alcohols 6,7% (5/75) p-Toluenediamine

Table 5. Overview of the most common allergens divided over age groups and atopic status. 1Potassium

dichromate, cobalt chloride, fragrance mix I and wool alcohols.

SECONDARY ANALYSIS; EMERGING ALLERGENS?

We analyzed all the allergens outside the EBS from routinely tested series and series tested on

indication in order to detect emerging allergens. A cut-off value of 200 times tested at

minimum was used. There were 1362 reactions in total. Sensitization rate (children with ≥ 1

reactions) over the series tested routinely and on indication was 52% (528/1362). The

following allergens were the most common; CAPB (13.5%), amerchol L-101 (11.2%),

DMAPA (5.2%), toluenediamine (4.4%) and oleamidopropyl dimethylamine (3.9%) as listed

in table 6. Toluenediamine had a positive patch test result in 18 women (5.6%) and no

positive reactions in males were found, this difference was significant (p<0.03).

Interestingly, when comparing atopic dermatitis versus non atopic dermatitis, CAPB is

significantly more common in the group of children with atopic dermatitis (p<0.02). This

difference was not observed in the primary analysis. DMAPA was just as common in both

groups. CAPB and oleamidopropyl dimethylamine were both more common in the male

versus female population. For CAPB it was 21% versus 11% (p<0.01), and for

oleamidopropyl dimethylamine it was 11% versus 2% (p<0.03).

Outside EBS Substances tested ≥200 times

13,5% (73/539) Cocamidopropyl betaïne,2

11,2% (49/436) Amerchol L-1011

5,2% (11/210) Dimethylaminopropylamine

4,4% (18/412) p-Toluenediamine3

3,9% (8/204) Oleamidopropyl dimethylamine2

Table 6. Allergens from series tested routinely and on indication (outside the European baseline series), that

were tested at least 200 times. CAPB en Amerchol L-101 was significantly more common in the children with

atopic dermatitis. 1Significantly more common in atopic dermatitis as in the primary analysis. 2CAPB en

oleamidopropyl dimethylamine had significantly more reactions in males. 3Toluenediamine reacted significantly

more frequent in the female population (p<0.03).


13

Table 7. Reactions in TRUE-test and chamber patch test preparations.

TRUE-TEST VERSUS CHAMBER PATCH TEST PREPARATIONS

When analyzing the data fewer reactions were observed in patients tested with the TRUE-test.

Only 34% of the children tested with the TRUE-test had one or more reactions. In the

population tested with the chamber methods this percentage was 42%. The population

characteristics were the same in patients tested with TRUE-test and chamber techniques with

respectively a mean age of 12.8 and 13.5 years, atopic dermatitis 53% and 51%.

It was noticed that in one University Hospital which only used the TRUE-test there were no

positive reactions to wool alcohols. When data from testing with the TRUE-test were

compared with data from chamber patch test preparations, only four reactions to wool

alcohols were found in the TRUE-test data vs. 59 reactions in the chamber test preparations.

Reactions to fragrance mix I were also significantly less commonly found in the TRUE-test

versus the patch test with chamber patch test preparations (p<0.01). This was also observed

for balsam of Peru (p<0.03) and caine mix (p<0.01).

TRUE-test Chamber devices p-value

Nickel 17,10% 16,10% 0.703

Black rubber mix/ IPPD 3,40% 4,40% 0.445

Cobalt chloride 4,30% 6,80% 0.126

Fragrance mix I 3,70% 12,70% p<0,01 (0,00)

Potassium dichromate 2,80% 3,40% 0,631

Colophonium 2,50% 1,90% 0,557

p-Phenylenediamine 2,20% 2,50% 0,74

p-tertButylfenolformaldehyderesin 2,20% 1,30% 0,322

Cl/Me-isothiazolinone 2,20% 1,50% 0,424

Myroxylon pereirae 1,90% 4,70% p<0,03 (0,028)

Mercapto mix 1,20% 1,60% 0,648

Wool alcohols 1,20% 8,60% p<0,01 (0,000)

Carba mix 0,90% 1,50% 0,523

Ethylene diamine dihydrochloride 0,90% 1,10% 1

Epoxy resin 0,90% 0,70% 0,718

Caine mix 0,60% 3,50% p<0,01 (0,008)

Quaternium 15 0,60% 1,00% 0,726

Neomycine sulfate 0,60% 1,90% 0,164

Thiuram mix 0,60% 1,80% 0,247

Thiomersal 0,30% 1,80% 0,124

Formaldehyde 0,30% 0,70% 0,67

Mercaptobenzothiazole (MBT) 0,30% 1,30% 0,181

Parabenen mix 0 1,30% 0,065

Children ≥ 1 reaction 34% 42%


14

DISCUSSION

In previous studies positive patch test rates in children have been reported ranging from 25%

to 83% [9;10;16;17]. In this retrospective study 46% of the children had one or more positive

patch test reactions which were of current relevance in 87% and of past relevance in 12%. The

number of reactions in males and females was about equal (35% versus 31%). The most

common allergens were metals, fragrances, wool alcohols, rubbers and detergents which are

discussed in this paper.

Nickel had the highest sensitization rate of 16,4%. In spite of nickel regulation rules initiated

by the government, nickel is still the most common allergen [18]. Contact dermatitis for

nickel and cobalt were significantly more common in females (p<0,05). This was found in

multiple studies [10;16;19;20] and may be due to the use of jewelry and ear piercings which is

an important source of nickel sensitization [21;22]. Nevertheless the reliability of patch test

reactions to metals in children was questioned. In a study of Mortz et al. [23] a low

reproducibility was demonstrated indicating a low clinical relevance and false positive

reactions to metals. In our research nickel had a current ("certain-probable") relevance of 25%

and past relevance of 29%.

Cocamidopropyl betaine (CAPB) and dimethylaminopropyl amine (DMAPA) are detergents

used in rinse off products like liquid soaps. CAPB was one of the leading substances which

was tested positive frequently with 15,9%. In 56% of the cases the current relevance was

"certain-probable". Apart from eight reactions, all the 54 reactions had a crescendo pattern

suggestive of contact allergy. This suggests that CAPB could be an important cause of contact

dermatitis in children. However, detergents are difficult to patch test because they are known

to have irritating properties. Also in previous studies CAPB showed to be a substance with

dermally irritating properties [24;25]. Male sex was a risk factor for a positive patch test

(p<0.05). This was also observed in the study of Schnuch et al. [24] and might be related to

males being more reactive to irritating substances. CAPB can contain multiple impurities like

dimethylaminopropyl amine (DMAPA) and aminoamine which may be the real sensitizers in

CAPB [24]. DMAPA had a high percentage of positive reaction with 5% and was patch tested

positive with CAPB in six out of 10 cases.

Wool alcohols as tested in the European baseline series (wool alcohols 30% pet) and

amerchol L-101 frequently showed positive patch test reactions. In this research we observed

a positive patch test reaction to wool alcohols in 6% of cases. Also amerchol L-101 was one

of the most common allergens with a prevalence of 9%. A high number of children with

atopic dermatitis (52%) could be the cause of this observation as described later in this paper.

The reactions had a strong relation with the clinical symptoms in about half of all cases.

Varying sensitization rates to wool alcohols have been reported. A study by Seidenari et al.

[10] tested 1094 children with a suspected contact dermatitis below 12 years old and observed

in 10.1% a positive patch test. In a study by Roul et al. [9] in 337 children aged 1 to 15 years

a rate of 8.6% was found. In a study of Goon et al. [19] where 2340 patients below the age of

21 were tested , lanolin was one of the most common allergens with a positive patch test rate

of 8%. However, some studies in children showed a much lower prevalence of reactions to

wool alcohols [16]. This might be explained by the low prevalence of atopic dermatitis in

these populations.

Fragrances (fragrance mix I, fragrance mix II and myroxylon pereirae) were also among the

most common allergens and found to be important causes of allergic contact dermatitis in

children. Contact dermatitis to fragrances in children might be an underestimated problem.

Children are exposed at early age to a variety of different fragrance allergens in cosmetics and


15

toiletries [26] which are a common source of sensitization. There was no difference in

frequency of reactions to fragrances related to gender.

Cobalt and black rubber mix frequently show more positive patch test reactions in children

without atopic dermatitis. This was the first study, to my knowledge, to report this. We found

zero reactions to clioquinol, an antibacterial agent, while it was tested in 996 children. This

suggests that contact allergy to clioquinol is a very rare cause of contact sensit ization in

children and routine testing is not indicated.

ATOPIC DERMATITIS AND CONTACT DERMATITIS

The relation between atopic dermatitis (AD) and allergic contact dermatitis is not clear and is

a matter of controversies. Higher, lower and equal positive patch test reactions in patients

with AD have been reported in several studies [8-12]. In this study the sensitization rates were

about the same; in children with AD it was 48% versus 47% in patients without AD. A lower

sensitization rate in atopic dermatitis is traditionally explained by the activated immune

response resulting in a decreased risk of contact dermatitis [27]. In spite of this, AD might be

a risk factor for developing ACD [28]. The skin of patients with atopic dermatitis may be

more vulnerable because of an impaired skin barrier and due to this dysfunctional barrier

allergens could penetrate leading to sensitization [28-31]. As a result sensitization to weak

allergens can occur more frequently in patients with AD [32;33]. Also fillagrin mutations

were associated with contact sensitization in patients with atopic dermatitis as described by

Thyssen et al [31]. Patients with AD often use topical medicaments which can contain

multiple allergens. We found reactions to tixocortol- 21-pivalate to be more common in

children with AD (seven out of eight reactions). Budesonide had only two reactions, both in

patient with AD. Previous research by Maihol et al [34] found that the use of topical

medicaments and emollients was associated with allergic contact dermatitis in AD.

In spite of children with AD being more susceptible for allergic contact dermatitis because of

a decreased barrier function also irritation is more common in this group due to the same

reason. Therefore AD is a risk factor for both allergic and irritative dermatitis. Patients with

AD have a lower threshold for irritation compared with healthy controls [35]. As a

consequence more false positive reactions due to irritation in patch testing can occur and the

reactions should be interpreted with caution because of this. However, irritancy might also

play a role in the development of contact cutaneous hypersensitivity, as argued in the danger

hypothesis that only in the presence of a 'danger' signal for example irritancy a patient

becomes senstitized [35]. Also it is not uncommon for irritative and allergic dermatitis to

coexist [36]. Nevertheless, in some studies it has been argued that children with atopic

dermatitis have hyperirritable skin and therefore false positive reactions could be more

prominent in this group (so called ‘angry back’ reactions or the excited skin syndrome) [37-

39]. In our research there was a current, "certain-probable" relevance of 45% of all observed

reactions in which there was a strong relation of the allergen with the clinical symptoms and

therefore contradicts false positive reactions.

Reactions to wool alcohols (wool alchohols 30% pet and amerchol L-101) and fragrances

(fragrance mix I and myroxylon pereirae) were significantly more common in the group of

children with atopic dermatitis. Wool alcohols (lanolin) is a substance that comes from the

sebaceous glands of sheep, and it is a complex mixture containing lanolin alcohols and acids

[40]. It is used in a variety of cosmetics, emollients and topical medicaments. Most

researchers agree that the most allergenic potential lies in the alcoholic fraction of lanolin

[40]. We found that a positive patch test for wool alcohols was significantly more common in

the group of children with atopic dermatitis (8% versus 4%, p<0.04). This difference was also

found for amerchol L-101 (13% versus 5%, p<0.04). A positive patch test for wool alcohols

was also of much higher relevance compared to children without atopic dermatitis (66%


16

versus 29% "certain- probable", current relevance), indicating that these reactions are not only

more common in children with atopic dermatitis, but they are also more relevant.

In a retrospective study of the North American Contact Dermatitis Group (NACDG) lanolin

was among the allergens with the highest clinical relevance [41]. A large retrospective

analysis of 26,479 patients of all ages with a suspected allergic contact dermatitis, patch tested

by the NACDG found positive patch test reactions for wool alcohols in 2.5% which were of

current relevance in 83,4% [42]. This is a lower prevalence than we observed in our study but

might be explained by our younger population below 18 years old. Lanolin-positive patients

were 1.4 times more likely to have a history of atopic dermatitis when compared to allergic,

but lanolin-negative, patients (p<0.01) [42]. Whether this was due to an ‘angry skin’ reaction

of patients with atopic dermatitis or if these were true allergies caused by lanolin containing

medication was not known. Another large retrospective study of contact allergy to wool

alcohols with 24,449 patients of all ages by Wakelin et al. [43] did not find a significant

difference in patients with or without atopic dermatitis. This is a discrepancy with our study

which might be explained by our focus on children who often have atopic dermatitis and

therefore a high exposure to wool alcohols.

Apparently the value of a positive patch test to wool alcohols in the detection of lanolin

allergy is a matter of debate. Several studies have shown conflicting evidence as outlined in

reviews [40;44]. Kligman claimed that lanolin is at most a weak allergen which may also have

slight irritancy potential [45] and that sensitization rates only exist in patients with chronic

dermatitis [46]. A lanolin paradox has been described by Wolf et al. [47] which states that

patients with a impaired skin barrier can easily be sensitized by wool alcohol containing

medicaments but can use wool alcohols in cosmetics on intact skin without any problems.

These discrepancies have led to an alternative hypothesis that the high frequency of positive

patch test reactions to wool alcohols were caused by hyperirritable skin [45;46]. However, the

high clinical relevance score for wool alcohols in our research indicates that lanolin allergy is

a significant problem in children, especially those with atopic dermatitis. The clinical

experience is that it can be a real issue in children with atopic dermatitis. Children with atopic

dermatitis are exposed to lanolin based medicaments at frequent basis, sometimes for years.

This might result in sensitization and allergic contact dermatitis. It is possible that atopic

patients respond to very low concentrations of contact allergens due to the impaired skin

barrier. It is imperative that contact dermatitis should be suspected in children with

recalcitrant atopic dermatitis. When despite adequate therapy the dermatitis does not respond,

or even gets worse instead of better, contact allergy to wool alcohols needs to be considered.

However, to rule out false positive reactions to wool alcohols a provocative use test should be

recommended.

Also the fragrances, fragrance mix I and myroxylon pereirae were more common in the group

of children with atopic dermatitis. Myroxylon pereirae, better known as balsam of Peru, had

significantly more reactions in children with atopic dermatitis (p<0,01). These observations

are confirming previous research performed by Thyssen et al. [27] who also found reactions

to fragrances significantly more common in patients with atopic dermatitis. Herro et al. [48]

also found fragrance and myroxylon pereirae to be significantly more common in children

with atopic dermatitis. Apparently these are important allergens especially in children with

atopic dermatitis and sensitization should be prevented by reducing the use of fragrance

containing products.

AGE AND CONTACT DERMATITIS

The sensitization rate of the routinely tested allergens in the group of children between 0-4

years old was 54%, this was higher compared with the other age groups (42% in 5-11 years

and 48% in 12-18 years) but no significance was reached. Although it was generally accepted


17

that sensitivity to allergens increases with age because of the increased exposure to allergens

[1;19] a high sensitization rate in young children was reported in several papers [8-11;49]. In

a study of Seidenari et al. [10] in 1094 children an overall sensitization rate of 52.1% was

found, while children under three years had the highest sensitization rate of 63,4% compared

with other age groups. In the study of Roul et al. [9] in 337 children the highest sensitization

rate was among the children of less than three years old with 88%. An age-related barrier

dysfunction in young children who in the majority of cases suffer from atopic dermatitis was

suggested as a cause of the high rates [9]. These high rates of positive patch tests could be

caused by irritant reactions [1] as children below the age of 8 years are considered more

susceptible to skin irritation [50]. However multiple other studies have not observed any

differences in sensitization rates [1;16;51;52].

Fragrances were common in all age groups. Wool alcohols frequently show more positive

reactions in the age group of 0-4 years compared with the age group of 12 to 17 years

(p<0.05) and the sensitization rates seems to be decreasing with age. When looking at the

allergens divided over age groups and atopic dermatitis we found that the wool alcohols are

the most prominent in the group of children with atopic dermatitis. This can be related to

young children having more active atopic dermatitis and the use of topical medicaments but

also an age-related barrier dysfunction leading to false positive reactions have to be

considered. This is consequently the explanation why there were less reactions to wool

alcohols in the older age-groups.

SECONDARY ANALYSIS; EMERGING ALLERGENS?

We performed the secondary analysis on the allergens that were tested on a routine bases and

on indication outside the EBS with the aim to detect new allergens that frequently have

positive reactions and might be emerging. Although there is a risk of selection bias with

testing on indication some observations were interesting. Cocamidopropyl betaine (CAPB)

was the leading allergen with 14%, also substances that are related to CAPB frequently have

positive reactions. These were dimethylaminopropylamine (DMAPA) and oleamidopropyl

dimethylamine. In the study of Militello et al. [53] it was argued that CAPB in the pediatric

population might be a emerging allergen. Although the allergenic potential of these

substances have been questioned they might be a cause of sensitization. However additional

research is needed to detect the allergenic potential of these substances before concluding that

they are important emerging allergens.

When performing the secondary analysis we observed some other interesting differences,

cocamidopropyl betaine was more common in children with atopic dermatitis (p<0.02). This

is confirming the research by Schnuch et al. [24]. CAPB and DMAPA were more common in

the male population, this might be explained by hyper reactivity to irritant stimuli in the male

population [24].

p-Toluenediamine, which often is used as a component in commercial hair dyes, had

significantly more reactions in females (p<0.02, with 6% versus 0%, relevance 94%). This is

associated to the use of these products in the female population which is a source of

sensitization. Also the relevance was remarkably high illustrating the clear association with

the clinical symptoms and use of these products. This is not a emerging allergen but is

important to patch test when allergy for hair dyes is suspected.

TRUE-TEST VERSUS CHAMBER DEVICES

When comparing both test methods we observed some differences in the frequency of

reactions. Strikingly the number of children with a positive reaction to allergens using the

TRUE-test was significantly lower with 34% compared with the chamber method with 42%

(p<0.02). When looking at the allergens, significant differences for wool alcohols, fragrance


18

mix, myroxylon pereirae and caine mix were found which all had less positive reactions using

the TRUE-test. However these test methods were not tested simultaneously in one patient

what hinders the forming of strong conclusions. Previous research has been conducted in

TRUE-test versus Finn chambers [54-56]. A study by Suneja et al. [54] also demonstrated

significantly fewer (relevant) reactions to fragrance mix and balsam of Peru using the TRUE-

test. As the TRUE-test is easy to use in children because it is a "ready to use-test", one should

keep in mind that reactions to fragrances, wool alcohols and caine mix might be missed when

using this patch test system.


19

CONCLUSION

In conclusion, allergic contact dermatitis can be a problem in children and is related to

exposure to a variety of allergens. The children in this population most commonly reacted to

metals, fragrances, wool alcohols, detergents and rubbers. Clioquinol had zero reactions and

routine patch testing of this substance therefore is not indicated in children. Cocamidopropyl

betaine was tested positive frequently and might be an important source of contact allergy in

children. However reactions need to be interpreted with caution because of the possibility of a

higher frequency of irritative reactions. Further research is necessary to determine the allergic

potential of cocamidopropyl betaine and its related substances and data is needed after

elimination to estimate the clinical relevance of the substance.

It is important to consider allergic contact dermatitis in children with atopic dermatitis. The

sensitization rate in children with and without atopic dermatitis was almost equal.

Nonetheless we observed children with atopic dermatitis reacting to different allergens.

Children with atopic dermatitis reacted significantly more frequent to wool alcohols. This is

the first study, to my knowledge, to report significantly more reactions to wool alcohols in

children with atopic dermatitis. The reactions to these allergens were of high relevance, this

indicates that it can be an important problem in this group of children who are exposed to

lanolin-based medicaments. Therefore atopic dermatitis is a risk factor for developing contact

dermatitis to wool alcohols and should always be considered in children with recalcitrant

atopic dermatitis who do not respond to their therapy. However, the main pitfall in patch

testing children with atopic dermatitis is reactions to wool alcohols due to hyperirritable skin.

This is why a provocative use test (a repeat open application test) should be recommended

and the patients with a true allergy for wool alcohols can be detected. Further research is

needed to collect data of provocative use testing, excluding reactions due to the excited skin

syndrome.

Children with atopic dermatitis reacted significantly more frequent to fragrances. These

children are at risk for developing contact dermatitis to fragrances. The use of fragrances in

children with atopic dermatitis should be restricted to prevent sensitization to these allergens.

Finally the differences between the TRUE-test and chamber patch test preparations were

striking and needs further investigation. Reactions to fragrances, wool alcohols and caine mix

were significantly less frequent using the TRUE-test. This was an important observation as

the TRUE-test is a ready to use system and is easy to use in children. It has to be kept in

mind that these allergens might be missed using the TRUE-test and this observation needs

requires further investigation.


20

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allergic contact dermatitis in children - a review of current data. Contact Dermatitis

2011;65:254-265.

2 Bonitsis NG, Tatsioni A, Bassioukas K, Ioannidis JP: Allergens responsible for

allergic contact dermatitis among children: a systematic review and meta-analysis.

Contact Dermatitis 2011;64:245-257.

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21

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22

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APPENDIX

TUSSENTIJDSE EVALUATIE WEEK 6


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TUSSENTIJDSE EVALUATIE WEEK 12


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