patch testing children with aluminium chloride hexahydrate ... · tested with aluminium chloride...

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REVIEW Patch testing children with aluminium chloride hexahydrate in petrolatum: A review and a recommendation Elisabet Bergfors 1 | Annica Inerot 2 | Lars Falk 3,4 | Ulla Nyström 5 | Birger Trollfors 6 1 Department of Public Health and Community Medicine, Unit of Family Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden 2 Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg Sahlgrenska Academy, Göteborg, Sweden 3 Department of Dermatology and Venereology, County Council of Östergötland, Linköping, Sweden 4 Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden 5 Allergy Centre, Linköping University Hospital, Linköping, Sweden 6 Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden Correspondence Dr Elisabet Bergfors, Department of Public Health and Community Medicine, Unit of Family Medicine, University of Gothenburg Sahlgrenska Academy, Box 454 Goteborg 405 30, Sweden. Email: [email protected] Abstract Background: According to studies on adults, patch testing with aluminium chloride hexahydrate 2% pet. is insufficient to detect aluminium allergy, and a 10% prepara- tion is recommended. Other studies suggest that a 2% preparation is sufficient for testing children. Objectives: To review three previously published Swedish studies on patch testing children with aluminium chloride hexahydrate 2% pet. Patients/Methods: Altogether, 601 children with persistent itching subcutaneous nodules (granulomas) induced by aluminium-adsorbed vaccines were patch tested with aluminium chloride hexahydrate 2% pet. and metallic aluminium in (a) a pertussis vaccine trial, (b) clinical practice, and (c) a prospective study. Results: Overall, 459 children had positive reactions to the 2% pet. preparation. Another 10 reacted positively only to metallic aluminium. An extreme positive reac- tion (+++) was seen in 65% of children aged 1 to 2 years as compared with 22% of children aged 7 years. From 8 years onwards, extreme positive reactions were scarce. Conclusions: Aluminium chloride hexahydrate 2% pet. is sufficient to trace aluminium allergy in children. Small children are at risk of extreme reactions. We thus suggest that aluminium chloride hexahydrate 10% pet. should not be used routinely in chil- dren before the age of 7 to 8 years. KEYWORDS allergic contact dermatitis, aluminium, aluminium-adsorbed vaccines, children, itching subcutaneous granulomas, patch test 1 | INTRODUCTION Detecting contact allergy to aluminium by patch testing has been practised since 1980, when Clemmensen tested a young girl with standard allergens enclosed in aluminium chambers (Finn Chambers), and found uniformly strong positive reactions to the edges of the chambers, but no reactions where the vehicles and filter paper discs were interposed. 1 The patient had been hyposensitized with aluminium-precipitated grass allergens during the previous 2 years, and presented with itching erythema in both axillae associated with the use of aluminium-containing antiperspirants. Contact allergy to aluminium was considered to be extremely rare 1-3 until the 1990s, when an unexpectedly high number of cases (n = 377) was reported following vaccination with an aluminium- adsorbed acellular pertussis vaccine in clinical trials in the greater Goth- enburg area in Sweden. 4,5 All vaccines against diphtheria, tetanus, and pertussis (DTP), hepatitis A and B, human papilloma virus and tick- borne encephalitis, as well as some conjugated vaccines against pneu- mococcal and meningococcal infections, are adsorbed to aluminium salts (mostly hydroxide and phosphate) as adjuvants. Most allergen extracts used for allergen-specific immunotherapy (hyposensitization) also contain aluminium adjuvants. Received: 25 March 2019 Revised: 25 April 2019 Accepted: 6 May 2019 DOI: 10.1111/cod.13303 © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis. 2019;81:8188. wileyonlinelibrary.com/journal/cod 81

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Page 1: Patch testing children with aluminium chloride hexahydrate ... · tested with aluminium chloride hexahydrate 2% pet.; all of them reacted positively to this preparation.27 The aims

R E V I EW

Patch testing children with aluminium chloride hexahydratein petrolatum: A review and a recommendation

Elisabet Bergfors1 | Annica Inerot2 | Lars Falk3,4 | Ulla Nyström5 | Birger Trollfors6

1Department of Public Health and Community

Medicine, Unit of Family Medicine, Institute of

Medicine, Sahlgrenska Academy, University of

Gothenburg, Göteborg, Sweden

2Department of Dermatology and

Venereology, Institute of Clinical Sciences,

Sahlgrenska Academy, University of

Gothenburg Sahlgrenska Academy, Göteborg,

Sweden

3Department of Dermatology and

Venereology, County Council of Östergötland,

Linköping, Sweden

4Department of Clinical and Experimental

Medicine, Linköping University, Linköping,

Sweden

5Allergy Centre, Linköping University Hospital,

Linköping, Sweden

6Department of Pediatrics, Sahlgrenska

University Hospital, Göteborg, Sweden

Correspondence

Dr Elisabet Bergfors, Department of Public

Health and Community Medicine, Unit of

Family Medicine, University of Gothenburg

Sahlgrenska Academy, Box 454 Goteborg

405 30, Sweden.

Email: [email protected]

Abstract

Background: According to studies on adults, patch testing with aluminium chloride

hexahydrate 2% pet. is insufficient to detect aluminium allergy, and a 10% prepara-

tion is recommended. Other studies suggest that a 2% preparation is sufficient for

testing children.

Objectives: To review three previously published Swedish studies on patch testing

children with aluminium chloride hexahydrate 2% pet.

Patients/Methods: Altogether, 601 children with persistent itching subcutaneous

nodules (granulomas) induced by aluminium-adsorbed vaccines were patch tested

with aluminium chloride hexahydrate 2% pet. and metallic aluminium in (a) a pertussis

vaccine trial, (b) clinical practice, and (c) a prospective study.

Results: Overall, 459 children had positive reactions to the 2% pet. preparation.

Another 10 reacted positively only to metallic aluminium. An extreme positive reac-

tion (+++) was seen in 65% of children aged 1 to 2 years as compared with 22% of

children aged 7 years. From 8 years onwards, extreme positive reactions were scarce.

Conclusions: Aluminium chloride hexahydrate 2% pet. is sufficient to trace aluminium

allergy in children. Small children are at risk of extreme reactions. We thus suggest

that aluminium chloride hexahydrate 10% pet. should not be used routinely in chil-

dren before the age of 7 to 8 years.

K E YWORD S

allergic contact dermatitis, aluminium, aluminium-adsorbed vaccines, children, itching

subcutaneous granulomas, patch test

1 | INTRODUCTION

Detecting contact allergy to aluminium by patch testing has been

practised since 1980, when Clemmensen tested a young girl with

standard allergens enclosed in aluminium chambers (Finn Chambers),

and found uniformly strong positive reactions to the edges of the

chambers, but no reactions where the vehicles and filter paper discs

were interposed.1 The patient had been hyposensitized with

aluminium-precipitated grass allergens during the previous 2 years,

and presented with itching erythema in both axillae associated with

the use of aluminium-containing antiperspirants.

Contact allergy to aluminium was considered to be extremely

rare1-3 until the 1990s, when an unexpectedly high number of cases

(n = 377) was reported following vaccination with an aluminium-

adsorbed acellular pertussis vaccine in clinical trials in the greater Goth-

enburg area in Sweden.4,5 All vaccines against diphtheria, tetanus, and

pertussis (DTP), hepatitis A and B, human papilloma virus and tick-

borne encephalitis, as well as some conjugated vaccines against pneu-

mococcal and meningococcal infections, are adsorbed to aluminium

salts (mostly hydroxide and phosphate) as adjuvants. Most allergen

extracts used for allergen-specific immunotherapy (“hyposensitization”)

also contain aluminium adjuvants.

Received: 25 March 2019 Revised: 25 April 2019 Accepted: 6 May 2019

DOI: 10.1111/cod.13303

© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Contact Dermatitis. 2019;81:81–88. wileyonlinelibrary.com/journal/cod 81

Page 2: Patch testing children with aluminium chloride hexahydrate ... · tested with aluminium chloride hexahydrate 2% pet.; all of them reacted positively to this preparation.27 The aims

Another side-effect of aluminium-adsorbed vaccines and allergen

extracts that is associated with aluminium allergy is the formation of

long-lasting, intensely itching subcutaneous nodules (granulomas) at

the injection site.1,4,6-12 The nodules appear remarkably late, that is,

weeks or months, after vaccination. Pruritus may last for years and be

very annoying for both child and family. Exacerbation of the symp-

toms with swelling of the nodules and intensified itching is seen in

about 40% of the children when they have common colds or other

ongoing infections.4 Local hypertrichosis, hyperpigmentation and

eczema are common.4,13,14 Vaccination granulomas have been mis-

taken for tumours.15-17 Histopathological examination shows granu-

loma formations surrounding aluminium crystals.18-20 The incidence

of itching granulomas after routine vaccination with DTP at 3, 5 and

12 months was 0.63%, as calculated in a prospective study performed

in eastern Sweden. If a second aluminium-adsorbed (pneumococcal)

vaccine was given concomitantly, the incidence was almost doubled

(1.18%).14

From 2000 to 2014, three separate Swedish studies on vaccine-

induced subcutaneous itching granulomas and contact allergy to alu-

minium were published. They were performed in different settings:

A. In a pertussis vaccine trial4,5

B. In clinical practice by the use of spontaneous reports13

C. In a prospective study in clinical practice14

Altogether, 601 children with persistent itching vaccination granu-

lomas were patch tested with aluminium in these three studies, as

described below in more detail. Sensitization to aluminium was con-

firmed in 475 (79%) of the children. Fortunately, and in contrast to

previous notions, contact allergy to aluminium acquired in childhood

seems to weaken or disappear with time, as shown in follow-up stud-

ies on participants in the pertussis vaccine trials by Gente Lidholm; of

241 children with known aluminium allergy, only 55 (23%) remained

positive when retested 5 to 9 years after the initial patch test.5,21

Traditionally in Sweden, contact allergy to aluminium has been

diagnosed by patch testing with metallic aluminium (an empty Finn

Chamber) and aluminium chloride hexahydrate 2% pet.22,23 A higher

concentration, namely 10% pet., was used by Netterlid et al in a study

including 37 children and young adults who had undergone hyposen-

sitization therapy with aluminium-adsorbed antigen extracts. Eight

patients aged 9 to 21 years reacted positively to the 10% preparation,

but only three of them also reacted positively to the 2% prepara-

tion.23 Another case of a negative result with aluminium chloride

hexahydrate 2% pet. but a positive reaction to the 10% preparation

was described by Bruze in a 15-year-old girl with itchy nodules at the

injection sites of aluminium-adsorbed pollen extracts.24 In a study by

Siemund et al aimed at finding the optimal compound and concentra-

tion for establishing contact allergy to aluminium, 21 adult patients

(aged 23-71 years, mean 48 years) with previously known aluminium

allergy were retested with several aluminium compounds and concen-

trations. Fifteen patients reacted positively to aluminium chloride

hexahydrate 10% pet., but only four of them also reacted positively to

the 2% preparation. The authors’ conclusion was that patch testing

with aluminium chloride hexahydrate 2% pet. is insufficient to detect

contact allergy to aluminium.25

In contrast, our experience of patch testing children with alumin-

ium in the three studies mentioned above (A-C) was that very high

proportions (74%, 86%, and 85%, respectively) not only reacted posi-

tively, but often also reacted strongly to aluminium chloride hexahy-

drate 2% pet.4,5,13,14 This is consistent with a Danish study by Salik

et al, in which 39 of 42 children with vaccine-induced persistent pru-

ritic subcutaneous nodules aged 3 months to 6 years reacted posi-

tively to aluminium chloride hexahydrate 2% pet.26 In a recent French

study by Goiset on the prevalence of contact sensitization to alumin-

ium in a paediatric population, 10 children (mean age 3.7 years) with a

history of vaccine-induced itching subcutaneous nodules were patch

tested with aluminium chloride hexahydrate 2% pet.; all of them

reacted positively to this preparation.27

The aims of this survey were to review three Swedish studies on

patch testing children with aluminium chloride hexahydrate 2% pet.

published previously, and to discuss whether this concentration is suf-

ficient and appropriate for detecting delayed hypersensitivity to alu-

minium in childhood. All photographs in this article are published with

the permission of the children’s parents and, in Figure 4, the (now

adult) persons themselves. The studies were approved by the Regional

Ethical Review Boards in Gothenburg in 2000 (study A) and Linköping

2011 and 2009 (B and C).

2 | STUDIES

2.1 | Study A: Vaccine trial

Four hundred and ninety-five children with itching granulomas after

vaccination with aluminium-adsorbed pertussis vaccines in a clinical

trial in Gothenburg, Sweden, in the 1990s were patch tested for con-

tact allergy to aluminium.4,5 The test kits used comprised aluminium

chloride hexahydrate 2% pet. in a plastic IQ chamber (Chemotechniqe

Diagnotics, Vellinge, Sweden) and an empty Finn Chamber (Epitest,

Tuusula, Finland). All applications were performed by specially trained

nurses. The patches were removed after 2 days, and the test was read

on day (D) 3 by a dermatologist (A.I.). The results were interpreted

according to the recommendations of the ICDRG. Positive reactions

from + to +++ to one or both testing agents were regarded as delayed

(type IV) hypersensitivity. In doubtful cases when the result of the alu-

minium testing did not fulfil the criteria for a + reaction, it was classi-

fied as negative. The children had either been vaccinated at 3, 5 and

12 months with DTP according to the Swedish child vaccination

schedule, or had received one to three doses of pertussis vaccine

alone at 18 months to 10 years. The study vaccines contained 0.5 mg

of aluminium per dose, and were mainly injected subcutaneously.

A positive test result, that is, at least a + reaction to at least one of

the testing agents, was found in 377 children aged 1.6 to 15 years

(median 6.6 years) (76%). The outcomes of the tests in relation to age

are shown in Table 1. Positive results were associated with young age

(<12 years) (relative risk 3.30, 95% confidence interval: 1.86-5.84,

P < 0.0001, Fisher’s exact test). Another 31 children aged 3 to

12 years (median 7 years) had doubtful reactions (?+) to aluminium

chloride hexahydrate 2% pet. and negative results with the Finn

82 BERGFORS ET AL.

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Chamber. They were judged not to be sensitized to aluminium. All but

nine of 377 children reacted positively to aluminium chloride hexahy-

drate 2% pet.; 69% of the reactions were strong (++) or extreme (+++)

positive (Table 2). One of the children with a +++ reaction to alumin-

ium chloride hexahydrate 2% pet., a 3-year-old girl who had

experienced itching subcutaneous nodules induced by the study vac-

cine for half of her life, is shown in Figure 1.

Clinical presentations of contact allergy to aluminium were

reported for several children. Four of them are described here:

Case 1 (Figure 2): This was a 13-year-old girl with persisting

itching granulomas at the injection site of three doses of the study

vaccine given at 6 to 7 years of age. Patch testing at 11 years gave a +

++ positive reaction to aluminium chloride hexahydrate 2% pet., and a

+ positive reaction to an empty Finn Chamber. When the patient

began using deodorants as a teenager, she experienced vast, intensely

itching dermatitis in both axillae that prevented her from using any

effective antiperspirants. A new patch test performed at 15 years of

age yielded a ++ reaction to her own aluminium-containing deodorant,

but no reaction to colophonium, Myroxylon pereirae, or fragrance mix.

Case 2 (Figure 3): This was a 6-year-old boy with persistent itching

granulomas at the injection sites of the study vaccine given at 1 to

2 years of age. The day after he used his father’s aluminium-

containing deodorant, itching dermatitis was seen in both axillae. His

patch test gave a +++ reaction to aluminium chloride hexahydrate 2%

pet., and a + reaction to an empty Finn Chamber.

Case 3 and 4 (Figure 4): These cases were siblings, aged 6 and

4 years, who had both received the study vaccine 1 year earlier. The

girl had an itching nodule at the injection site, and had ++ reactions to

both aluminium chloride hexahydrate 2% pet. and an empty Finn

Chamber. Her brother had no history of itching nodules after the vac-

cination, but did have a ++ reaction to the aluminium salt, and a +

reaction to an empty Finn Chamber. The day after Easter Day, when

the patients had been painted for fun with a rouge containing magne-

sium aluminium silicate on their cheeks and foreheads to resemble

“Easter hags,” both developed red itching dermatitis where the make-

up had been applied. Their older cousin, who had not received the

study vaccine, was painted on his face in the same way without any

reaction.

TABLE 1 Outcome of patch testing for aluminium allergy relatedto age in 495 children with persistent itching subcutaneous nodulesafter vaccination with aluminium-adsorbed vaccines in theGothenburg Pertussis Vaccine trials

Age (y) Number of tested children Positivea (n) Positive (%)

1 1 1 100

2 13 13 100

3 42 38 90

4 53 42 79

5 61 50 82

6 85 76 89

7 77 64 83

8 39 31 79

9 33 19 58

10 37 24 65

11 17 10 59

12 19 5 26

13 4 1 25

14 5 1 20

15 5 2 40

16 3 0 0

18 1 0 0

Total 495 377 76

aPositive reaction: at least a + reaction to aluminium chloride hexahydrate

2% pet. and/or metallic aluminium (empty Finn Chamber).

TABLE 2 Results of patch testing for aluminium allergy in three Swedish studies

Study Median age (y)

at the time of testing(minimum-maximum)

No. of testedchildren with

itchinggranulomas

No. of childrenwho reactedpositively to

aluminium (metaland/or 2% salta)

No. of children (%)with documentedpositive reactionsto 2% salta

(proportion of alltested)

Reaction to aluminium chloridehexahydrate 2% pet.

No. of childrenwith ++ and +++reactions of allwho reacted

positively to 2%salta0 + ++ +++ Positiveb

A. Vaccine trial

7 (1.5-18)

495 377 368 (74) 93 114 159 95 254/368 (69)

B. Spontaneous

reports

3.3 (1.5-11)

72 69 62 (86) 2d 6 18 31 7 49/62 (79)

C. Prospective study

2.6 (1.3-4.5)

34 29 29 (85) 0 4 10 15 25/29 (86)

Total 601 475 459 11 124 187 141 7

a2% salt = aluminium chloride hexahydrate 2% pet.bPositive reaction but unknown strength.cNine children with negative results with aluminium chloride hexahydrate 2% pet. had positive reactions to metallic aluminium.dOne child with a negative result with aluminium chloride hexahydrate 2% pet. had a positive reaction to metallic aluminium. The second had a positive

reaction to aluminium chloride hexahydrate 10% pet.

BERGFORS ET AL. 83

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2.2 | Study B: Spontaneous reports from clinicalpractice

From 1999 to 2014, the project leader (E.B.) was spontaneously con-

tacted by nurses, physicians and parents of 84 children with problem-

atic long-lasting itching nodules at the injection sites of commercial

DTP-polio-Haemophilus influenzae type B (Hib) and pneumococcal

vaccines given at 3, 5 and 12 months of age at Child Health Centres

all over Sweden. The vaccines contained 0.125 to 0.5 mg of alumin-

ium per dose, and were injected intramuscularly. Seventy-two chil-

dren, aged 1.5 to 11 years, were patch tested at their local

dermatology clinic with aluminium chloride hexahydrate 2% pet. and

an empty Finn Chamber. Three children were also tested with alumin-

ium chloride hexahydrate 10% pet. The first 64 of these spontane-

ously reported children were described in a study in 2012,13 and the

remaining 20 were added in 2012 to 2014.

Positive patch test reactions to either aluminium chloride hexahy-

drate 2% pet. and/or metallic aluminium were found in 69 of 72 tested

children (96%). The specific details of the reactions to the salt and the

metal were obtainable for 64 children. Sixty-two of them had positive

reactions to aluminium chloride hexahydrate 2% pet., as shown in

Table 2. At least 79% of the positive reactions to aluminium chloride

hexahydrate 2% pet. were strong (++) or extreme (+++) positive. Three

children were tested with both 2% and 10% aluminium chloride hexa-

hydrate pet. One of them (aged 2 years) had ++ reactions and another

(aged 4 years) had +++ reactions to both concentrations. The third

(aged 2 years) had no reaction to aluminium chloride hexahydrate 2%

pet., but did have a + reaction to the 10% preparation. One of the

spontaneously reported children with a +++ reaction to aluminium

chloride hexahydrate 2% pet., a 2-year-old girl with persistent itching

granulomas on the injection sites of two doses of a commercial DTP-

polio-Hib vaccine (Pentavac) and two doses of hepatitis B vaccine

(Engerix-B), is shown in Figure 5.

2.3 | Study C: Prospective study in clinical practice

In 2009 to 2014, a prospective cohort study comprising 4758 children

was performed in Östergötland county in Sweden with the aim of

investigating the risk of itching granulomas and contact allergy to alu-

minium after vaccination with commercial aluminium-adsorbed DTP-

polio-Hib and pneumococcal vaccines in clinical practice. The vaccines

were injected intramuscularly at 3, 5 and 12 months, and contained

0.125 to 0.5 mg of aluminium per dose. Thirty-eight children with

itching granulomas were identified, and all but four were patch tested

for aluminium allergy at 1.3 to 4.5 years of age. The tests, with

aluminium chloride hexahydrate 2% pet. in a plastic chamber

(Chemotechnique Diagnostics) and metallic aluminium (an empty Finn

F IGURE 1 Positive reactions (+++) to aluminium chloridehexahydrate 2% pet. (middle) and to an empty Finn Chamber (++,bottom) in a 3-year-old girl sensitized by an aluminium-adsorbedvaccine. Above are scratch marks as far down on the back as the childreached with her nails

F IGURE 2 Contact dermatitis of the axilla after the use of analuminium-containing deodorant in a 13-year-old girl with aluminiumallergy after vaccination. There was a similar reaction in the rightaxilla. The photograph was taken after 1 week of treatment withstrong local steroids

84 BERGFORS ET AL.

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Chamber; SmartPractice, Phoenix, Arizona), were applied by E.B. or a

specially trained nurse, removed by the parents 2 days after applica-

tion, and read on D3 by a dermatologist (L.F.) or an allergologist

(U.N.). The test results were interpreted according to the recommen-

dations of the ICDRG. Positive reactions from + to +++ to one or both

testing agents were regarded as indicating delayed (type IV)

hypersensitivity.

Twenty-nine of the 34 tested children were found to be sensitized

to aluminium. All of them reacted positively to aluminium chloride

hexahydrate 2% pet. (Table 2). One child had no reaction when read

on D3, but became positive on D4 according to the parents (verified

by a photograph on D5). One of the children in the prospective study

with a +++ reaction to aluminium chloride hexahydrate 2% pet., an

18-month-old boy, is shown in Figure 6. He had experienced intensely

itching nodules on his right thigh since the second dose of a commer-

cial DTP-polio-Hib vaccine containing aluminium hydroxide (0.5 mg of

aluminium per dose) (Infanrix-polio+Hib) at 5 months of age, but no

lesions on the opposite leg, where he received two doses of a pneu-

mococcal vaccine containing aluminium phosphate (0.125 mg

F IGURE 3 Contact dermatitis of the axilla after the use of analuminium-containing deodorant in a 6-year-old boy with aluminiumallergy after vaccination

F IGURE 4 Local patches of contact dermatitis on the cheeksafter the use of aluminium-containing rouge in a 6-year-old girl andher 4-year-old brother (middle). Both had vaccine-induced aluminiumallergy. A non-vaccinated cousin (right) who was face-painted in thesame way had no reaction

F IGURE 5 Positive patch test reactions to an empty FinnChamber and aluminium chloride hexahydrate 2% pet. in a 2-year-oldgirl sensitized by aluminium-adsorbed vaccines. Above are scratch

marks as far as the child reached with her nails

F IGURE 6 Positive test reactions (+++/++) to aluminium chloridehexahydrate 2% pet. (above) and an empty Finn Chamber (below) inan 18-month-old boy sensitized by an aluminium-adsorbed vaccine

BERGFORS ET AL. 85

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aluminium per dose) (Prevenar). Because of the intensity of his symp-

toms and the strong reaction to the aluminium test, his vaccination

programme was delayed for 3 years.

2.4 | Summary of studies A-C: Clinical aspects

Altogether, 452 children from the three studies had positive reactions

with documented strengths to aluminium chloride hexahydrate 2%

pet. The relationship between age and strength of reaction is shown

in Table 3. The strongest reactions were seen in the youngest chil-

dren. As many as 65% of those aged 1 to 2 years had an extreme posi-

tive (+++) reaction. The frequency diminished to 22% at 7 years. From

8 years onwards, the frequency of extreme reactions was very low.

Children vaccinated in infancy with aluminium-containing vaccines

(in Sweden, DTP and pneumococcal infections at 3, 5 and 12 months)

are by far the most vulnerable with regard to developing persistent

itching granulomas and aluminium allergy. In the three studies

presented here, altogether 204 children belonging to this group were

patch tested. All but five reacted positively to aluminium chloride

hexahydrate 2% pet.; almost 80% of the reactions were extreme posi-

tive (+++) or strong positive (++) (Table 4).

3 | DISCUSSION

In the studies by Netterlid, Bruze, and Siemund,23-25 altogether

24 patients who were tested with both concentrations of aluminium

chloride hexahydrate pet. reacted positively to the 10% preparation,

but only seven of them also reacted positively to the weaker 2% prep-

aration. Therefore, aluminium chloride hexahydrate 10% pet. was rec-

ommended for the detection of aluminium allergy by these authors

and also by de Groot.28 On the other hand, there were no small chil-

dren in these studies; their median ages were >14 years (Netterlid),

15 years (Bruze), and 48 years (Siemund), respectively.

TABLE 3 Relationship between age and strength of reaction to aluminium chloride hexahydrate 2% pet. in 452 children with vaccine-inducedaluminium allergy in three Swedish studies (A, vaccine trial; B, spontaneous reports; C, prospective study)

No. of children from each study Total no. of children with reactionsPercentage of Childrenwith extreme positivereactions (+++)Age (y) A B C

Total

A-C + ++ +++

1 1 12 4 17 1 5 11 65

2 12 17 17 46 3 17 26 57

3 35 9 6 50 6 16 28 56

4 43 10 2 55 9 22 24 44

5 41 4 0 45 11 21 13 29

6 77 1 0 78 22 37 19 25

7 67 1 0 68 24 29 15 22

8 30 0 0 30 15 14 1 3

9 19 0 0 19 9 9 1 5

10 22 0 0 22 9 10 3 13

11 12 1 0 13 9 4 0 0

12 5 0 0 5 2 3 0 0

13 1 0 0 1 1 0 0 0

14 0 0 0 0 0 0 0 0

15 3 0 0 3 3 0 0 0

Total 368 55 29 452 124 187 141

TABLE 4 Summary of three Swedish studies: results of patch testing with aluminium chloride hexahydrate 2% pet. in 204 preschool childrenwith aluminium allergy induced by primary vaccination at 3, 5 and 12 months

Study

No. of small childrenwith positive reactionsto aluminium chloridehexahydrate 2% pet.

Strengths of reactions to aluminium chloride hexahydrate 2% pet.Median age (y) attesting(minimum-maximum)0 + ++ +++ Positive but unknown strength

A. Vaccine trial 111 3 20 36 52 4.2 (1.6-7.9)

B. Spontaneous reports 64 2 6 18 31 7 3 (1.5-11)

C. Prospective study 29 0 4 10 15 2.6 (1-4)

Total 204 5 30 (15%) 64 (31%) 98 (48%) 7

86 BERGFORS ET AL.

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We agree with the above authors that the 10% preparation seems

to be adequate for patch testing older children and adults. With this

knowledge, it is possible that at least some of the 31 children with

doubtful reactions (?+) to aluminium chloride hexahydrate 2% pet. in

our vaccine trial (study A above) would have reacted positively if they

had been tested with the stronger preparation. Only three children in

our studies (aged 2-4 years) were tested with both 2% and 10% alu-

minium chloride hexahydrate pet. The result—one of them reacted

only to the stronger preparation, whereas the other two had positive

reactions to both—is evidently not conclusive.

On the basis of the results from our three studies, aluminium chlo-

ride hexahydrate 2% pet. is sufficient to trace contact allergy to alu-

minium in small children. In the vaccine trial, 368 of 377 of the

children with verified aluminium allergy reacted positively to this con-

centration (98%), 62 of 69 among the spontaneously reported chil-

dren (97%), and 29 of 29 in the prospective study in clinical practice

(100%). This is in accordance with the Danish and French studies

mentioned in the introduction, in which 93% to 100% reacted posi-

tively to aluminium chloride hexahydrate 2% pet.26,27

It is also obvious that the majority of children reacted very

strongly to aluminium chloride hexahydrate 2% pet. (Tables 3 and 4

and Figures 1, 5 and 6). Altogether 69%, 79% and 86%, respectively,

of the children in studies A, B and C who reacted positively to this

preparation had ++ or +++ reactions. The differences may be

explained by age—the younger the children, the stronger the

reactions—and possibly also by the intensity of symptoms of the

itching granulomas. In the vaccine trials (study A), there was a wide

age range, and the intensity and duration of the itching granulomas

varied from moderate itching for 6 to 12 months to intense itching for

years and a total duration of symptoms for up to 10 years. Almost all

spontaneously reported children (study B) had intense and long-

lasting symptoms, but also a wide age range. The prospective cohort

study (study C) comprised only small children with a median age of

2.6 years at the time of testing, but varying symptoms, from mild and

short (months) to intense and long-lasting (years).

The reactions were also often seen rapidly after application of the

tests. Several children already had such strong reactions on D1 that

the test material had to be removed immediately (Figures 1, 5 and 6).

Only a few were negative on D3 and required a second reading. The

test reactions could take a long time to resolve, even when treated

with local steroids. Some children later experienced a small patch of

itching dermatitis in the former test area on the back during an acute

infection along with an exacerbation of the itching granuloma on the

thigh or upper arm. In others, the itching and swelling of the nodules

on the former injection site flared during the patch test, suggesting

that systemic allergy had developed. Our experience of cases such as

these was one of the reasons why we considered it unethical to use

the 10% preparation in the retest study on the long-term prognosis of

aluminium allergy, in which children from the vaccine trial were tested

a second time.5,21

The role of metallic aluminium (eg, an empty Finn Chamber) in

patch testing for aluminium allergy has been discussed and questioned

lately.21,22 In our three studies, the diagnosis would have been missed

in 10 of 601 cases if we had tested only with the aluminium salt. This

is consistent with our earlier conclusion that metallic aluminium is of

very little benefit in patch testing for aluminium contact allergy.21

In summary, we think that aluminium chloride hexahydrate 2%

pet. is sufficient for detection of contact allergy to aluminium in small

children, and recommend that the stronger 10% preparation should

not be used, because of the risk of unwanted strong allergic reactions

to the test. Already the 2% preparation can cause strong or extreme

positive reactions soon after application, and parents should be

advised to check the test area from the first day.

The age at which aluminium chloride hexahydrate 10% pet. should

be used instead of 2% is a matter for discussion, and needs further

study. According to our findings, we suggest that this concentration

should not be used routinely before the age of 7 to 8 years, when

extremely strong reactions were scarce, in order not to risk intense

and long-lasting local symptoms in the test area and/or systemic

allergy. In clinical practice, this corresponds to the group of preschool

children with persistent itching nodules after their primary vaccination

against DTP, hepatitis B and pneumococcal infections at 3, 5 and

12 months. On the other hand, if the suspicion of aluminium allergy is

strong and the test with aluminium chloride hexahydrate 2% pet.

gives a negative result, a test with a 10% preparation should be

considered.

ACKNOWLEDGEMENTS

Our sincere thanks go to Dr Anette Gente Lidholm at the Department

of Dermatology, Sahlgrenska University Hospital, Göteborg, Sweden,

for careful and creative revision of the manuscript, and to the Unit of

Family Medicine, Department of Public Health and Community Medi-

cine, Sahlgrenska Academy, University of Gothenburg, for providing

me (E.B.) with a working room and writing facilities during the drafting

of the manuscript.

CONFLICTS OF INTEREST

The authors have no conflicts of interest to report.

ORCID

Elisabet Bergfors https://orcid.org/0000-0002-4520-7967

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Nyström U, Trollfors B. Patch testing children with aluminium

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88 BERGFORS ET AL.