Measles immunisation in children with allergy to egg

Introduction

Measles immunisation in children with allergy to egg remains controversial. The measles and mumps components of measles and mumps (MM-Vax) and measles, mumps, rubella (MMR-II) vaccines are produced by passage of virus in a culture of fibroblast cells from chick embryos.1 The vaccines contain nanogram quantities of protein that cross reacts with ovalbumin.2 Hypersensitivity reactions to measles vaccine in children allergic to egg have been reported.*RF 3-5* As most anaphylactic reactions to measles vaccine have occurred in children not allergic to eggs other components (such as gelatin) may be responsible.6 The American Academy of Pediatrics recommends skin testing with vaccine before its administration to children with egg allergy7 and that children who test positive to the vaccine should undergo a desensitisation process of six injections with the vaccine. These recommendations seem to be influenced by medico-legal considerations8 as much as by the scientific evidence and have been challenged.2,9 We present data on a series of 410 children with egg allergy who have had measles immunisation without any notable adverse reactions.

Subjects and methods

Data were collected by review of the records of children referred to the children's allergy centre, Royal Children's Hospital, in 1986-92. We examined the records of 529 children who received measles immunisation. Children were included in the study if they had a history of an immediate hypersensitivity reaction after eating egg or a history of immediate reaction to other foods with a positive result of a skin test with egg white and had never eaten egg. Children for whom there was insufficient documentation were excluded. We identified 410 children for whom there were enough data for inclusion. Department policy during this time was for all children to be immunised.

Classification of egg allergy

Most children developed an immediate reaction after ingestion of egg protein. Clinical reactions to egg were classified into four grades: grade 1 - localised facial erythema/urticaria; grade 2 - generalised urticaria/angioedema or vomiting, or both; grade 3 - generalised urticaria/angioemeda and stridor or wheeze; and grade 0 - never eaten egg, but immediate hypersensitivity to other foods and positive result in skin test with egg.9 Some children had a definite history of hypersensitivity to egg but insufficient information was recorded to classify the severity of the reaction with certainty. These children were recorded as “un-specified.”

Data were encoded in digital form on computer file and analysed by using the SPSS/PC+ statistical software package. We used X² analysis and one way analysis of variance to investigate relations between variables.

Measles immunisation

Measles immunisation was performed on the same day as or within four weeks of skin testing. Children were observed for four hours for rash, blood pressure, and respiratory symptoms. Before 1989 a divalent measles-mumps vaccine was used (Enders' attenuated Edmonsten strain, MM Vax, Merck Sharp and Dohme), and after this time trivalent mumps, measles, and rubella vaccine was used (Enders' attenuated Edmonsten strain MMR II).

Skin testing

A drop of egg white extract (Hollister Steir, Spokane, Washington), undiluted measles vaccine, histamine 1 mg/ml, histamine 10 mg/ml (positive controls), and diluent solution (negative control) were applied to the flexor aspect of the forearm. The skin was pricked with a single use lancet (Hollister Steir, Spokane, Washington) for each solution. Positive controls were read at 10 minutes, other sites were read at 15 minutes.

Intradermal tests were performed by injection of 0.02 ml of 1:100 dilution of measles vaccine in normal saline (as recommended by the American Academy of Pediatrics7) and a negative control of 0.02 ml of normal saline. Skin tests were expressed in mm diameter of weal greater than control or as a ratio of the diameter of the test reaction to the diameter of the reaction to histamine 1 mg/ml on a standard 1-5 scale.10 For intradermal tests any weal over 2 mm more than the control was recorded.

The age of the child at the time of the first and the most recent reaction to egg, dose of egg, severity of reaction to egg, age at immunisation, reactions to vaccine, and results of skin tests were recorded.

Results

We studied 410 children. The mean (median) age at immunisation was 26.2 (17.0) months. One hundred and fifty seven children were given measles and mumps vaccine; 253 children received trivalent measles, mumps, and rubella vaccine.

Skin prick test results

The mean (median) skin prick test result with egg white was 7.7 (8.0) mm (SD 5.0 mm). Table I shows the skin test result of clinical reactions to vaccine with children divided into groups according to the grade of clinical reaction to egg. Five children (1.2%) had a positive result in a skin prick test with the vaccine.

None of these five children had a reaction after immunisation with the standard dose of vaccine given as a single injection. None of the 33 children who had a history of severe reaction to egg with respiratory symptoms (grade 3) had a reaction after measles immunisation. Children with more severe reactions to egg were not more likely to have a positive result in a prick test with vaccine than were those with milder reactions.

Intradermal test results

Intradermal testing with vaccine was performed in 96 consecutive children of the total of 410. The clinical features of these children did not differ on X² analysis from the children who had only skin prick tests. Previous authors have used differing definitions for a definite positive reaction for intradermal tests.2,4 The results are shown according to the weal size to allow comparison with earlier studies (table II). If a reaction of 2 mm or more greater than the control is accepted as definite then 46 children had a positive result. With 3 mm as the threshold 38 had a positive result; with 5 mm as the threshold 17 had a positive result.

Reactions after immunisation

Only four of the 410 children had a reaction after immunisation (table III). The reactions were mild and did not require treatment. They were not necessarily due to immediate hypersensitivity to an injected antigen. None of the children who reacted had a positive result in a prick test with vaccine. These four children did not differ significantly from the rest of the study group in any of the variables. Only one of the children who reacted to vaccine had an intradermal test. This was a 13 month old girl with a history of generalised urticaria and vomiting after exposure to a trace of egg at 12 months. She had a 3 mm weal on intradermal testing. She developed isolated perioral urticaria one hour after immunisation.

The rate of minor adverse reactions (not requiring treatment) was 0.98% (95% confidence interval with the exact binomial method 0.27% to 2.48%). The rate of serious adverse reactions (requiring treatment) was 0% (0.0% to 0.9%).

Discussion

The value of skin testing as a predictor for hypersensitivity reactions to measles vaccine is unproved. Previous studies indicate that a positive result in a skin prick with measles vaccine is common (2-7% of atopic children) and not related to immediate reactions to immunisation.2,11 Most studies have been limited by small numbers of children. Our study describes 410 children with egg allergy who have been successfully immunised with live attenuated measles vaccine. We included 124 children who had never eaten egg but who had a history of immediate hypersensitivity to other food and a positive result in a skin test with egg white because there is strong evidence to support the correlation between strongly positive skin test reactivity and the development of clinical symptoms on ingesting the allergen.10,12 Although such children are not included in current recommendations for screening, they represent one third of cases referred.

All 410 children had skin prick testing with vaccine before immunisation. A standard single injection method of immunisation was used without any desensitisation procedure. A positive result on prick testing with vaccine occurred in five (1.2%) children and a reaction to immunisation in four (0.9%) children, none of whom had a positive result in a vaccine skin prick test. The practice of restricting skin testing and desensitisation in the children most severely allergic to egg13 is not supported by our results as all of the reactions occurred in children with grade 2 or grade 0 egg allergy. None of the children with grade 3 egg allergy had positive results in skin prick or intradermal tests (5 mm weal) with vaccine or a reaction after immunisation.

Threshold for positive result

Intradermal testing with vaccine has been recommended for children allergic to egg with a negative result in a vaccine skin prick test,3,4,7 followed by desensitisation in children who have a positive result in either type. Others have suggested using skin prick tests alone as an indication for desensitisation.13 In our study 96 children had intradermal tests with diluted vaccine. The number of children with a positive result in an intradermal test is determined by the size of weal which is regarded as meaningful. Our results of 18% positive with 5 mm as the threshold are consistent with those previously reported by Lavi et al, who found 17% positive.4 Taking a 3 mm weal as positive increases the rate to 40% in our group and 50% in another study2 (of only six subjects).2 In the only other study of comparable size in which children with a positive result in a vaccine skin test had been given measles immunisation Lavi et al identified 24 of 114 children allergic to egg with positive results in an intradermal (>=5 mm) or a skin prick test with vaccine.4 All these subjects were desensitised with a graded vaccine challenge, and three of the 24 (12.5%) developed generalised urticaria between the second and fourth vaccine dose. In contrast, none of our 22 subjects with positive results in a vaccine skin test on identical criteria developed generalised urticaria. These findings do not provide support for a graded dose regimen. The apparently higher rate of reactions with desensitisation raises the possibility that this might increase the reaction rate. The one child who had a clinical reaction to the vaccine in our intradermal positive group had an intradermal result of 3 mm. If a 5 mm weal is used as the threshold, none of the intradermal positive children had a reaction to vaccine. If a 3 mm weal is used, 2.6% (one of 38) of the intradermal positive children had a reaction to vaccine.

Low risk of reactions

This study does not answer the question of how common adverse events are after measles immunisation in children who are not allergic to egg or what the relative risk is for children with egg allergy. We believe that the findings in our 410 cases and the 247 cases previously described who have not had desensitisation*RF 2,9,13-15* and the epidemiological data suggest that the risk is low. The reactions to immunisation were mild and did not require active treatment. As the children were under close observation the reactions may not have been reported under normal circumstances. Thus the incidence of such reactions in the general population is unknown. Furthermore, the reactions were much less severe than those which have been described in children not allergic to egg.16,17 Children allergic to egg may not have a higher rate of serious reactions to vaccines than the general population. Our data suggest that at least 99% of children with egg allergy can have measles immunisation without any notable adverse reaction (using 95% confidence intervals).

We agree with the opinion of Fasano et al that guidelines regarding skin testing and administration of mumps, measles, and rubella vaccine to children allergic to egg should be reviewed.2 We conclude that neither skin prick nor intradermal testing with measles vaccine is useful, and the scientific validity of this process can be questioned. A positive result on either skin prick or intradermal testing with the vaccine is not sufficiently predictive of a reaction to the vaccine to warrant withholding immunisation or using desensitisation procedures. We believe that children with a history of allergic reactions to egg should have their allergy investigated and managed by practitioners with specific knowledge in this subject. Measles immunisation should be performed in a setting where any adverse reactions can be dealt with appropriately but vaccine skin tests and desensitisation are not necessary.

We thank Sisters Jenny Brown, Liz Miller, Carmel Swingler, and Glenda Stewart for performing skin tests and immunisation. We also thank Joan Sedmak and Drs Brian Feery, Rick Jarman, and John Carlin for help in collecting and presenting these data.