A practical approach to immunization in atopic children
Authors: C. Grüber, B. Niggemann
Journal: Allergy (2002)

Many parents and physicians are concerned that early childhood immunizations may promote allergies. Given the current epidemic of allergic diseases (1) in western countries, a loss of confidence in vaccines providing efficient protection against known risks of communicable diseases may result in a decrease of vaccination coverage and subsequent increase in infectious disease morbidity. While there is little evidence that routine childhood immunizations promote or prevent the development of clinical manifestations of atopy (2), it is well known that immunization can result in allergic reactions to the vaccines, including life-threatening events, though severe allergic reactions are rare. Live virus vaccines, which have been grown on egg-derived media, are of particular concern, but vaccine adjuvants (aluminum) or contaminants (gelatin or antibiotics) also cause allergic reactions (2). It is, however, difficult to predict those at high risk of allergic reaction. Various guidelines have been published on how to proceed with children believed to be at risk for allergic reaction to vaccines have been published (3–8). Conservative recommendations may reduce unnecessarily the vaccination coverage among children believed to be at risk for allergic symptoms. In this review, the evidence for allergic reactions to early childhood vaccines is summarized. Based on this, we propose in a separate chapter a practical approach for immunization in atopic children. The prevalence of egg allergy in infancy and early childhood may approximate the prevalence found for allergy to cow's milk (2%) (9). Measles vaccine, which in many countries is given together with vaccines against mumps and rubella, has been regarded as a potential hazard for egg-allergic children, since the virus used is grown on chick-embryo fibroblasts. This is also true for the mumps vaccine. An ovalbumin-free measles–mumps–rubella (MMR) vaccine with the Edmoston-Zagreb strain grown in human diploid cell culture (Triviraten®, Berna Biotech Ltd, Bern, Switzerland) has been recommended for very sensitive egg-allergic children. The immunogenicity with regard to measles however, seems inferior (10, 11) and concerns have been raised regarding the efficacy of this strain against mumps (12, 13). Though the incidence of anaphylactic reactions due to measles immunization in the general public is low, they can be life-threatening (8, 14–18). There is a large body of evidence demonstrating the low incidence of anaphylactic reactions to measles immunization in the general population. In an Australian Measles Control Campaign, there was only one anaphylactic reaction among 1.7 million vaccinees, giving a rate of 0.06 per 100 000 doses; the combined rate for anaphylaxis, anaphylactoid and allergic reactions was 1.06 per 100 000 administered doses in this study (19). In Germany, nine allergic reactions and six anaphylactic reactions, possibly or probably due to measles immunization, were spontaneously reported among 10 773 776 doses sold from 1995 to 1999 (0.04 per 100 000 doses) (20). In Denmark, 18 of 1200 000 vaccinees (1.5 per 100 000) reacted with a possible IgE-mediated reaction, including one egg-allergic child who reacted with respiratory symptoms (21). In the United States, the reported rate of possible anaphylaxis after immunization with measles-containing vaccine was less than one case per one million doses distributed (5). In Finland 2 990 000 doses of MMR vaccine were distributed (1982–96) to 1.8 million individuals, the vaccination coverage being ∼ 95%. In addition, 2570 doses of the egg protein-free vaccine were administered to allergic vaccinees in 1992–96. During this period of more than 14 years, 73 presumably allergic reactions were reported, including 30 cases with anaphylaxis (1.0 per 100 000 doses). Statistically, this was not unexpected; no such reactions were reported to the egg protein-free vaccine (22). A subpopulation of 36 patients from this study who had shown allergic reactions; 20 experienced reactions within one hour, one child was egg-allergic, two children had outgrown their egg allergy (still sensitized), and five were sensitized to gelatin (23). Examining 21 studies, Khakoo and Lack have counted 10 cases with cardiorespiratory compromise among 1803 egg-allergic children (0.55 %) (4). As a general incidence rate for egg-allergic children, this would be an overestimate since several of these studies included case reports without proper controls. No anaphylaxis to measles immunization was observed in a large population comprising 500 egg-allergic children (24) and none in a group of 54 egg-allergic children including 26 children who reacted anaphylactically after ingestion of hen's egg (25). Thus, even among egg-allergic children the risk for an allergic reaction to an egg-derived MMR vaccine is low. Generally, the amount of residual egg-related protein in MMR vaccines is very low; quantities of 0–1 ng per immunization dose have been found (8, 14, 26). In most instances, allergic reactions to MMR vaccine are not due to egg (14, 16, 25, 27). Other components of the vaccine, such as neomycin (about 25 µg per dose) or gelatin (about 15 mg per dose), are more probable causes (see below). The positive predictive value of skin tests with the vaccine prior to immunization is below 10% (14, 25, 28). Most egg-allergic children tolerate the vaccine well, and egg allergy does not predict reactions to MMR immunization (14, 24, 25, 29). Further studies are needed to clarify whether an elevated risk in the small subpopulation of severely egg-allergic children can be ruled out. Recently, Khakoo and Lack proposed to treat egg-allergic children with mild symptoms after egg ingestion and concomitant chronic asthma as a high-risk group (4). This suggestion is based on the observation that cases of fatal, or near fatal, anaphylaxis due to food allergy frequently have concomitant asthma (in most cases also atopic dermatitis and allergic rhinitis) (30); also three case reports, one case of an egg-allergic child with concomitant asthma, who reacted with respiratory symptoms on egg ingestion and MMR skin test (18); one case of egg-allergy, with no asthma, who reacted with respiratory symptoms after egg ingestion and MMR immunization; and one case with egg allergy who reacted with cardiorespiratory symptoms after MMR immunization (8). These children have not been gelatin-tested. IgE-results provided in the latter report suggest that, in contrast to only egg-sensitive children, patients with a positive vaccine skin test or an allergic vaccine reaction reacted not only to ovalbumin but also to the MMR vaccine (8). While airways as a target of egg-allergy may mark children with more severe egg allergy, these circumstantial reports do not establish a predictive value of concomitant asthma concerning anaphylaxis after MMR immunization. Desensitization has been proposed in order to increase immunization rates in egg-allergic children (27). However, it may cause systemic hypersensitivity reactions (27, 31) and therefore this approach is no longer recommended. Higher concentrations of residual host protein were detected more than 30 years ago in influenza vaccines (7.4 µg/ml) and yellow fever vaccine (15.6 µg/ml) which were produced in embryonated eggs (26). Concentrations found in today's vaccine are also in the low microgram range or below (32). Other vaccines that may contain egg protein include those against rabies and tick-borne encephalitis. In double-blind, placebo-controlled food challenges, an oral dose of 100 µg crude egg elicits objective reactions, including generalized reactions in rare cases, and the minimum dose required may be even less (33). The minimum parenteral ovalbumin dose needed to elicit an anaphylactic reaction in children is unknown. The body of scientific literature on which recommendations can be based is considerably smaller than the one for MMR vaccines. Although anaphylaxis rates to vaccines containing higher amounts of egg protein may not be exceptionally high, and anaphylactic reactions also may be due to other vaccine components (e.g. gelatin), egg-allergic individuals may be more prone to react anaphylactically (34). Thus, more careful management seems justified for children who are allergic to these proteins. Some MMR vaccines contain gelatin that is frequently added as a stabilizer. MMR vaccines may contain considerably higher doses (about 15 mg per dose) of gelatin than of egg-related protein (23). Gelatin is also found in other vaccines including brands against diphtheria–tetanus–pertussis (DTaP), varicella, influenza, typhoid, and yellow fever (Table 1). A review of Japanese cases with anaphylactic reactions to MMR vaccine revealed that these patients were sensitized not to hen's egg but to gelatin (35, 36). Some of these cases also had a history of urticaria on eating food containing gelatin (36). In Finnish vaccinees, gelatin allergy was detected by the immunospot and CAP system RAST methods in 28% of Finnish vaccinees, with immediate or nonimmediate adverse allergic events, partially overlapping with sensitization to avian proteins or to cow's milk (23). Incubation with gelatin of PBMCs from patients reacting allergically to gelatin-containing vaccines induces mRNA production for IL-4 and IL-13 (37). In Japan, a shift from acellular DTaP vaccine with no gelatin, given after MMR immunization, to a gelatin-containing DTaP vaccine, given before MMR immunization, was followed by numerous anaphylactic reactions to the MMR vaccine (38). This report suggests that sensitization to gelatin can be caused by a DTaP vaccine that contains gelatin, and anaphylaxis may be induced by subsequent gelatin-containing MMR vaccine. Conversely, elimination of gelatin-containing vaccines from the market is associated with fewer reported allergic vaccine reactions (39). The propensity to develop anaphylaxis following gelatin-containing live virus vaccines may be genetically coinfluenced, as demonstrated by a four-fold relative risk of HLA-DR9 positive individuals for developing IgE antibodies to gelatin and allergy (40). Patients allergic to gelatin in food are not necessarily allergic to gelatin as a stabilizer, and vice versa. Gelatin in food may be of bovine origin whereas gelatin used in vaccines is mostly from porcine sources. In addition, epitopes between different gelatin preparations may differ. It has been shown that the reactivity of gelatin with IgE antibodies depends on its molecular weight (41). This opens avenues for producing less allergenic gelatin for use in vaccines while maintaining necessary pharmaceutical properties. Avoidance of gelatin as a stabilizer, however, would be preferable. Triviraten® contains neither gelatin nor egg protein. Antibiotics (mostly neomycin) are commonly added to vaccines as preservatives. Neomycin can cause both local and systemic allergic reactions and has been held to be responsible for rare, possibly IgE-mediated allergic reactions to the MMR vaccine in neomycin-allergic individuals (42). Contact dermatitis to neomycin does not seem to be a risk factor for anaphylactic reactions to vaccines (43). The amount of neomycin per vaccine dose has been reported to be up to 25 µg (14), though most vaccines contain just traces. It is questionable whether antibiotics are responsible for all attributed cases of anaphylaxis. It may well be that in vaccines that also contain gelatin in higher doses, the latter is responsible for observed cases of post-immunization anaphylaxis (Table 1). In contrast to the increasing evidence for a negligible role of egg in allergy to MMR vaccines, however, there is still insufficient evidence about the importance of antibiotic traces. Thus, a more cautious approach is justified. Persons who have experienced proven anaphylactic reactions to an antibiotic should not receive a vaccine containing the same antibiotic (5). Aluminum salts (aluminum hydroxide, aluminum phosphate) are widely used adjuvants (e.g. DTaP, Hepatitis A and B, Haemophilus influenzae B vaccines), with up to 1 mg per dose. In animal models, aluminum hydroxide is known to enhance both IgG and IgE responses to the vaccinated antigens (44–46). Secretion of IL-4 by human monocytes is promoted in vitro (47). Aluminum adjuvants in vaccines are not a concern because of anaphylaxis but because of local side effects. Nodules containing aluminum crystals are occasionally found at the injection site and can persist for a long time (48, 49). Intramuscular administration is less associated with these nodules than is subcutaneous administration. The subcutaneous route, however, is used in specific immunotherapy when administering aluminum hydroxide-adsorbed depot allergen extracts or allergoids. Since the advantages of specific immunotherapy outweigh the disadvantage of transient nodules, injection sites are alternated to reduce accumulation of nodules. While alternative preparations without aluminum may reduce local reactions, they also elicit immediate-type systemic reactions (50, 51). A possible allergy-promoting effect of routine immunizations in general has been debated recently (52). It has been proposed that immunizations either directly promote development of allergy by skewing the immune system towards a Th2-type cytokine pattern (53), or indirectly promote allergy by hindering Th1-associated infections, thereby strengthening the Th2-type arm of the immune system (53, 54). While a direct effect would pose a challenge to develop less Th2-deviating vaccines, the indirect effects have to be balanced against the risks imposed on non-vaccinated children. Direct Th2-associated effects have been described for DTaP immunization. IgE formation to vaccinated antigens has been observed in atopic and nonatopic individuals. In atopic individuals, however, this immune response is prolonged (55) and has a higher titer (55, 56). In contrast to immunization with whole-cell pertussis vaccine, a Th2-skewed cytokine secretion pattern has been found in PBMC of children immunized with acellular pertussis vaccine (57). It is important to note, however, that sensitization to inhalant or nutritive allergens or allergic diseases were not more frequent among those vaccinated (58). In fact, whole-cell pertussis vaccine may be associated with Th2-suppressive effects, since IgE to co-vaccinated antigens is suppressed in children (59). Currently, there is no evidence of diminished vaccine efficacy in atopics. Lymphoproliferative responses to tetanus toxoid have been found negatively associated with total serum IgE in infancy (60), but in later life the immune response in atopics was not suppressed (61). Indirect promotion of allergy by a deprivation of natural infections due to immunization was suggested by a comparison between 295 children from Swedish anthroposophic Waldorf schools and 380 children from regular schools. At the Waldorf schools, MMR immunization was less common at the Steiner schools than in regular schools (18% vs 93%), similarly allergic symptoms (13% vs 25%, respectively) but a history of measles was more common (61% vs 1%, respectively) (62). However, many other lifestyle factors also differed. Some other cross-sectional retrospective studies indicated a lower prevalence of allergic symptoms among children with a lower vaccination coverage but are hampered by the small size of unvaccinated subsamples (63, 64). An international study relating national immunization rates to the prevalence of allergic symptoms found in the corresponding regions observed a negative association of DTaP and measles immunization rates and IgE-mediated disease (65). In summary, there is no convincing evidence that routine childhood immunizations promote allergy. Children predisposed to allergy exaggerate the Th2-dependent regular response to some vaccinated antigens but immunization does not further increase their elevated risk for allergy. The immunizations in question are effective in hindering infections that are associated with potentially life-threatening or disabling risks. Because the risks of not vaccinating far outweigh the questionable risks of vaccine-induced allergy, atopic as well as nonatopic children should be included as much as possible in routine immunization programs. Management of children with presumed egg allergy before immunization against measles–mumps–rubella (MMR). Anaphylactic reactions due to measles immunization are very rare events, even among egg-allergic children, and prediction of cases is not possible. Thus, all children should be vaccinated against measles. As for all immunizations, availability of resuscitation facilities (including epinephrine) and observation for at least 30 min after administration, should be the rule. Further observation is indicated if allergic symptoms develop. Sensitization to hen's egg without anaphylaxis is no contraindication for MMR immunization. If egg allergy is suspected but not certain, oral food challenges (preferably double-blind, placebo-controlled) can help to identify egg-allergic children. A mild local reaction to a previous vaccine dosage is no contraindication for the next dosage. Children with a more severe allergic reaction to the next dose, or with a history of severe anaphylactic reactions to egg who have not outgrown their egg allergy, should be immunized under close supervision in a pediatric clinic prepared to treat anaphylaxis. Children with elevated risk should be observed for 2 h post-immunization, with continuous monitoring of cardiorespiratory function parameters for the first 20 min after immunization, and an assessment immediately prior to discharge (4). Management of children with a presumed allergy to an agent contained in the vaccine. For MMR immunization in egg-allergic children, see Fig. 1. If current egg allergy is suspected but not certain before administration of vaccines other than MMR, analysis of serum IgE against egg should be used as a screening instrument. Because serum IgE against egg may be still present in formerly egg-allergic children who have outgrown their egg allergy, double-blind, oral food challenges (preferably placebo-controlled) may help to assess the current clinical relevance of egg allergy. Regular immunization should be performed if there is no clinical evidence of current egg allergy. If the history is convincing for current egg allergy or the provocation with egg is positive, administration of a brand that is free of egg-related protein is recommended. If this is not possible, a child should be vaccinated in a pediatric clinic that is prepared to treat anaphylaxis as described above. Individuals with known or suspected hypersensitivity to gelatin, to an antibiotic, or to another vaccine constituent can also be managed according to Fig. 2. Management of children with previous systemic allergic reaction to a vaccine before a subsequent immunization dose. Children who have previously reacted anaphylactically to a vaccine or its components in another vaccine are at elevated risk. Some cases of even severe symptoms, however, may be due to a nonallergic reaction. In adolescents and adults fainting is more common than anaphylaxis. A combination of cutaneous and cardiorespiratory symptoms, usually within 1 h of vaccine administration, is suggestive of an anaphylactic reaction. The need for a future dose of the offending vaccine (or another vaccine containing the putative causal component) should be established. In these cases, an immunological work-up of the etiology of systemic reactions is warranted and should help to identify the causative agent. Hypersensitivity to gelatin should be considered in cases with immediate adverse events to gelatin-containing vaccines. Determination of IgE antibody in serum can be used for screening of sensitization to common vaccine components, such as gelatin or hen's egg. However, egg sensitization in particular does not necessarily predict an allergic reaction at least to MMR vaccine. If clinical allergy in children who are sensitized to a component other than egg protein is confirmed by a strongly suggestive history or oral food challenge, the vaccine should be replaced by a brand without the offending component. If immunization is essential and a brand without the offending component is not available, immunization should be performed in a setting prepared to treat possible anaphylactic symptoms as described above. If IgE antibody is not detectable in serum, skin testing may be performed in an effort to identify the causative agent. Since skin testing also carries a risk of anaphylaxis, vaccine dilutions may be used in children with a history of life-threatening anaphylactic vaccine reactions. The predictive value of skin prick tests for egg, however, is limited due to false positive results, and is not established for other allergens. Children with a positive skin test to the vaccine should be evaluated for hypersensitivity to single vaccine components. If a component is identified as probable cause, a vaccine without the offending component should be used for the next dose. Children with negative skin tests should be vaccinated in a setting prepared to treat possible anaphylactic symptoms. Immunization in graded doses has been suggested (3) but the value of this proceeding is unclear. There is no convincing evidence that routine childhood immunizations promote allergy in general. The immunizations in question are effective in hindering infections that are associated with potentially life-threatening or disabling risks. The risks of not vaccinating outweigh the questionable risk of vaccine-induced allergy by far. Moreover, the available evidence suggests no generally increased risk of atopic children to react severely allergic to immunization. Thus, children predisposed to allergy should be included as far as possible in routine immunization programs. With very few exceptions, all atopic children (including those with atopic dermatitis) can be immunized safely. True exceptions with an elevated risk for anaphylactic reactions to vaccines are children who have reacted anaphylactically to a vaccine or its components. Special precautions for these rare cases are outlined above. Most anaphylactic reactions, however, will occur in children who have no history of previous allergy to a vaccine. Thus, whenever a vaccine is administered, the child should be observed for at least 30 min after administration because of possible immediate-type allergic reactions. With the proposed approach it should be possible to perform safe routine immunizations of the vast majority of children, to leave as few children as possible without protection against potentially life-threatening or disabling infectious diseases. The authors thank Klaus Magdorf, MD (Pediatric Department, Chest Clinic Heckeshorn, Berlin, Germany), Sabine Schmidt, MD (Kinderumwelt gGmbH, Osnabrück, Germany) and Lennart Nilsson, MD, PhD (Department of Health and Environment, Division of Pediatrics, Linköping, Sweden) for critical reading and valuable comments.