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Abstract: Exposure to elemental aluminum and its salts is unavoidable. Aluminum as a metal is present in transport, construction, packaging, and electronic equipment. Aluminum salts are present in consumer products, food items and drinking water, vaccines, drugs, and antiperspirants. Aluminum in vaccines and preparations for allergen-specific immunotherapy are the major sensitization sources. The predominent clinical manifestations of aluminum allergy are pruritic subcutaneous nodules and eczematous dermatitis. Patch testing shall be performed with aluminum chloride hexahydrate (ACH) in petrolatum. The preparation with ACH 10% detects substantially more aluminum allergy than ACH 2%. A patch test with elemental aluminum, for example, an empty Finn Chamber, is only positive when there is a strong aluminum allergy. A patch test reading should be performed 1 week after the application so as not to miss 15% to 20% of aluminum allergy. Aluminum should be included in any baseline patch test series for children and investigated for a possible inclusion in baseline series for adults. Aluminum test chambers can interfere with the testing resulting in both false-negative and false-positive patch test reactions to nonaluminum contact sensitizers., Competing Interests: The authors have no funding or conflicts of interest to declare., (Copyright © 2021 American Contact Dermatitis Society. All Rights Reserved.)

Immunization is highly effective in preventing infectious diseases and therefore an indispensable public health measure. Allergic patients deserve access to the same publicly recommended immunizations as non-allergic patients unless risks associated with vaccination outweigh the gains. Whereas the number of reported possible allergic reactions to vaccines is high, confirmed vaccine-triggered allergic reactions are rare. Anaphylaxis following vaccination is rare, affecting <1/100 000, but can occur in any patient. Some patient groups, notably those with a previous allergic reaction to a vaccine or its components, are at heightened risk of allergic reaction and require special precautions. Allergic reactions, however, may occur in patients without known risk factors and cannot be predicted by currently available tools. Unwarranted fear and uncertainty can result in incomplete vaccination coverage for children and adults with or without allergy. In addition to concerns about an allergic reaction to the vaccine itself, there is fear that routine childhood immunization may promote the development of allergic sensitization and disease. Thus, although there is no evidence that routine childhood immunization increases the risk of allergy development, such risks need to be discussed., (© 2017 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd.)

Type I sensitizations and atopic dermatitis (AD) often appear in the same patient. Beneficial effects of allergen-specific immunotherapy (ASIT) in patients with both AD and type I allergies have been reported. The predisposing role of AD to the development of type IV sensitization is discussed. Whether ASIT for type I allergy also influences type IV allergies is unknown. To compare the number of contact allergies between patients with and without AD, before and after one year's treatment with ASIT. A controlled, single-blind multicentre study of children/adults with allergic asthma and/or rhinoconjunctivitis, treated or untreated with ASIT, was performed. The history of AD was collected using questionnaires. The number of contact allergies was assessed by patch testing with a baseline series. 205 individuals completed the study; 133 treated with ASIT (exposed) and 72 before starting ASIT (unexposed). For participants with AD, significantly more contact allergies were found in the groups of all children (p = 0.002), all exposed children (p<0.001), and all exposed study persons (p = 0.013). Independent of AD, significantly more contact allergies were noted in the groups of all unexposed adults (p = 0.004) and all unexposed study persons (p = 0.004). The higher number of contact allergies in patients with AD indicates that AD may be a risk factor for type IV sensitization in those with allergic asthma and/or rhinoconjunctivitis. The lower number of contact allergies in patients exposed to ASIT suggests an immunomodulatory effect on type IV sensitization.

Background: The Swedish school-based vaccination programme offers HPV vaccine to girls born ≥1999 in 5-6th grade. In 2012, all counties introduced free-of-charge catch-up vaccination campaigns targeting girls born 1993-1998. Varying vaccine uptake in the catch-up group by December 2012 suggested that some implementation strategies were more successful than others. In order to inform future vaccination campaigns, we assessed the impact of different implementation strategies on the county-level catch-up vaccine uptake., Methods: We conducted an ecological study including all Swedish counties (n = 21), asking regional health offices about the information channels they used and where vaccination of the catch-up target group took place in their counties. The uptake of ≥1 dose by 30 September 2014 was estimated using data from the voluntary national vaccination register. We investigated associations between counties' catch-up vaccine uptake, information channels and vaccination settings by calculating incidence rate ratios (IRR) and 95% confidence intervals (CI), using negative binomial regression models., Results: County level catch-up vaccine uptake varied between 49-84%. All counties offered vaccination through primary health care settings. Apart from this eight (34%) also offered the vaccine in some of their schools, four (19%) in all their schools, and two (10%) in other health care centres. The information channels most frequently used were: information at the national on-line health care consulting web-page (100%), letter/invitations (90%), and advertisement (81%). Counties offering vaccination to girls in all schools and counties offering vaccination in some of their schools, reached higher vaccine uptake compared to counties not offering vaccination in any of their schools (all schools adjusted IRR: 1.3, 95% CI: 1.1-1.5, some schools adjusted IRR: 1.2, 95% CI: 1.1-1.3)., Conclusion: Counties offering HPV vaccination to catch-up groups in schools reached the highest vaccine uptake. No information channel explained differences in county-level vaccine uptake. Our findings suggest that catch-up vaccination outside the national vaccination program can reach a high uptake at the population level if it is implemented primarily with an organized delivery (e.g. in schools).

Background: Concerns have been raised that HPV-vaccination might affect women's cervical screening behavior. We therefore investigated the association between opportunistic HPV-vaccination and attendance after invitation to cervical screening., Methods: A cohort of all women resident in Sweden, born 1977-1987 (N=629,703), and invited to cervical screening, was followed October 2006 - December 2012. Invitations to screening were identified via the National Quality Register for Cervical Cancer Prevention, as was the primary outcome of a registered smear. Vaccination status was obtained from two nationwide health data registers. Hazard ratios (HR) were estimated using Cox regression adjusted for age, education level and income (HRadj). Women were individually followed for up to 6 years, of which the first and second screening rounds were analyzed separately., Results: Screening attendance after three years of follow-up was 86% in vaccinated women (N=4,897) and 75% in unvaccinated women (N=625,804). The crude HR of screening attendance in vaccinated vs. unvaccinated women was 1.31 (95% CI 1.27-1.35) in the first screening round. Adjustment for education and income reduced but did not erase this difference (HRadj=1.09, 95% CI 1.05-1.13). In the second screening round, attendance was likewise higher in HPV-vaccinated women (crude HR=1.26, 95% CI 1.21-1.32; HRadj=1.15, 95% CI 1.10-1.20)., Conclusions: HPV-vaccination is so far associated with equal or higher attendance to cervical screening in Sweden in a cohort of opportunistically vaccinated young women. Most but not all of the difference in attendance was explained by socioeconomic differences between vaccinated and unvaccinated women. HPV vaccine effectiveness studies should consider screening attendance of HPV-vaccinated women when assessing incidence of screen-detected cervical lesions.

In order to impede the increase in pertussis incidence in the adolescent group, a school-leaving booster dose administered at the age of 14 to 16 years will be introduced in Sweden in 2016. Preceding this introduction, an open-label, randomized, multicenter, clinical trial without a control group and with blinded analysis was performed, investigating both safety and immunogenicity. Reported here are the memory B-cell and serological responses detected in a smaller cohort (n = 34) of the 230 subjects recruited to the study. All subjects had received primary vaccination consisting of three doses of diphtheria-tetanus-5-component pertussis (DTaP5) vaccine, at 3, 5, and 12 months of age, and a tetanus-low-dose diphtheria-5-component pertussis (Tdap5) vaccine booster at 5.5 years. In this study, the subjects were randomly assigned and received either a Tdap1 or Tdap5 booster. Of the 230 participants, 34 subjects had samples available for evaluation of IgG-producing memory B-cell responses. Both vaccine groups had significant increases in pertussis toxin-specific serum IgG levels, but only the 1-component group showed significant increases in pertussis toxin-specific memory B cells. The 5-component group had significant increases in filamentous hemagglutinin- and pertactin-specific memory B-cell and serum IgG levels; these were not seen in the 1-component group, as expected. In conclusion, this study shows that a 5th consecutive dose of an acellular pertussis vaccine induces B-cell responses in vaccinated adolescents. (This study has been registered at EudraCT under registration no. 2008-008195-13 and at ClinicalTrials.gov under registration no. NCT00870350.)., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Background: Children and adolescents with atopic disease who have allergic asthma and/or rhinitis with and without atopic dermatitis may have hidden, clinically relevant contact allergies., Objective: The objective of this study was to survey contact allergies in children and adolescents who had been offered allergen-specific immunotherapy and accepted (exposed)/not accepted (unexposed) such treatment., Methods: Thirty-seven exposed and 24 unexposed individuals with atopic disease were patch tested with a standard series supplemented with aluminum chloride hexahydrate, an empty Finn Chamber, and 8 antigen preparations., Results: In the exposed group, 18 allergies were detected in 13 individuals with atopic disease when excluding reactions to aluminum and antigen preparations, whereas the corresponding figures for the unexposed group were 9 and 6, respectively (non-significant difference). Independent of the allergen-specific immunotherapy, significantly more (P = 0.013) individuals with atopic dermatitis had at least 1 contact allergy. Clinically relevant allergies were represented by sesquiterpene lactone mix, para-tertiary butylphenol-formaldehyde resin, tixocortol pivalate, and colophony., Conclusions: Clinically relevant contact allergies are not uncommon in children and adolescents with atopic disease, which is why patch testing always should be considered in the management of dermatitis in individuals with atopic disease.

Importance: Determining vaccine dose-level protection is essential to minimize program costs and increase mass vaccination program feasibility. Currently, a 3-dose vaccination schedule is recommended for both the quadrivalent and bivalent human papillomavirus (HPV) vaccines. Although the primary goal of HPV vaccination programs is to prevent cervical cancer, condyloma related to HPV types 6 and 11 is also prevented with the quadrivalent vaccine and represents the earliest measurable preventable disease outcome for the HPV vaccine., Objective: To examine the association between quadrivalent HPV vaccination and first occurrence of condyloma in relation to vaccine dose in a population-based setting., Design, Setting, and Participants: An open cohort of all females aged 10 to 24 years living in Sweden (n = 1,045,165) was followed up between 2006 and 2010 for HPV vaccination and first occurrence of condyloma using the Swedish nationwide population-based health data registers., Main Outcomes and Measures: Incidence rate ratios (IRRs) and incidence rate differences (IRDs) of condyloma were estimated using Poisson regression with vaccine dose as a time-dependent exposure, adjusting for attained age and parental education, and stratified on age at first vaccination. To account for prevalent infections, models included a buffer period of delayed case counting., Results: A total of 20,383 incident cases of condyloma were identified during follow-up, including 322 cases after receipt of at least 1 dose of the vaccine. For individuals aged 10 to 16 years at first vaccination, receipt of 3 doses was associated with an IRR of 0.18 (95% CI, 0.15-0.22) for condyloma, whereas receipt of 2 doses was associated with an IRR of 0.29 (95% CI, 0.21-0.40). One dose was associated with an IRR of 0.31 (95% CI, 0.20-0.49), which corresponds to an IRD of 384 cases (95% CI, 305-464) per 100,000 person-years, compared with no vaccination. The corresponding IRDs for 2 doses were 400 cases (95% CI, 346-454) and for 3 doses, 459 cases (95% CI, 437-482). The number of prevented cases between 3 and 2 doses was 59 (95% CI, 2-117) per 100,000 person-years., Conclusions and Relevance: Although maximum reduction in condyloma risk was seen after receipt of 3 doses of quadrivalent HPV vaccine, receipt of 2 vaccine doses was also associated with a considerable reduction in condyloma risk. The implications of these findings for the relationship between number of vaccine doses and cervical cancer risk require further investigation.

B-cell responses after infection or vaccination are often measured as serum titers of antigen-specific antibodies. Since this does not address the aspect of memory B-cell activity, it may not give a complete picture of the B-cell response. Analysis of memory B cells by ELISpot is therefore an important complement to conventional serology. B-cell ELISpot was developed more than 25 years ago and many assay protocols/reagents would benefit from optimization. We therefore aimed at developing an optimized B-cell ELISpot for the analysis of vaccine-induced human IgG-secreting memory B cells. A protocol was developed based on new monoclonal antibodies to human IgG and biotin-avidin amplification to increase the sensitivity. After comparison of various compounds commonly used to in vitro-activate memory B cells for ELISpot analysis, the TLR agonist R848 plus interleukin (IL)-2 was selected as the most efficient activator combination. The new protocol was subsequently compared to an established protocol, previously used in vaccine studies, based on polyclonal antibodies without biotin avidin amplification and activation of memory B-cells using a mix of antigen, CpG, IL-2 and IL-10. The new protocol displayed significantly better detection sensitivity, shortened the incubation time needed for the activation of memory B cells and reduced the amount of antigen required for the assay. The functionality of the new protocol was confirmed by analyzing specific memory B cells to five different antigens, induced in a limited number of subjects vaccinated against tetanus, diphtheria and pertussis. The limited number of subjects did not allow for a direct comparison with other vaccine studies. Optimization of the B-cell ELISpot will facilitate an improved analysis of IgG-secreting B cells in vaccine studies., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Incidence of condyloma, or genital warts (GW), is the earliest possible disease outcome to measure when assessing the effectiveness of human papillomavirus (HPV) vaccination strategies. Efficacy trials that follow prespecified inclusion and exclusion criteria may not be fully generalizable to real-life HPV vaccination programs, which target a broader segment of the population. We assessed GW incidence after on-demand vaccination with quadrivalent HPV vaccine using individual-level data from the entire Swedish population., Methods: An open cohort of girls and women aged 10 to 44 years living in Sweden between 2006 and 2010 (N > 2.2 million) was linked to multiple population registers to identify incident GW in relation to HPV vaccination. For vaccine effectiveness, incidence rate ratios of GW were estimated using time-to-event analyses with adjustment for attained age and parental education level, stratifying on age at first vaccination., Results: A total of 124 000 girls and women were vaccinated between 2006 and 2010. Girls and women with at least one university-educated parent were 15 times more likely to be vaccinated before age 20 years than girls and women whose parents did not complete high school (relative risk ratio = 15.45, 95% confidence interval [CI] = 14.65 to 16.30). Among those aged older than 20 years, GW rates declined among the unvaccinated, suggesting that HPV vaccines were preferentially used by women at high risk of GW. Vaccination effectiveness was 76% (95% CI = 73% to 79%) among those who received three doses of the vaccine with their first dose before age 20 years. Vaccine effectiveness was highest in girls vaccinated before age 14 years (effectiveness = 93%, 95% CI = 73% to 98%)., Conclusions: Young age at first vaccination is imperative for maximizing quadrivalent HPV vaccine effectiveness.

The prevalence of IgG ELISA antibodies against Haemophilus influenzae polyribosyl ribitol phosphate (anti-Hib) was studied in two Swedish seroepidemiologic materials. One study was performed in 1997 5 years after the introduction of universal Hib vaccination (N=3320). Ten years later, a similar study was carried out to analyze the effect of vaccination on anti-Hib prevalence (N=2383). The median values of anti-Hib concentrations (EU/mL) were almost identical in the two materials. The antigenic pressure including vaccination, natural infections and possible cross-immunizations was thus assumed to be constant. The joint median was 0.50 EU/mL (95% confidence interval: 0.46, 0.56). However, there were also indications of reduced exposure to 'Hib-antigens' over a 10-year period. The proportion above the cut-off point for protection, 0.15 EU/mL, decreased significantly for children aged 2-19 years from 78% in 1997 to 74% in 2007 (p=0.034), and there was a significant increase in values below the minimal level of detection for adults from 17% in 1997 to 20% in 2007 (p=0.009). In the 2007 material no specific age group could be identified with a lower immune profile than other age groups older than 3 years and there was a significant downward trend of invasive infections caused by Hib according to notification data for the period 1997-2008. Therefore, the conclusion is that presently there is no need for a booster dose of Hib vaccine in Sweden after primary vaccination but the situation should be carefully monitored., (© 2010 The Authors. Journal Compilation © 2010 APMIS.)

The paper presents the first results from the European project VACSATC which aimed to track parental attitudes on vaccinations across several European countries. We compared five cross-sectional surveys of parents with children less than 3 years of age in England, Norway, Poland, Spain and Sweden carried out during 2008-2009. Data were collected from 6611 respondents. Two countries used face-to face interviews, one used telephone interviews, and two other countries used mail-in questionnaires. In all countries health professionals were indicated as the most important and trusted source of information on vaccination. The study results also show that parental attitudes on vaccinations in the childhood vaccination programs are generally positive. However, there were differences in attitudes on vaccination between the five countries, possibly reflecting different methods of sampling the respondents, context-specific differences (e.g. level of activity of governmental agencies), but also individual-level parental variation in demographic and socioeconomic status variables., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The prevalence of IgG ELISA antibodies against pertussis toxin (anti-PT) was studied in two Swedish seroepidemiological studies. One was performed in 1997 when the new pertussis vaccination program was 1 year old (n = 3420). In 2007, when Pa vaccines had been used countrywide for 10 years in the universal child vaccination program, this study was repeated to analyze the effect of vaccination on anti-PT prevalence (n = 2379). Before the statistical analysis of seroprevalence, children vaccinated within the last 2 years before the serosurveys were excluded. The results indicate a reduced exposure to Bordetella pertussis in the population. The proportion of sera without measurable anti-PT antibodies increased significantly, aggregated over all comparable age groups, from 3.8% in people sampled in 1997 to 16.3% in people sampled in 2007. For cord blood, 1% was without measurable anti-PT antibodies in 1997 compared to a significantly higher level, 12%, in 2007. With anti-PT concentrations of > or =50 and > or =100 EU/ml as cutoff points for 'recent infection' the proportion above the cutoff points for younger children was significantly higher in 1997 than in 2007 at both cutoff points. For all adults, 20 years of age and older, the difference in proportions above the lower cutoff point was close to statistically significant, comparing 1997 with 2007. This was not the case at 100 EU/ml. In the 1997 samples of children, there was a significant downward trend of 'recent infections' at both cutoff points for three sampled age groups between 5 and 15 years of age from 21% at 5.0-5.5 years of age to 7% at 14.7-15.7 years for the lowest cutoff. In the 2007 samples of children, on the contrary, there was a significant continuous upward trend of 'recent infections', at both cutoff points, for four sampled age groups between 4 and 18 years of age - from 4% at 4-5 years of age to 16% at 17-18 years at the lowest cutoff. The continuous increase, with age of children with high anti-PT concentrations, supports the recent change in the general Swedish childhood vaccination program to include a pre-school booster at 5-6 years and a school-leaving booster at 14-16 years of age.

One way to maintain confidence in vaccination programmes is to improve monitoring of immunisation safety. We studied active parental reporting of adverse events after a booster dose of diphtheria-tetanus toxoid (DT). 7193 children received the vaccine. Questionnaires were submitted by 84.2% of the parents, who reported reactions for 9.2% of the children. Four percent of events were classified as moderate/severe by interviews. Relative risk of redness and swelling reported was 0.24 (95% CI, 0.13-0.42) compared to a clinical trial, while it was 71.0 (44-114) compared to passive surveillance. Active surveillance by parental reports is a useful complement to passive surveillance of childhood immunisations to generate hypotheses for evaluation in controlled studies.

Background: The development of persistent itchy nodules at the injection site following hyposensitization therapy with aluminium-precipitated antigen extract has been described in several reports. Occasionally, contact allergy to aluminium has been reported in individuals with such nodules., Objectives: To investigate if hyposensitization therapy can induce contact allergy to aluminium and examine if there is any association between persistent subcutaneous nodules and aluminium allergy., Patients/methods: Sixty-one children with allergic asthma and/or allergic rhinitis participated in the study of whom 37 had had hyposensitization therapy. The study consisted of a non-clinical part based on a questionnaire and a clinical part with a physical examination, self-assessment of itching, and patch testing. To secure an unbiased evaluation of possible reactions, the investigators were blinded., Results: Contact allergy to aluminium was found in eight participants, all in the exposed group (8/37 versus 0/24, P = 0.02). Examination showed nodules on the upper arms in 13 participants, all in the group exposed to hyposensitization therapy. Nodules were over-represented in patients with contact allergy to aluminium., Conclusions: There was a statistically significant association between contact allergy to aluminium and persistent subcutaneous nodules in children who had had hyposensitization therapy.