Elisabet Bergfors

Unexpectedly high incidence of persistent itching nodules and delayed hypersensitivity to aluminium in children after the use of adsorbed vaccines from a single manufacturer

During trials of aluminium adsorbed diphtheria-tetanus/acellular pertussis vaccines from a single producer, persistent itching nodules at the vaccination site were observed in an unexpectedly high frequency. The afflicted children were followed in a longitudinal observational study, and the presence of aluminium sensitization was investigated in the children with itching nodules and their symptomless siblings by patch tests. Itching nodules were found in 645 children out of about 76,000 vaccinees (0.8%) after both subcutaneous (s.c.) and intramuscular (i.m.) injection. The itching was intense and long-lasting. So far, 75% still have symptoms after a median duration of 4 years. Contact hypersensitivity to aluminium was demonstrated in 77% of the children with itching nodules and in 8% of the symptomless siblings who had received the same vaccines (P<0.001). Children with persistent itching nodules and/or aluminium sensitization should be warned about aluminium containing products (e.g. vaccines and antiperspirants). The reason for the high incidence of itching nodules after SSI vaccines is unknown and should be further investigated.

Mass vaccination of children with pertussis toxoid: decreased incidence in both vaccinated and nonvaccinated persons

During 1979-1995, there was no vaccination against pertussis in Sweden. With the aim of studying the epidemiology and transmission of pertussis, mass vaccination with pertussis toxoid of children born during the 1990s was instituted in the Göteborg area (population, 778,597) in 1995. Infants were offered 3 doses of pertussis toxoid combined with diphtheria and tetanus toxoids. Children aged > or =1 year were offered 3 doses of pertussis toxoid alone. From June 1995 through February 1999, 167,810 doses of pertussis toxoid were given to 61,219 children born during the 1990s (56% received 3 doses). The number of Bordetella pertussis isolates per year declined from 1214 (1993-1995) to 64 (January 1997 through June 1999; P<.0001), and hospitalizations due to pertussis declined from 62 to 5 (P<.0001). Significant decreases in B. pertussis isolates and hospitalizations occurred in all age groups, including adults and nonvaccinated infants. Thus, mass vaccination of children with pertussis toxoid decreases spread of B. pertussis in the population.

Parapertussis and pertussis: differences and similarities in incidence, clinical course, and antibody responses.

OBJECTIVES To compare the incidence, clinical course, and serologic response to Bordetella antigens in patients with parapertussis and pertussis. DESIGN Two studies were performed in Sweden during the 1990s, when pertussis vaccines were used only in clinical trials. Study I was a retrospective study of patients with positive Bordetella cultures obtained in clinical routine, and study II involved an active search for patients with Bordetella infections during a placebo-controlled trial of a pertussis toxoid vaccine. RESULTS Study I includes 58, and study II 23 patients with parapertussis. In study I, the incidence of parapertussis was 0.016 cases per 100 person years in children 0 to 6 years old and 0 in older children and adults. In study II, the incidence rates of parapertussis and pertussis were 0.2 and 16.2 per 100 person years, respectively, in children followed from 3 months to 3 years of age. The median number of days with cough was 21 in parapertussis and 59 in pertussis. The proportions of children with whooping and vomiting were lower in parapertussis than in pertussis. Geometric mean serum filamentous hemagglutinin IgG increased from 6 to 63, and pertactin IgG from 4 to 12 units/mL in parapertussis patients, which was similar to increases in children with pertussis. CONCLUSIONS Disease caused by Bordetella parapertussis is diagnosed less commonly and is milder and of shorter duration than disease caused by Bordetella pertussis. Parapertussis induced serum IgG against filamentous hemagglutinin and pertactin of similar magnitude as does pertussis, and did not induce serum IgG against pertussis toxin.

Unexpected loss of contact allergy to aluminium induced by vaccine.

Background. In studies in Gothenburg, Sweden, in the 1990s of an aluminium hydroxide‐adsorbed pertussis toxoid vaccine, 745 of ∼76 000 vaccinated children developed long‐lasting itchy subcutaneous nodules at the vaccination site. Of 495 children with itchy nodules patch tested for aluminium allergy, 376 (76%) were positive.

Immunogenicity and reactogenicity of diphtheria, tetanus and pertussis toxoids combined with inactivated polio vaccine, when administered concomitantly with or as a diluent for a Hib conjugate vaccine.

In an open trial, 400 infants were randomized to vaccination with a combined diphtheria-tetanus-pertussis-inactivated polio vaccine (DTaP-IPV) either mixed with a Haemophilus influenzae type b (Hib) tetanus toxoid conjugate immediately before injection (DTaP-IPV/Hib (mix)) or given concurrently with the Hib conjugate at separate injection sites (DTaP-IPV+Hib (sep)). The pertussis component consisted of pertussis toxoid alone. The vaccines were given intramuscularly at 3, 5 and 12 months of age. No vaccine-related serious adverse events occurred. Local reactions were evaluated from diary cards completed by the parents. Infants who received DTaP-IPV/Hib (mix) experienced fewer local reactions. Sera were obtained 28-45 days after the second and third vaccinations. Total Hib capsular antibodies were similar in the two groups after the second injection but lower in the group receiving DTaP-IPV/Hib (mix) than in the group receiving DTaP-IPV+Hib (sep) after the third injection (geometric mean 6.1 vs 10.4 microg/ml). Mixing of the vaccines also led to somewhat lower diphtheria toxin antibodies (5.9 vs. 7.7 IU/ml after the third injection) while tetanus antibodies were higher (3.9 vs. 2.5 IU/ml after the third injection). Antibodies against pertussis toxin and the three polio virus types were similar in the two groups. The moderate impairment of the Hib antibody response caused by mixing of the Hib conjugate with aluminium adsorbed DTaP may be due to physicochemical interference but is probably of little clinical importance because of the ability of the Hib conjugates to induce an immunologic memory.

Serum immunoglobulin G antibody responses to Bordetella pertussis lipooligosaccharide and B. parapertussis lipopolysaccharide in children with pertussis and parapertussis.

ABSTRACT Serum immunoglobulin G (IgG) antibodies against the lipooligosaccharide (LOS) of Bordetella pertussis and the lipopolysaccharide (LPS) of Bordetella parapertussiswere measured by enzyme-linked immunosorbent assay in paired sera from 40 children with pertussis and 14 with parapertussis. Wide differences in the individual responses were noted. Both anti-LOS and -LPS IgG levels increased significantly in the children with pertussis, as did anti-LPS but not anti-LOS in those with parapertussis.

A child with a long-standing, intensely itching subcutaneous nodule on a thigh : an uncommon (?) reaction to commonly used vaccines

A 2-year-old girl presented with an intensely itching subcutaneous nodule on the front of a thigh. The nodule persisted for 10 months until it was excised. Subsequent investigation for malignancy and systemic disease showed no pathological findings. The diagnosis, persistent itching vaccination granuloma, was revealed by hazard almost 2 years after the onset of symptoms. Persistent itching subcutaneous nodules at the injection site for aluminium containing vaccines (mostly diphtheria-tetanus-pertussis combination vaccines for primary immunisation of infants) may appear with a long delay after the vaccination (months), cause prolonged itching (years) and are often associated with contact allergy to aluminium. The condition is poorly recognised in Health Care which may lead to prolonged symptoms and unnecessary investigations.

Comparison of reactivity to a metallic disc and 2% aluminium salt in 366 children, and reproducibility over time for 241 young adults with childhood vaccine-related aluminium contact allergy

An aluminium hydroxide‐adsorbed pertussis toxoid vaccine was studied in 76 000 children in the 1990s in Gothenburg, Sweden. Long‐lasting itchy subcutaneous nodules at the vaccination site were seen in 745 participants. Of 495 children with itchy nodules who were patch tested for aluminium allergy, 377 were positive. In 2007‐2008, 241 of the positive children were retested. Only in one third were earlier positive results reproduced.

Contact allergy to aluminium induced by commonly used pediatric vaccines

© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. We would like to complete the paragraph on Adjuvants (page 6) in the review Vaccination in children with allergies to non active vaccine components by Francheschini et al. [1] which was initiated by the Italian Pediatric Society of Allergy and Immunology in 2013 and published in Clinical and Translational Medicine in 2015. As mentioned in the review, aluminium (Al) salts are widely used as adjuvants in diphtheria-tetanus-pertussis (DTP) and hepatitis A and B vaccines. The list can be completed with pneumococcal and meningococcal conjugate vaccines, which today are included in the national vaccination schedules in most countries in Europe and the Americas, and also in vaccines against human papilloma virus (HPV) and tick-bore encephalitis (TBE). According to the authors, the most known and frequent reaction to Al salts is “a palpable nodule at the injection site”. This sounds harmless enough—but in typical cases the nodules are most annoying to the child due to severe pruritus for a very long time [2, 3]. Besides, most children with persistent itching vaccination granulomas become sensitized against Al [4]. Itching vaccination granulomas are described since 1960 [5] but considered very rare [6] until the 1990s when they were reported in 745 of 76,000 children participating in studies on a monocomponent acellular pertussis vaccine in Sweden [7]. Since then, another 102 children in Sweden who received commercial DTaPpolio-Hib-(HepB) combinations (Infanrix®, Pentavac®) and/or pneumococcal vaccines (Prevenar, Synflorix) are described [4, 8, 9]. The vaccines were given intramuscularly in three doses at 3, 5 and 12 months. In a prospective cohort study on 4758 toddlers the frequency of granulomas was 0.63% in those who received a DTaP combination vaccine alone and 1.18% in those who received an Al adsorbed pneumococcal vaccine at the same time. The risk for granulomas increased with the number of Alcontaining vaccine doses [4]. The itching nodules appear remarkably late (months or even years) after the vaccination. Histopathological examination shows granuloma formations in which Al crystals can be demonstrated [10]. Clinically, pruritus is the dominating symptom with intense local itching in the vaccination area on the thigh, often causing skin alterations like eczema, hypertrichosis and hyperpigmentation. Intensified itching and swelling of the nodules is often reported when the child has a cold or another infection. After a duration of 1⁄2–12 years (median 3–4 years) the nodules eventually disappear and the pruritus ceases. In some cases nodules were mistaken as tumours leading to unnecessary anxiety, investigations and surgery [11, 12]. Contact allergy to aluminium was verified in 77–95% of children with itching vaccination granulomas by epicutaneous testing with Al Chloride hexahydrate 2% and metallic Al (4, 7, 9). Sensitized individuals have reported contact dermatitis after the use of Al containing deodorants, pharmaceutics (ear drops, antiseptics), sun protectors, tattooing pigments and metallic aluminium [13]. Fortunately, and contrary to earlier belief, the sensitization to aluminium seems to vane with time [14]. The consequences of future vaccination with Al adsorbed vaccines in children who once reacted with itching granulomas and/or contact allergy to Al is only partially studied. Our clinical experience so far is that the risk for new granulomas diminishes with time and is very low when the original one has vanished and the itching ceased. In case of on-going severe pruritus the next dose may be postponed 6–12 months. The Al allergy is a delayed type IV reaction not associated with increased risk for anaphylaxis. We want to point out that itching granulomas are benign and self-limiting and no cause to refrain from vaccination in consideration of the risk for a serious infectious disease. They are poorly known but easy to Open Access

Safety Experience with a Monocomponent Acellular Pertussis Vaccine:No Reported Hypotonic-Hyporesponsive Episodes in >50,000 Infants |[dagger]| 921

Results from several clinical trials involving acellular pertussis vaccines containing one or more pertussis antigens have demonstrated these vaccines to have fewer local and systemic reactions than whole-cell pertussis vaccines. However, true rates of less common serious adverse reactions, e.g. hypotonic-hyporesponsive episodes (HHE), known to be associated with whole-cell vaccines have yet to be determined. In a clinical trial of multicomponent acellular pertussis vaccines in Sweden with 80,000 participants the incidence of HHE requiring hospitalization was about one in 3,000 (Heijbel H et al., Dev Biol Stand 1997:89:101).