European Journal of Pediatrics

, Volume 173, Issue 10, pp 1297–1307 | Cite as

How common are long-lasting, intensely itching vaccination granulomas and contact allergy to aluminium induced by currently used pediatric vaccines? A prospective cohort study

  • Elisabet Bergfors
  • Göran Hermansson
  • Ulla Nyström Kronander
  • Lars Falk
  • Lars Valter
  • Birger Trollfors
Original Article


The frequency of long-lasting, intensely itching subcutaneous nodules at the injection site for aluminium (Al)-adsorbed vaccines (vaccination granulomas) was investigated in a prospective cohort study comprising 4,758 children who received either a diphtheria-tetanus-pertussis-polio-Haemophilus influenzae type b vaccine (Infanrix®, Pentavac®) alone or concomitant with a pneumococcal conjugate (Prevenar). Both vaccines were adsorbed to an Al adjuvant. Altogether 38 children (0.83 %) with itching granulomas were identified, epicutaneously tested for Al sensitisation and followed yearly. Contact allergy to Al was verified in 85 %. The median duration of symptoms was 22 months in those hitherto recovered. The frequency of granulomas induced by Infanrix® was >0.66 % and by Prevenar >0.35 %. The risk for granulomas increased from 0.63 to 1.18 % when a second Al-adsorbed vaccine was added to the schedule. Conclusion: Long-lasting itching vaccination granulomas are poorly understood but more frequent than previously known after infant vaccination with commonly used diphtheria-tetanus-pertussis-polio-Haemophilus influenzae type b and pneumococcal conjugate vaccines. The risk increases with the number of vaccines given. Most children with itching granulomas become contact allergic to aluminium. Itching vaccination granulomas are benign but may be troublesome and should be recognised early in primary health care to avoid unnecessary investigations, anxiety and mistrust.


Itching nodule Granuloma Contact allergy Aluminium Adsorbed vaccines Child health care 





Child health care (center)


Diphtheria-tetanus-acellular pertussis (vaccine)

DTaP comb

Combination vaccine including DTaP, polio, Hib, (hepatitis B)


Elisabet Bergfors (project leader of the study)


Haemophilus influenzae type b (vaccine)


Human papilloma virus (vaccine)


Intramuscular (injection)


Measles-mumps-rubella (vaccine)


Tick-borne encephalitis (vaccine)



We thank Anna-Karin Schöld for handling the epicutaneous testing, Sara Sävemyr for registration of thousands of enquiry responses and Mikael Åkeborg at the Care Data Warehouse of Östergötland County Council for providing us with names, dates of birth and personal code numbers of children born in 2008. The study was carried out with ALF grants from Linköping University and the County Council of Östergötland.

Ethical statements

The study was approved by the Ethical Review Board in Linköping, Sweden (Dnr M110-09) and registered in the County Council of Östergötland according to the Personal Data Ordinance. The parents of all children participating in the clinical study gave informed consent before taking part in it.

Conflict of interest

The authors declare that they have no financial relationship with the organization that sponsored the research, nor any other conflict of interest.


  1. 1.
    Al-Suliman NN, Grabau DA, Kiaer H, Rasmussen M, Bak M (1999) A tumour in the breast: vaccination granuloma as a differential diagnosis. Eur J Surg Oncol 25:34–37PubMedCrossRefGoogle Scholar
  2. 2.
    Beck MH, Wilkinson SM (2004) Contact dermatitis: allergic contact dermatitis to specific allergens. In: Burns T, Breathnach S, Cox N, Griffiths C (ed) Rook’s textbook of dermatology, 7th edn. Blackwell Science, Volume 1, Chapter 20, page 47Google Scholar
  3. 3.
    Bergfors E (2006) Aspects of pertussis, pertussis vaccination and adverse events associated with aluminium adsorbed vaccines [dissertation]. Department of Primary Health Care, The Sahlgrenska Academy, University of Gothenburg ISBN 91-628-6714-8Google Scholar
  4. 4.
    Bergfors E, Björkelund C, Trollfors B (2005) Nineteen cases of persistent pruritic nodules and contact allergy to aluminium after injection of commonly used aluminium-adsorbed vaccines. Eur J Pediatr 164:691–697PubMedCrossRefGoogle Scholar
  5. 5.
    Bergfors E, Lundmark K, Nyström Kronander U (2013) A child with a long-standing, intensely itching subcutaneous nodule on a thigh: an uncommon (?) reaction to commonly used vaccines. BMJ Case Rep. doi: 10.1136/bcr-2012-007779 PubMedGoogle Scholar
  6. 6.
    Bergfors E, Trollfors B (2012) Sixty-four children with persistent itching nodules and contact allergy to aluminium after vaccination with aluminium-adsorbed vaccines—prognosis and outcome after booster vaccination. Eur J Pediatr 172:171–177PubMedCrossRefGoogle Scholar
  7. 7.
    Bergfors E, Trollfors B, Inerot A (2003) Unexpectedly high incidence of persistent itching nodules and delayed hypersensitivity to aluminium in children after the use of adsorbed vaccines from a single manufacturer. Vaccine 22:64–69PubMedCrossRefGoogle Scholar
  8. 8.
    Beveridge MG, Polcari IC, Burns JL, Adler A, Hendrickson B, Stein SL (2012) Local vaccine site reactions and contact allergy to aluminum. Pediatr Dermatol 29:68–72PubMedCrossRefGoogle Scholar
  9. 9.
    Bordet AL, Michenet P, Cohen C, Arbion F, Ekindi N, Bonneau C et al (2001) Post-vaccination granuloma due to aluminium hydroxide. Ann Pathol 21:149–152PubMedGoogle Scholar
  10. 10.
    Bruze M, Lundh K, Gruvberger B, Hindsen M (2008) Aluminium chloride hexahydrate at 2 % is insufficient to trace contact allergy to aluminium. Contact Dermatitis 59:183–184Google Scholar
  11. 11.
    Chong H, Brady K, Metze D, Calonje E (2006) Persistent nodules at injection sites (aluminium granuloma)—clinicopathological study of 14 cases with a diverse range of histological reaction patterns. Histopathology 48(2):182–188PubMedCrossRefGoogle Scholar
  12. 12.
    Clemmensen O, Knudsen HE (1980) Contact sensitivity to aluminium in a patient hyposensitized with aluminium precipitated grass pollen. Contact Dermatitis 6(5):305–308PubMedCrossRefGoogle Scholar
  13. 13.
    Cominos D, Strutton G, Busmanis I (1993) Granulomas associated with tetanus toxoid immunization. Am J Dermatopathol 15:114–117PubMedCrossRefGoogle Scholar
  14. 14.
    Committee on Infectious Diseases, American Academy of Pediatrics (2012): Vaccine administration. In: Pickering LK (ed) Red book 2012, 29th edn. Elk Grove Village, IL, Section 1, page 22Google Scholar
  15. 15.
    Cosnes A, Flechet ML, Revuz J (1990) Inflammatory nodular reactions after hepatitis B vaccination due to Al sensitization. Contact Dermatitis 23:65–67PubMedCrossRefGoogle Scholar
  16. 16.
    Croce S, Lhermitte B, Tomasetto C et al (2008) Late-onset vaccination-induced subcutaneous pseudolymphoma. Ann Pathol 28:146–149PubMedCrossRefGoogle Scholar
  17. 17.
    Culora GA, Ramsay AD, Theaker JM (1996) Aluminium and injection site reactions. J Clin Pathol 49:844–847PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Fawcett HA (1985) Persistent vaccination granuloma due to aluminium hypersensitivity. Br J Dermatol 113:101–102CrossRefGoogle Scholar
  19. 19.
    Fawcett HA, Smith NP (1984) Injection-site granuloma due to aluminum. Arch Dermatol 120:1318–1322PubMedCrossRefGoogle Scholar
  20. 20.
    Frost L, Johansen P, Pedersen S, Veien N, Ostergaard PA, Nielsen MH (1985) Persistent subcutaneous nodules in children hyposensitized with aluminium-containing allergen extracts. Allergy 40(5):368–372PubMedCrossRefGoogle Scholar
  21. 21.
    Garg S, Loghdey S, Gawkrodger DJ (2010) Allergic contact dermatitis from aluminium in deodorants. Contact Dermatitis 62:57–58PubMedCrossRefGoogle Scholar
  22. 22.
    Gente Lidholm A, Bergfors E, Inerot A, Blomgren U, Gillstedt M, Trollfors B (2013) Unexpected loss of contact allergy to aluminium induced by vaccine. Contact Dermatitis 68:286–292PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Josefson A, Färm G, Magnuson A, Meding B (2009) Nickel allergy as a risk factor for hand eczema: a population based study. Br J Dermatol 160:828–834PubMedCrossRefGoogle Scholar
  24. 24.
    Kaaber K, Nielsen AO, Veien NK (1992) Vaccination granulomas and aluminium allergy: course and prognostic factors. Contact Dermatitis 26:304–306PubMedCrossRefGoogle Scholar
  25. 25.
    Lafaye S, Authier FJ, Fraitag S, Rethers L, Bagot M, Wechsler J (2004) Granuloma with lymphocytic hyperplasia following vaccination: 10 cases. Presence of aluminium in the biopsies. Ann Dermatol Venereol 8–9:769–772CrossRefGoogle Scholar
  26. 26.
    Marsee DK, Williams JM, Velazquez EF (2008) Aluminum granuloma after administration of the quadrivalent human papillomavirus vaccine. Report of a case. Am J Dermatopathol 30:622–624PubMedCrossRefGoogle Scholar
  27. 27.
    Maubec E, Pinquier L, Viguier M, Caux F, Amsler E, Aractingi S et al (2005) Vaccination-induced cutaneous pseudolymphoma. J Am Acad Dermatol 52(4):623–629PubMedCrossRefGoogle Scholar
  28. 28.
    McFadden N, Lyberg T, Hensten-Pettersen A (1989) Aluminum-induced granulomas in a tattoo. J Am Acad Dermatol 20:903–908PubMedCrossRefGoogle Scholar
  29. 29.
    Meding B, Augustsson A, Hansson C (1984) Patch test reactions to aluminium. Contact Dermatitis 10:107PubMedCrossRefGoogle Scholar
  30. 30.
    Nielsen VT, Hjorth L, Moller JC (1991) Vaccination granuloma in the breast region—differential diagnosis. Ugeskr Laeger 153:2180–2182PubMedGoogle Scholar
  31. 31.
    Nielsen AO, Kaaber K, Veien NK (1992) Aluminum allergy caused by DTP vaccine. Ugeskr Laeger 154:1900–1901PubMedGoogle Scholar
  32. 32.
    Pembroke AC, Marten RH (1979) Unusual cutaneous reactions following diphtheria and tetanus immunization. Clin Exp Dermatol 4:345–348PubMedCrossRefGoogle Scholar
  33. 33.
    Schwarze HP, Giordano-Labadie F, Loche F, Gorguet MB, Bazex J (2000) Delayed-hypersensitivity granulomatous reaction induced by blepharopigmentation with aluminum-silicate. J Am Acad Dermatol 42:888–891PubMedCrossRefGoogle Scholar
  34. 34.
    Skowron F, Grezard P, Berard F, Balme B, Perrot H (1998) Persistent nodules at sites of hepatitis B vaccination due to aluminium sensitization. Contact Dermatitis 39:135–136PubMedCrossRefGoogle Scholar
  35. 35.
    Slater DN, Underwood JC, Durrant TE, Gray T, Hopper JP (1982) Al hydroxide granulomas: light and electron microscopic studies and X-ray microanalysis. Br J Dermatol 107:103–108PubMedCrossRefGoogle Scholar
  36. 36.
    Taranger J, Trollfors B, Bergfors E, Knutsson N, Sundh V et al (2001) Mass vaccination of children with pertussis toxoid—decreased incidence in both vaccinated and nonvaccinated persons. Clin Infect Dis 33:1004–1010PubMedCrossRefGoogle Scholar
  37. 37.
  38. 38.
    Veien NK, Hattel T, Justesen O, Norholm A (1986) Aluminium allergy. Contact Dermatitis 15:295–297PubMedCrossRefGoogle Scholar
  39. 39.
    Wahlberg J (2001) Patch testing. In: Rycroft R, Menné T, Frosch P, Lepoittevin J, editors. Textbook of contact dermatitis. 3rd edition Berlin, Heidelberg, New York: Springer Verlag 435-68Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Elisabet Bergfors
    • 1
    • 4
  • Göran Hermansson
    • 2
  • Ulla Nyström Kronander
    • 3
  • Lars Falk
    • 4
    • 5
  • Lars Valter
    • 4
  • Birger Trollfors
    • 6
  1. 1.Department of Primary Health Care, The Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
  2. 2.Central Unit of Child Health CareCounty Council of ÖstergötlandLinköpingSweden
  3. 3.Allergy CenterLinköping University HospitalLinköpingSweden
  4. 4.The Research & Development Unit in Local Health CareCounty Council of ÖstergötlandLinköpingSweden
  5. 5.Department of Dermatology and VenereologyCounty Council of ÖstergötlandLinköpingSweden
  6. 6.Department of PaediatricsSahlgrenska University Hospital-EastGothenburgSweden

Personalised recommendations