Immunologic Research

, Volume 65, Issue 1, pp 8–16 | Cite as

Severe manifestations of autoimmune syndrome induced by adjuvants (Shoenfeld’s syndrome)

  • Luis J. JaraEmail author
  • Grettel García-Collinot
  • Gabriela Medina
  • Maria del Pilar Cruz-Dominguez
  • Olga Vera-Lastra
  • Rosa A. Carranza-Muleiro
  • Miguel A. Saavedra
Environment and Autoimmunity


Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) encompassing conditions linked to previous exposure to an adjuvant substance. The clinical picture is very heterogeneous, from mild to severe manifestations, including death. However, the systematic analysis of severe ASIA cases has not been performed. The aim of this study was to systematically review the literature on severe ASIA cases. A systematic review of the literature was performed investigating severe ASIA cases. All publications were identified through PubMed, EMBASE, MEDLINE and Cochrane. Articles published from 2011 to 2016 were included. Severe ASIA was arbitrarily defined as follows: major organ involvement, life-threatening conditions, intensive treatment, disability, hospitalization and outcome (survival and death). Cases described before 2011 were excluded. From 2011 to 2016, we identified 4479 ASIA cases, of them 305 fulfilled arbitrary criteria of severe ASIA including our case presentation and 11 deaths. The majority of severe ASIA cases were related to HPV vaccine, silicone, influenza vaccine and mineral oil injections. The interval from exposition to severe manifestation was from 2 days to 23 years. (1) This is the first study that analyzes all cases published on ASIA with severe manifestations. (2) The current HPV vaccine is both effective and generally safe. However, it should be noted that severe autoimmune side effects have been reported in several studies. Severe ASIA may be observed after influenza vaccines, and other vaccines. (3) Efforts should be made to discover the connection between adjuvants, autoimmunity and autoimmune diseases, because there is an increase in cases severe and life-threatening of ASIA.


Autoimmune syndrome induced by adjuvants Severe ASIA HPV vaccines Silicone breast implants Mineral oil injection 


  1. 1.
    Shoenfeld Y, Agmon-Levin N. ASIA-Autoimmune/inflammatory syndrome induced by adjuvants (ASIA). J Autoimmun. 2011;36:4–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Meroni PL. Autoimmune or auto-inflammatory syndrome induced by adjuvants: old truths and a new syndrome? J Autoimmun. 2011;36:1–3.CrossRefPubMedGoogle Scholar
  3. 3.
    Vera-Lastra O, Medina G, Cruz-Domínguez MP, Ramirez P, Gayosso-Rivera JA, Anduaga-Dominguez H, Lievana-Torres C, Jara LJ. Human adjuvant disease induced by foreign substances: a new model of ASIA (Shoenfeld’s syndrome). Lupus. 2012;21:128–35.CrossRefPubMedGoogle Scholar
  4. 4.
    Loyo E, Jara LJ, López PD, Puig AC. Autoimmunity in connection with a metal implant: a case of autoimmune/autoinflammatory syndrome induced by adjuvants. Auto Immun Highlights. 2012;4:33–8.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Cruz-Domínguez MP, Vera-Lastra O, Deras-Quiñones A, Jandete-Rivera F, Grajeda-Lopez P, Montes-Cortez DH, et al. Mercury tissue deposits: a new adjuvant in autoimmune/inflammatory syndrome. Isr Med Assoc J. 2013;15:716–9.PubMedGoogle Scholar
  6. 6.
    Esposito S, Prada E, Mastrolia MV, Tarantino G, Codeca C, Rigante D. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA: clues and pitfalls in the pediatric background. Immunol Res. 2014;60:366–75.CrossRefPubMedGoogle Scholar
  7. 7.
    Vera-Lastra O, Medina G, Cruz-Domínguez MP, et al. Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld’s syndrome): clinical and immunological spectrum. Expert Rev Clin Immunol. 2013;9:361–73.CrossRefPubMedGoogle Scholar
  8. 8.
    Lidar M, Agmon-Levin N, Langevitz P, et al. Silicone and scleroderma revisited. Lupus. 2012;21:121–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Green H, Eliakim-Raz N, Zimra Y, et al. Paroxysmal nocturnal hemoglobinuria diagnosed after influenza vaccine: coincidence or consequence? Isr Med Assoc J. 2014;16:122–4.PubMedGoogle Scholar
  10. 10.
    Jordana R, Tolosa C, Selva A, et al. Autoimmune hemolytic anemia and CREST syndrome. Med Clin (Barc). 1990;94:740–1.Google Scholar
  11. 11.
    Butnaru D, Shoenfeld Y. Adjuvants and lymphoma risk as part of the ASIA spectrum. Immunol Res. 2015;61:79–89.CrossRefPubMedGoogle Scholar
  12. 12.
    Cheng MP, Kozoriz MG, Ahmadi AA, Kelsall J, Paquette K, Onrot JM. Post-vaccination myositis and myocarditis in a previously healthy male. Allergy Asthma Clin Immunol. 2016;12:6.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Herrera-Aguilar F, López-Íñiguez A, Gómez-Fregoso J, Martín-Nares E, Cerpa-Cruz S. ADEM como presentación de lupus eritematoso sistémico: ampliando el espectro de neuro-ASIA. Reumatol Clin. 2016;12(1):47.CrossRefGoogle Scholar
  14. 14.
    Nesher G, Soriano A, Shlomai G, Iadgarov Y, Shulimzon TR, Borella E, Dicker D, Shoenfeld Y. Severe ASIA syndrome associated with lymph node, thoracic, and pulmonary silicone infiltration following breast implant rupture: experience with four cases. Lupus. 2015;24:463–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Dagan A, Kogan M, Shoenfeld Y, Segal G. When uncommon and common coalesce: adult onset Still’s disease associated with breast augmentation as part of autoimmune syndrome induced by adjuvants (ASIA). Clin Rheumatol. 2015;22:1–6.Google Scholar
  16. 16.
    De Backer H, Darquennes K, Dooms C, Yserbyt J, Coolen J, Verschakelen J, Verbeken E, Vrints I, Wuyts W. The inner and outer of our thorax: silicone breast implants and pulmonary alveolar proteinosis. Acta Clin Belg. 2015;70:384–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Austin A, Tincani A, Kivity S, Arango MT, Shoenfeld Y. Transverse Myelitis Activation Post- H1N1 Immunization: a case of adjuvant induction? Isr Med Assoc J. 2015;17(2):120–2.PubMedGoogle Scholar
  18. 18.
    Homsi Y, Carlson JA, Homsi S. Polyarteritis nodosa presenting as digital gangrene and breast lesion following exposure to silicone breast implants. Case Rep Rheumatol. 2015;2015:765170.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Flores-Padilla G, Mora-Mendoza B, Pedraza-Montenegro A. Síndrome autoimmune/inflamatorio inducido por adyuvante que debuta con manifestaciones pulmonares y articulares. Reumatol Clin. 2014;10(6):406–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Tomljenovic L, Colafrancesco S, Perricone C, Shoenfeld Y. Postural orthostatic tachycardia with chronic fatigue after HPV vaccination as part of the “autoimmune/auto-inflammatory syndrome induced by adjuvants”: case report and literature review. J Investig Med High Impact Case Rep. 2014;2(1):2324709614527812.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Poddighe D, Castelli L, Marseglia GL, Bruni P. A sudden onset of a pseudo-neurological syndrome after HPV-16/18 AS04-adjuvated vaccine: might it be an autoimmune/inflammatory syndrome induced by adjuvants (ASIA) presenting as a somatoform disorder? Immunol Res. 2014;60(2–3):236–46.CrossRefPubMedGoogle Scholar
  22. 22.
    Al Aranji G, White D, Solanki K. Scleroderma renal crisis following silicone breast implant ruptura: a case report and review of the literature. Clin Exp Rheumatol. 2014;32:262–6.PubMedGoogle Scholar
  23. 23.
    Pineda JC, Díaz JC, Agualimpia A, García JF. Autoimmune/inflammatory syndrome induced by adjuvants causing myositis and pulmonary fibrosis. Isr Med Assoc J. 2013;15(11):720–1.PubMedGoogle Scholar
  24. 24.
    Colafrancesco S, Perricone C, Tomljenovic L, Shoenfeld Y. Human papilloma virus vaccine and primary ovarian failure: another facet of the autoimmune/inflammatory syndrome induced by adjuvants. Am J Reprod Immunol. 2013;70(4):309–16.CrossRefPubMedGoogle Scholar
  25. 25.
    Jara LJ, Medina G, Gomez-Bañuelos E, Saavedra MA, Vera-Lastra O. Still’s disease, lupus-like syndrome, and silicone breast implants. A case of ‘ASIA’ (Shoenfeld’s syndrome). Lupus. 2012;21(2):140–5.CrossRefPubMedGoogle Scholar
  26. 26.
    Kivity S, Katz M, Langevitz P, Eshed I, Olchovski D, Barzilai A. Autoimmune Syndrome Induced by Adjuvants (ASIA) in the Middle East: morphea following silicone implantation. Lupus. 2012;21:136–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Pellegrino P, Perrone V, Pozzi M, Carnovale C, Perrotta C, Clementi E, Radice S. The epidemiological profile of ASIA syndrome after HPV vaccination: an evaluation based on the Vaccine Adverse Event Reporting Systems. Immunol Res. 2015;61(1–2):90–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Kinoshita T, Abe R, Hineno A, Tsunekawa K, Nakane S, Ikeda S. Peripheral sympathetic nerve dysfunction in adolescent Japanese girls following immunization with human papilloma virus vaccine. Intern Med. 2014;53:2185–200.CrossRefPubMedGoogle Scholar
  29. 29.
    Cerpa-Cruz S, Paredes-Casillas P, Landeros-Navarro E, Bernard-Medina AG, Martínez-Bonilla G, Gutiérrez-Ureña S. Adverse events following immunization with vaccines containing adjuvants. Immunol Res. 2013;56:299–303.CrossRefPubMedGoogle Scholar
  30. 30.
    Soriano A, Verrecchia E, Marinaro A, Giovinale M, Fonnesu C, Landolfi R, et al. Giant cell arteritis and polymyalgia rheumatica after influenza vaccination: report of 10 cases and review of the literature. Lupus. 2012;21:153–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Alijotas-Reig J, Garcia-Gimenez V, Llurba E, Vilardell-Tarrés M. Autoimmune/inflammatory syndrome (ASIA) induced by biomaterials injection other than silicone medical grade. Lupus. 2012;21(12):1326–34.CrossRefPubMedGoogle Scholar
  32. 32.
    Zafrir Y, Agmon-Levin N, Paz Z, Shilton T, Shoenfeld Y. Autoimmunity following hepatitis B vaccine as part of the spectrum of ‘autoimmune (auto-inflammatory) syndrome induced by adjuvants’ (ASIA): analysis of 93 cases. Lupus. 2012;21(2):146–52.CrossRefPubMedGoogle Scholar
  33. 33.
    Maijers MC, de Blok CJ, Niessen FB, van der Veldt AA, Ritt MJ, Winters HA, et al. Women with silicone breast implants and unexplained systemic symptoms: a descriptive cohort study. Neth J Med. 2013;71(10):534–40.PubMedGoogle Scholar
  34. 34.
    Cohen Tervaert JW, Kappel RM. Silicone implant incompatibility syndrome (SIIS): a frequent cause of ASIA (Shoenfeld’s syndrome). Immunol Res. 2013;56:293–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Manoloudakis N, Labiris G, Karakitsou N, Kim JB, Sheena Y, Niakas D. Characteristics of women who have had cosmetic breast implants that could be associated with increased suicide risk: a systematic review, proposing a suicide prevention model. Arch Plast Surg. 2015;42:131–42.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Goren I, Segal G, Shoenfeld Y. Autoimmune/inflammatory syndrome induced by adjuvant (ASIA) evolution after silicone implants. Who is at risk? Clin Rheumatol. 2015;34(10):1661–6.CrossRefPubMedGoogle Scholar
  37. 37.
    O’Shaughnessy K. Evolution and update on current devices for prosthetic breast reconstruction. Gland Surg. 2015;4(2):97–110.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Barros SM, Carvalho JF. Shoenfeld’s syndrome after pandemic influenza A/H1N1 vaccination. Acta Reumatol Port. 2011;36(1):65–8.PubMedGoogle Scholar
  39. 39.
    Baker B, Eça Guimarães L, Tomljenovic L, Agmon-Levin N, Shoenfeld Y. The safety of human papilloma virus-blockers and the risk of triggering autoimmune diseases. Expert Opin Drug Saf. 2015;14(9):1387–94.CrossRefPubMedGoogle Scholar
  40. 40.
    Martínez-Lavin M. Hypothesis: human papillomavirus vaccination syndrome—small fiber neuropathy and dysautonomia could be its underlying pathogenesis. Clin Rheumatol. 2015;34:1165–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Luis J. Jara
    • 1
    • 6
    Email author
  • Grettel García-Collinot
    • 2
  • Gabriela Medina
    • 3
    • 6
  • Maria del Pilar Cruz-Dominguez
    • 2
    • 6
  • Olga Vera-Lastra
    • 4
    • 6
  • Rosa A. Carranza-Muleiro
    • 2
  • Miguel A. Saavedra
    • 5
    • 6
  1. 1.Direction of Education and ResearchHospital de Especialidades Centro Médico Nacional La Raza, IMSSMexico CityMexico
  2. 2.Research DivisionHospital de Especialidades Centro Médico Nacional La Raza, IMSSMexico CityMexico
  3. 3.Clinical Research UnitHospital de Especialidades Centro Médico Nacional La Raza, IMSSMexico CityMexico
  4. 4.Internal Medicine DepartmentHospital de Especialidades Centro Médico Nacional La Raza, IMSSMexico CityMexico
  5. 5.Rheumatology DepartmentHospital de Especialidades Centro Médico Nacional La Raza, IMSSMexico CityMexico
  6. 6.Universidad Nacional Autónoma de MéxicoMexico CityMexico

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