Immunologic Research

, Volume 60, Issue 2–3, pp 376–383 | Cite as

Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the ‘autoimmune (auto-inflammatory) syndrome induced by adjuvants’ (ASIA)

  • Nancy Agmon-Levin
  • Yaron Zafrir
  • Shaye Kivity
  • Ari Balofsky
  • Howard Amital
  • Yehuda ShoenfeldEmail author


The objectives of this study were to gather information regarding demographic and clinical characteristics of patients diagnosed with either fibromyalgia (FM) or chronic fatigue (CFS) following hepatitis B vaccination (HBVv) and furthermore to apply the recently suggested criteria of autoimmune (auto-inflammatory) syndromes induced by adjuvants (ASIA), in the aim of identifying common characteristics that may suggest an association between fibromyalgia, chronic fatigue and HBV vaccination. Medical records of 19 patients with CFS and/or fibromyalgia following HBVv immunization were analyzed. All of which were immunized during 1990–2008 in different centers in the USA. All medical records were evaluated for demographics, medical history, the number of vaccine doses, as well as immediate and long term post-immunization adverse events and clinical manifestations. In addition, available blood tests, imaging results, treatments and outcomes were analyzed. ASIA criteria were applied to all patients. The mean age of patients was 28.6 ± 11 years, of which 68.4 % were females. 21.05 % had either personal or familial background of autoimmune disease. The mean latency period from the last dose of HBVv to onset of symptoms was 38.6 ± 79.4 days, ranging from days to a year. Eight (42.1 %) patients continued with the immunization program despite experiencing adverse events. Manifestations that were commonly reported included neurological manifestations (84.2 %), musculoskeletal (78.9 %), psychiatric (63.1 %), fatigue (63.1 %), gastrointestinal complains (58 %) and mucocutaneous manifestations (36.8 %). Autoantibodies were detected in 71 % of patients tested. All patients fulfilled the ASIA criteria. This study suggests that in some cases CFS and FM can be temporally related to immunization, as part of ASIA syndrome. The appearance of adverse event during immunization, the presence of autoimmune susceptibility and higher titers of autoantibodies all can be suggested as risk factors. ASIA criteria were fulfilled in all patients eluding the plausible link between ASIA and CFS/FM.


Autoimmune (auto-inflammatory) syndromes induced by adjuvants (ASIA) Vaccines Autoimmunity Hepatitis B vaccine Fibromyalgia Chronic fatigue syndrome 


Conflict of interest

Prof. Yehuda Shoenfeld has served as an expert witness in cases involving adverse vaccine reactions in the no-fault U.S. National Vaccine Injury Compensation Program. All other authors have no conflict of interest.


  1. 1.
    Yunus MB. Central sensitivity syndromes: a new paradigm and group nosology for fibromyalgia and overlapping conditions, and the related issue of disease versus illness. Semin Arthritis Rheum. 2008;37(6):339–52.CrossRefPubMedGoogle Scholar
  2. 2.
    Maquet D, Demoulin C, Crielaard JM. Chronic fatigue syndrome: a systematic review. Ann Readapt Med Phys. 2006;49(6):337–47 418–27.CrossRefPubMedGoogle Scholar
  3. 3.
    McKay PG, Duffy T, Martin CR. Are chronic fatigue syndrome and fibromyalgia the same? Implications for the provision of appropriate mental health intervention. J Psychiatr Ment Health Nurs. 2009;16(10):884–94.CrossRefPubMedGoogle Scholar
  4. 4.
    Podolecki T, Podolecki A, Hrycek A. Fibromyalgia: pathogenetic, diagnostic and therapeutic concerns. Pol Arch Med Wewn. 2009;119(3):157–61.PubMedGoogle Scholar
  5. 5.
    Griffith JP, Zarrouf FA. A systematic review of chronic fatigue syndrome: don’t assume it’s depression. Prim Care Companion J Clin Psychiatry. 2008;10(2):120–8.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Lavergne MR, Cole DC, Kerr K, Marshall LM. Functional impairment in chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivity. Can Fam Physician. 2010;56(2):e57–65.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Prins JB, van der Meer JW, Bleijenberg G. Chronic fatigue syndrome. Lancet. 2006;367(9507):346–55.CrossRefPubMedGoogle Scholar
  8. 8.
    Devanur LD, Kerr JR. Chronic fatigue syndrome. J Clin Virol. 2006;37(3):139–50.CrossRefPubMedGoogle Scholar
  9. 9.
    Bannwarth B, Blotman F, Roué-Le Lay K, Caubère JP, André E, Taïeb C. Fibromyalgia syndrome in the general population of France: a prevalence study. Jt Bone Spine. 2009;76(2):184–7.CrossRefGoogle Scholar
  10. 10.
    Chakrabarty S, Zoorob R. Fibromyalgia. Am Fam Physician. 2007;76(2):247–54.PubMedGoogle Scholar
  11. 11.
    Buskila D. Pediatric fibromyalgia. Rheum Dis Clin North Am. 2009;35(2):253–61.CrossRefPubMedGoogle Scholar
  12. 12.
    Elgen I, Hikmat O, Aspevik TN, Hagen EM. CFS in children and adolescent: ten years of retrospective clinical evaluation. Int J Pediatr. 2013;2013:270373.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Martínez-Jauand M. Pain sensitivity in fibromyalgia is associated with catechol-O-methyltransferase (COMT) gene. Eur J Pain. 2013;17(1):16–27.CrossRefPubMedGoogle Scholar
  14. 14.
    Ablin JN, Cohen H, Buskila D. Mechanisms of disease: genetics of fibromyalgia. Nat Clin Pract Rheumatol. 2006;2(12):671–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Clauw DJ, Arnold LM, McCarberg BH. FibroCollaborative. The science of fibromyalgia. Mayo Clin Proc. 2011;86(9):907–11.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Ablin JN, Buskila D, Van Houdenhove B, Luyten P, Atzeni F, Sarzi-Puttini P. Is fibromyalgia a discrete entity? Autoimmun Rev. 2012;11(8):585–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Rosenblum H, Shoenfeld Y, Amital H. The common immunogenic etiology of chronic fatigue syndrome: from infections to vaccines via adjuvants to the ASIA syndrome. Infect Dis Clin North Am. 2011;25(4):851–63.CrossRefPubMedGoogle Scholar
  18. 18.
    Colafrancesco S, Agmon-Levin N, Perricone C, Shoenfeld Y. Unraveling the soul of autoimmune diseases: pathogenesis, diagnosis and treatment adding dowels to the puzzle. Immunol Res. 2013;56(2–3):200–5.CrossRefPubMedGoogle Scholar
  19. 19.
    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
  20. 20.
    Altman A, Szyper-Kravitz M, Shoenfeld Y. HBV vaccine and dermatomyositis. Rheumatol Int. 2008;28(6):609–12.CrossRefPubMedGoogle Scholar
  21. 21.
    Choffray A, Pinquier L, Bachelez H. Exacerbation of lupus panniculitis following anti hepatitis B vaccination. Dermatology. 2007;215(2):152–4.CrossRefPubMedGoogle Scholar
  22. 22.
    Stübgen JP. Immune-mediated myelitis following hepatitis B vaccination. Autoimmun Rev. 2012;12(2):144–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Stübgen JP. Neuromuscular disorders associated with hepatitis B vaccination. J Neurol Sci. 2010;292(1–2):1–4.CrossRefPubMedGoogle Scholar
  24. 24.
    Mikaeloff Y, Caridade G, Suissa S, Tardieu M. Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood. Neurology. 2009;72(10):873–80.CrossRefPubMedGoogle Scholar
  25. 25.
    Shoenfeld Y, Agmon-Levin N. ‘ASIA’—autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun. 2011;36(1):4–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Satoh M, Reeves WH. Induction of lupus-associated autoantibodies in BALB/c mice by intraperitoneal injection of pristane. J Exp Med. 1994;180:2341–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Reeves WH, Lee PY, Weinstein JS, Satoh M, Lu L. Induction of autoimmunity by pristane and other naturally occurring hydrocarbons. Trends Immunol. 2009;30(9):455–64.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Santoro D, Stella M, Montalto G, Castellin S. Lupus nephritis after hepatitis B vaccination: an uncommon complication. Clin Nephrol. 2007;67(1):61–3.CrossRefPubMedGoogle Scholar
  29. 29.
    Nancy AL, Shoenfeld Y. Chronic fatigue syndrome with autoantibodies–the result of an augmented adjuvant effect of hepatitis-B vaccine and silicone implant. Autoimmun Rev. 2008;8(1):52–5.Google Scholar
  30. 30.
    Exley C, Swarbrick L, Gherardi RK, Authier FJ. A role for the body burden of aluminium in vaccine-associated macrophagic myofasciitis and chronic fatigue syndrome. Med Hypotheses. 2009;72(2):135–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Evans D, Cauchemez S, Hayden FG. “Prepandemic” immunization for novel influenza viruses, “swine flu” vaccine, Guillain–Barré syndrome, and the detection of rare severe adverse events. J Infect Dis. 2009;200(3):321–8.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Adak B, Tekeoğlu I, Ediz L, Budancamanak M, Yazgan T, Karahocagil K, Demirel A. Fibromyalgia frequency in hepatitis B carriers. J Clin Rheumatol. 2005;11(3):157–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Rinaldi M, Perricone R, Blank M, Perricone C, Shoenfeld Y. Anti-Saccharomyces cerevisiae autoantibodies in autoimmune diseases: from bread baking to autoimmunity. Clin Rev Allergy Immunol. 2013;45(2):152–61.Google Scholar
  34. 34.
    Shaw CA, Tomljenovic L. Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity. Immunol Res. 2013;56(2–3):304–16.CrossRefPubMedGoogle Scholar
  35. 35.
    Cohen Tervaert JW, Kappel RM. Silicone implant incompatibility syndrome (SIIS): a frequent cause of ASIA (Shoenfeld’s syndrome). Immunol Res. 2013;56(2–3):293–8.CrossRefPubMedGoogle Scholar
  36. 36.
    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(2–3):299–303.CrossRefPubMedGoogle Scholar
  37. 37.
    Jovanova-Nesic K, Shoenfeld Y, Spector NH. Aluminum excytotoxicity and neuroautotoimmunity: the role of the brain expression of CD32+ (FcγRIIa), ICAM-1+ and CD3ξ in aging. Curr Aging Sci. 2012;5(3):209–17.CrossRefPubMedGoogle Scholar
  38. 38.
    Katzav A, Kivity S, Blank M, Shoenfeld Y, Chapman J. Adjuvant immunization induces high levels of pathogenic antiphospholipid antibodies in genetically prone mice: another facet of the ASIA syndrome. Lupus. 2012;21(2):210–6.CrossRefPubMedGoogle Scholar
  39. 39.
    Shaw CA, Petrik MS. Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration. J Inorg Biochem. 2009;103(11):1555–62.PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Suk JH, Lee JH, Kim JM. Association between thyroid autoimmunity and fibromyalgia. Exp Clin Endocrinol Diabetes. 2012;120(7):401–4.CrossRefPubMedGoogle Scholar
  41. 41.
    Romano TJ. Coexistence of fibromyalgia syndrome (FS) and systemic lupus erythematosus (SLE). Scand J Rheumatol. 1992;21(Suppl 94):12.Google Scholar
  42. 42.
    Abu-Shakra M, Mader R, Langevitz P, et al. Quality of life in systemic lupus erythematosus: a controlled study. J Rheumatol. 1999;26:306–9.PubMedGoogle Scholar
  43. 43.
    Buskila D, Gladdman DD, Langevitz P, Urowitz S, Smythe HA. Fibromyalgia in human immunodeficiency virus infection. J Rheumatol. 1990;17:1202–6.PubMedGoogle Scholar
  44. 44.
    Wolfe F, Michaud K. Severe rheumatoid arthritis (RA), worse outcomes, comorbid illness, and sociodermographic disadvantage characterize RA patients with fibromyalgia. J Rheumatol. 2004;31:695–700.PubMedGoogle Scholar
  45. 45.
    Rodriguez-Pintó I, Agmon-Levin N, Howard A, Shoenfeld Y. Fibromyalgia and cytokines. Immunol Lett. 2014;161(2):200–3.Google Scholar
  46. 46.
    Nishikai M, Tomomatsu S, Hankins RW, et al. Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders. Rheumatology. 2001;40:806–10.CrossRefPubMedGoogle Scholar
  47. 47.
    Tagoe CE, Zezon A, Khattri S, Castellanos P. Rheumatic manifestations of euthyroid, anti-thyroid antibody-positive patients. Rheumatol Int. 2013;33(7):1745–52.CrossRefPubMedGoogle Scholar
  48. 48.
    Clark P, Burgos-Vargas R, Medina-Palma C, et al. Prevalence of fibromyalgia in children: a clinical study of Mexican children. J Rheumatol. 1998;25:2009–14.PubMedGoogle Scholar
  49. 49.
    Nijhof SL, Maijer K, Bleijenberg G, Uiterwaal CS, Kimpen JL, van de Putte EM. Adolescent chronic fatigue syndrome: prevalence, incidence, and morbidity. Pediatrics. 2011;127(5):e1169–75.CrossRefPubMedGoogle Scholar
  50. 50.
    Kivity S, Agmon-Levin N, Blank M, Shoenfeld Y. Infections and autoimmity. Trends Immunol. 2009;30(8):409–14.CrossRefPubMedGoogle Scholar
  51. 51.
    Israeli E, Agmon-Levin N, Blank M, Shoenfeld Y. Macrophagic myofaciitis a vaccine (alum) autoimmune-related disease. Clin Rev Allergy Immunol. 2011;41(2):163–8.CrossRefPubMedGoogle Scholar
  52. 52.
    Savory J, Herman MM, Ghribi O. Mechanisms of aluminum-induced neurodegeneration in animals: implications for Alzheimer’s disease. J Alzheimers Dis. 2006;10(2–3):135–44.PubMedGoogle Scholar
  53. 53.
    Hernán MA, Jick SS, Olek MJ, Jick H. Recombinant hepatitis B vaccine and the risk of multiple sclerosis: a prospective study. Neurology. 2004;63(5):838–42.CrossRefPubMedGoogle Scholar
  54. 54.
    Iñiguez C, Mauri JA, Larrodé P, et al. Acute transverse myelitis secondary to hepatitis B vaccination. Rev Neurol. 2000;31(5):430–2.PubMedGoogle Scholar
  55. 55.
    Renard JL, Guillamo JS, Ramirez JM, et al. Acute transverse cervical myelitis following hepatitis B vaccination. Evolution of anti-HBs antibodies. Presse Med. 1999;28(24):1290.PubMedGoogle Scholar
  56. 56.
    Fonseca LF, Noce TR, Teixeira ML, et al. Early-onset acute transverse myelitis following hepatitis B vaccination and respiratory infection: case report. Arq Neuropsiquiatr. 2003;61(2A):265–8.CrossRefPubMedGoogle Scholar
  57. 57.
    Piaggio E, Ben Younes A, Desbois S, et al. Hepatitis B vaccination and central nervous system demyelination: an immunological approach. J Autoimmun. 2005;24(1):33–7.CrossRefPubMedGoogle Scholar
  58. 58.
    Tomljenovic L, Shaw CA. Mechanisms of aluminum adjuvant toxicity and autoimmunity in pediatric populations. Lupus. 2012;21(2):223–30.CrossRefPubMedGoogle Scholar
  59. 59.
    Silva AF, Aguiar MS, Carvalho OS, Santana LDN, Franco EC, Lima RR, Siqueira NV, Feio RA, Faro LR, Gomes-Leal W. Hippocampal neuronal loss, decreased GFAP immunoreactivity and cognitive impairment following experimental intoxication of rats with aluminum citrate. Brain Res. 2013;1491:23–33.CrossRefPubMedGoogle Scholar
  60. 60.
    Liang RF, Li WQ, Wang XH, Zhang HF, Wang H, Wang JX, Zhang Y, Wan MT, Pan BL, Niu Q. Aluminium-maltolate-induced impairment of learning, memory and hippocampal long-term potentiation in rats. Ind Health. 2012;50(5):428–36.CrossRefPubMedGoogle Scholar
  61. 61.
    Kaneko N, Takada J, Yasui H, Sakurai H. Memory deficit in mice administered aluminum-maltolate complex. Biometals. 2006;19(1):83–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Nancy Agmon-Levin
    • 1
    • 2
  • Yaron Zafrir
    • 1
  • Shaye Kivity
    • 1
    • 2
    • 3
  • Ari Balofsky
    • 1
  • Howard Amital
    • 2
    • 4
  • Yehuda Shoenfeld
    • 1
    • 5
    Email author
  1. 1.The Zabludowicz Center for Autoimmune DiseasesChaim Sheba Medical CenterTel-HashomerIsrael
  2. 2.Sackler Faculty of MedicineTel-Aviv UniversityTel AvivIsrael
  3. 3.The Dr. Pinchas Borenstein Talpiot Medical Leadership Program 2013Sheba Medical CenterTel-HashomerIsrael
  4. 4.Department of Medicine BSheba Medical CenterTel-HashomerIsrael
  5. 5.Sackler Faculty of Medicine, Incumbent of the Laura Schwarz-Kip Chair for Research of Autoimmune DiseasesTel-Aviv UniversityTel AvivIsrael

Personalised recommendations