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


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.

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  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.

    Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Podolecki T, Podolecki A, Hrycek A. Fibromyalgia: pathogenetic, diagnostic and therapeutic concerns. Pol Arch Med Wewn. 2009;119(3):157–61.

    PubMed  Google 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.

    PubMed Central  Article  PubMed  Google 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.

    PubMed Central  PubMed  Google Scholar 

  7. 7.

    Prins JB, van der Meer JW, Bleijenberg G. Chronic fatigue syndrome. Lancet. 2006;367(9507):346–55.

    Article  PubMed  Google Scholar 

  8. 8.

    Devanur LD, Kerr JR. Chronic fatigue syndrome. J Clin Virol. 2006;37(3):139–50.

    CAS  Article  PubMed  Google 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.

    Article  Google Scholar 

  10. 10.

    Chakrabarty S, Zoorob R. Fibromyalgia. Am Fam Physician. 2007;76(2):247–54.

    PubMed  Google Scholar 

  11. 11.

    Buskila D. Pediatric fibromyalgia. Rheum Dis Clin North Am. 2009;35(2):253–61.

    Article  PubMed  Google 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.

    PubMed Central  Article  PubMed  Google 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.

    Article  PubMed  Google Scholar 

  14. 14.

    Ablin JN, Cohen H, Buskila D. Mechanisms of disease: genetics of fibromyalgia. Nat Clin Pract Rheumatol. 2006;2(12):671–8.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Clauw DJ, Arnold LM, McCarberg BH. FibroCollaborative. The science of fibromyalgia. Mayo Clin Proc. 2011;86(9):907–11.

    PubMed Central  Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Altman A, Szyper-Kravitz M, Shoenfeld Y. HBV vaccine and dermatomyositis. Rheumatol Int. 2008;28(6):609–12.

    Article  PubMed  Google Scholar 

  21. 21.

    Choffray A, Pinquier L, Bachelez H. Exacerbation of lupus panniculitis following anti hepatitis B vaccination. Dermatology. 2007;215(2):152–4.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Stübgen JP. Immune-mediated myelitis following hepatitis B vaccination. Autoimmun Rev. 2012;12(2):144–9.

    Article  PubMed  Google Scholar 

  23. 23.

    Stübgen JP. Neuromuscular disorders associated with hepatitis B vaccination. J Neurol Sci. 2010;292(1–2):1–4.

    Article  PubMed  Google 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.

    Article  PubMed  Google Scholar 

  25. 25.

    Shoenfeld Y, Agmon-Levin N. ‘ASIA’—autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun. 2011;36(1):4–8.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    PubMed Central  CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

  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.

    CAS  Article  PubMed  Google 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.

    PubMed Central  Article  PubMed  Google 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.

    Article  PubMed  Google 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.

  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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  40. 40.

    Suk JH, Lee JH, Kim JM. Association between thyroid autoimmunity and fibromyalgia. Exp Clin Endocrinol Diabetes. 2012;120(7):401–4.

    CAS  Article  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    PubMed  Google Scholar 

  45. 45.

    Rodriguez-Pintó I, Agmon-Levin N, Howard A, Shoenfeld Y. Fibromyalgia and cytokines. Immunol Lett. 2014;161(2):200–3.

  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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  PubMed  Google 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.

    Article  PubMed  Google Scholar 

  50. 50.

    Kivity S, Agmon-Levin N, Blank M, Shoenfeld Y. Infections and autoimmity. Trends Immunol. 2009;30(8):409–14.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    PubMed  Google 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.

    Article  PubMed  Google 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.

    PubMed  Google 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.

    CAS  PubMed  Google 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.

    Article  PubMed  Google 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.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Tomljenovic L, Shaw CA. Mechanisms of aluminum adjuvant toxicity and autoimmunity in pediatric populations. Lupus. 2012;21(2):223–30.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google Scholar 

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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.

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Correspondence to Yehuda Shoenfeld.

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Nancy Agmon-Levin and Yaron Zafrir have contributed equally to this article.

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Agmon-Levin, N., Zafrir, Y., Kivity, S. et al. Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the ‘autoimmune (auto-inflammatory) syndrome induced by adjuvants’ (ASIA). Immunol Res 60, 376–383 (2014).

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