Immunologic Research

, Volume 66, Issue 6, pp 744–754 | Cite as

Autonomic dysfunction and HPV immunization: an overview

  • Svetlana Blitshteyn
  • Louise Brinth
  • Jeanne E. Hendrickson
  • Manuel Martinez-LavinEmail author
Original Article


This article reviews the case series reported from several countries describing patients with suspected severe side effects to the HPV vaccines. The described symptom clusters are remarkably similar and include disabling fatigue, headache, widespread pain, fainting, gastrointestinal dysmotility, limb weakness, memory impairment episodes of altered awareness, and abnormal movements. This constellation of symptoms and signs has been labeled with different diagnoses such as complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), small fiber neuropathy (SFN), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), or fibromyalgia. It is known that autoimmunity and autoantibodies are present in a subset of patients with CRPS, POTS, SFN, ME/CFS, and fibromyalgia. This article proposes that vaccine-triggered, immune-mediated autonomic dysfunction could lead to the development of de novo post-HPV vaccination syndrome possibly in genetically susceptible individuals. Being cognizant that a temporal relationship between vaccination and symptom onset does not necessarily equate to causality, mounting evidence of case series calls for well-designed case-control studies to determine the prevalence and possible causation between these symptom clusters and HPV vaccines. Since personalized medicine is gaining momentum, the use of adversomics and pharmacogenetics may eventually help identify individuals who are predisposed to HPV vaccine adverse events.


HPV vaccine Autonomic dysfunction Autoimmunity Postural orthostatic tachycardia syndrome Chronic regional pain syndrome Small fiber neuropathy Fibromyalgia Myalgic encephalomyelitis Chronic fatigue syndrome 


Authors’ contributions

All authors actively participated in the design and writing of the article. All authors approved the final version of the manuscript.

Compliance with ethical standards

Conflicts of interest

Manuel Martínez-Lavín declares no conflict of interest. Jeanne Hendrickson declares no conflict of interest. Svetlana Blitshteyn has served as a medical expert witness on cases of POTS and other neurologic syndromes after Gardasil vaccine. Louise Brinth declares no conflict of interest.


  1. 1.
    Keam SJ, Harper DM. Human papillomavirus types 16 and 18 vaccine (recombinant, AS04 adjuvanted, adsorbed) [Cervarix]. Drugs. 2008;68:359–72.CrossRefGoogle Scholar
  2. 2.
    Siddiqui MA, Perry CM. Human papillomavirus quadrivalent (types 6, 11, 16, 18) recombinant vaccine (Gardasil). Drugs. 2006;66:1263–71.CrossRefGoogle Scholar
  3. 3.
    Vesikari T1, Brodszki N, van Damme P, Diez-Domingo J, Icardi G, Petersen LK, et al. A Randomized, Double-Blind, Phase III Study of the Immunogenicity and Safety of a 9-Valent Human Papillomavirus L1 Virus-Like Particle Vaccine (V503) Versus Gardasil(R) in 9–15-Year-Old Girls. Pediatr Infect Dis J. 2015;34:992–8.CrossRefGoogle Scholar
  4. 4.
    European Medicines Agency. Report from the Danish Health and Medicines Authority for consideration by EMA and rapporteurs in relation to the assessment of the safety profile of HPV-vaccines. (accessed on 05 03 2018).
  5. 5.
    Gardasil:EPAR-Scientific Discussions 5-10-2016, European Medicines Agency, 2017 (accessed on 05 03 2018).
  6. 6.
    Kinoshita T, Ab RT, Hineno A, Tsunekawa K, Nakane S, Ikeda S. Peripheral sympathetic nerve dysfunction in adolescent Japanese girls following immunization with the human papillomavirus vaccine. Intern Med. 2014;53:2185–200.CrossRefGoogle Scholar
  7. 7.
    Brinth L, Theibel AC, Pors K, Mehlsen J. Suspected side effects to the quadrivalent human papilloma vaccine. Dan Med J. 2015;62:A5064.Google Scholar
  8. 8.
    Brinth LS, Pors K, Hoppe AG, Badreldin I, Mehlsen J. Is Chronic Fatigue Syndrome/Myalgic Encephalomyelitis a Relevant Diagnosis in Patients with Suspected Side Effects to Human Papilloma Virus Vaccine? Int J Vaccines Vaccination. 2015;1:1–5.CrossRefGoogle Scholar
  9. 9.
    Brinth LS, Pors K, Theibel AC, Mehlsen J. Orthostatic intolerance and postural tachycardia syndrome as suspected adverse effects of vaccination against human papilloma virus. Vaccine. 2015;33:2602–5.CrossRefGoogle Scholar
  10. 10.
    Blitshteyn S. Postural tachycardia syndrome after vaccination with Gardasil. Eur J Neurol. 2010;17:17. Scholar
  11. 11.
    Blitshteyn S. Postural tachycardia syndrome following human papillomavirus vaccination. Eur J Neurol. 2014;21:135–9.CrossRefGoogle Scholar
  12. 12.
    Martinez-Lavin M. Fibromyalgia-like illness in 2 girls after human papillomavirus vaccination. J Clin Rheumatol. 2014;20:392–3.CrossRefGoogle Scholar
  13. 13.
    Nishioka, K. Clinical features and preliminary diagnostic criteria of human papillomavirus vaccination associated with neuroimmunopathic syndrome (HANS). Yokota, S and Matsumoto, K. Internat J Rheum Dis 2014,17 Suppl 2, 6–29.Google Scholar
  14. 14.
    Martinez-Lavin M, Martinez-Martinez LA, Reyes-Loyola P. HPV vaccination syndrome. A questionnaire-based study. Clin Rheumatol. 2015;34:1981–3.CrossRefGoogle Scholar
  15. 15.
    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;70:309–16.CrossRefGoogle Scholar
  16. 16.
    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;2:232470961452781. Scholar
  17. 17.
    Blitshteyn S, Brook J. Postural tachycardia syndrome (POTS) with anti-NMDA receptor antibodies after human papillomavirus vaccination. Immunol Res. 2017;65:282–4.CrossRefGoogle Scholar
  18. 18.
    Kafaie J, Kim M, Krause E. Small fiber neuropathy following vaccination. J Clin Neuromuscul Dis. 2016;18:37–40.CrossRefGoogle Scholar
  19. 19.
    Martinez-Lavin M. Hypothesis: human papillomavirus vaccination syndrome--small fiber neuropathy and dysautonomia could be its underlying pathogenesis. Clin Rheumatol. 2015;34:1165–9.CrossRefGoogle Scholar
  20. 20.
    Dysautonomia Information Page. National Institute of Neurological Disorders and Stroke. (accessed 05 03 2018).
  21. 21.
    Martínez-Martínez LA, Mora T, Vargas A, Fuentes-Iniestra M, Martínez-Lavín M. Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of case-control studies. J Clin Rheumatol. 2014;20:146–50.CrossRefGoogle Scholar
  22. 22.
    McLachlan EM, Janig W, Devor M, Michaelis M. Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature. 1993;363:543–6.CrossRefGoogle Scholar
  23. 23.
    Brouwer BA, Merkies IS, Gerrits MM, Waxman SG, Hoeijmakers JG, Faber CG. Painful neuropathies: the emerging role of sodium channelopathies. J Peripher Nerv Syst. 2014;19:53–65.CrossRefGoogle Scholar
  24. 24.
    Low PA, et al. Postural tachycardia syndrome (POTS). Neurology. 1995;45:S19–S2.Google Scholar
  25. 25.
    Mar, P. L, Raj, S. R., Neuronal and hormonal perturbations in postural tachycardia syndrome. Front Physiol 2014, 5, 220. doi:
  26. 26.
    Thieben MJ, et al. Postural orthostatic tachycardia syndrome: the Mayo clinic experience. Mayo Clin Proc. 2007;82:308–13.CrossRefGoogle Scholar
  27. 27.
    Grubb BP. Postural tachycardia syndrome. Circulation. 2008;117:2814–7.CrossRefGoogle Scholar
  28. 28.
    Sheldon RS, et al. Heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm. 2015;2015(12):e41–63.CrossRefGoogle Scholar
  29. 29.
    Garland EM, Celedonio JE, Raj SR. Postural Tachycardia Syndrome: Beyond Orthostatic Intolerance. Curr Neurol Neurosci Rep. 2015;15:15. Scholar
  30. 30.
    Blitshteyn S. Autoimmune markers and autoimmune disorders in patients with postural tachycardia syndrome (POTS). Lupus. 2015;24:1364–9.CrossRefGoogle Scholar
  31. 31.
    Wallman D, Weinberg J, Hohler AD. Ehlers-Danlos syndrome and postural tachycardia syndrome: a relationship study. J Neurol Sci. 2014;340:99–102.CrossRefGoogle Scholar
  32. 32.
    Hoffman-Snyder C, Lewis JC, Harris LA, Dhawan P, and Goodman B. Evidence of Mast Cell Activation Disorder in Postural Tachycardia Syndrome. American Academy of Neurology Scientific Meeting . 2015.Google Scholar
  33. 33.
    Vernino S, Sandroni P, Singer W, Low PA. Invited article: autonomic ganglia: target and novel therapeutic tool. Neurology. 2008;70:1926–32.CrossRefGoogle Scholar
  34. 34.
    Ross AJ , Tewart JM , Edow MS , and Owe PC. Risk Factors for Postural Tachycardia Syndrome in Adolescents and Young Adults. The 24th International Symposium on the Autonomic Nervous System, October 2013.[Oral Presentation] . 2013.Google Scholar
  35. 35.
    Souayah N, Ajroud-Driss S, Sander HW, Brannagan TH, Hays AP, Chin RL. Small fiber neuropathy following vaccination for rabies, varicella or Lyme disease. Vaccine. 2009;27:7322–5.CrossRefGoogle Scholar
  36. 36.
    DuVernoy TS, Braun MM. Hypotonic-hyporesponsive episodes reported to the vaccine adverse event reporting system (VAERS), 1996-1998. Pediatrics. 2000;106:E52.CrossRefGoogle Scholar
  37. 37.
    Birklein F. Complex regional pain syndrome. J Neurol. 2005;252:131–8.CrossRefGoogle Scholar
  38. 38.
    Martinez-Lavin M. Biology and therapy of fibromyalgia. Stress, the stress response system, and fibromyalgia. Arthritis Res Ther. 2007;9:216.CrossRefGoogle Scholar
  39. 39.
    Martinez-Lavin M. Fibromyalgia: when distress becomes (un)sympathetic pain. Pain Res Treat. 2012;981565.Google Scholar
  40. 40.
    Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, et al. Myalgic encephalomyelitis: international consensus criteria. J Intern Med. 2011;270:327–33.CrossRefGoogle Scholar
  41. 41.
    Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Board on the Health of Select Populations, and Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an illness. 2015. The National Academies Press. Google Scholar
  42. 42.
    Agmon-Levin N, Zafrir Y, Kivity S, Balofsky A, Amital H, Shoenfeld Y. 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. 2014,60,:376–83.Google Scholar
  43. 43.
    Li J, Zhang Q, Liao Y, Zhang C, Hao H, Du J. The value of acetylcholine receptor antibody in children with postural tachycardia syndrome. PediatrCardiol. 2015;36:165–70.Google Scholar
  44. 44.
    Watari M, Nakane S, Mukaino A, Nakajima M, Mori Y, Maeda Y, et al. Autoimmune postural orthostatic tachycardia syndrome. Ann Clin Transl Neurol. 2018;5:486–92.CrossRefGoogle Scholar
  45. 45.
    Martinez-Lavin M, Amezcua-Guerra L. Serious adverse events after HPV vaccination: a critical review of randomized trials and post-marketing case series. Clin Rheumatol. 2017;36:2169–78.CrossRefGoogle Scholar
  46. 46.
    Pellegrino P, Perrone V, Pozzi M, Carnovale C, Perrotta C, Clementi E, et al. The epidemiological profile of ASIA syndrome after HPV vaccination: an evaluation based on the vaccine adverse event reporting systems. Immunol Res. 2015;61:90–6.CrossRefGoogle Scholar
  47. 47.
    Slade BA, Leidel L, Vellozzi C, Woo EJ, Hua W, Sutherland A, Izurieta HS, Ball R, Miller N, Braun MM, Markowitz LE, Iskander. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA 2009 , 302, 750–757.Google Scholar
  48. 48.
    Li H1, Yu X, Liles C, Khan M, Vanderlinde-Wood M, Galloway A, et al. Autoimmune basis for postural tachycardia syndrome. J Am Heart Assoc. 2014;3:3. Scholar
  49. 49.
    Blaes F, Schmitz K, Tschernatsch M, Kaps M, Krasenbrink I, Hempelmann G, et al. Autoimmune etiology of complex regional pain syndrome (M. Sudeck). Neurology. 2004;63:1734–6.CrossRefGoogle Scholar
  50. 50.
    Kohr D, Tschernatsch M, Schmitz K, Singh P, Kaps M, Schäfer KH, et al. Autoantibodies in complex regional pain syndrome bind to a differentiation-dependent neuronal surface autoantigen. Pain. 2009;143:246–51.CrossRefGoogle Scholar
  51. 51.
    Kohr D, Singh P, Tschernatsch M, Kaps M, Pouokam E, Diener M, et al. Autoimmunity against the beta2 adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome. Pain. 2011;152:2690–700.CrossRefGoogle Scholar
  52. 52.
    Dubuis E, Thompson V, Leite MI, Blaes F, Maihöfner C, Greensmith D, et al. Longstanding complex regional pain syndrome is associated with activating autoantibodies against alpha-1a adrenoceptors. Pain. 2014;155:2408–17.CrossRefGoogle Scholar
  53. 53.
    Goebel A, Leite MI, Yang L, Deacon R, Cendan CM, Fox-Lewis A, et al. The passive transfer of immunoglobulin G serum antibodies from patients with longstanding complex regional pain syndrome. Eur J Pain. 2011;15:504–6.Google Scholar
  54. 54.
    Ortega-Hernandez OD, Shoenfeld Y. Infection, vaccination, and autoantibodies in chronic fatigue syndrome, cause or coincidence? Ann N Y Acad Sci. 2009;1173:600–9. Scholar
  55. 55.
    Loebel M, Grabowski P, Heidecke H, Bauer S, Hanitsch LG, Wittke K, et al. Antibodies to beta adrenergic and muscarinic cholinergic receptors in patients with chronic fatigue syndrome. Brain Behav Immun. 2015;155:2408–17. Scholar
  56. 56.
    Yamamoto S, Ouchi Y, Nakatsuka D, Tahara T, Mizuno K, Tajima S, et al. Reduction of [11C](+)3-MPB binding in brain of chronic fatigue syndrome with serum autoantibody against muscarinic cholinergic receptor. PLoS One. 2012;7:e51515. Scholar
  57. 57.
    Nishikai M, Tomomatsu S, Hankins RW, Takagi S, Miyachi K, Kosaka S, 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 (Oxford). 2001;40:806–10.CrossRefGoogle Scholar
  58. 58.
    Palmieri B, Poddighe D, Vadala M, Laurino C, Carnovale C, Clementi E. Severe somatoform and dysautonomic syndromes after HPV vaccination: case series and review of literature. Immunol Res. 2017;65:106–16.CrossRefGoogle Scholar
  59. 59.
    Molbak K, Hansen ND, Valentiner-Branth P. Pre-vaccination care-seeking infemales reporting severe adverse reactions to HPV vaccine. A registry based case-control study. PLoSOne. 2016,11,:e0162520.23.Google Scholar
  60. 60.
    Hendrickson JE, Tormey CA. Human papilloma virus vaccination and dysautonomia: considerations for autoantibody evaluation and HLA typing. Vaccine. 2016;34:4468.CrossRefGoogle Scholar
  61. 61.
    Richards S, Chalkiadis G, Lakshman R, Buttery JP, Crawford NW. Complex regional pain syndrome following immunization. Arch Dis Child. 2012;97:913–5.CrossRefGoogle Scholar
  62. 62.
    Donegan K, Beau-Lejdstrom R, King B, Seabroke S, Thomson A, Bryan P. Bivalent human papillomavirus vaccine and the risk of fatigue syndromes in girls in the UK. Vaccine. 2013;31:4961–7.CrossRefGoogle Scholar
  63. 63.
    Arnheim-Dahlstrom L, Pasternak B, Svanstrom H, Sparen P, Hviid A. Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study. BMJ. 2013;347:f5906.CrossRefGoogle Scholar
  64. 64.
    Arana J, Mba-Jonas A, Jankosky C, Lewis P, Moro PL, Shimabukuro TT, et al. Reports of postural orthostatic tachycardia syndrome after human papillomavirus vaccination in the vaccine adverse event reporting system. J Adolesc Health. 2017;61:577–82.CrossRefGoogle Scholar
  65. 65.
    Vandenbroucke JP. In defense of case reports and case series. Ann Intern Med. 2001;134:330–4.CrossRefGoogle Scholar
  66. 66.
    Chandler RE, Juhlin K, Fransson J, Caster O, Edwards IR, Noren GN. Current safety concerns with human papillomavirus vaccine: a cluster analysis of reports in VigiBase(R). Drug Saf. 2016;40:81–90.CrossRefGoogle Scholar
  67. 67.
    Suzuki S, Hosono A. No association between HPV vaccine and reported post-vaccination symptoms in Japanese young women: results of the Nagoya study. Papillomavirus Res. 2018;5:96–103.CrossRefGoogle Scholar
  68. 68.
    Ozawa K, Hineno A, Kinoshita T, Ishihara S, Ikeda SI. Suspected adverse effects after human papillomavirus vaccination: a temporal relationship between vaccine administration and the appearance of symptoms in Japan. Drug Saf. 2017;40:1219–29.CrossRefGoogle Scholar
  69. 69.
    Hendrickson JE, Hendrickson ET, Gehrie EA, Sidhu D, Wallukat G, Schimke I, et al. Complex regional pain syndrome and dysautonomia in a 14-year-old girl responsive to therapeutic plasma exchange. J Clin Apher. 2016;31:368–74.CrossRefGoogle Scholar
  70. 70.
    Schofield JR, Hendrickson JE. Autoimmunity, autonomic neuropathy, and the HPV vaccination: a vulnerable subpopulation. Clin Pediatr (Phila). 2017;57:603–6. Scholar
  71. 71.
    Takahashi Y, Matsudaira T, Nakano H, Nasu H, Ikeda H, Nakaoka K. Immunological studies of cerebrospinal fluid from patients with CNS symptoms after human papillomavirus vaccination. J Neuroimmunol. 2016;298:71–8.CrossRefGoogle Scholar
  72. 72.
    Bradford Hill AB. The environment and disease: association or causation? Proceed Roy Soc Medicine – London. 1965;58:295–300.Google Scholar
  73. 73.
    Joura EA, Giuliano AR, Iversen OE, Bouchard C, Mao C, Mehlsen J, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015;372:711–23.CrossRefGoogle Scholar
  74. 74.
    Poland GA, Kennedy RB, McKinney BA, Ovsyannikova IG, Lambert ND, Jacobson RM, et al. Vaccinomics, adversomics, and the immune response network theory: individualized vaccinology in the 21st century. Semin Immunol. 2013;25:89–103.CrossRefGoogle Scholar
  75. 75.
    Feenstra B, Pasternak B, Geller F, Carstensen L, Wang T, Huang F, et al. Common variants associated with general and MMR vaccine-related febrile seizures. Nat Genet. 2014;46:1274–82.CrossRefGoogle Scholar
  76. 76.
    Partinen M, Kornum BR, Plazzi G, Jennum P, Julkunen I, Vaarala O. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neuro. 2014;13:600–13.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018
corrected publication 2018

Authors and Affiliations

  • Svetlana Blitshteyn
    • 1
  • Louise Brinth
    • 2
  • Jeanne E. Hendrickson
    • 3
  • Manuel Martinez-Lavin
    • 4
    Email author
  1. 1.Department of NeurologyJacobs School of Medicine and Biomedical Sciences, University at BuffaloBuffaloUSA
  2. 2.Syncope UnitBispebjerg and Frederiksberg HospitalCopenhagenDenmark
  3. 3.Laboratory Medicine and PediatricsYale University School of MedicineNew HavenUSA
  4. 4.Rheumatology DepartmentNational Institute of CardiologyMexico CityMexico

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