Autonomic dysfunction and HPV immunization: an overview
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.
KeywordsHPV vaccine Autonomic dysfunction Autoimmunity Postural orthostatic tachycardia syndrome Chronic regional pain syndrome Small fiber neuropathy Fibromyalgia Myalgic encephalomyelitis Chronic fatigue syndrome
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.
- 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.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.http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Human_papillomavirus_vaccines/human_referral_prac_000053.jsp&mid=WC0b01ac05805c516f (accessed on 05 03 2018).
- 5.Gardasil:EPAR-Scientific Discussions 5-10-2016, European Medicines Agency, 2017 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000703/human_med_000805.jsp (accessed on 05 03 2018).
- 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
- 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. https://doi.org/10.1177/2324709614527812.CrossRefGoogle Scholar
- 20.Dysautonomia Information Page. National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/Disorders/All-Disorders/Dysautonomia-Information-Page (accessed 05 03 2018).
- 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
- 25.Mar, P. L, Raj, S. R., Neuronal and hormonal perturbations in postural tachycardia syndrome. Front Physiol 2014, 5, 220. doi: https://doi.org/10.3389/fphys.2014.00220.
- 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
- 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
- 39.Martinez-Lavin M. Fibromyalgia: when distress becomes (un)sympathetic pain. Pain Res Treat. 2012;981565.Google Scholar
- 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.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.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
- 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
- 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. https://doi.org/10.1371/journal.pone.0051515.CrossRefPubMedPubMedCentralGoogle Scholar
- 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
- 72.Bradford Hill AB. The environment and disease: association or causation? Proceed Roy Soc Medicine – London. 1965;58:295–300.Google Scholar