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Human papillomavirus (HPV) vaccine and autonomic disorders: a position statement from the American Autonomic Society

      Abstract

      Introduction

      Human papillomavirus (HPV) vaccination has been anecdotally connected to development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome.

      Objectives

      To critically evaluate a potential connection between HPV vaccination and above noted conditions.

      Methods

      We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders.

      Results

      At this time the American Autonomic Society finds that there are no data to support a causal relationship between HPV vaccination and CRPS, chronic fatigue, POTS or other forms of dysautonomia.

      Conclusions

      Certain conditions are prevalent in the same patient populations that are vaccinated with the HPV vaccine (peri-pubertal males and females). This association, however, is insufficient proof of causality.

      1. Impact of human papilloma virus on human health

      Human papillomaviruses (HPV) are non-enveloped viruses with a double-stranded circular DNA genome. The genome is enclosed in an icosahedral capsid, which is made up of two proteins: the major capsid protein (L1) and the minor capsid protein (L2). HPV is the most common sexually transmitted infection in the United States. An estimated 14 million persons are newly infected with HPV each year in the US with nearly half occurring in adolescents and young adults (
      • In
      ). Although HPV infection is common (40–80% lifetime probability of infection) (
      • O'Leary S.T.
      • Campbell J.D.
      • Kimberlin D.W.
      Update from the advisory committee on immunization practices.
      ), most infections are cleared by a cell-mediated immune response (
      • Doorbar J.
      • Egawa N.
      • Griffin H.
      • Kranjec C.
      • Murakami I.
      Human papillomavirus molecular biology and disease association.
      ).
      Epidemiological data support the existence of a group of high-risk human papilloma viruses associated with cancer: HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 (
      • Doorbar J.
      • Egawa N.
      • Griffin H.
      • Kranjec C.
      • Murakami I.
      Human papillomavirus molecular biology and disease association.
      ;
      • Bruni L.
      • Diaz M.
      • Castellsagué X.
      • Ferrer E.
      • Bosch F.X.
      • de Sanjosé S.
      Cervical human papillomavirus prevalence in 5 continents: meta-analysis of 1 million women with normal cytological findings.
      ). These high-risk viruses cause dysfunction of cell cycle regulators and cause neoplasia (
      • Doorbar J.
      • Egawa N.
      • Griffin H.
      • Kranjec C.
      • Murakami I.
      Human papillomavirus molecular biology and disease association.
      ;
      • Doorbar J.
      Model systems of human papillomavirus-associated disease.
      ). Inability of the immune system to clear this high-risk infection is another hypothesized pathway leading to cancer (
      • Doorbar J.
      Host control of human papillomavirus infection and disease.
      ). HPV infection causes cancers at transformation zones between different kinds of epithelium: cervix, anus, and oropharynx7. In addition to oncogenic HPV infection, concomitant sexually transmitted diseases, multiparity, smoking, and hormonal contraceptive use are other identified risk factors for cervical cancer (
      • Schiffman M.
      • Castle P.E.
      • Jeronimo J.
      • Rodriguez A.C.
      • Wacholder S.
      Human papillomavirus and cervical cancer.
      ). There is a severity-dependent infection prevalence: tests for HPV DNA are positive in 11.7% with normal cervical cytology, 50–70% of cervical intraepithelial neoplasia (CIN) 1, 85% of CIN 2, 90–100% of CIN 3, 85% of vaginal cancer, 80–96% of anal cancer, 40–70% of invasive penile cancer, and 72% of squamous cell head and neck cancer (
      • Doorbar J.
      • Egawa N.
      • Griffin H.
      • Kranjec C.
      • Murakami I.
      Human papillomavirus molecular biology and disease association.
      ;
      • Bruni L.
      • Diaz M.
      • Castellsagué X.
      • Ferrer E.
      • Bosch F.X.
      • de Sanjosé S.
      Cervical human papillomavirus prevalence in 5 continents: meta-analysis of 1 million women with normal cytological findings.
      ).
      Infection with HPV is recognized as one of the major causes of infection-related cancer worldwide (
      • Bosch F.X.
      • Broker T.R.
      • Forman D.
      • et al.
      Comprehensive control of human papillomavirus infections and related diseases.
      ). Persistent oncogenic HPV infections cause over 500,000 cancers worldwide and 30,000 cancers (
      • Schiffman M.
      • Castle P.E.
      • Jeronimo J.
      • Rodriguez A.C.
      • Wacholder S.
      Human papillomavirus and cervical cancer.
      ;
      • Forman D.
      • de Martel C.
      • Lacey C.J.
      • et al.
      Global burden of human papillomavirus and related diseases.
      ;
      • Khode S.R.
      • Dwivedi R.C.
      • Rhys-Evans P.
      • Kazi R.
      Exploring the link between human papilloma virus and oral and oropharyngeal cancers.
      ) in the US annually, with more than half of those cases leading to death11. Cervical cancer is the fourth most common cancer in women and the second largest cause of mortality from cancer in the developing world (
      • Bryan J.T.
      • Buckland B.
      • Hammond J.
      • Jansen K.U.
      Prevention of cervical cancer: journey to develop the first human papillomavirus virus-like particle vaccine and the next generation vaccine.
      ;
      WHOEa. Human papillomavirus vaccines: WHO position paper, May 2017-recommendations.
      ;
      • Markowitz L.E.
      • Dunne E.F.
      • Saraiya M.
      • et al.
      Quadrivalent human papillomavirus vaccine: recommendations of the advisory committee on immunization practices (ACIP).
      ; (
      • (CDC) CfDCaP
      FDA licensure of quadrivalent human papillomavirus vaccine (HPV4, Gardasil) for use in males and guidance from the Advisory Committee on Immunization Practices (ACIP).
      ; (
      • (CDC) CfDCaP
      FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP).
      ). HPV also has a major role in the etiology of squamous cell carcinoma of the anus (men and women), vulva, vagina, penis, mouth and oropharynx (
      • Dalianis T.
      Human papillomavirus and oropharyngeal cancer, the epidemics, and significance of additional clinical biomarkers for prediction of response to therapy (review).
      ;
      • Jain K.S.
      • Sikora A.G.
      • Baxi S.S.
      • Morris L.G.
      Synchronous cancers in patients with head and neck cancer: risks in the era of human papillomavirus-associated oropharyngeal cancer.
      ;
      • Jelihovschi I.
      • Bidescu A.C.
      • Tucaliuc S.E.
      • Iancu L.S.
      Detection Of Human Papilloma Virus In Head And Neck Squamous Cell Carcinomas: a literature review.
      ).

      2. Current approach to treatment of HPV related diseases

      Education, abstinence, and condom use can all reduce infection risk, but even strict condom use is not completely protective in males (
      • Schiffman M.
      • Castle P.E.
      • Jeronimo J.
      • Rodriguez A.C.
      • Wacholder S.
      Human papillomavirus and cervical cancer.
      ). Current treatments cannot eliminate HPV, thus contributing to high infection prevalence (
      • Bruni L.
      • Diaz M.
      • Castellsagué X.
      • Ferrer E.
      • Bosch F.X.
      • de Sanjosé S.
      Cervical human papillomavirus prevalence in 5 continents: meta-analysis of 1 million women with normal cytological findings.
      ).
      HPV vaccination is effective in prevention of infection and prevention of high-grade precancerous lesions (
      • Schiffman M.
      • Castle P.E.
      • Jeronimo J.
      • Rodriguez A.C.
      • Wacholder S.
      Human papillomavirus and cervical cancer.
      ;
      • Angioli R.
      • Lopez S.
      • Aloisi A.
      • et al.
      Ten years of HPV vaccines: state of art and controversies.
      ). Phase III randomized controlled trials of prophylactic HPV vaccination were designed to prevent incident-related HPV infection and thus pre-neoplastic lesions (
      • Schiller J.T.
      • Castellsagué X.
      • Garland S.M.
      A review of clinical trials of human papillomavirus prophylactic vaccines.
      ;
      • Maver P.J.
      • Poljak M.
      Progress in prophylactic human papillomavirus (HPV) vaccination in 2016: a literature review.
      ). All vaccines demonstrated high immunogenicity and efficacy in preventing persistent infection (90% infection reduction, 90% reduction in genital warts) and precancerous (CIN3) lesions (85% reduction) (
      • Schiller J.T.
      • Castellsagué X.
      • Garland S.M.
      A review of clinical trials of human papillomavirus prophylactic vaccines.
      ). This makes HPV vaccination a high-value public health intervention (
      • Bosch F.X.
      • Broker T.R.
      • Forman D.
      • et al.
      Comprehensive control of human papillomavirus infections and related diseases.
      ).
      Three HPV vaccines licensed in the US (Cervarix, Gardasil and Gardasil-9) protect against infection with HPV types 16 and 18 which cause over 60% of cervical and oropharyngeal HPVrelated cancers. In addition, quadrivalent (Gardasil) and nonavalent (Gardasil 9) HPV vaccines protect against HPV types 6 and 11, which cause 90% of genital warts, and Gardasil 9 protects against five additional oncogenic HPV serotypes. These vaccines are composed of virus-like particles (VLPs) derived from the major capsid protein (L1) of HPV, contain no genetic viral material and are highly immunogenic. All three available vaccines are most effective in preventing HPV-related disease in naïve patients only and ideally should be administered before onset of sexual activity. As the vaccines induce humoral immunity and not cell-mediated immunity, they have no therapeutic effect in patients who already have genital lesions or HPVrelated cancer (
      • Angioli R.
      • Lopez S.
      • Aloisi A.
      • et al.
      Ten years of HPV vaccines: state of art and controversies.
      ).
      Based on phase III trial data, in 2006, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC), recommended routine vaccination of females 11–12 years of age and catch-up vaccination of females 13–26 years of age with a series of 3 doses of Gardasil given at baseline, 1–2 months after initiation, and 6 months after initiation13. Routine Gardasil vaccination of males 11–12 years of age, with catchup vaccination of males 13–21 years of age, was recommended by the ACIP in 2011 (
      • Ackerson B.
      • Hechter R.
      • Sidell M.
      • et al.
      Human papillomavirus vaccine series completion in boys before and after recommendation for routine immunization.
      ). The FDA licensed the nonavalent Gardasil vaccine in 2009 for females and in 2014 for males (
      • Gee J.
      • Weinbaum C.
      • Sukumaran L.
      • Markowitz L.E.
      Quadrivalent HPV vaccine safety review and safety monitoring plans for nine-valent HPV vaccine in the United States.
      ). Given the high immunogenicity of Gardasil among males (97.4–99.2% seroconversion at seven months) (
      • Hillman R.J.
      • Giuliano A.R.
      • Palefsky J.M.
      • et al.
      Immunogenicity of the quadrivalent human papillomavirus (type 6/11/16/18) vaccine in males 16 to 26 years old.
      ) and suboptimal vaccination coverage among females, HPV vaccination of males benefitsfemales through herd immunity23. Furthermore, HPV vaccination will play an important role in stemming the increasing incidence of HPV-related oropharyngeal cancers in males which is expected to exceed that of cervical cancer in the US by 2020 (
      • Ackerson B.
      • Hechter R.
      • Sidell M.
      • et al.
      Human papillomavirus vaccine series completion in boys before and after recommendation for routine immunization.
      ).

      3. HPV vaccine safety

      Population-based vaccination program implementation includes monitoring of coverage, impact and safety (
      • Bosch F.X.
      • Broker T.R.
      • Forman D.
      • et al.
      Comprehensive control of human papillomavirus infections and related diseases.
      ). There are passive monitoring programs which have limitations, like incomplete reporting and coincidental associations. Because of this shortcoming, routine formal evaluations of the passive report systems are performed. There have been multiple post-licensure vaccine safety evaluations, independent of the manufacturers, both in the USand internationally (
      • Bosch F.X.
      • Broker T.R.
      • Forman D.
      • et al.
      Comprehensive control of human papillomavirus infections and related diseases.
      ). In addition, comprehensive, independent scientific reviews have been conducted to assess the safety of the HPV vaccines (
      • Macartney K.K.
      • Chiu C.
      • Georgousakis M.
      • Brotherton J.M.
      Safety of human papillomavirus vaccines: a review.
      ;
      • Phillips A.
      • Patel C.
      • Pillsbury A.
      • Brotherton J.
      • Macartney K.
      Safety of human papillomavirus vaccines: an updated review.
      ).
      The most common adverse events associated with HPV vaccines (as a group) reported in the literature are injection site-related: local pain, redness, and swelling. Reported systemic side effects include: fatigue, fever, GI symptoms (diarrhea, nausea, vomiting), headache, myalgia and arthralgia (
      • Angioli R.
      • Lopez S.
      • Aloisi A.
      • et al.
      Ten years of HPV vaccines: state of art and controversies.
      ;
      • Ackerson B.
      • Hechter R.
      • Sidell M.
      • et al.
      Human papillomavirus vaccine series completion in boys before and after recommendation for routine immunization.
      ;
      • van Klooster T.M.
      • Kemmeren J.M.
      • van der Maas N.A.
      • de Melker H.E.
      Reported adverse events in girls aged 13-16 years after vaccination with the human papillomavirus (HPV)- 16/18 vaccine in the Netherlands.
      ;
      • Rambout L.
      • Hopkins L.
      • Hutton B.
      • Fergusson D.
      Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials.
      ). Syncope is a manageable side effect of vaccination in general and simple measures can be adopted to avoid it (
      • Phillips A.
      • Patel C.
      • Pillsbury A.
      • Brotherton J.
      • Macartney K.
      Safety of human papillomavirus vaccines: an updated review.
      ). All reported symptoms are transient and do not worsen with subsequent vaccine doses. To date, the data from clinical trials and available post-marketing periodic safety updates have indicated acceptable safety of HPV vaccines. In fact, systemic side effects did not differ between vaccinated and placebo groups for bivalent, quadrivalent and nonavalent vaccines, and there is no increased risk of death associated with HPV vaccination (
      • Phillips A.
      • Patel C.
      • Pillsbury A.
      • Brotherton J.
      • Macartney K.
      Safety of human papillomavirus vaccines: an updated review.
      ).
      Data released by the Global Advisory Committee on Vaccine Safety (GACVS) in June 2017 (
      • Meeting of the Global Advisory Committee on Vaccine Safety
      7–8 June 2017.
      ) included a safety update on HPV vaccines. Since licensure in 2006, over 270 million doses of HPV vaccines have been distributed. The committee evaluated safety data for this vaccine in 2007, 2008, 2009, 2013, 2014, and 2015. Evaluation of large population-based data by the GACVS from multiple countries found no causal association between HPV vaccinationand diverse symptoms that included chronic pain, motor dysfunction, complex regional pain syndrome (CRPS), or postural tachycardia syndrome (POTS) (
      • Meeting of the Global Advisory Committee on Vaccine Safety
      7–8 June 2017.
      ).
      A review of reports of POTS following HPV vaccination by the Vaccine Adverse Reporting system (VAERS), commissioned by the Centers for Disease Control and Prevention (CDC) and the U.S. Food and Drug Administration (FDA), found approximately one POTS case for every 6.5 million worldwide distributed HPV vaccine doses (29 cases total) between 2006 and 2015. Twenty of these cases had a history of pre-existing medical conditions: chronic fatigue, asthma and chronic headaches. For this time period, the crude reporting rate of POTS after HPV vaccination was rare, measuring 0.07% (
      • Arana J.
      • Mba-Jonas A.
      • Jankosky C.
      • et al.
      Reports of postural orthostatic tachycardia syndrome after human papillomavirus vaccination in the vaccine adverse event reporting system.
      ).
      To understand the association between HPV vaccination and autonomic and/or pain disorders, a large registry-based hospital study in Finland investigated the incidence of autonomic or pain disorders for the years 2002–2012, which were PRIOR to the introduction of the HPV vaccine in Finland. In 2002, there were 2 cases of POTS per 100,000 person-years, and this increased by 2012 to almost 13 cases of POTS per 100,000 person-years31. The investigators found that one cause for the higher annual incidence rate for POTS and chronic fatigue syndrome (CFS) was increased physician awareness of these diagnoses. It is imperative that this general increase in incidence and/or awareness of autonomic disorders is accounted for in the interpretation of data concerning any potential impact of HPV vaccination on autonomic disorders.

      4. Dissenting opinions regarding safety

      Anecdotal reports alleging possible adverse events following HPV vaccination have been published (
      • Blitshteyn S.
      Postural tachycardia syndrome following human papillomavirus vaccination.
      ;
      • Brinth L.S.
      • Pors K.
      • Theibel A.C.
      • Mehlsen J.
      Orthostatic intolerance and postural tachycardia syndrome as suspected adverse effects of vaccination against human papilloma virus.
      ;
      • Brinth L.S.
      • Mehlsen J.
      Response to letter to the editor.
      ;
      • Martínez-Lavín M.
      Hypothesis: human papillomavirus vaccination syndrome--small fiber neuropathy and dysautonomia could be its underlying pathogenesis.
      ;
      • Hendrickson J.E.
      • Hendrickson E.T.
      • Gehrie E.A.
      • et al.
      Complex regional pain syndrome and dysautonomia in a 14-year-old girl responsive to therapeutic plasma exchange.
      ;
      • Takahashi Y.
      • Matsudaira T.
      • Nakano H.
      • et al.
      Immunological studies of cerebrospinal fluid from patients with CNS symptoms after human papillomavirus vaccination.
      ;
      • Baker B.
      • Eça Guimarães L.
      • Tomljenovic L.
      • Agmon-Levin N.
      • Shoenfeld Y.
      The safety ofhuman papilloma virus-blockers and the risk of triggering autoimmune diseases.
      ;
      • 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”.
      ). Cited adverse events include: dysautonomia, CFS, CRPS, and POTS (
      • Baker B.
      • Eça Guimarães L.
      • Tomljenovic L.
      • Agmon-Levin N.
      • Shoenfeld Y.
      The safety ofhuman papilloma virus-blockers and the risk of triggering autoimmune diseases.
      ).
      A presumed immunological or inflammatory response to vaccination is considered the linking mechanism to the development of POTS, pain syndrome or other form of dysautonomia (
      • Blitshteyn S.
      Postural tachycardia syndrome following human papillomavirus vaccination.
      ;
      • Brinth L.S.
      • Pors K.
      • Theibel A.C.
      • Mehlsen J.
      Orthostatic intolerance and postural tachycardia syndrome as suspected adverse effects of vaccination against human papilloma virus.
      ;
      • Brinth L.S.
      • Mehlsen J.
      Response to letter to the editor.
      ;
      • Martínez-Lavín M.
      Hypothesis: human papillomavirus vaccination syndrome--small fiber neuropathy and dysautonomia could be its underlying pathogenesis.
      ;
      • Hendrickson J.E.
      • Hendrickson E.T.
      • Gehrie E.A.
      • et al.
      Complex regional pain syndrome and dysautonomia in a 14-year-old girl responsive to therapeutic plasma exchange.
      ;
      • Takahashi Y.
      • Matsudaira T.
      • Nakano H.
      • et al.
      Immunological studies of cerebrospinal fluid from patients with CNS symptoms after human papillomavirus vaccination.
      ;
      • Baker B.
      • Eça Guimarães L.
      • Tomljenovic L.
      • Agmon-Levin N.
      • Shoenfeld Y.
      The safety ofhuman papilloma virus-blockers and the risk of triggering autoimmune diseases.
      ;
      • 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”.
      ). In a review of these publications, several key factors are apparent:
      Despite having issues in case ascertainment and classification, unsuitable analytic methods and misleading conclusions (
      • Phillips A.
      • Patel C.
      • Pillsbury A.
      • Brotherton J.
      • Macartney K.
      Safety of human papillomavirus vaccines: an updated review.
      ), these case reports have drawn media attention to a small numbers of individuals with purported adverse reactions to HPV vaccination. The reports influence how providers communicating risks associated with not vaccinating (
      • Iwata S.
      • Okada K.
      • Kawana K.
      • ECoPo Vaccination
      Consensus statement from 17 relevant Japanese academic societies on the promotion of the human papillomavirus vaccine.
      ;
      • Dixon G.N.
      Making vaccine messaging stick: perceived causal instability as a barrier to effective vaccine messaging.
      ) are confounded by patient care-seeking behavior patterns pre- and post-vaccination45, thus reducing the number of vaccinated individuals. In fact, the reports have created widespread fear, resulting in decreased vaccination rates or even dismantling of vaccination programs in some countries (
      • Skufca J.
      • Ollgren J.
      • Ruokokoski E.
      • Lyytikäinen O.
      • Nohynek H.
      Incidence rates of Guillain Barré (GBS), chronic fatigue/systemic exertion intolerance disease (CFS/SEID) and postural orthostatic tachycardia syndrome (POTS) prior to introduction of human papilloma virus (HPV) vaccination among adolescent girls in Finland, 2002–2012.
      ; ).
      It is common for a diagnosis of any syndrome or disease, including a persistent autonomic or pain disorder, to be attributed to a recent life event such as a recent illness, trauma or even vaccination (
      • Macartney K.K.
      • Chiu C.
      • Georgousakis M.
      • Brotherton J.M.
      Safety of human papillomavirus vaccines: a review.
      ;
      • Phillips A.
      • Patel C.
      • Pillsbury A.
      • Brotherton J.
      • Macartney K.
      Safety of human papillomavirus vaccines: an updated review.
      ). The fact that certain conditions peak in incidence at the same age, and in the same population that is being vaccinated (peri-pubertal males and females), is insufficient proof of causality, especially with chronic illness such as dysautonomia and POTS, which have relapsing-remitting courses and frequent exacerbations caused by a variety of factors. Attribution of causality requires solid epidemiological data demonstrating evidence for causality at the population level, with supporting evidence of biological plausibility (
      • Tafuri S.
      • Fortunato F.
      • Gallone M.S.
      • et al.
      Systematic causality assessment of adverse events following HPV vaccines: analysis of current data from Apulia region (Italy).
      ;
      • Works Health Organization
      Causality Assessment of an Adverse Event Following Immunization (AEFI): User Manual for the Revised WHO Classification.
      ).

      5. American autonomic society position

      At this time, the American Autonomic Society (AAS) finds that the data do not support a causal relationship between HPV vaccination and CRPS, POTS, or other forms of dysautonomia. Large population studies and exposure of over 270 million people to the HPV vaccine have not resulted in an identifiable pattern of adverse events, and no evidence of an increase in dysautonomia or POTS with use of the vaccine.
      The AAS acknowledges that several groups have dissenting opinions (
      • Blitshteyn S.
      Postural tachycardia syndrome following human papillomavirus vaccination.
      ;
      • Brinth L.S.
      • Pors K.
      • Theibel A.C.
      • Mehlsen J.
      Orthostatic intolerance and postural tachycardia syndrome as suspected adverse effects of vaccination against human papilloma virus.
      ;
      • Brinth L.S.
      • Mehlsen J.
      Response to letter to the editor.
      ;
      • Martínez-Lavín M.
      Hypothesis: human papillomavirus vaccination syndrome--small fiber neuropathy and dysautonomia could be its underlying pathogenesis.
      ;
      • Hendrickson J.E.
      • Hendrickson E.T.
      • Gehrie E.A.
      • et al.
      Complex regional pain syndrome and dysautonomia in a 14-year-old girl responsive to therapeutic plasma exchange.
      ;
      • Takahashi Y.
      • Matsudaira T.
      • Nakano H.
      • et al.
      Immunological studies of cerebrospinal fluid from patients with CNS symptoms after human papillomavirus vaccination.
      ;
      • Baker B.
      • Eça Guimarães L.
      • Tomljenovic L.
      • Agmon-Levin N.
      • Shoenfeld Y.
      The safety ofhuman papilloma virus-blockers and the risk of triggering autoimmune diseases.
      ;
      • 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”.
      ; ). However, the data at this time constitute only weak temporal associations between events, and their hypothesized mechanisms have not been scientifically proven. The small sample sizes, inherent selection biases, and lack of control populations preclude drawing any scientifically valid conclusions of causality (
      • Arana J.
      • Mba-Jonas A.
      • Jankosky C.
      • et al.
      Reports of postural orthostatic tachycardia syndrome after human papillomavirus vaccination in the vaccine adverse event reporting system.
      ;
      • Butts B.N.
      • Fischer P.R.
      • Mack K.J.
      Human papillomavirus vaccine and postural orthostatic tachycardia syndrome: a review of current literature.
      ;
      • Works Health Organization
      Causality Assessment of an Adverse Event Following Immunization (AEFI): User Manual for the Revised WHO Classification.
      ).
      The AAS recognizes that HPV increases the risk of cancer in patients who become infected. In the absence of compelling data for harm from vaccination, we are concerned that isolated reports linking HPV vaccination to autonomic disorders or chronic pain disorders may cause needless panic in those at risk for HPV infection and decrease the rate of HPV vaccinations. Neglecting HPV vaccination has the potential for significant public harm by eliminating equitable protection from vaccination against HPV-related cancer26. For example, in Japan where HPV vaccination was not proactively recommended, mortality from cervical cancer increased by 3.4% between 2005 and 2015 (
      • Iwata S.
      • Okada K.
      • Kawana K.
      • ECoPo Vaccination
      Consensus statement from 17 relevant Japanese academic societies on the promotion of the human papillomavirus vaccine.
      ). In contrast, herd immunity seems to develop in countries with a vaccination rate greater than 50%, with an associated decline in cancer rates (
      WHOEa. Human papillomavirus vaccines: WHO position paper, May 2017-recommendations.
      ;
      • Drolet M.
      • Bénard É.
      • Boily M.C.
      • et al.
      Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis.
      ).
      As with any reported autonomic disorder, the AAS supports ongoing surveillance and collection of data including the type and timing of symptom onset after vaccination, and theobjectively measured severity of potential autonomic adverse effects related to HPVvaccination (
      • Gee J.
      • Weinbaum C.
      • Sukumaran L.
      • Markowitz L.E.
      Quadrivalent HPV vaccine safety review and safety monitoring plans for nine-valent HPV vaccine in the United States.
      ;
      • Skufca J.
      • Ollgren J.
      • Ruokokoski E.
      • Lyytikäinen O.
      • Nohynek H.
      Incidence rates of Guillain Barré (GBS), chronic fatigue/systemic exertion intolerance disease (CFS/SEID) and postural orthostatic tachycardia syndrome (POTS) prior to introduction of human papilloma virus (HPV) vaccination among adolescent girls in Finland, 2002–2012.
      ;
      • Mølbak K.
      • Hansen N.D.
      • Valentiner-Branth P.
      Pre-vaccination care-seeking in females reporting severe adverse reactions to HPV vaccine. A registry based case-control study.
      ;
      • Cameron R.L.
      • Ahmed S.
      • Pollock K.G.
      Adverse event monitoring of the human papillomavirus vaccines in Scotland.
      ;
      • Petousis-Harris H.
      Proposed HPV vaccination syndrome is unsubstantiated.
      ;
      • Andrews N.
      • Stowe J.
      • Miller E.
      No increased risk of Guillain-Barré syndrome after human papilloma virus vaccine: a self-controlled case-series study in England.
      ;
      • 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.
      ;
      • Miranda S.
      • Chaignot C.
      • Collin C.
      • Dray-Spira R.
      • Weill A.
      • Zureik M.
      Human papillomavirus vaccination and risk of autoimmune diseases: a large cohort study of over 2million young girls in France.
      ;
      • Grimaldi-Bensouda L.
      • Rossignol M.
      • Koné-Paut I.
      • et al.
      Risk of autoimmune diseases and human papilloma virus (HPV) vaccines: six years of case-referent surveillance.
      ;
      • Liu E.Y.
      • Smith L.M.
      • Ellis A.K.
      • et al.
      Quadrivalent human papillomavirus vaccination in girls and the risk of autoimmune disorders: the Ontario Grade 8 HPV Vaccine Cohort Study.
      ). The AAS also supports ongoing, well-designed long-term populationbased epidemiological studies that assess the safety and efficacy of vaccines of any sort. However, the AAS warns against drawing premature conclusions from poorly designed trials or small cohort studies that do not adequately assess the risks and benefits of population level vaccination.

      Funding source

      None.

      Declaration of Competing Interest

      AB – None.
      CHG – C.H.G. has received research support at Beth Israel Deaconess Medical Center from Grifols Inc. C.H.G has served as a scientific consult for Lundbeck. C.H.G. has served as a consultant for the United States Department of Justice (Vaccine Court). CHG has receivedcompensation for editorial activities (Associate Editor) with Autonomic Neuroscience – Basic and Clinical.
      FA – None.
      EEB – None.
      IB – None related to this topic. IB is a consultant for and recipient of research grants from Lundbeck Pharmaceuticals and Theravance Biopharma for the development of treatments for orthostatic hypotension.
      MWC - None.
      GC – Co-owner of PainStakers LLC, a company dedicated to teaching primary care physicians effective pain management.
      TC – Co-owner of PainStakers LLC, a company dedicated to teaching primary care physicians effective pain management.
      WPC – None.
      VEC – Research grants from the Heart and Stroke Foundation of Canada, Craig H Nielsen Foundation, and International Collaboration On Repair Discoveries.
      RF – RF received personal compensation and/or stock options for serving on scientific advisory boards of: Abide, Applied Therapeutics, Astellas, Aptinyx, Biogen, Chromacel, Cutaneous NeuroDiagnostics, Ironwood, Lundbeck, MundiPharma, NeuroBo, Novartis, Pfizer, Regenacy, Spinifex, Toray and Theravance. RF received personal compensation for editorial activities (Editor) with Autonomic Neuroscience – Basic and Clinical.
      DSG – None.
      MJJ – None.
      HK – HK has served as an expert witness for the US Department of Justice in a case alleging that POTS was caused by HPV vaccination.
      PAL – PAL has served as an expert witness for the US Department of Justice in Vaccine Court.
      LNK – LNK has served as a consultant for PTC Therapeutics.
      DR – None.
      CAS – C.A.S. received grant support from Office of Orphan Products Development. Food and Drug Administration, Grant #FD-R-04778-01-A3. C.A.S. has received speaker honorarium from Lundbeck Pharmaceuticals. C.A.S. received consulting honoraria from Lundbeck. CAS has received research support from the CDC, Clinical Immunization and Safety Assessment Program at Vanderbilt University Medical Center.
      WS - None.
      HS - None.
      SV – SV receives research support from Dysautonomia International, Genentech, Grifols, Rex Griswold Foundation, and Athena/Quest Diagnostics and personal compensation for consulting for Argenx, Alexion, and Lundbeck. SV has provided medicolegal consultation related to HPV vaccination.
      SRR – SRR has grant support from the Canadian Institutes of Health Research (Ottawa, Canada), Cardiac Arrhythmia Network of Canada (London, ON, Canada), and Dysautonomia International (East Moriches, NY, USA). SRR is a consultant for GE Healthcare and Lundbeck LLC, and has performed medicolegal consulting on diagnosis and causation of POTS. SRR has received compensation for editorial activities (Associate Editor) with Autonomic Neuroscience – Basic and Clinical.

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