Vaccination has been one of the most successful public health strategies in the history of medicine. Dreadful diseases like smallpox and poliomyelitis have practically been eradicated. This undeniable success has multiple programs of universal immunization. However, as in any effective biological therapy, an excessive dosage can provoke damage. This would appear to be the situation of vaccination against human papillomavirus (HPV).

The present review reports how having seen two cases of a serious syndrome that appeared to be like fibromyalgia that developed soon after HPV vaccination1 led us to investigate the strength of the possible link between these two events. The study suggests that there is an actual relationship between vaccination against HPV and the development of chronic painful conditions.2 This article proposes that the controversial HPV vaccination syndrome could become a new tragic and undesirable model of fibromyalgia. On the other hand, recent research on the pathogenesis and treatment of fibromyalgia could provide diagnostic and therapeutic guidelines for those individuals affected by a chronic condition soon after immunization against HPV.

Our group has been dedicated to investigate the mechanisms that lead to fibromyalgia. We propose that dysautonomia is the common underlying pathogenesis of fibromyalgia and other related syndromes, such as complex regional pain syndrome and chronic fatigue.3 We also suggest that fibromyalgic pain is of neuropathic origin4 and, moreover, that the sodium channels located in the dorsal root ganglia may have an important role as sympathetic-nociceptive short-circuit sites.5 This proposal has recently been supported by the finding of small fiber neuropathy in a considerable percentage of individuals with fibromyalgia6 and complex regional pain syndrome.7

In 2014, we published the findings in two girls who developed a serious condition that was similar to fibromyalgia soon after receiving the HPV vaccine.1 In evidence-based scientific medicine, case reports are located in the lowest level of the hierarchy of evidence. However, the issuing of case reports is also considered an early and important warning in the process of drug surveillance.8

After the publication of those cases, we received messages from a number of countries in which physician, but especially the mothers of patients, wrote about similar incidents. Prior to this, the association between vaccination against HPV and another type of dysautonomia—postural orthostatic tachycardia syndrome—had also been reported.9 A short time later, two case series similar to ours were published by authors from Denmark10 and Japan.11 The symptoms reported were very similar, but the diagnoses differed. The Japanese patients were mostly considered to have complex regional pain syndrome, whereas the Danish patients were often diagnosed with postural orthostatic tachycardia syndrome or chronic fatigue syndrome. The clinical manifestations of those affected included repetitively headache, myalgia, arthralgia, fatigue, dizziness, nausea and, less frequently, myoclonic disorders.10,11 On the basis of our research on fibromyalgia, we speculated that dysautonomia and small fiber neuropathy could be the hypothetical pathogeneses underlying HPV vaccination syndrome.12

This type of reaction to vaccination against HPV appears to be rare. With our current knowledge it is not possible to calculate the incidence. However, there is general information about reports of adverse events in HPV vaccination. In a study performed in the Spanish Valencian Community between 2007 and 2011, the rate of reports of adverse effects was approximately 1 of 1000 doses of HPV vaccine administered. The reports were made by qualified healthcare professionals (physicians or nurses). Approximately a third of these undesirable events were classified as “serious”. This rate of notification was 10 times higher than that reported for other vaccines administered during the same period to girls of similar ages.13

Subsequently, we asked individuals who had had a chronic disease after vaccination against HPV to complete three validated questionnaires: the 2010 American College of Rheumatology (ACR-2010), which enabled the diagnosis of fibromyalgia and established its severity; the Composite Autonomic Symptom Score (COMPASS-31), which detects symptoms of dysautonomia; and the Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS), which measures the neuropathic component of chronic pain. Over a period of one month, we received 45 completed questionnaires from 13 different countries. In all, 29% of those surveyed detected the onset of their condition within 24h after HPV vaccination. The most frequent presenting symptoms were headache, musculoskeletal pain, fatigue, dizziness/vertigo and paresthesias/allodynia. Overall, 53% of those surveyed met the diagnostic criteria of fibromyalgia. The high COMPASS-31 and S-LANSS scores indicated the presence of severe dysautonomia and severe neuropathic pain. After an average of 4.2±2.5 years, 92% of those affected remained disabled.14 In those patients who met the criteria for fibromyalgia, there was a correlation between the severity of the fibromyalgia measured by ACR-2010 and the intensity of dysautonomia scored by COMPASS-31.15

The reaction of international health authorities to these independent publications was firm and adverse. The European Medicines Agency judged that there was no relationship between the vaccine against HPV and the development of complex regional pain syndrome or postural orthostatic tachycardia.16 Reviews conducted by British,17 Canadian18 and Spanish13 health authorities supported the safety of immunization against HPV. A powerful argument put forward by the defenders of this vaccine was that the large, double-blind, randomized preclinical studies guaranteed the safety of the HPV vaccine. These randomized studies have a higher level of reliability in evidence-based scientific medicine. Randomized studies eliminate the contrivances that have nothing in common with the intervention and the results are totally independent of the judgment of the researchers. Our next step was to analyze in detail the randomized preclinical studies and the case series that reported adverse incidents involving vaccination against HPV.

A critical analysis of the safety profile of the vaccine against HPV2 reveals the following data:

• 1.

  The great majority of the randomized trials with the HPV vaccine did not utilize as control a true placebo, but an aluminum adjuvant. In clinical trials, the placebo is defined as an inert substance. Obviously, the aluminum adjuvant does not have this property. The innocuousness of the aluminum adjuvant has been put into question.2 Strictly speaking, these controlled trials do not compare the efficacy or the safety of the HPV vaccine. They compare only the part of the vaccine that contains particles similar to HPV.

• 2.

  Two of the large preclinical randomized trials demonstrated more serious adverse incidents after vaccination against HPV. The VIVIANE study compared 2881 women injected with the bivalent HPV vaccine versus 2871 injected with the aluminum “placebo”. Over the 4-year follow-up period, there were 14 deaths in the immunized group versus 3 deaths in the control group. The difference is statistically significant. Fisher's exact test produced a P-value of .01. The researchers who conducted this randomized trial deemed that none of the deaths were attributable to the injections administrated.19

The largest double-blind study involving Gardasil compared the efficacy and safety of the new Gardasil-9 versus the tetravalent Gardasil employed at the present time. Gardasil-9 contains more than twice the HPV virus-like particles and more than twice the aluminum adjuvant than its predecessor. Serious adverse incidents were more frequent with Gardasil-9 (3.3%) than with the tetravalent formula (2.6%). We calculate a P-value of .012. The researchers considered that 0% of the adverse events in the two arms of the study were due to the intervention.20

The results of the statistical analyses of these two pivotal studies are distressing. There are more serious adverse effects in the patients who received the HPV vaccine being investigated. Nevertheless, these findings were avoided by the authors, who turned to stressing the fact that the researchers in both cases deemed that 0% of the adverse incidents were related to the intervention. In these two fundamental studies of vaccination against HPV, the solid and disturbing statistical results were ignored and subordinated to the opinion of the investigators.

Other data that support the veracity of HPV vaccination syndrome lie in the fact that independent reports from different parts of the world describe a similar group of post-vaccine symptoms that include headache, fatigue, myalgias, paresthesias and dizziness, among others.9–11,13 This composite of adverse symptoms had been mentioned in randomized preclinical trials. The difficulty arises upon attempting to label this pleiad of symptoms with a precise diagnosis. The study of the database of adverse effects of the World Health Organization (VigiBase) highlights this problem. Cases of headache, dizziness, fatigue and syncope were reported more frequently and were more severe after vaccination against HPV when compared with other types of immunizations administered to individuals of a similar age. However, a minority of the reports mentioned a specific diagnosis.21 The lack of an explicit diagnosis and the dilution of the vaccine employed in cases of the HPV vaccination syndrome in different diagnoses is a possible explanation for the failure to recognize the adverse effects of this vaccine on the part of drug regulatory agencies.

In many cases, the syndrome reported as an adverse effect of immunization against HPV meets the diagnostic criteria of fibromyalgia. This was the situation of approximately half of the patients with whom we contacted.13

Human papillomavirus vaccination syndrome described independently by a number of researchers could become a model that would aid in the understanding of the pathogenesis of fibromyalgia. This disabling disease generally presents in healthy young individuals. It could be that, in some cases, vaccination against HPV acts as a trigger for fibromyalgia or chronic fatigue in predisposed persons or with a history of previous disorders. A study conducted in Denmark demonstrated that the patients who developed symptoms after HPV vaccination had a significantly higher rate of pre-vaccination care-seeking than those who did not.22

In cases of HPV vaccination syndrome, the date of onset of the condition and that of administration of the trigger are well identified. The most widespread symptoms are typical of fibromyalgia: headache, generalized pain, paresthesias and fatigue. It must be stressed that some of these individuals have also mentioned movement disorders such as tremors and myoclonus. These motor disorders are a well-recognized complication of complex regional pain syndrome. Those affected by HPV vaccination syndrome have severe dysautonomia.13 In these cases, there is a correlation between the severity of fibromyalgia and the severity of dysautonomia.14 Individuals who develop a chronic condition after vaccination against HPV have antibodies against key elements of the autonomic nervous system, such as antibodies against adrenergic and muscarinic receptors.23,24 In the few patients in whom this has been investigated, physicians encountered small fiber neuropathy.9,11,24 Should this be verified, this new tragic model would support the dysautonomic and neuropathic pathogenesis of fibromyalgia.

The dysautonomic–neuropathic model of fibromyalgia could provide diagnostic guidelines for those individuals who develop a chronic condition after HPV vaccination. A major problem in these cases has been the absence of a proper diagnosis. The application of the COMPASS-31, S-LANSS and ACR-2010 questionnaires would help to identify the existence of dysautonomia, neuropathic pain and fibromyalgia, respectively. The tilt-table test would recognize postural orthostatic tachycardia or other syndromes involving orthostatic intolerance. Skin biopsy would identify the presence of small fiber neuropathy. The search for antibodies to adrenergic and muscarinic receptors could become a useful tool in the diagnostic process of HPV vaccination syndrome.

At the present time, drug treatment for fibromyalgia leaves much to be desired. However, based on new pathophysiological knowledge, there is investigation underway involving selective blockers of sodium channels located in the dorsal root ganglia25 These substances could become an effective analgesic for HPV vaccination syndrome. The infusion of immunoglobulins or plasmapheresis could be useful in those cases of HPV vaccination syndrome in which there are antibodies against adrenergic or muscarinic receptors.23,24 Pyridostigmine, fludrocortisone and propranolol utilized in orthostatic intolerance syndromes9 could be extrapolated to the therapeutic armamentarium for HPV vaccination syndrome.

It is evident that these diagnostic and therapeutic considerations are hypothetical and need to be subjected to the judgment of investigation.

Independent investigators have reported the development of a fibromyalgia-like chronic syndrome after HPV vaccination. It is difficult to categorize the condition within a specific diagnosis. Recent advances in our understanding of fibromyalgia could provide diagnostic and therapeutic guidelines for the hypothetical HPV vaccination syndrome. On the other hand, should the veracity of HPV vaccination syndrome be corroborated, it could become a new tragic and undesired model of fibromyalgia. International health authorities deny the existence of such a syndrome. More research will be necessary to define HPV vaccination syndrome as a clinical mirage or as a new clinical entity.

The author declares he has no conflicts of interest.