A new report provides details on 45 individuals from 13 countries who developed a chronic ailment soon after receiving the human papillomavirus (HPV) vaccine.

After a mean period of 4 years after HPV vaccination, 43 of these individuals (93%) "continue to have incapacitating symptoms and remain unable to attend school or work," write the authors in a report published online September 10 in Clinical Rheumatology.

"A disabling syndrome of chronic neuropathic pain, vexing fatigue, and profound autonomic dysfunction may appear after HPV vaccination," say the authors, headed by Manuel Martínez-Lavín, MD, from the Rheumatology Department, Instituto Nacional de Cardiología Ignacio Chávez, in Mexico City.

The symptoms are similar to those described by other clinicians in previous reports in the medical literature, including case reports of 53 individuals in Denmark, 40 in Japan, and six in the United States.

However, experts point out that all of these publications are case reports with no control subjects, and cannot determine causality.

Health officials at the US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) emphasize that controlled clinical trials in tens of thousands of individuals plus postlicensure monitoring of millions of individuals have found no causal association between HPV vaccination and atypical pain syndromes or autonomic dysfunction.

The fact that all the publications are case reports is key, says one expert.

"In a nutshell, this is not adequate science," Eduardo L. Franco, DrPH, FRSC, FCAHS, professor of oncology and director of cancer epidemiology at McGill University in Montreal, told Medscape Medical News.

"Undoubtedly, some people who received the HPV vaccine won the lottery after buying a ticket or met the love of their lives. If you had seen a case series of these people, would you think the vaccine causes good luck? Bad things happen all the time, and good things too. When you have many millions of girls and boys receiving a medical intervention and then paying attention to them, you will have lots of cases of poor clinical outcomes. This does not mean causation," Dr Franco emphasized.

Given to More Than 72 Million Worldwide

HPV vaccines have been given to more than 72 million people worldwide, according to an estimate from the European Medicines Agency (EMA).

Marketed as Gardasil (Merck & Co.) and Cervarix (GlaxoSmithKline), these vaccines are now routinely given in immunization programs in many countries around the world, and are recommended by many leading medical organizations. They offer protection against HPV-associated cervical cancer as well as other conditions that are associated with the virus, including anal cancer and genital warts.

The EMA is currently conducting a safety review of HPV vaccines following reports of complex regional pain syndrome (CRPS) and postural orthostatic tachycardia syndrome (POTS), but the agency emphasizes that this review "does not question that the benefits of HPV vaccines outweigh their risks."

Dr Martínez-Lavín recently published a hypothesis (Clin Rheumatol. 2015;34:1165-1169), which suggested that small fiber neuropathy and dysautonomia could be the mechanism behind the development of CRPS, POTS, and fibromyalgia after HPV vaccination.

"These illnesses are difficult to diagnose and have overlapping clinical features," Dr Martínez-Lavín and colleagues write in their latest report.

In order to investigate the syndrome further, they collected a cohort of individuals who "had the onset of a chronic disease soon after HPV vaccination," and asked them to complete three recently validated self-applied questionnaires that may help to appraise these syndromes. The questionnaires were the 2010 American College of Rheumatology Fibromyalgia Diagnostic Criteria survey, which can detect the presence of fibromyalgia, the COMPASS 31 survey, which evaluates the burden of autonomic symptoms, and the S-LANSS questionnaire, which may suggest a neuropathic component in the pain experience.

"The target population was identified with the help of HPV vaccine blog managers," the authors write. Also included were patients who had emailed Dr Martínez-Lavín after his previous publication and two patients with fibromyalgia after HPV vaccination who he had seen personally (and published these two case histories last year [J Clin Rheumatol. 2014;20:392-393]).

Dr Martínez-Lavín told Medscape Medical News: "I am a fibromyalgia researcher. My interest in HPV vaccination adverse reactions started after taking care of two girls with a fibromyalgia-like illness after HPV immunization. I was impressed by their illness severity. I had not seen before such devastating painful dysautonomic illness at this young age."

The clear limitation of our study is the lack of direct medical examination of affected individuals.

However, these were the only two patients seen directly by the authors. "The clear limitation of our study is the lack of direct medical examination of affected individuals," they acknowledge.

Approached for comment, Maurie Markman, MD, clinical professor at Drexel University College of Medicine, president of medicine and science at the Cancer Treatment Centers of America in Philadelphia, and Medscape video blogger for Markman on Oncology, highlighted this limitation of the report.

"All reports of potential adverse reactions to vaccines, including HPV vaccination, need to be taken seriously," Dr Markman told Medscape Medical News. "However, this particular report of a survey with limited direct examination of individuals involved has very serious limitations. Evaluation through well-established epidemiological strategies and appropriate medical exams is required before any statement regarding a possible cause and effect relationship is scientifically acceptable."

The FDA told Medscape Medical News: "This report is not a hypothesis-testing epidemiologic study and does not provide evidence that administration of HPV vaccines is either statistically associated or causally associated with the symptoms reported by the individuals contacted by Dr Martínez-Lavín's group."

Details of Symptoms Reported

The participants in the survey conducted by Dr Martínez-Lavín and colleagues are from various countries worldwide: United States, Canada, Philippines, Denmark, England, Ireland, Spain, Finland, Australia, Colombia, Mexico, Uruguay, and New Zealand. The majority (79%) received Gardasil and 21% received Cervarix.

The mean time span between vaccination and onset of symptoms was 2.3 ± 3.1 weeks, but 29% of the cases had immediate (within 24 hours) postvaccination illness onset, the authors write.

The most common presenting complaints were musculoskeletal pain (66%), fatigue (57%), headache (57%), dizziness/vertigo (43%), and paresthesias/allodynia (36%).

Responses on the validated questionnaires show that half of the affected individuals (53%) fulfilled the fibromyalgia criteria, and there was also evidence of advanced autonomic dysfunction and ongoing pain with a neuropathic component, note the authors.

They also highlight the longevity of many of the symptoms. All but two of these individuals have "escalating vexing symptoms," they comment, after a mean period of 4.2 ± 2.5 years postvaccination.

At this point in time, the most common reported symptoms were fatigue/tiredness (88%), muscle pain (76%), headache (74%), muscle weakness (69%), problems with thinking or remembering (63%), dizziness (63%), pain/cramps in the abdomen (60%), numbness/tingling (60%), and nausea (60%).

Because of these symptoms, 93% of patients are unable to regularly attend school or work, the authors point out.

"These results suggest that a patterned illness of neuropathic pain and autonomic dysfunction may appear after HPV vaccination," the authors comment.

"The fact that 29% of cases had an immediate (within 24 hours) onset of their illness after HPV vaccination, plus the fact that a patterned illness may develop after HPV immunization suggest a cause–effect relationship between this type of immunization and the subsequent chronic ailment," Dr Martínez-Lavín told Medscape Medical News. "There is not known predisposition," he added.

In their report, the researchers write: "Based on our previous research on fibromyalgia, we speculate that in susceptible individuals the vaccine recombinant virus-like particles adsorbed on aluminum-containing adjuvant may damage dorsal root ganglia. This damage may induce small fiber neuropathy and dysautonomia."

Similar to Previous Reports

Dr Martínez-Lavín and colleagues say that the HPV postvaccination cluster of symptoms they describe in their current report is "analogous" to those described in two previous reports.

One of these is a report from Denmark (Dan Med J. 2015;62:A5064) describing 53 Danish patients, where the most common complaints were headache (100%), orthostatic intolerance (96%), fatigue (96%), cognitive dysfunction (89%), and nausea (91%).

The authors, Louise Brinth and colleagues from the Frederiksberg Hospital, Denmark, say all the patients had been referred to their syncope unit. "All patients had symptoms consistent with pronounced autonomic dysfunction including different degrees of orthostatic intolerance, severe nonmigraine-like headache, excessive fatigue, cognitive dysfunction, gastrointestinal discomfort, and widespread pain of a neuropathic character," they write.

The authors note that they "found a close chronologic association to the vaccination, but are well aware that this does not necessarily imply a causal relationship." In the 53 cases they report, the mean time between vaccination and onset of symptoms was 11.1 ± 12.5 days (range, 0 - 58 days), and symptoms were reported to appear after the first vaccination in 21 patients (40%), after the second vaccination in 19 patients (36%), and after the third vaccination in 13 patients (25%).

Further research is urgently warranted in order to clarify the pathophysiology of the symptoms experienced.

"Our findings do not confirm or dismiss a causal link to the HPV vaccine," the authors emphasize, "but they do suggest that further research is urgently warranted in order to clarify the pathophysiology of the symptoms experienced, to evaluate the possible link to the vaccine, and to establish targeted treatment options for the affected patients."

The other report is from Japan (Intern Med. 2014;53:2185-2200) and describes 40 Japanese girls with postvaccination symptoms of headache (70%), fatigue (53%), coldness of the legs (53%), limb pain (50%), and limb weakness (48%). Japan has withdrawn its national recommendation for HPV vaccination and has set up a national scheme to manage HPV postvaccination symptoms, as recently reported by Medscape Medical News.

There are also case reports from the United States in the medical literature. Svetlana Blitshteyn, MD, clinical assistant professor of neurology at the State University of New York at Buffalo School of Medicine and Biomedical Sciences, described six patients who developed new-onset POTS from 6 days to 2 months after HPV vaccination in a report published last year in the European Journal of Neurology (2014;21:135-139).

"Three patients also had neurocardiogenic syncope, and three patients were diagnosed with possible small fiber neuropathy," Dr Blitshteyn wrote. "Symptoms in all patients improved over 3 years with pharmacotherapy and nonpharmacological measures but residual symptoms persisted."

"Since publishing the case series, I have seen about a dozen other patients with POTS, small fiber neuropathy, fibromyalgia, chronic daily headache, and other disorders that began shortly after vaccination with Gardasil," Dr Blitshteyn told Medscape Medical News. "Most of these young women were healthy prior to vaccination, and many were competitive athletes. After developing postvaccination syndrome, these patients became very ill, experienced significant decline in functioning, and were unable to attend school, participate in their previous athletic activities, or maintain their grades," she added.

Five years ago, Dr Blitshteyn described the first case of POTS after Gardasil vaccine (Eur J Neurol. 2010;17:e52). At that time, "I thought it was a unique and rare occurrence," she said. But she has since been contacted by other patients and parents of the affected teens who experienced the onset of disabling symptoms after vaccination with Gardasil, and after seeing the case series of post-HPV vaccine syndrome reported from Denmark, Japan, and now Mexico, she said: "I think the evidence is compelling that there may be a problem with HPV vaccine that needs to be thoroughly examined."

Clinicians have always been at the front lines of new observations.

"Clinicians have always been at the front lines of new observations," Dr Blitshteyn told Medscape Medical News. "I think it goes back to basic history taking: first, we need to be aware that new symptoms may arise after vaccination with HPV vaccine, and second, we need to ask the right questions. I believe that patients and parents should be listened to and trusted, not dismissed, when they report that shortly after vaccination, their child became sick with new symptoms."

Case Reports Are Observations

Several of the reports cited above have been roundly criticized on the Skeptical Raptor blog, which has published a one stop shop science myth-debunking Gardasil. The main argument is that these are case reports, and a case report "represents nothing more than observations, and it doesn't qualify as real scientific data. It cannot and does not show causality." A major issue with case reports is that there are no controls, it adds, and then there is a question of plausibility, of how "a little shot of four antigens would somehow cause the very complex set of events that lead to POTS."

The Skeptical Raptor blog has posted over 50 articles about Gardasil over recent years, which highlight the fact that many large, long-term studies have confirmed its safety and have found no serious adverse events. These include safety studies of:

189,629 females in the United Sates, which found only same-day syncope and skin infections in the 2 weeks after vaccination as adverse events related to the quadrivalent HPV vaccine (Gardasil) (Arch Pediatr Adolesc Med. 2012;166:1140-1148).

997,585 girls aged 10 to 17 in Denmark and Sweden, which found no evidence supporting associations between exposure to the qHPV vaccine (Gardasil) and autoimmune, neurological, and venous thromboembolic adverse events. Although associations for three autoimmune events were initially observed, on further assessment, these were weak and not temporally related to vaccine exposure, say the authors (BMJ. 2013;347:f5906).

Excellent Safety Record, Says CDC

"HPV vaccines have an excellent safety record," Tom Shimabukuro, MD, MPH, MBA, deputy director of the Immunization Safety Office at the CDC, told Medscape Medical News.

The vaccine has been in use for nearly a decade. The first, the quadrivalent HPV vaccine (Gardasil), was licensed in the United States in 2006, followed by the bivalent HPV vaccine (Cervarix), which was licensed in 2009, and the 9-valent HPV vaccine (Gardasil 9), which was licensed in 2014.

"Approximately 79 million doses of HPV vaccines have been distributed for use in the United States, and no causal association or links between HPV vaccines and atypical or unusual pain syndromes or autonomic dysfunction have been identified in either prelicensure clinical trials or postlicensure safety monitoring conducted by CDC," Dr Shimabukuro said.

"Most side effects to HPV vaccines are mild and go away on their own, like pain and redness from the shot. Occasionally, patients might faint after receiving HPV, or any injectable vaccine," he noted.

The FDA told Medscape Medical News in an emailed comment that over the "substantial timeframe since the first licensure (Gardasil in 2006), no causal association between HPV vaccines and a patterned illness of neuropathic pain and autonomic dysfunction, CRPS, POTS, or fibromyalgia has been identified in either the prelicensure clinical trials evaluated by the FDA or in postlicensure safety monitoring conducted by the CDC and FDA."

The FDA and CDC monitor the safety of all vaccines, including each HPV vaccine, using multiple safety systems: the Vaccine Adverse Event Reporting System (VAERS), the Vaccine Safety Datalink (VSD), the Post-Licensure Rapid Immunization Safety Monitoring (PRISM) system, and the Clinical Immunization Safety Assessment (CISA) network.

Dr Martínez-Lavín and coauthors have disclosed no relevant financial relationships. Dr Blitshteyn reports serving as an expert witness on a number of Gardasil cases in the US National Vaccine Injury Compensation Program. Dr Franco reports serving as a consultant or advisory board member for companies involved in HPV vaccination (Merck, GlaxoSmithKline), HPV diagnostics (Roche, Qiagen, Gen-Probe), and cytology (Cytyc, Ikonisys). McGill University has received grants from Merck to support investigator-initiated research by Dr Franco. Dr Markman reports receiving fees from Celgene, Caris Life Sciences, Novartis, sanofi-aventis, Amgen, and Genentech, and is a Medscape video blogger.