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.
According to Eduardo L. Franco, DrPH, FRSC, FCAHS, professor of oncology and director of cancer epidemiology at McGill University in Montreal, “In a nutshell, this is not adequate science,”.
“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 is a fibromyalgia researcher and his interest in HPV vaccination adverse reactions started after taking care of two girls with a fibromyalgia-like illness after HPV immunization. He was impressed by their illness severity because He had never seen before such devastating painful dysautonomic illness at this young age.
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.
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.
According to Dr Martínez-Lavín, 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. “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%).
“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%). Because of that, Japan has withdrawn its national recommendation for HPV vaccination and has set up a national scheme to manage HPV postvaccination symptoms.
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.”
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.”