Chronic Symptoms After HPV Vaccination: Danes Start Study
The controversies surrounding the human papillomavirus (HPV) vaccination and a possible association with chronic symptoms in girls and young women appear to be ongoing, despite a recent major review that dismissed the link.
Last week, the European Medicines Agency (EMA) announced that a task force found no causality between the vaccination and two sets of chronic symptom syndromes in girls and young women, which echoes previous reassurances from the Centers for Disease Control and Prevention (CDC).
Now, some clinicians and scientists say the EMA report is "not valid" and is marred by conflict of interest and reliance on already published data and are calling for an independent study of the association.
Perhaps even more notably, Denmark has announced that it is conducting its own independent investigation. More than 1300 girls and young women with such symptoms have been referred to five specialist centers in the country.
It was Denmark that requested the recent review by the EMA into the safety of HPV vaccines. That review, which began in July, focused in particular at reports of complex regional pain syndrome (CRPS), a chronic pain condition affecting the limbs, and postural orthostatic tachycardia syndrome (POTS), a condition in which the heart rate increases abnormally after sitting or standing up, causing symptoms such as dizziness and fainting, as well as headache, chest pain, and weakness.
As reported last week, the EMA review found that "evidence does not support that vaccines cause CRPS or POTS."
The EMA said that reports of CRPS and POTS after HPV vaccination "are consistent with what would be expected in this age group." Both syndromes are recognized to occur in the general population, including adolescents, regardless of vaccination, the agency pointed out.
But the findings of this review are being questioned by specialists who have been treating girls with symptoms after HPV vaccination.
One of these is Jesper Mehlsen, MD, director of research at the Coordinating Research Centre/Syncope Unit at Frederiksberg Hospital, Denmark. This Syncope Unit has seen approximatley 250 young women and girls with symptoms that began less than 2 months after vaccination, he says.
The researchers describe a "collection of symptoms consistent with pronounced autonomic dysfunction coupled with severe nonmigraine-like headache, excessive fatigue, cognitive dysfunction, gastrointestinal discomfort, and widespread pain of a neuropathic character."
"We suspect a connection to the HPV vaccine due to the close temporal association and the lack of alternative explanations," Dr Mehlsen told Medscape Medical News.
Asked for a reaction to the EMA review findings, Dr Mehlsen said: "Unfortunately the decision is based on register studies with a focus on POTS and CRPS. These diagnostic entities are only part of the symptom complex, which bear a closer relationship to chronic fatigue syndrome. In some countries, POTS is not registered as a diagnosis and patients are classified under different diagnoses in different countries. Finally, a lot of the reporting stems from the producers of the vaccines, allowing for possible heavy bias in the data.”
"I would therefore strongly question the validity of the derived conclusion," Dr Mehlsen told Medscape Medical News.
A similar reaction comes from another specialist who has been treating girls with chronic symptoms after HPV vaccination, this time in the Unites States.
Svetlana Blitshteyn, MD, clinical assistant professor of neurology at the University at Buffalo School of Medicine in New York, runs a dysautonomia clinic in Getzville, New York. She has documented six cases of POTS after HPV vaccination (Eur J Neurol. 2014;21:135-139), and has since seen about a dozen more. These patients present with POTS, small fiber neuropathy, fibromyalgia, chronic daily headache, and other disorders that began shortly after HPV vaccination, Dr Blitshteyn recently 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.
Now approached for a reaction to the EMA review findings, Dr Blitshteyn said: "I think we need a thorough investigation of the safety of the HPV vaccine with a special prospective study designed to address the question of whether HPV vaccine is associated with a higher incidence of POTS and CRPS than what would be expected to occur in the age and gender-matched population. Until such study is done by researchers with no relationship or affiliation with the pharmaceutical industry, there cannot be a claim made that there is no association between HPV vaccine and POTS or CRPS."
"The conclusion that resulted from the EMA review was not based on any special study designed to address the very question of HPV vaccine and POTS/CRPS association, and therefore, it cannot be considered as valid," she said.
"Those of us who are involved in the care of patients who developed post-HPV vaccine syndrome know that for these girls, getting HPV vaccine has not been life-saving, as the pharmaceutical industry and medical professionals have been claiming, but has been life-changing in the sense that these previously healthy girls became severely ill and disabled within days to weeks after vaccination," Dr Blitshteyn told Medscape Medical News.
"Additionally, there are a number of girls whose symptoms became progressively worse after each subsequent HPV vaccine injection, suggesting that there is evidence of rechallenge," she said.
"With a large number of injured patients reported from Denmark, Japan, Mexico, United States, and the United Kingdom, the link between HPV vaccine and POTS/CRPS cannot be denied for these affected individuals, despite the conclusion of the EMA review," Dr Blitshteyn commented.
The conclusions have also been questioned by an independent researcher who has not been involved with HPV vaccination or treating individuals with symptoms. Karsten Juhl Jørgensen MD, DMedSci, senior researcher at the Rigshospitalet in Copenhagen, and part of the Nordic Cochrane Group, which is well known for repeatedly questioning data for mammography screening and other practices, told Medscape Medical News that the EMA review "highlights a fundamental problem in the way we authorize and control use of medications, including vaccines.”
"The framework allows that the decisive evidence is produced by industry and that those who evaluate this evidence and make official recommendations are allowed to have substantial conflicts of interest with the same companies. In this case, a further problem seems to be that those involved in the original investigations of the vaccine are involved in evaluating the same evidence in the present EMA report and make recommendations," he said.
"It is never a good solution to allow people to be their own judges; indeed, there are strict regulations against this in many other societal contexts. Current procedures do not create the trust in medications and vaccines we would like," Dr Jørgensen said.
As for how the EMA review was conducted, he says: "As I understand it, the actual background material for their recommendations is not made available to the public, which can certainly be criticized. However, it must be based on already published studies and safety reports submitted to EMA. It is not a new primary study. This means that many of the limitations to the original studies also applies to this context (e.g., the original studies did not have sufficient follow-up to monitor harms and they did not compare vaccine to placebo, but to inactive vaccine)."
"The limitations of the original studies does not allow strong conclusions about the harms of the intervention. A new thorough independent study would be necessary to re-establish trust in the vaccine," Dr Jørgensen told Medscape Medical News.
Denmark is continuing its own investigation into the issue. The Ministry of Heath has given 7 million DKK (US$1.01 million) for research to be conducted by specialists who are seeing girls with symptoms after HPV vaccination and who are independent of the pharmaceutical industry.
"In Denmark, we have five regional centers for these patients," Dr Mehlsen told Medscape Medical News. Investigations are "focusing on autoantibodies in particular against receptors in the autonomic nervous system and we are exploring the possibility of neuroinflammation, small fiber disease, and mitochondrial dysfunction as a basis for the symptoms." He hopes that there may be some results available within the first half of 2016.
Danish Health Minister Sophie Løhde was quoted in the Danish press as saying that "no one should ignore that these girls are sick."
"The girls must continue to be taken seriously and offered the diagnosis and treatment they need," she said.
Japan also has designated specialist centers to deal specifically with individuals who develop symptoms after HPV vaccination, and has issued guidelines for healthcare professionals.
In other countries, there have been media reports of girls who have developed symptoms and have struggled to find medical help, and media reports of chronic symptoms following HPV vaccination continue to appear from countries all around the world.
Just this week, a television documentary in New Zealand detailed cases of four girls with chronic pain who had been fit and active and are now in wheelchairs, as well as two deaths
In the United Kingdom, these media reports date back to 2008, when a national program of HPV vaccination in schools was launched. Earlier this year, affected families established the UK Association of HPV Vaccine Injured Daughters (AHVID).
AHVID has conducted a member questionnaire and, so far, has received almost 100 responses. Information for the first 94 responses had been already shared with the EMA, the group notes, and highlights several findings from these 94 responses, as follows:
Twenty-seven girls had reactions on the same day as the vaccine, some of them within minutes. A further 22 had reactions within 7 days of vaccination and a further 16 within 30 days.
Twenty-four have confirmed POTS diagnosis, some took 6.5 years from vaccination to be diagnosed. Another 37 have not been diagnosed with POTS but have an average of 16 typical POTS symptoms; some had 33 typical POTS symptoms. Nineteen were refused POTS assessments.
Eight have confirmed diagnoses of CRPS. A further 76 have not been diagnosed with CRPS but have an average of five typical CRPS symptoms. Fourteen were refused CRPS assessments.
Heath Authorities Emphasize Safety
Meanwhile, health authorities continue to emphasize the safety of the HPV vaccines.
The recent EMA review pointed out that the use of HPV vaccines "is expected to prevent many cases of cervical cancer (cancer of the neck of the womb, which is responsible for tens of thousands of deaths in Europe each year) and various other cancers and conditions caused by HPV. The benefits of HPV vaccines therefore continue to outweigh their risks."
"HPV vaccines have an excellent safety record," Tom Shimabukuro, MD, MPH, MBA, deputy director of the Immunization Safety Office at the CDC, recently 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 nine-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 US Food and Drug Administration (FDA) told Medscape Medical News in a recent 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.”