Chronic Symptoms After HPV Vaccine: Part of Wider Syndrome?

Zosia Chustecka

August 11, 2016

Editor's note: After this study was published, vaccine expert Paul Offit, MD, professor of pediatrics in the Division of Infectious Diseases at the Children's Hospital of Philadelphia, wrote a letter to the editor in which he expressed disappointment that Medscape had highlighted "an article claiming that the HPV vaccine caused chronic disease when such a claim is without basis."

Another case series of rare chronic symptoms among young females seen after vaccination against the human papillomavirus (HPV) has been reported in the medical literature, this time from Italy.

The paper was published online August 9 in Immunologic Research.

This latest case series joins other similar reports from other countries that have been published in the medical literature, as previously reported by Medscape Medical News.

However, a causative relationship between chronic symptoms and HPV vaccination has never been established.

As Eduardo L. Franco, DrPH, professor of oncology and director of cancer epidemiology at McGill University in Montreal, Quebec, Canada, commented on a previous case series, "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."

Official medical bodies, including the European Medicines Agency, the US Centers for Disease Control and Prevention, and the US Food and Drug Administration, have said that there is no causative relationship and have repeatedly emphasized the safety of the HPV vaccine, as also previously reported by Medscape Medical News.

What is new in the latest report is the authors' speculation that the symptoms fit in with a recently described phenomenon known as autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome).

The theory behind the syndrome suggests that heterogeneous postvaccination conditions, which are rare but have been chronicled among multiple individuals receiving different vaccines, might be the consequence of some immune dysfunction, putatively activated by the adjuvant rather than by the antigenic vaccine fraction, they note.

Long-Lasting Impairment

In the latest paper, a team led by Beniamino Palmieri, MD, from the University of Modena and Reggio Emilia Medical School, Surgical Clinic, Modena, Italy, report a series of 18 females (aged 12 to 24 years; mean age, 15.2 years) who were referred to the Second Opinion Medical Network for the evaluation of ''neuropathy with autonomic dysfunction'' after HPV vaccination.

These girls had received the HPV vaccine (9 with Gardasil [Merck & Co], 9 with Cervarix [GlaxoSmithKline]) when they were aged 11 to 12 years.

All the girls in this series reported long-lasting and invalidating somatoform symptoms (including asthenia, headache, cognitive dysfunction, myalgia, sinus tachycardia, and skin rashes), the Italian doctors report.

They add that the symptoms were consistent with severe fibromyalgia and chronic pain syndrome, according to the literature criteria.

"Because of these symptoms, at least 10 of these eighteen young girls developed a long-standing social impairment (school absence, sport suspension and daily activity impairment)," they comment.

"Previously, all these girls declared excellent fitness and wellness, including sport practice. No significant co-morbidities or previous relevant diseases were reported before the HPV immunization," they note.

"Our study highlighted some important post-vaccination phenomena temporally linked to HPV immunization, which needs further epidemiological analysis and biological investigations in order to establish or exclude a causal relation, Dr Palmieri and colleagues comment.

Details of the Reported Symptoms

In their paper, the doctors provide details of the reported symptoms, and these are reported below because Medscape Medical News readers who have commented on previous stories have asked for further detail.

The symptoms occurred after the first intramuscular injection of the HPV vaccine in 4 girls, after the second dose in 8 patients, and after the third boost in 8 girls. "As expected, the first two groups refused the following doses of the HPV immunization protocol," Dr Palmieri and colleagues comment.

On the basis of the time interval between vaccination and symptom onset, the team divided the girls into three groups:

  1. Girls whose symptoms appeared 1 to 5 days after vaccination (n = 11); the systemic reactions observed include low-grade fever (n = 9), headache (n = 12), recurrent syncope (n = 7), persistent convulsive hunger (n = 1), irritability (n = 3), epileptic seizures (n = 1), transient speech loss (n = 1), lower-limb paresthesia and paresis (n = 1), hot flushes (n = 1), severe stomach pain (n = 4), insomnia (n = 5), hypersensitivity reactions (eg, itchy skin rash, rhinitis) (n = 1), muscle pain (n = 5), severe gait impairment and orthostatic intolerance (n = 1), excessive sweating (n = 1), and vomiting (n = 1).

  2. Girls whose symptoms appeared 5 to 15 days after the vaccination (n = 5); here symptoms included asthenia (n = 8), excessive thirst (n = 3), severe itching of hands and feet (n = 1), and optic neuritis (n = 1).

  3. Girls whose symptoms occurred 15 to 20 days after vaccination (n = 2), with symptoms including the following: amenorrhea (n = 1), skin rashes (n = 2), tachycardia (n = 2), difficulty breathing (n = 1), and weight loss (n = 3).

Dr Palmieri and colleagues comment that among the most common and persistent symptoms, the girls reported memory and concentration impairment (n = 17), muscle pain (n = 13), finger and toe vascular abnormalities with skin color and temperature changes (n = 13), headache (n = 12), asthenia (n = 9), dizziness (n = 6), abdominal pain (n = 4), low-grade fever (n = 3), sinus tachycardia (n = 2), and skin rashes (n = 1).

The symptoms cover a wide spectrum, the team acknowledges.

They comment that most of the girls showed an ''acute phase'' characterized by a variable combination of clinical manifestations, including low-grade fever, skin rashes, muscle pain, headache, and sensorial disturbances. Its onset occurred at a variable time after HPV immunization, ranging from hours to days.

"Then, this acute phase subsided in some weeks, but the girls developed some chronic and/or recurrent symptoms resembling chronic fatigue, fibromyalgia or other functional somatic syndromes. The clinical pictures displayed by each patient were actually polymorphous, except for asthenia, concentration problems, sensorial impairment (related to temperature perception, especially), recurrent or persisting muscle pain, paresis and headache," they comment.

What Is Happening?

The team speculates about what might be happening. "The description of our case series aims at analysing clinical phenomena, being putatively immune mediated and arising after HPV immunization," the Italian doctors write. "The latency of the onset of symptoms is quite variable, but it can be consistent with the occurrence of cell-mediated and/or antibody response against some neurological/neuromuscular structures."

The Italian authors suggest that cases they describe fit into ASIA syndrome, a term coined by Yehuda Shoenfeld, MD, from the Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Sackler Faculty of Medicine, and chair for Research of Autoimmune Diseases, Tel-Aviv University, Israel, and colleagues.

Dr Shoenfeld elaborated on ASIA syndrome in a 2013 interview with BioMed Central.

"The idea of ASIA as a new syndrome developed after some studies on Gulf War syndrome reported that soldiers who had not been deployed to the Gulf area were suffering from symptoms such as severe fatigue, cognitive impairment, myalgias and arthralgias. This raised the question of whether it was the vaccines administered to the soldiers that induced these syndromes," Dr Shoenfeld commented in that interview. His team first used the term "ASIA syndrome" in a report of 93 cases of what was being described as Gulf War syndrome in individuals who had received hepatitis B vaccination (Lupus. 2012;21:146-152).

Dr Shoenfeld noted that the most common adjuvants are silicone implants (such as used for breast augmentation) and aluminum in vaccines.

He emphasized that he is "definitely not against vaccines! Vaccines are the best medical development that humankind has had in the last 300 years, and have helped to bring about almost complete eradication of some viral diseases. However, it should be considered that when you give millions of people an active substance, and vaccines are active substances, then some may suffer from adverse events. After all, vaccines contain viral or synthetic particles emulsified in adjuvant, which is supposed to enhance the immune reaction."

"So, we have to identify the people who are at risk of suffering from side effects due to the chronic stimulation of their immune system," he continued. "First of all we have to diagnose them, to treat them — and some of them should be compensated, because the vaccines are quite often imposed on them either by the state, the government, or by the employer."

"With regard to the ASIA syndrome, prevalence is higher in subjects that carry the gene HLA-DRB1," he noted. "Maybe in the future with further advances in personalized medicine, we will be able to screen those at risk based on their genetic composition, and therefore avoid onset of autoimmune diseases by avoiding administration of vaccines containing adjuvants that are known to be associated with the ASIA syndrome."

In their paper, the Italian team writes that "ASIA is thought to represent an infrequent side effect of vaccinations due to an adjuvant or adjuvant-like stimulus acting on a predisposed, but not well-defined, genetic background. Because of its rarity, its heterogeneous clinical expression and the frequent absence of objective pathological lesions and immunological signatures, ASIA might have escaped to pre-clinical and postmarketing safety studies on vaccines.

"Among commercialized vaccines, those against HPV have received a lot of descriptions of medical conditions being consistent with the diagnosis of ASIA, regardless of the type of vaccine," they write.

The point about the aluminum-containing adjuvant has also been raised by the Nordic Cochrane Research group. This group questions the assessment of safety that has been based on clinical trials of HPV vaccines, as they point out that "in all the vaccine trials apart from a small one, the control group was given a placebo that contained an aluminum adjuvant, which is suspected of being neurotoxic."

Dr Palmieri and colleagues also cite a paper from another group of Italian researchers, published in 2015 (Immunol Res2015;61:90-96), which presents the first systematic estimation of ASIA incidence.

Those authors analyzed HPV vaccine-related ASIA epidemiology in the Vaccine Adverse Event Reporting System, a large database collecting almost 30,000 postvaccination adverse drug reactions (ADRs) per year. Pooling the data until the end of 2013, these authors reported more than 26,000 ADRs after HPV vaccine. Of these, 2207 cases (about 8%) were labeled as being probable or possible ASIA, according to Shoenfeld and Agmon-Levin's guideline for the diagnosis. The most common clinical manifestation observed were pyrexia (58%), myalgia (27%), and arthralgia or arthritis (19%), and the estimated reporting rate was 3.6 cases per 100,000 doses of HPV vaccine distributed (95% confidence interval, 3.4 - 3.7).

Call for Further Investigation

In their conclusions, Dr Palmieri and colleagues call for further epidemiologic and genetic investigations to clarify the existence and pathophysiology of HPV-related syndromes. "Hopefully, this approach might lead to a screen test for this risk and, eventually, to prevent it," they comment.

"Last but not least, a proper treatment for these somatoform syndromes is urgently needed," they add, because current analgesics, including opiates, are ineffective or, paradoxically, even enhance the pain.

Immunologic Res. Published online August 9, 2016. Full text

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