Dan Med J 62/4
da n i s h m E d i c a l J O U R n a l
suspected side effects to the quadrivalent
human papilloma vaccine
Louise Brinth1, 2, Ann Cathrine Theibel1, 2, Kirsten Pors1 & Jesper Mehlsen1, 2
mune response for more effective and longer lasting
The quadrivalent vaccine that protects
protection. To date, approximately 480,000 girls and
against human papilloma virus types 6, 11, 16 and 18 (Q-
young women have been vaccinated with the Q-HPV
HPV vaccine, Gardasil) was included into the Danish child-
vaccine in Denmark .
hood vaccination programme in 2009. During the past
While vaccinations are generally safe, warranted
years, a collection of symptoms primarily consistent with
and will most likely reduce morbidity and mortality, they
sympathetic nervous system dysfunction have been de-
also carry an inherent risk of provoking side effects.
2) Department of
scribed as suspected side effects to the Q-HPV vaccine.
Clinical Physiology and
Post-licensure monitoring may be superior to pre-licen-
We present a description of suspected side ef-
sure reviews in detecting rare adverse events. A large
fects to the Q-HPV vaccine in 53 patients referred to our
Scandinavian study comparing almost 300,000 cases and
Syncope Unit for tilt table test and evaluation of autonomic
700,000 controls found that the Q-HPV vaccine is gener-
nervous system function.
ally well tolerated in the target population with no sig-
Dan Med J
All patients had symptoms consistent with pro-
nificant increase in the incidence of predefined auto-
nounced autonomic dysfunction including different degrees
immune diseases 180 days post vaccination .
of orthostatic intolerance, severe non-migraine-like head-
During the past years, a collection of symptoms has
ache, excessive fatigue, cognitive dysfunction, gastrointestinal
discomfort and widespread pain of a neuropathic character.
been described that does not readily fit into an existing
diagnostic entity, but seemingly represents or involves a
We found consistency in the reported symp-
toms as well as between our findings and those described
dysfunction in the autonomic nervous system. The
by others. Our findings neither confirm nor dismiss a causal
symptoms have been described as suspected side ef-
link to the Q-HPV vaccine, but they suggest that further re-
fects to both the Q-HPV vaccine and the divalent HPV
search is urgently warranted to clarify the pathophysiology
vaccine and they have been denoted differently, pos-
behind the symptoms experienced in these patients and to
sibly depending on the medical specialty of those evalu-
evaluate the possibility and the nature of any causal link
ating the patients [3-7].
and hopefully establish targeted treatment options.
In the following, we describe 53 patients referred to
our Syncope Unit for a tilt table test and evaluation of
autonomic nervous system function with suspected side
effects to the Q-HPV vaccine.
Genital human papilloma virus (HPV) infections are com-
monly acquired soon after sexual debut, and persistent
This was a retrospective analysis based on 75 patients
HPV infections can cause cervical cancer. In Denmark,
consecutively referred to the Syncope Unit from May
the incidence of cervical cancer is around 370 annual
2011 to December 2014 for a head-up tilt test due to
cases, and approximately 100 women die from this dis-
orthostatic intolerance and symptoms compatible with
ease each year .
autonomic dysfunction as suspected side effect follow-
The quadrivalent vaccine that protects against HPV
ing vaccination with the Q-HPV vaccine.
types 6, 11, 16 and 18 (Q-HPV vaccine) was introduced
In our analysis, we chose to include only those pa-
in Denmark in 2006 and was included into the Danish
tients who reported onset of symptoms consistent with
childhood vaccination programme in 2009. The HPV vac-
autonomic dysfunction within the first two post-vaccina-
cine is the only vaccine included in the childhood vacci-
tion months; this meant that 11 patients were excluded.
nation programme that has also been offered free of
Patients with known chronic diseases pre-vaccination as
charge to women outside the childhood programme in
well as patients in whom other possible eliciting factors
could be recognised (seven patients) were also excluded
The vaccine is based on virus-like particles contain-
as were patients who were unable to account for the
ing aluminum adjuvant to enhance and tailor the im-
temporal association between vaccination and symptom
2 da n i s h m E d i c a l J O U R n a l
Dan Med J 62/4
on symptoms and on the temporal association between
vaccination and symptom onset. The narrative report
Baseline characteristics of the included subjects.
was supplemented by the short form of the Inter na-
tional Physical Activity Questionnaire (IPAQ-SF) quantify-
ing the patient’s physical activity at the time of referral
and just before vaccinations on a recall basis .
We described the frequency of the most common
Body mass index, kg/m2
symptoms in this group of patients. As the diagnosis
Systolic blood pressure, mmHg
POTS has been debated in relation to this group of pa-
Diastolic blood pressure, mmHg
tients, we did a subgroup analysis describing the frequen-
Heart rate, bpm
cy of the different symptoms in patients with and without
SD = standard deviation.
the POTS diagnosis.
onset (four patients); in total, 53 patient were left for
All patients underwent a 60-degree head-up tilt ta-
The analysis includes a total of 53 girls/women aged 12-
ble test (HUT). The postural orthostatic tachycardia syn-
39 years at the time of examination. Clinical characteris-
drome (POTS) was diagnosed according to current
tics are given in Table 1
guidelines requiring orthostatic intolerance and a sus-
The mean age at symptom onset was 21.0 ± 7.4 years
tained heart rate increment of > 30/min or to levels
(range: 12-39 years). Mean time between vaccination and
above 120/min within 10 min of postural change in the
onset of symptoms was 11.1 ± 12.5 days (range: 0-58
absence of overt orthostatic hypotension. An increase of
days) and symptoms were reported to appear after the
> 40/min was required for patients aged 12 to 19 years
first vaccination in 21 patients (40%), after the second
vaccination in 19 patients (36%), and after the third vac-
The patients were interviewed with a special focus
cination in 13 patients (25%).
In Figure 1
, we present the symptoms that were ex-
perienced in more than 25% of the patients; and in the
following, we present the typical manifestations of these
Symptoms suspected to be side effects to vaccination against human
53 (100%) of the included patients re-
papilloma virus. The frequency of the symptoms is given as percentages
ported new-onset headache. Most of the patients de-
of patients reporting the given symptom out of all patients included in
scribed continuous, daily, severe, debilitating headache
the descriptive analysis.
with intermittent exacerbations and occasionally pain-
free periods. Only a few patients described typical mi-
51 (96%) of the patients re-
ported pronounced symptoms of orthostatic intolerance.
In all, 24 (45%) patients experienced recurrent syncopal
attacks, and 28 (53%) patients were diagnosed with POTS
at tilt table test.
Involuntary muscle activity
51 (96%) of the patients complained of ex-
cessive fatigue and increased mental and physical fatig-
47 (89%) of patients com-
plained of inability to concentrate, impairment of short-
term memory, diminished attention span – often accom-
panied by ”mental fog”, verbal dyspraxia and new-onset
45 (85%) patients reported a
change in sleep pattern – primarily described as new-
onset insomnia and non-refreshing sleep.
POTS = postural orthostatic tachycardia syndrome.
37 patients (70%) reported new-
onset hypersensitivity to bright light and (44 patients,
Dan Med J 62/4
da n i s h m E d i c a l J O U R n a l
83%) experienced intermittent blurring of vision.
In Figure 2
, we present the frequency of the above-
Patients reported new-
mentioned symptoms in patients with and without the
onset gastrointestinal discomfort such as nausea (48 pa-
POTS diagnosis, respectively, demonstrating that the two
tients, 91%); feeling bloated (41 patients, 77%); abdom-
groups have similar patterns and severities of symptoms
inal pain of varying character, intensity and location (37
regardless of the POTS diagnosis. The apparent trend to-
patients 70%); and changes in bowel habits (29 patients,
wards POTS patients having a more severe symptom-
burden did not reach statistical significance.
35 (66%) of the patients com-
Based on the IPAQ-SF questionnaire, 67% had a
plained of pain described as “burning”, “a deep stabbing”,
high and 33% had a moderate activity level before symp-
or “jolts of electricity” starting distally, often in one limb,
tom onset. Five patients had a very high activity level and
and then progressing proximally and often spreading to
were competing on a national or international level in
the contralateral side.
35 (66%) of the patients experi-
Fifty-two out of 53 patients (98%) reported that their
enced involuntary muscle activity in the form of intermit-
activities of daily living were seriously affected and 40
tent tremor and myoclonic twitches.
(75%) had had to quit school or work for more than two
35 (66%) reported new-onset intermit-
months due to their symptoms.
tent dyspnoea often described as air hunger combined
with chest tightness or actual chest pain.
34 (64%) of the patients experienced
The present study is a systematic review of 53 patients re-
a relapse or – in the adolescent girls – aggravation of
ferred to our unit with symptoms of orthostatic intoler-
ance and generalised dysautonomia as a suspected side
Only one patient reported new-
effect of vaccination against human papilloma virus.
onset incontinence, but 31 (59%) patients reported void-
The main finding of our study was a high degree of
ing dysfunction with respect to frequency, urge, nocturia
and incomplete bladder emptying.
30 (57%) of the patients experienced
muscle weakness in the extremities, most often intermit-
tent in nature, confined to the lower extremities and usu-
Symptoms suspected of being side effects to vaccination against human papilloma virus in patients with
postural orthostatic tachycardia syndrome (POTS) and without the POTS-diagnosis. The frequency of the
ally lateralised. The intensity varied in parallel with other
symptoms is given as percentages of patients reporting the given symptom out of all patients with ( )
symptoms, and in six cases it led to invalidity with very
and without ( ) the POTS diagnosis, respectively.
limited walking distances and confinement to a wheel-
chair for longer periods of time.
27 (51%) patients described
intermittent changes in skin colour to blue, red, pale or
blotchy in the lower parts of the legs and in fingers and
toes – the colour changes were often accompanied by
painful swelling of the involved limbs. Many patients re-
ported side differences in temperature during these epi-
sodes combined with exacerbation of pain in the af fected
Of the 31 patients who were not
on treatment with oral contraception, 15 (48%) reported
irregular periods and many reported hypermenorrhoea
and worsening of menstrual discomfort and pain.
Involuntary muscle activity
21 (40%) patients experienced new-
onset dry mouth, and 15 patients (28%) complained of
18 (34%) patients reported a new-
onset tendency for hyperventilation or excessive sighing.
Besides the actual orthostatic intolerance (syncope
and dizziness), the patients described that fatigue, cogni-
tive dysfunction, hyperventilation and dyspnoea and to
some degree headache and nausea were accentuated in
the upright position.
4 da n i s h m E d i c a l J O U R n a l
Dan Med J 62/4
consistency in the symptoms experienced by these pa-
well aware that this does not necessarily imply a causal
tients. The most common symptoms reported were head-
ache, dysautonomia symptoms, excessive fatigue, cogni-
It is our clinical experience that substantial improve-
tive dysfunction and widespread pain of a neuropathic
ment is possible in POTS patients with multi-
faceted treatment consisting of a variety of both pharma-
Many of the symptoms described in our review as
cological and non-pharmacological treatment modal ities
well as in the product resume and adverse event reports
may at first seem both diffuse and very common. How-
A clarification of the probability and nature of a pos-
ever, having evaluated more than 70 patients with the
sible causal link between the symptoms and the HPV vac-
suspected side effects, we believe that there is a recognisa-
cine is important in order to ensure that future vaccines
ble pattern of symptoms. Our findings correlate well with
may give informed consent based on updated informa-
the clinical picture presented by Kinoshita et al  and
tion about possible side effects.
Nishioka et al , except for the greater proportion of pa-
Establishing a relevant and coherent diagnosis and
tients suffering from orthostatic intolerance in our group
treatment for these patients would contribute to main-
of patients – which may be expected as patients are pri-
taining the trust and credibility in this vaccine which is
marily referred to our unit due to orthostatic intolerance.
important as a preventive measure against HPV-related
The patients in our study were characterised by re-
markably high levels of physical activity before symptom
onset, which may have affected their immune response to
In this study we present symptoms reported by patients
In analysing our data, we have considered the possi-
referred for orthostatic intolerance suspected to be sec-
bility of the phenomenon known as mass psychogenic ill-
ondary to vaccina tion against HPV. We found consist-
ness, which has been defined as the collective occurrence
ency in the reported symptoms as well as between our
of a constellation of symptoms suggestive of organic ill-
findings and those reported by others. Given the symp-
ness, but without an identified cause in a group of people
tomatology, we suggest that the pathogenic alteration is
with shared beliefs about the cause of the symptoms .
located in the autonomic nervous system. Our findings
However, we do not find it likely that such a reaction
do not confirm or dismiss a causal link to the HPV vac-
constitutes the background for symptoms and signs
cine – but they do suggest that further research is urgent-
found in our patients given their prevaccination history,
ly warranted in order to clarify the pathophysiology of
the chronicity of their symptoms and the temporal and
the symptoms experienced, to evaluate the possible link
to the vaccine and to establish targeted treatment options
Some of the patients have been suspected of suffer-
for the affected patients.
ing from a functional disorder. However, as the auto-
nomic nervous system innervates, monitors and controls
cORREsPOndEncE: Louise Brinth,
Synkopecenteret, Vej 3, Indgang 4, Frederiksberg Hospital, Nordre Fasanvej 57,
most of the tissues and organs in the body – autonomic
2000 Frederiksberg, Denmark. E-mail: email@example.com
dysfunction often presents with a very diffuse and wide-
25 February 2015 cOnFlicTs OF inTEREsT:
Disclosure forms provided by the authors are
spread pattern of symptoms . The differential diag-
available with the full text of this article at www.danmedj.dk
nostic procedure – especially with emphasis on the differ-
entiation between functional disorder and autonomic
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