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Dan Med J 62/4    April 2015
da n i s h  m E d i c a l  J O U R n a l    1
suspected side effects to the quadrivalent  
human papilloma vaccine
Louise Brinth1, 2, Ann Cathrine Theibel1, 2, Kirsten Pors1 & Jesper Mehlsen1, 2
aBsTRacT
mune response for more effective and longer lasting 
ORiginal 
INTRODUCTION: The quadrivalent vaccine that protects 
protection. To date, approximately 480,000 girls and 
aRTiclE
against human papilloma virus types 6, 11, 16 and 18 (Q-
young women have been vaccinated with the Q-HPV 
1) Coordinating 
HPV vaccine, Gardasil) was included into the Danish child-
vaccine in Denmark [1].
Research Centre/
hood vaccination programme in 2009. During the past 
While vaccinations are generally safe, warranted 
Syncope Unit, 
years, a collection of symptoms primarily consistent with 
and will most likely reduce morbidity and mortality, they 
Frederiksberg Hospital
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-
Nuclear Medicine, 
METHODS: We present a description of suspected side ef-
sure reviews in detecting rare adverse events. A large 
Frederiksberg Hospital, 
fects to the Q-HPV vaccine in 53 patients referred to our 
Scandinavian study comparing almost 300,000 cases and 
Denmark
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 
RESULTS: All patients had symptoms consistent with pro-
nificant increase in the incidence of predefined auto-
2015;62(4):A5064
nounced autonomic dysfunction including different degrees 
immune diseases 180 days post vaccination [2].
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 
CONCLUSION: 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 
FUNDING: not relevant. 
our Syncope Unit for a tilt table test and evaluation of 
TRIAL REGISTRATION: not relevant.
autonomic nervous system function with suspected side 
effects to the Q-HPV vaccine. 
Genital human papilloma virus (HPV) infections are com-
mEThOds
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 [1].
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 
catch-up programmes.
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 

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Dan Med J 62/4    April 2015
on symptoms and on the temporal association between 
TaBlE 1
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-
 
mean
sd
Range
ing the patient’s physical activity at the time of referral 
Age, yrs
23
7
12-39
Weight, kg
64
15
49-106
and just before vaccinations on a recall basis [9].
Height, cm
169
6
149-180
We described the frequency of the most common 
Body mass index, kg/m2
22
5
15-37
symptoms in this group of patients. As the diagnosis 
Systolic blood pressure, mmHg
123
10
103-144
POTS has been debated in relation to this group of pa-
Diastolic blood pressure, mmHg
83
8
65-98
tients, we did a subgroup analysis describing the frequen-
Heart rate, bpm
79
15
54-130
cy of the different symptoms in patients with and without 
SD = standard deviation. 
the POTS diagnosis. 
Trial registration: not relevant.
onset (four patients); in total, 53 patient were left for 
further analysis. 
REsUlTs
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 
[8]. 
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 
FigURE 1
symptoms: 
Symptoms suspected to be side effects to vaccination against human 
Headache: 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-
Headache
Orthostatic intolerance
free periods. Only a few patients described typical mi-
Fatigue
graine. 
Nausea
Orthostatic intolerance: 51 (96%) of the patients re-
Cognitive dysfunction
Disordered sleep
ported pronounced symptoms of orthostatic intolerance. 
Blurred vision
In all, 24 (45%) patients experienced recurrent syncopal 
Feeling bloated
Abdominal pain
attacks, and 28 (53%) patients were diagnosed with POTS 
Light sensitive
at tilt table test. 
Involuntary muscle activity
Neuropathic pain
Fatigue: 51 (96%) of the patients complained of ex-
Dyspnoea
cessive fatigue and increased mental and physical fatig-
Skin problems
Voiding dysfunction
ability.
Limb weakness
Cognitive dysfunction: 47 (89%) of patients com-
Constipation
plained of inability to concentrate, impairment of short-
Diarrhoea
POTS
term memory, diminished attention span – often accom-
Vascular abnormalities
panied by ”mental fog”, verbal dyspraxia and new-onset 
Recurrent syncope
Dry mouth
dyslexia.
Hyperventilation
Disordered sleep: 45 (85%) patients reported a 
Irregular periods
Dry eyes
change in sleep pattern – primarily described as new- 
0
20
40
60
80
100 %
onset insomnia and non-refreshing sleep. 
POTS = postural orthostatic tachycardia syndrome.
Visual symptoms: 37 patients (70%) reported new-
onset hypersensitivity to bright light and (44 patients, 

Dan Med J 62/4    April 2015
da n i s h  m E d i c a l  J O U R n a l    3
83%) experienced intermittent blurring of vision. 
In Figure 2, we present the frequency of the above-
Gastrointestinal symptoms: 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-
55%).
burden did not reach statistical significance. 
Neuropathic pain: 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. 
their sport. 
Motor symptoms: 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 
Dyspnoea: 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. 
discUssiOn
Skin disorders: 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-
acne. 
ance and generalised dysautonomia as a suspected side 
Voiding dysfunction: 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. 
Limb weakness: 30 (57%) of the patients experienced 
FigURE 2
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-
Headache
chair for longer periods of time. 
Orthostatic intolerance
Vascular abnormalities: 27 (51%) patients described 
Fatigue
intermittent changes in skin colour to blue, red, pale or 
Nausea
blotchy in the lower parts of the legs and in fingers and 
Cognitive dysfunction
toes – the colour changes were often accompanied by 
Blurred vision
painful swelling of the involved limbs. Many patients re-
Feeling bloated
Disordered sleep
ported side differences in temperature during these epi-
Abdominal pain
sodes combined with exacerbation of pain in the af fected 
Neuropathic pain
extremity. 
Dyspnoea
Irregular periods: Of the 31 patients who were not 
Light sensitive
on treatment with oral contraception, 15 (48%) reported 
Skin problems
irregular periods and many reported hypermenorrhoea 
Voiding dysfunction
and worsening of menstrual discomfort and pain. 
Involuntary muscle activity
Sicca symptoms: 21 (40%) patients experienced new-
Constipation
onset dry mouth, and 15 patients (28%) complained of 
Diarrhoea
Limb weakness
dry eyes. 
Vascular abnormalities
Hyperventilation: 18 (34%) patients reported a new-
Recurrent syncope
onset tendency for hyperventilation or excessive sighing.
Irregular periods
Besides the actual orthostatic intolerance (syncope 
Dry mouth
and dizziness), the patients described that fatigue, cogni-
Hyperventilation
tive dysfunction, hyperventilation and dyspnoea and to 
Dry eyes
some degree headache and nausea were accentuated in 
0
20
40
60
80
100 %
the upright position. 

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Dan Med J 62/4    April 2015
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-
relationship.
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- 
character. 
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 
[13].
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 [6] and 
tion about possible side effects. 
Nishioka et al [7], 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-
cancer. 
markably high levels of physical activity before symptom 
onset, which may have affected their immune response to 
cOnclUsiOn
vaccination [10]. 
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 [11]. 
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 
geographical dispersion. 
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, Koordinerende Forskningsenhed/ 
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: xxxxxx.xxxxxxxxx.xxxxxx@xxxxxxx.xx
dysfunction often presents with a very diffuse and wide-
accEPTEd: 25 February 2015 
cOnFlicTs OF inTEREsT: Disclosure forms provided by the authors are 
spread pattern of symptoms [12]. The differential diag-
available with the full text of this article at www.danmedj.dk
nostic procedure – especially with emphasis on the differ-
liTERaTURE
entiation between functional disorder and autonomic 
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neurological, and venous thromboembolic adverse events after immun-
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is still somewhat elusive and the prevalence of POTS is 
29. Abstract.
most common in the same subset of the population that 
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