Dear Editors,
The most common symptoms of coronavirus disease 19 (COVID-19) from severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) infection include fever, cough, sore throat, and
fatigue. As case numbers grow, neurological symptoms have been reported with increasing
frequency, including those of autonomic dysfunction [1]. Most neurological reports
detail symptoms in hospitalized patients during the para-infectious period; thus,
understanding of longer-term, post-infectious sequalae is limited. We report the case
of a patient who developed postural tachycardia syndrome (POTS) several months after
confirmed SARS-CoV-2 infection.
In early March of 2020, a 26-year-old emergency department nurse in Orange County,
California developed a mild cough and an itchy throat. She woke the next day with
palpitations, fatigue, and mild shortness of breath. On day 3 she presented to urgent
care and had a nasopharyngeal swab which returned negative for SARS-CoV-2 PCR. On
day 7 she woke up with palpitations, shortness of breath, and anorexia. She noted
that her resting seated HR was 110 bpm and would increase to 190 bpm after walking
up a flight of stairs. Her cough worsened and she developed burning chest pains on
inhalation. She presented to the emergency department for evaluation, where her temperature
was 100.4 ℉ and her SaO2 98%. A chest CT was performed and demonstrated moderate bronchitis
with right lower lobe atelectasis. Her SARS-CoV nasopharyngeal swab was repeated and
returned positive. IgG and IgM antibodies to the SARS-CoV-2 spike receptor binding
domain (RBD) also returned positive. She was given IV fluids, a 5-day prescription
of azithromycin, and discharged home.
Over the following week she noted continued tachycardia (standing HR of 150 bpm after
showering), chest pains, shortness of breath, fatigue and exercise intolerance, along
with subjective fevers and insomnia. Her seated, resting BP increased to 156/112 mmHg
(her typical seated, resting BP was 110/60 mmHg). On day 19 she developed orthostatic
lightheadedness and presyncope. She returned to the emergency department for evaluation,
where her seated BP was 146/100 mmHg, HR was 125 bpm, and SaO2 dropped from 98% to
94% with minimal exertion. She was given IV fluids, kept overnight, and discharged
the following day.
On day 22 she developed symptoms of hyperactivity with pressured speech and a feeling
of inner restlessness. On day 24 she developed episodic sensations of “adrenaline
surges” characterized by diarrhea, tremors, and worsening restlessness. Over the following
month her orthostatic intolerance worsened, despite ongoing ability to exercise. Increased
fluid and salt intake and compression garments were utilized, with minimal improvement
in symptoms. On day 45 she developed episodic facial flushing, dermatographia, and
non-pruritic hives. She presented to our autonomic clinic for evaluation at this time.
Her past medical history included exercise-induced asthma and obsessive–compulsive
disorder, diagnosed at age 16, which resolved without pharmacological treatment by
age 18. She had no history of autonomic symptoms or syncope. Her family history was
notable for similar symptoms in her twin sister, a close contact, who experienced
a similar infectious prodrome during the same time period; however, her sister tested
negative for SARS-CoV-2, twice, by the same lab that analyzed the patient’s samples.
Physical examination of our patient, including a detailed neurological examination,
was normal. There was no evidence of joint hypermobility. We prescribed propranolol
and clonidine which led to some improvement of her hyperadrenergic symptoms.
Despite these medications, her symptoms of orthostatic intolerance and spells of sympathetic
hyperactivity continued, and on day 107, over 3 months after symptom onset, she underwent
autonomic reflex testing in our laboratory, including quantitative sudomotor axon
reflex testing (QSART), heart rate variability with deep breathing, Valsalva maneuver,
and a 10-min head-up tilt (HUT) at an angle of 70°. Beat-to-beat BP was measured with
finger plethysmography and confirmed with an automated cuff sphygmomanometer over
the brachial artery. An intravenous catheter was placed, and supine and upright norepinephrine
(NE) levels were collected. All medications were held 1 week prior to testing.
Autonomic testing demonstrated an exaggerated postural tachycardia with an HR increase
of 65 bpm on HUT, episodic hypertensive systolic BP surges to 170 mmHg in an oscillatory
pattern, and robust BP responses to Valsalva maneuver pattern in the absence of hyperventilation,
suggestive of a hyperadrenergic state (Fig. 1). The heart rate response to HUT demonstrated
a sustained increase of greater than 30 bpm which persisted for the duration of the
tilt, arguing against an anxiety response. The remainder of her autonomic testing
and NE levels were normal (supplementary table). Her nasopharyngeal swab was repeated
and was negative for SARS-CoV-2. IgM and IgG RBD antibodies were repeated and were
also negative, as were ganglionic acetylcholine receptor antibodies. At the time of
this report, approximately 5.5 months after symptom onset, the patient’s symptoms
remain, and she has not yet returned to work.
Fig. 1
a Valsalva maneuver demonstrating a robust BP and HR response. b Head-up tilt testing
at 70° demonstrating an exaggerated postural tachycardia with an HR increase of 65 bpm
and episodic hypertensive systolic BP surges in an oscillatory pattern in the absence
of hyperventilation
We report the first case, to our knowledge, of POTS developing after SARS-CoV-2 infection.
Our patient developed tachycardia along with common respiratory symptoms of COVID-19
in the acute phase of her illness; however, these symptoms resolved within 3 weeks,
while her tachycardia and other symptoms of autonomic impairment persisted and intensified
over the following several months. Hyperadrenergic symptoms were a prominent feature
in our patient, and her autonomic testing demonstrated features often reported in
hyperadrenergic POTS; however, her serum NE levels returned normal, and in fact lower
than typically reported in POTS, which deserves further investigation in future cases.
It should also be noted that our patient’s symptoms have now persisted for 5.5 months,
and some definitions of POTS require a symptom duration of at least 6 months.
Infection is a well-described trigger of POTS, with 28–41% of patients reporting onset
after a viral prodrome [2, 3]. In addition, autonomic dysfunction has been described
in small cohorts after the 2002 SARS epidemic [4], and several other pathogens have
been associated with autonomic dysfunction [5]. While an immune-mediated mechanism
has been suggested, the pathophysiology remains to be elucidated. It is worth noting
that our patient’s antibodies were initially positive on day 7 but were undetectable
2 months later, as reported in other patients with COVID-19. While our patient had
no pre-existing symptoms of autonomic impairment, it is worth noting that her twin
sister also developed similar symptoms after a similar infectious prodrome. This reinforces
the importance of phenotyping to better understand vulnerability to both the severe
acute manifestations and the chronic sequalae of COVID-19. Given the magnitude of
the pandemic, COVID-19 represents a unique opportunity to study post-infectious autonomic
syndromes, research which will hopefully lead to greater understanding of the pathogenic
mechanisms of POTS.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Supplementary file1 (DOCX 16 kb)