key: cord-0855377-m5xsykux
authors: Larsen, Nicholas W.; Stiles, Lauren E.; Miglis, Mitchell G.
title: Preparing for the long-haul: Autonomic complications of COVID-19
date: 2021-07-03
journal: Auton Neurosci
DOI: 10.1016/j.autneu.2021.102841
sha: 48313d8f106b0d7c0a5b7a5df1560aceea3b2fe1
doc_id: 855377
cord_uid: m5xsykux

As global numbers of COVID-19 grow, chronic neurological symptoms, including those of autonomic dysfunction, are being reported with increasing frequency. Mounting evidence suggests that many patients experience chronic and sometimes debilitating symptoms long after their acute infectious period, leading to the new diagnostic category of post-acute COVID syndrome. Many symptoms of post-acute COVID syndrome appear autonomic in nature, suggesting that autonomic impairment may play a central role in the underlying pathophysiology. In this review, we discuss the autonomic symptoms and manifestations of post-acute COVID syndrome, potential mechanisms involved, and future directions for a better understanding of this novel condition.

has not been clearly defined, most reports have detailed symptoms extending beyond 12 weeks.

The United Kingdom's National Institute for Health and Care Excellence (NICE) has defined "post-COVID-19 syndrome" as symptoms that persist for >12 weeks, and "Long-COVID" as both ongoing symptomatic COVID-19 (symptoms lasting 4-12 weeks) and post-COVID-19 syndrome (symptoms >12 weeks: National Institute for Health and Care Excellence, 2020.).

While the US National Institutes of Health (NIH) has recently used the term post-acute sequalae of SARS-CoV-2 (PASC), the duration of illness required for this diagnosis has not been specified. Regardless, PACS appears to be a multisystem illness, the most common systemic symptoms being fatigue, headaches, and cognitive impairment ("brain fog"), as well as other symptoms suggestive of autonomic dysfunction such as dyspnea, orthostatic intolerance, palpitations and gastrointestinal dysfunction (Huang et al., 2021; López-León et al., 2021: table 1) .

In April to June of 2020, the Center for Disease Control (CDC) conducted a multistate telephone survey of 274 non-hospitalized COVID-19 survivors in the US and found that approximately 1/3 (52% female) had not returned to their usual state of health two to three weeks after infection, including 20% of younger patients with no prior medical conditions (Tenforde et al., 2020) . Fatigue (71%), cough (61%), and headache (61%) were the most frequently reported symptoms. In a study of 143 hospitalized COVID-19 survivors in Italy with more severe disease (53% female), 87% still had symptoms at 60 days, with 53% reporting fatigue, 43% reporting difficulty breathing, and 22% reporting chest pain (Carfì et al., 2020) . Another study of 767 COVID-19 survivors in Italy, 88% of whom had been hospitalized, reported that 51% remained symptomatic at a median of 105 days post-infection, with fatigue and exertional dyspnea being the most common symptoms (Venturelli et al., J o u r n a l P r e -p r o o f 2021). Females (32% of cohort) reported more symptoms than males and were twice as likely to report fatigue. In a study of 120 hospitalized COVID-19 patients in Paris (37% female), surveyed a mean of 111 days after admission, 55% of patients reported fatigue, 42% dyspnea, and 34% memory loss (Garrigues et al., 2020) . A preprint of a study of 84 COVID-19 survivors in New York found that 92% of patients (sex of patients not reported) still had fatigue, 74% loss of concentration/memory and 64% dizziness, with symptoms persisting a mean of 151 days (range 54-255 days: Tabacof et al., 2020) . A study of 1733 individuals in China (48% female) evaluated six months after hospital discharge for COVID-19 infection in the Wuhan province reported that 76% continued to experience at least one persistent symptom, with "fatigue or muscle weakness" (63%) and sleep difficulties (26%) among the most common (Huang et al., 2021) . Other symptoms included palpitations (9%), dizziness (6%), diarrhea or vomiting (5%), chest pain (5%), skin rash (3%), and headache (2%), symptoms also common in patients with autonomic disorders. Approximately one-quarter of these patients had an abnormal six-minute walk test. Patients who were more severely ill during their initial infection were more likely to report persistent symptoms, have impaired pulmonary diffusion capacity on pulmonary function testing and abnormal chest computed tomography (CT). Finally, a study of Swiss military recruits (13% female) demonstrated that 19% of those infected with SARS-CoV-2 had a reduction of >10% maximum oxygen uptake (VO2 max) on exercise testing performed at a median of 45 days post-infection, despite the severity of initial symptoms (Crameri et al., 2020) .

Reports from COVID-19 survivors themselves have been invaluable in raising awareness and understanding PACS, originally termed "long-haul COVID" by survivors. i Several "long-haul COVID" support groups, consisting of hundreds of thousands of COVID survivors from around the world, formed on social media and have conducted their own patient-experience surveys. One survey, created by the Body Politic COVID-19 support group, targeted those who continued to experience symptoms at least two weeks after initial infection (Assaf et al., 2020) .

Of the 640 respondents, a majority were never hospitalized for COVID-19. Sixty-three percent were between the ages of 30 and 49, and 77% were female. Among the most common symptoms were those often reported by patients with autonomic disorders including fatigue, tachycardia, lightheadedness, difficulty concentrating ("brain fog"), insomnia, headache, gastrointestinal upset and nausea. Many respondents reported no pre-existing conditions, and 90% had not fully recovered 40 days after the onset of their illness. Sixty percent of this population reported pre-existing conditions such as asthma, which the authors suggested might prolong recovery time.

Another patient advocacy group, the COVID-19 Longhauler Advocacy Project, surveyed 1,200 individuals who had been ill for five weeks or longer after SARS-CoV-2 infection (range 5-54 weeks; Bishof, 2020). Most respondents developed COVID-19 in March of 2020, and the survey was administered in October of 2020. Many reported mild to moderate symptoms during the period of acute infection. Respondents, who were advised not to include any preexisting medical conditions, reported the development of new onset neurological (67%), pulmonary (53%), gastrointestinal (51%), cardiac (49%), and sensory (27%) problems. Notably, 34% reported new diagnoses of autonomic dysfunction and 18% reported new diagnoses of autoimmune disease, however these diagnoses were not substantiated by medical records.

she was wearing, and has been used extensively by fellow patients, media outlets, government officials, and the scientific community. More than 10,000 "long haulers" have found each other though Ms. Watson's group to date.

More recently, the Patient-Led Research Collaborative, which grew out of the Body Politic COVID-19 support group, reported data on a follow-up survey of 3,762 individuals across 56 countries with either suspected or confirmed COVID-19 who reported symptoms >28 days after initial infection (Davis, et al. 2020) . Most respondents were female (79%) and white (85%). The most frequent symptoms reported after six months were fatigue (78%), postexertional malaise (72%) and cognitive dysfunction (55%). The authors found that in those who recovered within 90 days of symptom onset, the average number of symptoms peaked at week two, while in those who did not recover by 90 days, the average number of symptoms peaked at month two after symptom onset.

In a systematic review of 15 studies addressing persisting symptoms in COVID-19, the most commonly reported symptoms were fatigue (58%), headache (44%), "attention disorder" (27%), hair loss (25%) and dyspnea (24%, López-León et al., 2021) . The authors also reported symptoms commonly seen in those with autonomic disorders, including "post-activity polypnea" (21%), sweating abnormalities (17%), nausea/vomiting (16%), chest pains/discomfort (16%), "resting heart rate increase" (11%), sleep disorders (11%), flushing (5%) and dizziness (3%). A new diagnosis of hypertension was reported in 1% of patients. It should be acknowledged that not all studies reviewed assessed all symptom domains, and that prevalence estimates are in some cases limited by small sample sizes.

Other researchers have described persistent autonomic symptoms over 100 days after initial symptom onset in COVID-19 survivors, including autonomic symptoms such as night sweats, tachycardia upon mild exercise or standing, temperature dysregulation, constipation, loose stools and vasomotor instability, however some of these reports are anecdotal (Nath et al., 2020) . A group in the Paris-Ile-de-France area described a subset of younger female patients ("around 40 J o u r n a l P r e -p r o o f years-old" in a 4:1 female: male ratio), with persistent fatigue, myalgias, subjective fevers, shortness of breath, tachycardia, chest tightness, anxiety and headaches (Davido et al., 2020) , a presentation strikingly similar to that of a typical patient with POTS. The authors hypothesized that these symptoms were consistent with autonomic dysfunction and should be considered as such, proposing a theory of microangiopathy and endothelial injury in susceptible patients as the underlying mechanism. These later descriptive reports should be viewed as preliminary only, and at this stage in our understanding of PACS it is unclear whether the symptoms reported are reflective of a sustained systemic inflammatory response, damage to autonomic pathways, or other mechanisms.

More recently there have been several case reports focusing more specifically on autonomic dysfunction in post-acute COVID syndrome (Johansson et al., 2021; Kanjwal et al., 2020; Miglis et al., 2020; Novak, 2020) . Almost all cases were females, with prominent autonomic symptoms that emerged several weeks after acute infection (table 2) . Not all these patients had SARS-CoV-2 infection confirmed via real time-polymerase chain reaction (RT-PCR) or antibody testing, for the most part due to limited availability during the early stages of the pandemic. Common symptoms include orthostatic intolerance, exercise intolerance, palpitations, fatigue, and cognitive impairment. Several patients had features of a hyperadrenergic state (Johansson et al., 2021; Miglis et al., 2020) , and symptoms of mast cell activation were not uncommon (Johansson et al., 2021; Miglis et al., 2020) . In those that had standardized autonomic cardiovascular reflex testing performed, the majority had an exaggerated postural tachycardia, acknowledging that some referral bias is present in the reporting of these data. Most patients were treated symptomatically with a combination of fluid, salt, rate control agents, and volume expanders, with variable outcomes. One patient experienced resolution of post-COVID-19 onset severe leg J o u r n a l P r e -p r o o f pain consisting of a burning sensation in the hands and feet, brain fog, urinary incontinence and blurred vision, and partial improvement in headaches and chronic fatigue, with intravenous immunoglobulin (IVIG, Novak, 2020) , raising the possibility of an autoimmune mechanism.

However, it is difficult to confirm from a single case report whether the patient improved due to the passage of time or due to an actual immunomodulatory effect. Further research is needed to better understand potential autoimmune mechanisms in PACS and treatment approaches.

While POTS appears thus far to be the most common autonomic phenotype among PACS patients, OH and neurally-mediated syncope should also be considered. In a three-month followup study of 135 patients with confirmed COVID-19 in Austria, "orthostatic hypotension with vasovagal syncope due to autonomic dysregulation" was seen in 1% (Rass et al., 2021) . While it is presumed based on the description that these two patients had both orthostatic hypotension and vasovagal syncope, it is unclear how these diagnoses were made, and what role deconditioning may have played, as one patient was admitted to the ICU. The median age of patients in this study was 56 years, and most were male (61%). Other neurological diagnoses made at three months that were not present prior to SARS-CoV-2 infection included poly-neuro/myopathy (13%) with one patient presenting with Guillain-Barré syndrome (1%), mild encephalopathy (2%), parkinsonism (1%), and ischemic stroke (1%).

In a prospective study of 40 COVID-19 survivors (90% female), with a median follow-up of 166.5 days (range 154.5 -179 days), the authors reported no signs of cardiovascular autonomic dysfunction on reflex testing as measured by Ewing's autonomic battery with beat-to-beat blood pressure (BP) and heart rate (HR) measurement during deep breathing, Valsalva, cold pressor testing, and a five-minute stand test (Townsend et al., 2021) . Fourteen of the 20 fatigued patients (70%) reported palpitations, dizziness or lightheadedness, or chest discomfort on active stand, J o u r n a l P r e -p r o o f while these symptoms were reported by none of the non-fatigued patients. The authors reported normal autonomic testing in all 40 patients, however HR and BP analyses were not reported beyond three minutes, thus limiting sensitivity for diagnoses of POTS, delayed OH or neurallymediated syncope. Half of the study population had no fatigue and had returned to work, however it is unclear if this half of patients any post-viral symptoms at all. All patients in this cohort had mild to moderate initial disease. Furthermore, patients who had received any medication that could impact cardiovascular findings, such as beta blockers, were excluded, as were patients who could not complete the five-minute stand test and other study procedures.

Future research will explore whether these findings can be confirmed in larger cohort of patients with well-defined PACS.

In another study from Germany, 42 PACS patients presenting with persistent moderate to severe fatigue six months after mostly mild SARS-CoV-2 infections were assessed with the Composite Autonomic Symptom Score-31 (COMPASS-31, Kedor et al., 2021) . A majority had COMPASS-31 scores suggestive of moderate (n=21) or severe (n=11) autonomic dysfunction.

The extent of central and peripheral nervous system involvement in COVID-19 remains to be determined, and this extends to the autonomic nervous system. Reports of autonomic dysfunction with Guillain-Barré syndrome in patients with COVID-19 have been reported during the acute para-infectious period, suggesting the possibility of immune-mediated autonomic neuropathy (Ghosh et al., 2020; Su et al., 2020; Toscano et al., 2020) . In a study assessing sudomotor function using electrochemical skin conductance (ESC) in 50 patients (32% female) with a history of COVID-19, 48% of whom had been hospitalized, abnormal ESC was seen in 26% of patients (Hinduja et al., 2021) . In those patients with abnormal ESC, autonomic symptoms were common and included "rapid heartbeat" (77%), "bloating or belching" (39%), and "low blood (Das et al., 2017; Fraser, 2020; Hui et al., 2005) . These patients often report fatigue, exercise intolerance, cognitive impairment and reduced exercise capacity. Thus, some degree of autonomic symptomatology might be due to persisting cardiopulmonary injury. In support of this theory, a study of 100 COVID-19 patients demonstrated that 78% demonstrated signs of ongoing inflammation on cardiac MRI at a median of 71 days after initial infection (Puntmann et al., 2020) . Others have noted positive correlations between the severity of SARS-CoV-2 infection and signs of chronic lung injury, with considerable numbers of moderate to severely ill patients exhibiting pulmonary diffusion and chest CT abnormalities six months after symptom onset (Huang et al., 2021) . The most common finding on chest CT in these studies was pulmonary interstitial changes, similar to radiographic J o u r n a l P r e -p r o o f changes seen in SARS survivors (Xie et al., 2005) .

The possibility of renal impairment should also be considered. Epithelial cells of the proximal renal tubule contain ACE2 receptors that could facilitate SARS-CoV-2 entry, leading to cytotoxicity and inflammatory cell infiltration. Furthermore, SARS-CoV-2 downregulates ACE2 receptors after infection of cells, leading to excess production of angiotensin II, which may in turn lead to vasoconstriction, increased vascular permeability, inflammation and fibrosis (Rossi et al., 2020) . A review of 1,000 hospitalized COVID-19 patients reported that 34% developed acute kidney injury, and 13.8% of these required dialysis (Argenziano et al., 2020) . In our experience, new-onset hypertension in PACS in not uncommon, and while longitudinal outcome data are lacking, this presentation should be considered in the evaluation of patients with PACS.

The hypercoagulable state of COVID-19 may also contribute to chronic pulmonary emboli.

Indeed, small pulmonary emboli have been visualized in patients with persistently elevated Ddimers several months after their initial infection (Venturelli et al., 2021) , which may contribute to exertional dyspnea.

Finally, direct infection of neural tissues is possible. SARS-CoV-2 ribonucleic acid (RNA) has been isolated from the olfactory bulb, branches of the trigeminal nerve (including conjunctiva and cornea), the cerebellum, respiratory and cardiovascular nuclei in the medulla, and the carotid artery wall (Meinhardt et al., 2021) , the latter two sites of utmost importance in baroreflex function. Additionally, ACE2 receptors have recently been identified in the dorsal root ganglia, another potential pathway into the peripheral nervous system (Shiers et al., 2020) . It is plausible to consider that such receptors may also be expressed on autonomic ganglia given the close regulatory relationship between ACE2 and the autonomic nervous system, however this remains to be documented.

Immune-mediated mechanisms Viral infections are commonly reported triggers of autonomic dysfunction, and there are many viral pathogens that have been implicated (Carod-Artal, 2018) . Prior research suggests 41% of patients with POTS report symptom onset after a viral prodrome (Thieben et al., 2007) , raising suspicion of immune-mediated mechanisms. Recent evidence documenting high titers of adrenergic and other autoantibodies to G-protein-coupled receptors in POTS may support this theory (Fedorowski et al., 2017; Gunning et al., 2019; Wang et al., 2012; Ruzieh et al., 2017) , however further studies are needed to confirm causation. Such autoantibodies have also been reported in viral myocarditis and Chagas cardiomyopathy (Rodeles et al., 2016) . Rapidly evolving research is identifying a wide array of extracelluar autoantibodies in individuals with COVID-19 (Wang et al., 2020) . The role of autoimmunity in PACS is thus yet to be defined, and deserving of future research, especially as it relates to autonomic disorders of orthostatic intolerance such as POTS, OH, and neurally-mediated syncope. The interaction of the autonomic nervous system with aspects of immune, endocrine and allergic function are incredibly complex and while conceptual frameworks have been provided (Goldstein, 2021a (Goldstein, , 2021b , mechanistic studies in patients with PACS-related autonomic dysfunction will ultimately be necessary to explore these associations.

Mast cell activation syndrome (MCAS) resulting in cytokine storms and hyperinflammation has also been implicated in chronic post-COVID illness (Afrin et al., 2020) . Support for this theory comes from the observation that much of the systemic inflammation seen in COVID-19 is like that seen in those with MCAS. Furthermore, preliminary findings suggest that some drugs with activity against mast cells may be beneficial in those with COVID-19. Curiously, prior in vitro research demonstrates that adrenergic receptor autoantibodies cause mast cells in cardiomyocyte J o u r n a l P r e -p r o o f tissue to mature faster and degranulate more readily (Okruhlicova et al., 2007) . Symptoms of MCAS are also reported in those with PACS, many of whom had no prior history of allergic symptoms, though reports are limited to small sample sizes.

While we were only able to identify one publication detailing OH in post-acute COVID syndrome (two patients out of a cohort of 137, both of whom had been hospitalized due to severity of para-infectious symptoms, Rass et al., 2021) , this complication may be more common than reported due to the lack of routine orthostatic BP measurements in both inpatient and outpatient practice. Syncope can be a presenting sign of COVID-19. In one study syncope was reported in 35 out of 411 (8.5%) patients who were early in the disease course of COVID-19 (Canetta et al., 2020) , however another publication reported rates of syncope closer to 1% (Rass et al.,2021) . The syncope seen in patients with COVID-19 infection is presumed to be neurallymediated and possibly related to viral invasion or disruption of baroreflex pathways in the carotid artery or the nucleus tractus solitarious of the medulla, which contains ACE2 receptors, though mechanistic studies have not been performed. We and others have noted a predilection for a hyperadrenergic presentation in these patients, with exaggerated BP responses on Valsalva maneuver, orthostatic hypertension along with exaggerated orthostatic postural tachycardia, and labile BPs, suggestive of an exaggerated baroreflex response (Johansson et al., 2021; Miglis et al., 2020) . This is deserving of future research, with inclusion of patients across various age groups to gather a more comprehensive understanding of not only orthostatic HR but also BP complications of SARS-CoV-2 infection.

Based on available data, PACS appears to affect females more than males, and especially so in J o u r n a l P r e -p r o o f autonomic cardiovascular domains such as orthostatic intolerance and inappropriate tachycardia.

The reasons for this are unclear, however there are several possibilities. Most females have up to 1/3 less skeletal muscle mass than males (Janssen et al., 2000) and hence a less vigorous "muscle pump" on standing, have smaller hearts (Prabhavathi et al., 2014) , and are more prone to pelvic venous pooling (Summers et al., 2010) , all which may be significantly exacerbated if deconditioning is introduced, further worsening orthostatic intolerance.

Additionally, there are sex-based differences in innate and adaptive immune responses, which impact the immunological response to pathogens (Klein and Flanagan, 2016) . Females are also more prone to autoimmune disease, with an approximately 4:1 ratio compared to men by some estimates (Angum et al., 2020) . The role of autoimmunity in PACS will thus be critical in the understanding of post-COVID autonomic dysfunction, and how this impacts gender predilection.

Deconditioning Cardiovascular deconditioning is a potential consequence of COVID-19, as periods of prolonged bedrest can lead to resting tachycardia, reduced exercise capacity, and a predisposition to orthostatic intolerance (Hasser and Moffitt, 2001) . Cardiovascular deconditioning leading to persistent tachycardia has been described after SARS (Yu et al., 2006) , and may also play a role in PACS and its potential association with orthostatic intolerance. The role of deconditioning in POTS continues to be debated. While low stroke volume and decreased cardiac mass have been proposed as evidence of deconditioning in POTS (Parsaik, et al. 2012) , other authors suggest this may be the consequence of low ventricular filling pressures (Oldham et al., 2016) , inconsistent with the high filling pressures typically seen in deconditioned patients (Blitshteyn and Fries, 2016) . However deconditioning alone does not explain the many other symptoms present in POTS, also seen in PACS, such as cognitive impairment, gastrointestinal upset, sleep J o u r n a l P r e -p r o o f Journal Pre-proof disturbances, and neuropathic pain. In many POTS patients, reconditioning programs can lead to improvement, but rarely complete resolution of symptoms.

Further studies evaluating VO2 max, ventricular filling pressure and other parameters of exercise testing are needed to better understand the extent of deconditioning in PACS patients. Until we understand the role of deconditioning in PACS, it will be difficult to ascertain which autonomic symptoms are caused or worsened by the presence of deconditioning.

The first cases of COVID-19 were reported in Asia in December 2019, and the first cases in North America and Europe in January 2020, with many surges occurring in March-April 2020 and then again in December 2020-March 2021. We are in the early stages of our understanding of COVID-19 and in even earlier stages of understanding PACS: its prevalence, extent of disease, and effect on the autonomic nervous system. What cannot be denied is the wave of patients to come. If COVID-19 is the earthquake, PACS may well be the tsunami.

The first challenge will involve defining the post-viral illness: cardinal features, duration of disease, inclusion and exclusion criteria. As this definition is being shaped, well-characterized patient registries will be critical for future research. We and others hope to recruit such patients for further study including testing of autonomic cardiovascular reflexes, serological markers including those of allergic and immune function, skin biopsy and other sudomotor tests of small nerve fiber function, tests of mitochondrial function, cardiac and neuroimaging studies. Such studies should be collaborative, with the establishment of open access data registries across centers and harmonization of data sets. Funding sources should emphasize both acute and longterm care for COVID-19 patients, and centers of excellence for post-COVID care should be prioritized at academic institutions to lead the way in multidisciplinary rehabilitative care. We Palpitations/tachycardia* Temperature intolerance* Labile blood pressure* New-onset hypertension* Gastrointestinal symptoms (e.g., abdominal pain, bloating, nausea) * Symptoms of mast cell activation syndrome (e.g., pruritis, urticaria, flushing, angioedema, wheezing, gastrointestinal symptoms, tachycardia, labile blood pressure) * symptoms reflective of possible autonomic dysfunction 

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