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Corresponding author at: P.O.Box 11-0236, Department of Neurology, American University of Beirut, Riad El-Solh, Beirut 1107 2020, Diana Tamari Sabbagh Bldg, Suite 2-46, Lebanon.
Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, LebanonDepartment of Neurology, Faculty of Medicine, American University of Beirut, Lebanon
Patients with long COVID suffer from many neurological manifestations that persist for 3 months following infection by SARS-CoV-2. Autonomic dysfunction (AD) or dysautonomia is one complication of long COVID that causes patients to experience fatigue, dizziness, syncope, dyspnea, orthostatic intolerance, nausea, vomiting, and heart palpitations. The pathophysiology behind AD onset post-COVID is largely unknown. As such, this review aims to highlight the potential mechanisms by which AD occurs in patients with long COVID. The first proposed mechanism includes the direct invasion of the hypothalamus or the medulla by SARS-CoV-2. Entry to these autonomic centers may occur through the neuronal or hematogenous routes. However, evidence so far indicates that neurological manifestations such as AD are caused indirectly. Another mechanism is autoimmunity whereby autoantibodies against different receptors and glycoproteins expressed on cellular membranes are produced. Additionally, persistent inflammation and hypoxia can work separately or together to promote sympathetic overactivation in a bidirectional interaction. Renin-angiotensin system imbalance can also drive AD in long COVID through the downregulation of relevant receptors and formation of autoantibodies. Understanding the pathophysiology of AD post-COVID-19 may help provide early diagnosis and better therapy for patients.
From a mysterious case of pneumonia to a global pandemic, the coronavirus disease 2019 (COVID-19) or severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged as a threatening challenge that has greatly altered our lives. The virus shares 80 % of its genome with previous human coronaviruses (SARS-CoV) and binds the angiotensin-converting enzyme type 2 (ACE-2) receptor through its spike (S) glycoprotein to enter the cell by endocytosis (
). They are located in the venous and arterial endothelial cells and arterial smooth muscle cells of most body organs comprising the stomach, brain, lymph nodes, bone marrow, spleen, kidneys, oral and nasal mucosa, nasopharynx, and skin (
Multiple systems such as the nervous, gastrointestinal, endocrine, cardiovascular, renal, and respiratory systems are implicated in long COVID symptoms (
). These symptoms include brain fog, headache, myalgia, tingling, fatigue, chest pain, paraesthesia, shortness of breath, anosmia, and diarrhea among others (
). Phase 2 is characterized by long post-COVID-19 symptoms arising during weeks 12 to 24 while phase 3 includes persistent symptoms that last beyond week 24 (
). However, according to the WHO, a patient is diagnosed with post-COVID after 3 months post-infection where the symptoms persist for more than 2 months (
). An observational study noted that autonomic symptoms in the post-COVID-19 phase require monitoring even in patients without neurological manifestations (
). Autonomic dysfunction, which can be primary or secondary, refers to a malfunction in the autonomic nervous system (ANS) with orthostatic hypotension (OH) being the most critical complication (
). Its cause can be genetic like familial dysautonomia or acquired due to autoimmunity, traumatic injuries, infections, abnormal reflexia, and metabolic dysfunction among others (
). Although it is an overlooked condition that is sometimes underdiagnosed and undertreated, its occurrence as a post-COVID manifestation has highlighted its severity (
). This review aims to highlight the mechanisms by which AD occurs in patients with long COVID. First, a brief overview of the ANS anatomy and AD will be provided followed by a compilation of clinical reports of patients with AD symptoms after COVID-19 infection. Second, the potential routes of SARS-CoV-2 entry into the ANS will be discussed along with mechanisms of AD onset post-COVID-19.
2. Overview of the autonomic nervous system
The ANS is the part of the peripheral nervous system (PNS) responsible for regulating involuntary physiological functions such as blood pressure, heart rate, digestion, respiration, and sexual arousal (
). The hypothalamus is one of the chief autonomic centers in the brain, which contains various nuclear groups, among which the paraventricular nucleus (PVN) plays a crucial role in controlling ANS functions (
). This hypothalamic nucleus is extensively connected to several structures in the limbic system, brainstem, and spinal cord. Neurons in the PVN receive afferent inputs from several integrative centers in the hypothalamus (suprachiasmatic nucleus, median preoptic nucleus, subfornical organ, arcuate nucleus), and from different pre-autonomic nuclei in the pons (lateral parabrachial nucleus) and medulla (nucleus tractus solitarius, ventrolateral medulla, dorsal motor nucleus of the vagus) (
). Efferently, neurons in the PVN project their axons to the median eminence in the hypothalamus, nucleus tractus solitarius (NTS) and rostral ventrolateral medulla, as well as to intermediolateral cell column in the spinal cord (
The PVN is a pivotal hypothalamic nucleus that not only controls neuroendocrine and autonomic functions but also regulates the body's stress response (
). Moreover, the PVN controls the hypothalamic-pituitary-adrenal (HPA) axis through the release of corticotropin-releasing hormone (CRH) into the anterior pituitary via the portal vessels of the median eminence (
). Its remarkable integrative function is attributed to GABAergic and glutamatergic interneurons that can be synaptically modulated by chronic stress resulting in various autonomic pathologies (
Other nuclei in the hypothalamus have also been implicated in the central autonomic nexus, such as the lateral hypothalamic area, the posterior hypothalamic nucleus, the dorsomedial nucleus, and the mammillary nucleus (
). These nuclei are interconnected with the PVN, the dorsal motor nucleus of the vagus (DMV), NTS, the lateral and ventral medulla and intermediolateral spinal columns (
As a regulator of autonomic activities, the hypothalamus is interconnected with autonomic centers via three major pathways: the medial forebrain bundle (MFB), the dorsal longitudinal fasciculus (DLF), and the mammillotegmental tract (MTT) (
). The gray matter of the brainstem, especially the medulla oblongata, includes autonomic nuclei that are involved in respiratory, cardiocirculatory, immune, and digestive systems homeostasis (
). Syncope caused by AD usually occurs as a result of central neuropathy or peripheral ganglionopathy including neurally mediated syncope like vasovagal, situational, and carotid sinus syncope in addition to OH and postural orthostatic tachycardia syndrome (POTS) (
). Patients with these conditions show sympathetic nervous system (SNS) hyperactivity at rest with increased blood noradrenaline levels, which causes additional stress on the heart and kidneys (
). Orthostatic hypotension, a major characteristic of AD, is a drop in systolic blood pressure by a minimum of 20 mmHg or in diastolic blood pressure by 10 mmHg (
). As a result of OH, other non-specific symptoms may occur due to a decrease in tissue and organ perfusion such as dizziness, dyspnea, generalized weakness, chronic fatigue, or visual acuity dysfunction (
). The cause of the resultant brain fog remains unknown, yet several mechanisms have been proposed including decreased cerebral blood flow velocity in the middle cerebral artery and elevated levels of norepinephrine (
). In patients with chronic fatigue syndrome, symptoms of dysautonomia like OH include decreased cardiac adrenergic response, decreased blood pressure parameters, increased tonic sympathetic activity, and POTS (
4. Clinical reports of autonomic dysfunction post-COVID-19
Twelve clinical reports have demonstrated the development of AD in long COVID (Table 1). A retrospective study that included 9 patients with PASC showed reduced orthostatic cerebral blood flow velocity with or without orthostatic tachycardia (
Table 1Summary of clinical reports and case series of patients with autonomic dysfunction post-COVID-19. Abbreviations: POTS: postural orthostatic tachycardia syndrome; ECG: Electrocardiogram; OH: orthostatic hypotension; QSART: Quantitative Sudomotor Axon Reflex Testing; HRV: heart rate variability; SDNN: Standard Deviation of NN intervals; SDANN: Standard Deviation of the Average NN intervals; LF/HF: Low Frequency/High Frequency Ratio; SNS: sympathetic nervous system; PNS: peripheral nervous system; ANS: autonomic nervous system; NCS: Neurocardiogenic Syncope.
Day 7 Shortness of breath, palpitations, burning chest pains upon inhalation, and anorexia Day 14 Fatigue, tachycardia, shortness of breath, exercise intolerance, chest pains, and insomnia Day 19 Orthostatic presyncope and lightheadedness Day 22 Pressured speech and restlessness Day 24 Adrenaline surges and restlessness Day 30 Worsening of orthostatic intolerance Day 45 Non-pruritic hives, facial flushing, dermatographia Day 107 (over 3 months after symptoms onset) Diagnosis of POTS
Patients with Ventilation Dysfunction SDNN: 28.6 % had an abnormal HRV SDANN: 14.3 % had an abnormal circadian HRV LF/HF: 14.3 % had a SNS/PNS imbalance
Patients with Diffuse Dysfunction SDNN: 40.91 % had an abnormal HRV SDANN: 30 % had an abnormal circadian HRV LF/HF: 9.1 % had a SNS/PNS imbalance
Patients with Pulmonary Fibrosis SDNN: 38.1 % had an abnormal HRV SDANN: 14.3 % had an abnormal circadian HRV LF/HF: 4.5 % had a SNS/PNS imbalance
). A study showed that heart rate variability may be used as an indicator for AD in COVID-19 patients and may be associated with pulmonary fibrosis sequelae in patients within 6 months post-SARS-CoV-22 infection (
). In fact, normalized high frequency component of blood pressure variability marker (HF-nu-sBP), which regulates systolic blood pressure and illustrates parasympathetic activity, significantly increased in both mild and severe cases of COVID-19 when compared to the control group (
). Levels of normalized low frequency component of blood pressure variability marker (LF-nu-dBP), which regulates diastolic blood pressure and illustrates sympathetic activity, significantly decreased in both COVID-19 groups when compared to healthy individuals (
). These results demonstrate that sympathetic impairment is associated with COVID-19 infection; thus, the compensatory activity of the parasympathetic nervous system to modulate blood pressure (
5. Mechanisms of autonomic dysfunction by SARS-CoV-2
The pathophysiology of AD following COVID-19 is largely speculative due to the lack of investigative clinical studies in patients exhibiting symptoms of ANS dysfunction. Many previous reviews have attempted to decipher the possible mechanisms behind AD onset post COVID-19 (
). These virus-induced changes can impact the components of the autonomic network leading to symptoms of dysautonomia. Possible targets that can lead to dysautonomia include autonomic centers like the hypothalamus and medulla oblongata in the brainstem (
Table 2Direct of routes of entry by SARS-CoV-2 into the autonomic nervous system. Different cranial nerves can act as access points by SARS-CoV-2 to reach the hypothalamus or brainstem. The virus can reach the autonomic nervous system through the blood by crossing the blood-brain-barrier or the circumventricular organs. Abbreviations: ANS: autonomic nervous system; ACE-2: angiotensin-converting enzyme type 2; BBB: blood-brain barrier; CVOs: circumventricular organs; MFB: medial forebrain bundle; NTS: nucleus tractus solitarius; NRP1: neuropillin 1; PVN: paraventricular nucleus; TMPRSS2: transmembrane serine protease 2.
Route of entry
Anatomical site of entry
Findings suggesting entry through the route
Reference
Suggested pathway to ANS invasion
Neuronal
Olfactory nerve
Autopsy of patients with COVID-19 showed viral RNA of SARS-CoV-2 in the olfactory mucosa and olfactory bulb. Spike protein was colocalized with neuronal cells
In macaques, SARS-CoV-2 was detected in the olfactory cortex preferentially in neurons
Fig. 1Direct invasion of the hypothalamus or the medulla by SARS-CoV-2 through the neuronal or hematogenous routes can induce autonomic dysfunction. At the level of the hypothalamus, PVN plasticity may be modulated directly or indirectly by targeting GABAergic or glutamatergic interneurons. These interneurons synapse with the CRH neurons that connect to the pituitary gland. Inflammatory signals can also be translated into stress signals that overwhelm the PVN resulting in neuroinflammation and autonomic disruption. At the level of the medulla, viral invasion of GABAergic interneurons and astrocytes in the NTS can modulate normal autonomic function and/or cause cell death. Abbreviations: PVN: Paraventricular Nuclei; CRH: Corticotropin Releasing Hormone; NTS: nucleus tractus solitarius.
5.1.1 Direct routes of SARS-CoV-2 entry into the autonomic system
5.1.1.1 Neuronal route
Viruses are considered neuroinvasive if they can be carried by motor proteins across neurons through retrograde or anterograde axonal transport to reach nearby cells (
). Through that same pathway, we hypothesize that SARS-CoV-2 can spread to the brainstem through the MFB. The MFB establishes major hypothalamic connections with the olfactory bulb, septal nuclei, prefrontal cortex, and the dopaminergic neurons of the ventral tegmental area (
). Therefore, it possibly poses a direct pathway for SARS-CoV-2 from the olfactory epithelium to the hypothalamus.
However, immunolabeling has revealed that ACE2 receptors are expressed more abundantly on the apical side of sustentacular cells of the olfactory epithelium compared to the respiratory epithelium and are not found on ORNs (
). Similarly, another study showed that ACE-2 receptors and TMPRSS2 protein were mainly located in sustentacular cells while TMPRSS2 was detected in both neural and non-neural olfactory cells (
). An examination of infected hamster and human olfactory epithelia indicated that SARS-CoV-2 preferentially invades the sustentacular cells and not the olfactory neurons causing a downregulation in the expression of olfactory receptors and their signaling genes (
). It is also suggested that local inflammation in the upper respiratory tract causes axonal and microvascular damage in the olfactory tract and bulb (
). In this study, olfactory pathology did not correlate with the presence of SARS-CoV-2 in the olfactory bulb, so direct viral invasion of ORNs was excluded (
). These results oppose the viral neurotropism of SARS-CoV-2 as a cause for olfactory dysregulation. Therefore, more research is required to investigate whether direct viral invasion of the ORNs is possible to allow access to the ANS and to understand how SARS-CoV-2 can cause neuronal damage indirectly. The role of age and comorbid diseases should be investigated as factors that may facilitate the spread of the virus in the brain.
Other cranial nerves may act as viral entry points into the central nervous system (CNS) (
). The involvement of the optic nerve was suspected. Upon examination of retinal nerve fiber layer thickness in 8 COVID-19 patients, an increase was noted in 7 patients suggesting possible optic nerve inflammation caused by the virus (
). It can be hypothesized that the virus may use this route to affect circadian function. There is little evidence to explain how the virus impacts the optic nerve and whether it uses it for transneuronal entry to the brain.
The oral mucosa, taste buds, salivary gland, and trigeminal ganglion express ACE-2 receptors and TMPRSS2 (
). The cranial nerves involved in the sense of taste are the facial, glossopharyngeal, and vagus nerves that connect taste receptors to the brain through the NTS (
). Both the vagus and the glossopharyngeal nerves express ACE-2, NRP1, and TMPRSS2, which makes them potential sites of entry to the NTS in the brainstem (
). We can postulate that the virus uses the vagal nerve to spread from the respiratory tract to the vagal ganglia, NTS, and nucleus ambiguous. Viral infiltration may cause respiratory dysfunction, only worsening the already existing respiratory manifestations of SARS-CoV-2.
5.1.1.2 Hematological route
The CNS is immune privileged due to protection offered by physical barriers like the blood-brain barrier (BBB) or immunological barriers in order to evade inflammation (
). For example, the BBB can be breached through viral infection of the endothelial cells lining it or by using leukocytes as “Trojan horses” to cross it (
). Postmortem examination of a COVID-19 patient revealed the presence of viral-like particles in the capillary endothelium of the frontal lobe with active budding across the basolateral membrane of the endothelial cells (
). This observation supports the possible hematogenous spread of the virus to access the CNS through the infected endothelial cells. Moreover, endothelial cells of the BBB possess tight junctions that limit the paracellular transport of molecules (
). Viruses can damage these tight junctions through different ways to cross the BBB. For example, West Nile virus (WNV) is able to degrade claudin-1 and JAM-1 by endocytosis once it infects epithelial/endothelial cells (
). Another study noted that WNV upregulates the expression of matrix metalloproteinase 9 (MMP9) that in turn disrupts the BBB by damaging the basement membrane to enter the brain (
). It is worth investigating whether SARS-CoV-2 impacts tight junction proteins to cross the BBB or utilizes a transcellular route to access the CNS. Alternatively, viruses can use immune cells to cross the BBB through the “Trojan horse” mechanism, which is used by the human immunodeficiency virus-1 (HIV-1) (
). Viruses can increase the expression of intercellular adhesion molecule-1 (ICAM-1) on the surface of endothelial cells to facilitate the transmigration of leukocytes to the CNS, the site of inflammation (
). Viral particles of SARS have been detected in the monocytes, granulocytes, and lymphocytes of SARS patients with T cells as the most infected immune cells (
Another possible gateway for the virus is through the circumventricular organs (CVOs). Molecules in the blood stream can communicate with the brain through CVOs without crossing the BBB (
). Circumventricular organs are so called since they surround the third ventricle (neurohypophysis, vascular organ of the lamina terminalis, subfornical organ, pineal gland and subcommissural organ) and the fourth ventricle (area postrema) (
). They function to regulate molecular transport, carry out an immunological response against invaders, and interact with autonomic centers like the hypothalamus (
). Various chemicals signals are communicated with the hypothalamus and the brainstem through interconnections to regulate salt and water balance, cardiovascular function, immunomodulation and energy metabolism (
The design of barriers in the hypothalamus allows the median eminence and the arcuate nucleus to enjoy private milieus: the former opens to the portal blood and the latter to the cerebrospinal fluid.
). The relatively increased permeability enables the median eminence to access the portal blood, while the ARC accesses the CSF, providing them with a somewhat “private milieu” (
The design of barriers in the hypothalamus allows the median eminence and the arcuate nucleus to enjoy private milieus: the former opens to the portal blood and the latter to the cerebrospinal fluid.
). Also, the organum vasculosum and the subfornical zone govern important physiological functions. The organum vasculosum is located along the rostral wall of the third ventricle and is in charge of fluid homeostasis (
). On the other hand, the subfornical zone is located on the anterodorsal wall of the third ventricle and senses circulating hormones that send signals regarding fluid balance (
). We propose that through invading these fenestrated locations, the virus can target autonomic centers in the brain.
5.1.2 Hypothalamic impairment
Input to the hypothalamus is neural or hematogenous; thus, its connections can be utilized by SARS-CoV-2 to invade different nuclear groups resulting in loss of control over autonomic functions. As mentioned before, the PVN plays an important role in controlling the body's stress response. It has been suggested that direct binding of SARS-CoV-2 to ACE-2 receptors in the PVN circuitry can underlie daytime fluctuations in fatigue states, alertness, and anxiety following COVID-19 (
Does damage to hypothalamic paraventricular nucleus underlie symptoms of ultradian rhythm disorder and an increased anxiety in coronavirus disease 2019?.
). It can be hypothesized that chronic stress induced by long COVID can modulate the plasticity of PVN interneurons. Another viewpoint posits that SARS-CoV-2 may indirectly impair PVN function by translating inflammatory signals into stress signals that overwhelm the PVN resulting in neuroinflammation and autonomic disruption (
Various studies that have documented hypothalamic involvement in patients with COVID-19 and the correlation between severity of prognosis and the attenuation of hypothalamic-pituitary response (
). While the acute stage of virus infection leads to HPA hyperactivation and hypercorticolism, hypocorticolism has been reported as a more delayed symptom of COVID-19 (
). Hypothalamic-pituitary-adrenal hyporesponsiveness post-COVID may be explained by impaired functioning of adrenergic and catecholaminergic neurons in the nucleus of NTS and ventrolateral medulla oblongata of the brainstem responsible for directly activating PVN CRH neurons (
). We hypothesize that the plasticity of the PVN can also be utilized by SARS-CoV-2 to modulate the function of medial PVN CRH neurons resulting in GR upregulation and HPA suppression. Further investigation is required to understand the interplay between impaired autonomic function and the possible maladaptive plasticity of the PVN in long COVID.
5.1.3 Medulla oblongata damage
Autopsy studies have revealed the presence of SARS-CoV-2 viral proteins in the medulla oblongata either in neuronal and glial cells or in the vagus and glossopharyngeal nerves (
). Histopathological assessment of the brainstem highlighted an increase in neuronal damage along with an increase in ionized calcium binding adaptor molecule (Iba1) expression indicative of microglial activation (
). Hence, it has been suggested that long COVID can be accompanied by brainstem dysfunction caused by progressive neuroinflammation and neurodegeneration (
). Brainstem dysfunction may occur as a result of direct viral invasion via ACE2 and NRP1 receptors, neuroinflammation through microglial/astrocytic activation and leukocyte infiltration, and finally by vascular activation (
). It can be hypothesized that viral invasion of medullary nuclei and consequent cell lysis may lead to impaired autonomic reflexes. Moreover, GABAergic interneurons receive converging excitatory signals from multiple descending pathways or primary afferents of the NTS and send out inhibitory signals to modulate medullary reflexes (
). Astrocytes in the NTS release glutamate that acts on vagal afferents via NMDA receptors containing GluN2B and GluN2C/D subunits to modulate NTS excitability (
). Examination of the postmortem tissues of patients with COVID-19 has shown that astrocytes are predominantly infected by SARS-CoV-2 through NRP1 receptors (
). Neurotoxic factors were shown to be released by infected astrocytes leading to changes in cortical thickness in COVID-19 patients through promoting progressive neurodegeneration (
). Thus, it can be hypothesized that direct infection of NTS astrocytes can alter normal autonomic reflexes by promoting neuronal death or altered function in other medullary nuclei. We suggest that local GABAergic interneurons in the NTS along with astrocytes can be targeted by SARS-CoV-2 thus rewiring the interconnections of the medulla.
5.2 Autoimmunity
One of the mechanisms behind a common form of AD, POTS, has been attributed to the formation of autoantibodies suggesting an autoimmune basis (
) (Fig. 2). Receptor autoantibodies act as agonists and activate their corresponding receptors in a consistent fashion preventing normal desensitization (
). Specifically, patients with POTS exhibit high levels of G-protein-coupled adrenergic A1 receptor and muscarinic acetylcholine M4 receptor autoantibodies (
). Autoantibodies against adrenergic A2, B1, and B2 receptors along with muscarinic receptors are only observed in patients who express antibodies against adrenergic A1 receptors (
). Measuring the activity of autoantibodies against different subtypes of G-protein-coupled receptors (GPCRs) in the serum of patients with POTS revealed that the activity of adrenergic A1 receptors correlated with POTS symptoms more significantly than adrenergic B2 receptors, muscarinic M2 receptors, and opioid receptor-like 1 (
Fig. 2Autoimmunity is one mechanism by which SARS-CoV-2 might trigger autonomic dysfunction. Activation of the innate and adaptive immune responses contributes to inflammation and autoimmunity. The production of neuroactive and vasoactive autoantibodies leads to persistent activation of their corresponding receptors. Mechanisms of virus-induced autoimmunity include molecular mimicry, bystander activation, epitope spreading, and B lymphocyte immortalization Autoimmunity caused by long COVID impacts cell function, exacerbate immune-related symptoms, or initiate new symptoms of autonomic dysfunction. Abbreviations: GPCR: G-protein-coupled receptor.
There is an interesting interplay between viral infections and autoimmune disorders be it the modulation of existing autoimmune disorders like MS and rheumatoid arthritis or their initiation (
). These patients suffer from long COVID symptoms that include fatigue, attention deficit, tachycardia, hypertension, but most importantly POTS and dysautonomia (
). They also have variable levels of autoantibodies against adrenergic A1 receptors, adrenergic B2 receptors, muscarinic M2 receptors, nociceptin receptors, endothelin receptors, MAS receptors, angiotensin II AT1 receptor, but only the autoantibodies against adrenergic B2 and muscarinic M2 receptors are present in all recovered patients (
). Overall, the study demonstrated that the corresponding vasoactive changes induced by these autoantibodies in addition to inflammatory or ischemic mediators are responsible for the post-COVID-19 symptoms (
). Another study that utilized Rapid Extracellular Antigen Profiling to check for autoantibodies against 2770 proteins in patients with COVID-19 identified the presence of autoantibodies against orexin receptors (HCRT2R) in the hypothalamus that correlated negatively with the Glasgow Coma Scale scores (
). These receptors are GPCRs distributed throughout the PVN, tuberomammillary nuclei, and autonomic nuclei of the medulla to mediate arousal and the stress response (
). They receptors exert autonomic control by regulating arterial blood pressure, cardiovagal response, cardiovascular reflexes, respiratory function, and gastrointestinal function (
). Even though the study found autoantibodies against HCRT2R in 8 out of 194 COVID-19 patients, it is worth checking the involvement of this autoantibody in COVID-19 patients with dysautonomia. Another noteworthy antibody, which was found to be elevated in patients with long COVID (n = 9), is trisulfated heparin disaccharide (TS-HDS) antibody (44 %) (
). In the aforementioned study, dysautonomia without orthostatic hypotension was detected in all tested patients with long COVID and 78 % exhibited small fiber neuropathy with chronic mild pain (
In patients with an immune-mediated inflammatory disease, SARS-CoV-2 infection may induce the reemergence of immune-related symptoms or introduce new immune-mediated inflammatory diseases (
). For example, a patient with a history of small fiber neuropathy and orthostatic cerebral hypoperfusion syndrome, which developed due to Lyme disease treatment, experienced an exacerbation of symptoms post-COVID-19 infection (
Post COVID-19 syndrome associated with orthostatic cerebral hypoperfusion syndrome, small fiber neuropathy and benefit of immunotherapy: a case report.
). The patient had central symptoms including brain fog, fatigue, and orthostatic dizziness along with peripheral symptoms of painful burning sensation in the extremities that were resolved by immunotherapy (
Post COVID-19 syndrome associated with orthostatic cerebral hypoperfusion syndrome, small fiber neuropathy and benefit of immunotherapy: a case report.
Post COVID-19 syndrome associated with orthostatic cerebral hypoperfusion syndrome, small fiber neuropathy and benefit of immunotherapy: a case report.
). Another beneficial impact of immunotherapy was demonstrated by the use of BC 007 to neutralize autoantibodies against GPCRs in a patient with long COVID resulting in attenuated fatigue and capillary impairment (
Case report: neutralization of autoantibodies targeting G-protein-coupled receptors improves capillary impairment and fatigue symptoms after COVID-19 infection.
The mechanism by which SARS-CoV-2 is activating autoantibodies is not clear, yet proposed mechanisms of virus-induced autoimmunity include molecular mimicry, bystander activation, epitope spreading, and B lymphocyte immortalization (
). A dysregulated immune system may perpetuate inflammation resulting in organ damage affecting the cardiovascular, renal, pulmonary, digestive, and nervous systems (
). Autoimmunity can result from molecular mimicry whereby the similarity between the self and viral antigens causes the attack of host surface proteins (
). This was based on a study that showed a platelet delta granule storage pool deficiency in patients with POTS and GPCR autoantibodies suggesting innate system activation (
). It remains to be investigated whether the innate and adaptive immune systems contribute to autoantibody production against adrenergic and cholinergic receptors following SARS-CoV-2 infection.
5.3 Persistent inflammation, hypoxia, and sympathetic overactivation
Along with autoimmunity, persistent systemic inflammation may play a central role in the underlying pathophysiology of long COVID (
). The innate immune response releases inflammatory cytokines which in turn signal the transport of immune cells to the site of injury exacerbating tissue damage (
). Seven to eleven months following COVID-19, patients exhibit an upregulation in pro-inflammatory mediators such as TNF α, IL-6, IL-13, IL-17A, and IL1-β along with a sustained increase in naïve B cells and effector T cells (
). A chronic state of systemic inflammation potentiates the activities of the SNS and HPA axis resulting in chronic inflammatory effects like increased cardiovascular risk and hypertension (
). This occurs through lung alveolar epithelial injury and surfactant dysfunction that causes alveoli and air sacs to collapse decreasing oxygen levels (
Interestingly, hypoxia and inflammation work together in a positive feedback loop involving the enzyme prolylhydroxylase (PHD) and with the ability to exacerbate capillary damage in COVID-19 (
SARS CoV-2 related microvascular damage and symptoms during and after COVID-19: consequences of capillary transit-time changes, tissue hypoxia and inflammation.
) (Fig. 3). An increase in pro-inflammatory cells and ILs damages capillary endothelial cells and mitochondrial function in addition to promoting an influx of leukocytes and increased oxygen consumption by inflammatory cells (
). Consequently, the decrease in oxygen supply in the affected tissues promotes hypoxia by inhibiting PHD and allowing the activation of hypoxia inducible factor 1 alpha (HIF-1α) and nuclear factor kappa B (NF-κB), a master inducer of inflammation (
). This hypoxia-inflammation crosstalk can be responsible for persistent COVID-19 symptoms and microvascular disruptive processes like microthrombosis and endotheliitis (
SARS CoV-2 related microvascular damage and symptoms during and after COVID-19: consequences of capillary transit-time changes, tissue hypoxia and inflammation.
). In fact, an examination of the brains of SARS-CoV-2 infected non-human primates revealed significant neuroinflammation, neuronal injury and death, and microhemorrhages related to hypoxia/ischemia along with upregulated HIF-1α (
Fig. 3Persistent inflammation, hypoxia, and sympathetic overactivation can result in autonomic dysfunction in long COVID. The activation of the innate immune cells following SARS-CoV-2 infection results in a cytokine storm characterized by the great release of interleukins and chemokines. As more leukocytes migrate to the site of infection, more oxygen is consumed leading to a hypoxic state. The decrease in oxygen supply in the affected tissues promotes hypoxia by inhibiting PHD and allowing the activation of HIF-1α and NF-κB, a master inducer of inflammation. This positive loop promotes SNS overactivation that can eventually induce neuroinflammation and cell death. Abbreviations: PHD: Prolylhydroxylase; NF-κB: nuclear factor kappa B; HIF-1α: hypoxia inducible factor 1 alpha; SNS: sympathetic nervous system.
). This system plays an important role in the maintenance of blood pressure and volume thus impacting the cardiovascular, renal, and pulmonary systems (
). Patients with COVID-19 display AD one year after infection characterized by blunted heart rate recovery (HRR), and exaggerated blood pressure response to exercise (EBPR) in addition to high levels of uric acid (
). There exists a positive feedback loop between the ANS and RAS whereby angiotensin peptides can bind to receptors expressed in the medulla, sympathetic preganglionic neurons, sympathetic ganglia, nerve terminals, or vagal afferents that in turn control neurotransmitter release at the level of organs involved in the synthesis of these angiotensin peptides (
). Given the important role of RAS in autonomic regulation and the observed cardiovascular/metabolic dysfunction in patients with long COVID, RAS imbalance may play a role in the development of AD post-COVID-19.
In the RAS pathway, renin converts angiotensinogen (AGT) into angiotensin I (Ang I) (
). However, Ang II and Ang 1–7 support the protective anti-inflammatory pathway by binding to angiotensin type-2 receptor (AT2R) and GPCR Mas (MasR) respectively (
). Several brain regions contain AT1R including hypothalamic and brainstem nuclei such as PVN, NTS, supraoptic nuclei, median preoptic nucleus, and rostral ventrolateral medulla in addition to CVOs like the organum vasculosum and subfornical organs (
). Consequently, AT1R is hyperactivated by Ang II triggering the pro-inflammatory pathway and sympathetic effects. Studies examining RAS imbalance in patients with COVID-19 exhibit conflicting results. In one study, it was shown that patients with COVID-19 had elevated levels of Ang II and low levels of Ang 1–7 despite high ACE-2 activity compared to control subjects (
). Measuring ACE-2 activity in the tissues rather than in the blood may better reflect ACE-2 function and explain the contradictory results regarding ACE-2 activity in this study (
). In one of these studies, the Ang 1–7/Ang II ratio was increased from early to late in patients with severe COVID reflecting enhanced ACE-2 activity and a shift towards a preferential protective effect of RAS during late stages of COVID-19 (
). Unfortunately, the other study did not provide a measurement of ACE-2 activity nor Ang 1–7/Ang II ratio to explain the observed increase in Ang 1–7 and decrease in Ang II (
). However, the study was terminated due the high discharge rate of patients with only 3 remaining patients who completed the 10-day schedule of TXA 127 administration (
). Larger clinical trials that account for the length of hospital stay upon deciding the duration of drug administration are needed. The conflicting results regarding the change in angiotensin levels, Ang II/Ang 1–7 ratio, and ACE-2 activity highlight the need for further clinical studies with improved methods to assess the true activity of ACE-2. This could help investigate the role of the RAS imbalance in AD during long COVID.
Fig. 4An imbalance in the renin-angiotensin system can be responsible for autonomic dysfunction following SARS-CoV-2 infection. The downregulation of ACE-2 upon SARS-CoV-2 cell entry in addition to the formation of autoantibodies against ACE-2 and AT1R are important contributors to such imbalance. Consequently, levels of angiotensin I and angiotensin II increase while levels of angiotensin 1–9 and angiotensin 1–7 drop. This results in the hyperactivation of AT1R responsible for mediating the pro-inflammatory pathway and sympathetic effects. Abbreviations: ACE: angiotensin-converting enzyme.
The formation of ACE-2 and AT1R autoantibodies can also play a role in RAS imbalance post-COVID-19. Studies have shown elevated levels of ACE-2 and AT1R autoantibodies in patients with COVID-19 potentiating disease severity and inflammation (
). Up to our knowledge, there are no studies that investigated the association between AT1R autoantibodies and AD onset post-COVID-19. Such work would help diagnose AD in patients with long COVID by measuring the levels of RAS enzymes as useful biomarkers in addition to improving therapy via AT1R blockers.
6. Conclusion
The emergence of AD as one of many complications of long COVID has highlighted the importance of understanding AD pathophysiology. This can be challenging since the symptoms of AD are multifaceted, and dysregulation in the ANS can occur either at the level of the autonomic centers, the sympathetic and parasympathetic connections, or the target organs. In this review, it is hypothesized that direct invasion of the hypothalamus or the medulla by SARS-CoV-2 can induce AD. This direct mode of invasion may occur via neuronal routes or through the blood. At the level of the invaded autonomic centers, the plasticity of the PVN network may be modulated directly or indirectly by targeting GABAergic or glutamatergic interneurons or astrocytes. However, emerging studies are proposing that SARS-CoV-2 may cause neurological manifestations such as AD indirectly rather than directly via neuronal invasion (
). Indeed, one possible indirect mechanism is through autoimmunity in which neuroactive and vasoactive autoantibodies are produced resulting in persistent activation of their corresponding receptors. Autoimmunity caused by long COVID can also impact cell function, exacerbate immune-related symptoms, or initiate new symptoms of AD. Moreover, the interaction between persistent systemic inflammation, hypoxia, and SNS overactivation can play a major role in AD onset. Renin-angiotensin system imbalance is a possible inducer of AD in long COVID capable of triggering pro-inflammatory pathway with SNS effects. The downregulation of ACE-2 upon SARS-CoV-2 cell entry in addition to the formation of autoantibodies against ACE-2 and AT1R are important contributors to such imbalance. Further research is needed to investigate the effect of the above mechanisms on AD development post-COVID-19. Understanding AD in patients with long COVID would help in diagnosis and treatment. It is worth studying the effect of comorbidities such as diabetes or hypertension on AD post-COVID given the serious complications that may ensue.
Data availability
No data was used for the research described in the article.
Declaration of competing interest
None.
Acknowledgements
We would like to thank Mrs. Alia Trabolsi for her help in editing the paper.
References
Abdelnabi M.
Eshak N.
Almaghraby A.
COVID-19 Associated Dysautonomia in a Non-Critically Ill COVID-19 Patient.
Case report: neutralization of autoantibodies targeting G-protein-coupled receptors improves capillary impairment and fatigue symptoms after COVID-19 infection.
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