SARS-CoV-2 has been circulating in the global population for over a year. According to Worldometer, at the time of this writing on March 2, 2021, 115 million people have been infected with the virus, 2.5 million have died, and 90 million have survived the infection to go on to have possible immunity. The immune response to the virus can range from asymptomatic to severe illness and death and has aroused fear and uncertainty around the world. For those who have been infected with SARS-CoV-2 and survived, some experience prolonged symptoms beyond recovery from the acute illness. Long COVID presents with ongoing symptoms of fatigue, post-exertional malaise (PEM), sleep issues, headaches, brain fog, cognitive issues, depression, anxiety, musculoskeletal pain, respiratory distress, and muscle weakness that extends far beyond initial recovery.

Post-viral syndromes are not uncommon and are suspected of contributing to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM), disorders that can have lasting effects far beyond the initial infection. Cases of chronic post-SARS syndrome related to SARS-CoV-1 are noted in the literature and while currently we do not have the longer lens of time to evaluate the lasting effects of SARS-CoV-2, we know that issues exist and are similar to other post-viral syndromes.

The questions that arise related to the long-term effects of COVID-19 are:

(1) Who is likely to experience long COVID?

(2) What can we do to prevent its occurrence?

(3) Is there any way to effectively treat long COVID?

Apparently, the NIH has posed similar questions and just received $1.5 billion in funding from Congress to study issues surrounding long COVID. This new research may improve our understanding of other post-viral syndromes and ME/CFS.

In order to truly understand the long-term consequences of SARS-CoV-2, we have to carefully review what we know about other post-viral syndromes. Although SARS-CoV-2 has reached pandemic proportions, the good news is that this is still a virus that generally behaves like other viruses of similar origin. Reaching into past research will provide a conceptual foundation upon which to build further knowledge. Specific data regarding the long-term effects of SARS-CoV-2 on various systems in response to the infection will likely be forthcoming as we have more individuals who have recovered from the acute infection.

Evaluating issues related to the brain and nervous system, the immune system, mitochondrial function, hormones, and the hypothalamic-pituitary-adrenal (HPA) axis in response to the viral infection can direct us to some basic naturopathic and functional medicine assessment and treatment options to help long-haulers fully recover. In part one of this series, I will explore the long-term effects of viral infection on the central nervous system (CNS) and some current hypotheses that are emerging as scientists and physicians around the world observe, treat, research, and gather data on SARS-CoV-2.

Post-Viral Syndrome Related to SARS-CoV-1

SARS-CoV-2 and SARS-CoV-1 have a 78% genetic similarity so it is fair to assume that post-viral symptoms associated with the first SARS virus might also be associated with SARS-CoV-2. In March 2003, SARS-CoV-1 arrived in Ontario, Canada, where health authorities effectively contained the virus with only 273 confirmed cases and 44 total deaths. By June 2003, there were no new cases; however, a cohort of 50 post-SARS-CoV-1 patients out of Ontario, Canada, experienced ongoing symptoms marked by extreme fatigue, muscle weakness, sleep disruption, and cognitive difficulties resulting in an inability to return to work for several months to three years post-infection. In a 2011 BioMedCentral Neuroscience article, Modolfsky and Patcai conducted sleep studies on the above-mentioned cohort and discovered an association between the seemingly abnormal sleep patterns in the post-SARS group and common sleep patterns seen in ME/CFS and FM. All groups presented with sleep instability and poor-quality sleep as indicated by a delay in sleep onset and lack of deep sleep cycles throughout the night [1]. The authors presumed that symptoms associated with post-SARS may have been related to the virus crossing the blood-brain barrier (BBB), thus invading the CNS [1, 2]. Past research has demonstrated that viral particles could be isolated from neuronal tissues in the hypothalamus and cortex tissue from eight deceased patients who had tested positive for the virus, confirming that certain viruses cross the BBB into the brain  [1, 2]. Mouse studies reveal that viruses can enter the brain primarily through the olfactory bulb, resulting in chronic post-inflammatory CNS pathology affecting sleep, pain sensitivity, and energy [1].

In December 2009, the Journal of the American Medical Association published a study, “Mental Morbidities and Chronic Fatigue in Severe Acute Respiratory Syndrome Survivors.” This study focused on the fatigue and mental health symptoms associated with the first SARS virus among 181 survivors at a four-year follow-up. In those who did not have a psychiatric disorder prior to contracting SARS-CoV-1, 42% experienced at least one psychiatric illness post-infection with the most common diagnoses being post-traumatic stress disorder, depression, somatoform pain disorder, panic disorder, and obsessive-compulsive disorder. Chronic fatigue was common among both psychiatric and non-psychiatric groups as determined by the Chalder fatigue scale questionnaire. It was presumed that the relationship between fatigue and psychiatric disorders could be interactive and bidirectional; however, the high rate of fatigue among both groups suggested that psychiatric disorders did not account for the chronic fatigue. Because most SARS-CoV-1 patients were treated with high-dose steroids at the time of infection, there was some concern with ongoing hypocortisolism, developing  as a side effect of treatment, which was reported in about 40% of survivors one year after the infection [3].

What We Know About ME/CFS and FM

ME/CFS and FM are very similar to each other with FM having more specific body pain issues. Both syndromes involve fatigue lasting more than six months, brain fog and cognitive dysfunction, orthostatic intolerance, PEM, sleep disturbances, and muscle pain and weakness. PEM is a hallmark symptom of ME/CFS and involves an abnormal response following physical, emotional, mental or orthostatic exertion, resulting in loss of physical and mental stamina and rapid muscular and cognitive fatigability [4].

Although the first definition of ME/CFS was published back in 1988, there has been no isolated singular cause. A 2019 evaluation of ME/CFS concluded that 80% experienced an upper respiratory viral infection prior to the onset of their symptoms [5]. The consensus throughout the literature states that the trigger for ME/CFS can be related to infections, extreme stress or physical trauma but regardless of the cause, there is ample evidence for complex dysregulation of the immune and autonomic nervous systems [4], with broader effects extending to the cardiovascular system, musculoskeletal system, endocrine system, and more specifically the mitochondria within each cell. ME/CFS is a condition that can persist for years and there is no targeted treatment that works under all circumstances. 

A subset of ME/CFS patients can also develop antibodies against one or more muscarinic and adrenergic receptors that may contribute to unstable vascular dynamics affecting muscular and cerebral blood flow. This could lead to orthostatic dysfunction and potentially induces a state of hypoxia and ischemia within the brain and musculature, making physical and mental activities exhausting. Viral infections can often be the trigger for ME/CFS, leading to cerebral cytokine dysregulation and neuroinflammation, which can impact lymphatic/glymphatic clearance from the brain and CNS, and influence cerebral spinal fluid dynamics that further impact the function of the central and peripheral nervous system. Ongoing inflammation within the CNS can create an imbalance in the production of key neurotransmitters that produce inhibitory and excitatory signals, which keep the brain and nervous system balanced.

Sleep issues are also common among those suffering from ME/CFS and may be related to elevated sympathetic tone (i.e., high norepinephrine) and decreased vagal response. Lack of sleep can have severe health consequences; it is proposed to contribute to a reduction in prefrontal cortex gray matter volume and potentiates daytime fatigue and cognitive dysfunction. Additionally, evidence of a hypometabolic state and low urinary free cortisol excretion suggests mitochondrial and HPA axis dysfunction as a part of the total ME/CFS picture [4, 6].

Dysregulation of the Autonomic Nervous System

Many of the symptoms associated with post-viral syndromes extend from dysregulation of the autonomic nervous system and can include severe exhaustion, muscular and mental fatigue, exercise intolerance, PEM, impaired cognitive ability, poor sleep quality, muscle and joint pain, headache, orthostatic intolerance, dizziness, spatial disorientation, gut motility issues, sweating, and heart palpitations. In a 2020 study published in Autoimmunity Reviews, researchers isolated antibodies against key receptors that regulate vascular tone [4]. Autoantibodies to β2 adrenergic receptors (β2AdR) and M3 acetylcholine receptors were determined to be elevated in a subset of ME/CFS patients in which the removal of these antibodies led to rapid improvement in most of the patients [4]. Both β2AdR and M3 acetylcholine receptors play an important role in vasoregulation. Antibodies to these receptors result in enhanced vasoconstriction and consequential vascular dynamics that result in low blood pressure, low blood volume, ischemia, and hypoxia. This mechanism may explain why so many who have ME/CFS experience orthostatic dysfunction and postural tachycardia syndrome, along with mental and muscular fatigue. Autoantibodies against β2AdR and M3 acetylcholine receptors are presumed to occur following an infection resulting in immune dysregulation and autoimmunity in a subset of patients. It has also been noted that polymorphisms of β2AdR genes have been associated with adolescent chronic fatigue syndrome [4].

Overstimulation of the Sympathetic Nervous System

As noted by Wirth in Autoimmunity Reviews, studies on ME/CFS reveal a decrease in heart rate variability suggesting a chronic stimulation of the sympathetic nervous system. Under chronically elevated sympathetic tone, β2AdR can become desensitized and, along with autoantibodies and potential genetic mutations, this can lead to severe autonomic dysfunction. Under the conditions described above, low vascular, atrial, and ventricular filling due to hypovolemia leads to low cardiac output, which may further activate the sympathetic nervous system as compensation for low blood volume. The muscle weakness and pain associated with ME/CFS may be due to vasoconstriction that results from activation of the sympathetic nervous system. Vasoconstriction can also lead to decreased vascular flow within the brain, contributing to cognitive dysfunction, brain fog, and dizziness [4].

Lymphatic/Glymphatic Drainage and the CNS

In a letter to the editor of Medical Hypotheses, osteopathic physician Raymond Perrin, DO, PhD, Manchester University, School of Medicine, in the United Kingdom, proposed a possible mechanism by which COVID-19 might contribute to developing symptoms associated with post-viral syndrome. In a post-mortem evaluation of brain tissue samples, it was determined that SARS-CoV-1 crossed the BBB and entered the hypothalamus via the olfactory pathway, which disturbed lymphatic drainage from the microglia in the brain. The main pathway of lymphatic drainage for the brain is via the perivascular spaces along the olfactory nerves through the cribriform plate and into the nasal mucosa. The cribriform plate is a sieve-like structure between the anterior cranial fossa and the nasal cavity. The effect of the virus on this pathway may explain the anosmia (lack of smell) associated with SARS-CoV-2. The disturbance of this drainage pathway results in the buildup of pro-inflammatory cytokines affecting the neurologic control of the glymphatic system, which is commonly seen in ME/CFS [7]. This buildup of cytokines and toxins within the CNS and hypothalamus due to poor drainage, can lead to autonomic dysfunction manifesting as fatigue, interruptions of the sleep/wake cycle and cognitive difficulties associated with ME/CFS. Dr. Perrin proposed the use of lymphatic drainage techniques involving Osteopathic Manipulative Treatment (OMT) and lymphatic massage to aid central and peripheral lymphatic drainage [7].

In a similar article in Medical Hypotheses, Peter Wostyn, MD, proposed that post-COVID fatigue syndrome may result from damage to the olfactory sensory neurons causing an increased resistance to cerebrospinal fluid (CSF) outflow, leading to congestion of the glymphatic system with subsequent accumulation of toxins within the CNS. Inhibition of CSF outflow can lead to glymphatic overload within the CNS, resulting in postural idiopathic CSF hypertension. As mentioned above, the olfactory pathway is the major site for CSF drainage. Olfactory dysfunction was the most commonly reported neurological manifestation of SARS-CoV-2 presenting as anosmia in over 80% of those with symptomatic infection. Dr. Wostyn hypothesized that damage to the olfactory nerve fibers from infection with SARS-CoV-2 may contribute to poor glymphatic drainage within the CNS, leading to a buildup of CSF pressure and toxins. Dr. Wostyn recommended the use of a technique for glymphatic drainage in addition to OMT as mentioned above [8].

Hulens et al also maintains a similar hypothesis in relation to fibromyalgia and other chronic widespread pain disorders. He proposed that cerebrospinal pressure dysregulation could cause increased pressure within the CNS that then extends to the peripheral nervous system and contributes to chronic generalized pain [9]. While his focus was primarily on pain disorders, the mechanism that he suggested is similar to Wostyn and Perrin in that, whatever the cause, there is an increase in pressure due to faulty drainage within the CNS, which potentially leads to dysfunction within the autonomic and peripheral nervous systems.

Does SARS-CoV-2 Directly Infect the Brain and Nervous System?

Some studies on SARS-CoV-1 have isolated the virus in the brain and nervous system [2] while other studies have only found inflammatory markers associated with the infection [10]. Either way, what we know is that the virus is generating an immune response within the brain and nervous system that compromises normal neurological function. In past literature on SARS-CoV-1, the virus was detected in brain tissue specimens and given the similarity between SARS 1 and 2, there is suspicion that SARS-CoV-2 can in fact enter the brain and nervous system through either the olfactory route or by crossing the BBB [11, 12]. The epithelium in the nasal mucosa is rich in angiotensin-converting enzyme 2 (ACE2) receptors and transmembrane serine protease 2 (TMPRSS2), which work together synergistically to facilitate viral entry and replication.

Viral dissemination into systemic circulation along with the production of inflammatory cytokines could also disrupt the integrity of the BBB and facilitate entry of the virus into the brain. SARS-CoV-2 may also enter the brain through the hypothalamus, which is an area of the brain with a more permeable BBB due to small openings in the capillary walls. Some research states that hypothalamic capillaries express ACE2 and TMPRSS2, which could allow for viral entry and replication in the hypothalamus and provide a gateway to the rest of the brain and nervous system [7, 12, 13]. In a preprint study in bioRxiv, Nampoothiri et al summarized their current research article entitled, “The Hypothalamus as a Hub for SARS-CoV-2 Brain Infection and Pathogenesis,” by stating that the brain not only possesses the cellular and molecular machinery necessary to be infected, but that the hypothalamus, which contains neural circuits regulating a number of risk factors for severe COVID-19 and is linked to olfactory and brainstem cardiorespiratory centers, could be a preferred port of entry and target for the virus [13].

In a recent study on cancer patients infected with SARS-CoV-2 who experienced neurologic toxicity from the infection, an analysis of CSF revealed that virus particles were not detected; however, an increase in inflammatory cytokines nearly two months after the initial infection persisted [10]. Researchers proposed that the increase in CSF cytokines was likely due to an increase in BBB permeability and local production by cells within the CNS. These findings support the hypothesis that a secondary immune activation might be the cause of inflammatory cytokines in the CSF [10]. It is important to note that these studies using CSF samples were done two months after the initial infection. If there was a virus present within the CNS, two months may have been a long enough period of time for the initial infection to resolve but still leave behind an inflammatory footprint. Regardless of the trigger, neuroinflammation is widely regarded as a chronic condition that can have lasting effects on brain and nervous system function.

In October 2020, The Lancet called for a global consortium to coordinate studies and data as a means of elucidating the full impact of the virus on the nervous system. To that end, the Global Consortium Study of Neurological Dysfunction in COVID-19 was established to conduct a formal collaboration of research and data [14].

Evaluating the Effects of Neuroinflammation

Some of the symptoms of long COVID are related to mood and sleep, which suggests that inflammation within the CNS can manifest as depression, anxiety, cognitive dysfunction, and sleep issues. ZRT Laboratory can provide testing that may assess the potential effects of neuroinflammation in relation to neurotransmitters that impact mood, cognitive ability, and sleep. After all, neurotransmitter signaling in the periphery and in the brain is responsible for functionally integrating the nervous, immune and endocrine systems, indicating that neurotransmitter imbalances can influence symptoms beyond the brain.

ZRT Laboratory also offers testing to assess melatonin levels, cortisol, DHEA-S, hsCRP and vitamin D. Melatonin levels increase in response to decreased light in order to usher in sleep onset, but may be compromised due to dysregulated circadian rhythms. A four-point cortisol measurement can provide an evaluation of the HPA axis. Elevated cortisol together with high norepinephrine and epinephrine may indicate increased HPA axis activity and sympathetic tone due to common stressors, infection, pain, inflammation, and lack of sleep. Functioning in the brain and nervous system as a neurosteroid, DHEA-S is a potent immune-modulating hormone and works as a counter-regulatory hormone to cortisol. The main neurobiological effects of DHEA-S in the brain include neuroprotection, neurogenesis, apoptosis, catecholamine synthesis and secretion, antioxidant, and anti-inflammatory effects. Measuring sex hormones and thyroid markers can also provide much needed data that may help to address the symptoms associated with post-viral illness.

While an initial infection can resolve, it can leave behind an inflammatory footprint that propagates further damage. Measuring hsCRP can provide us with information regarding general inflammation and infection and is readily measured in a dried blood spot (DBS) sample, which can be combined with other cardiovascular and metabolic markers available through ZRT Laboratory. Lastly, healthy vitamin D levels are associated with a robust and balanced immune response and can also be measured in DBS.

The CDC suspects about 30% of COVID-19 survivors may go on to develop persistent symptoms after recovery from acute illness and has funded an initiative called the Innovative Support for Patients with SARS-CoV-2 Infection Registry to examine the causes of long COVID. Since the first definition for ME/CFS was developed over 30 years ago, scientists and physicians have struggled to find a singular cause of this potentially debilitating illness. While the trigger for the onset of post-viral syndromes may be a singular event, the effects are broad and involve multiple systems. As we face the burgeoning issue of long COVID, the approach to treatment will involve addressing inflammation and dysregulation within the CNS, autoimmune issues, mitochondrial function, and hormone and HPA axis dysregulation. In the next installment on long COVID, we will explore autoimmune activation and immune system dysregulation in the presence of a serious viral infection.

ZRT Tests to Consider

• NeuroAdvanced Profile with Add-on Diurnal Cortisol, Melatonin, Norepinephrine & Epinephrine
• Adrenal Profile
• Female/Male Saliva Profile III
• Female/Male Blood Spot Profile II
• Comprehensive Female/Male Profile II
• CardioMetabolic Profile
• Essential Thyroid Profile
• Elite Thyroid Profile
• hsCRP as a single test in blood spot
• Vitamin D as a single test in blood spot

Related Resources

• Blood Spot Testing
• Saliva Testing

References

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2. Gu J, Gong E, Zhang B, et al. Multiple organ infection and the pathogenesis of SARS. J Exp Med. 2005;202(3):415-424.
3. Lam MH, Wing Y, Yu MW, et al. Mental morbidities and chronic fatigue in severe acute respiratory syndrome survivors: long-term follow-up. Arch Intern Med.2009;169(22):2142–2147.
4. Wirth K, Scheibenbogen C. A unifying hypothesis of the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): recognitions from the finding of autoantibodies against ß2 -adrenergic receptors. Autoimmun Rev. 2020;19(6):102527.
5. Cortes Rivera MC, Mastronardi C, Silva-Aldana CT, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: a comprehensive review. Diagnostics (Basel). 2019;9(3):91.
6. Orjatsalo M, Alakuijala A, Partinen. Autonomic nervous system functioning related to nocturnal sleep in patients with chronic fatigue syndrome compared to tired controls. J Clin Sleep Med. 2018;14(2):163-171.
7. Perrin R, Riste L, Hann M. Into the looking glass: post-viral syndrome post COVID-19. Med Hypotheses. 2020;144:110055.
8. Wostyn P, Dam DV, Audenaert K, et al. Fibromyalgia as a glymphatic overload syndrome. Hypotheses. 2018;115:17-18.
9. Hulens M, Dankaerts W, Stalmans I, et al. Fibromyalgia and unexplained widespread pain: the idiopathic cerebrospinal pressure dysregulation hypothesis. Med Hypotheses. 2018;110:150-154.
10. Remsik J, Wilcox JA, Babady NE, et al. Inflammatory leptomeningeal cytokines mediate COVID-19 neurologic symptoms in cancer patients. Cancer Cell. 2021;39(2):276-283.
11. Xu J, Zhong S, Liu J, et al. Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis. Clin Infect Dis. 2005;41(8):1089-1096.
12. Iadecola C, Anrather J, Kamel H. Effects of COVID-19 on the nervous system. Cell. 2020;183(1):16-27.
13. Nampoothiri S, Sauve F, Ternier G, et al. The hypothalamus as a hub for SARS-CoV-2 brain infection and pathogenesis. bioRxiv. 2020.
14. Helbok R, Chou SH, Beghi E, et al. NeuroCOVID: it’s time to join forces globally. Lancet Neurol. 2020;19(10):805-806.