Long COVID: Immune and Systemic Effects of Post-Viral Infection Part II

Anyone who has dealt with issues related to chronic fatigue has likely evaluated their hypothalamic–pituitary–adrenal (HPA) axis performance through a multi-point salivary test. Cortisol is readily measured in saliva when samples collected at predetermined intervals throughout a single day reveal one’s physiological resilience and metabolic reserve in response to daily stressors. HPA axis testing is a mainstay in the world of integrative, naturopathic, and functional medicine. For the past 18 months, the world has existed under the constant shadow of COVID-19. To say that we have been “stressed” is an understatement. Mental-emotional stressors certainly trigger the activation of the stress response pathways, but physiological and lifestyle factors contribute to these physiological processes as well. Furthermore, inflammation due to infection provoke the adrenal glands to release cortisol to regulate the inflammatory response and support the immune system. In the case of COVID-19, the research cited below has shown that cortisol does not rise in response to the SARS-CoV-2 infection as expected. In fact, surprisingly, the opposite is true - cortisol levels drop in the presence of SARS-CoV-2, leaving the body vulnerable to escalating and unchecked inflammation, and predisposing the individual to the life-threatening adrenal crisis. HPA axis dysfunction can occur under many types of chronic stressors; however, viral infections can trigger specific dysfunction within the HPA axis, leaving its host with chronic fatigue and weakness long after the initial infection has been resolved. Some of the latest research also takes a closer look at other endocrine organs such as the thyroid, hypothalamus, pituitary, pancreatic and gonadal tissue, and how each may be affected by the SARS-CoV-2 virus. In the last installment of this four-part series on long COVID, we will look at the mechanisms involved with the SARS-CoV-2 virus and the HPA axis, and what this means for COVID long-haulers. SARS-CoV-2 and Adrenal Insufficiency SARS-CoV-2 can influence cortisol output through three different pathways: In a letter to the editor of the American Journal of Physiology-Endocrinology and Metabolism, Siejka postulates that adrenal insufficiency (AI) related to COVID-19 may occur for the following reasons: 1) hypophysitis and adrenalitis resulting from direct infection with the SARS-CoV-2 virus, leading to secondary or primary AI; 2) production of adrenocorticotropic hormone (ACTH) antibodies; and 3) critical illness-related corticosteroid insufficiency (CIRCI) [1]. It has been determined that the hypothalamus, pituitary, and the adrenal glands all have angiotensin-converting enzyme (ACE)2 receptors so direct infection of these organs is plausible. In fact, histological findings report focal necrosis and vasculitis of the small veins of the adrenal glands, and structural and functional damage within the hypothalamus and the pituitary in those who were infected with the SARS-CoV-2 virus [1]. According to the recent article published in Medical Hypotheses, the uncanny ability of SARS-CoV-2 to inhibit the host’s corticosteroid stress response is a means to evade the immune system [2]. SARS viruses have a unique mechanism to inhibit the activation of the stress response and prevent cortisol release by expressing a series of amino acids that mimic parts of the ACTH amino acid structure, a process that can be best described as molecular mimicry. What happens next is the immune system forms antibodies against both the coronavirus and ACTH, and the antibody-bound ACTH becomes completely ineffective at stimulating the release of cortisol, resulting in hypocortisolism [3]. It is postulated that the virulence of SARS-CoV-2 may be related to the degree of antigenic similarity between ACTH and its molecular mimic within the virus [2]. A condition referred to as critical illness-related corticosteroid insufficiency (CIRCI) occurs in patients with an acute stress response, leading to reduced cortisol levels that do not match the severity of the disease. CIRCI is presumed to occur in several critical conditions, including sepsis and septic shock, severe community-acquired pneumonia, acute respiratory distress syndrome, cardiac arrest, head injury, trauma, burns, and following major surgery [4]. Because of the mechanisms involved in suppressing the release of cortisol, Siejka recommends early use of steroids not only to replace what is deficient, but also because hydrocortisone protects against endothelial barrier dysfunction, which is strongly associated with COVID-19 [1]. Early Treatment of COVID-19 with Steroids to Inhibit Disease Progression Early in the COVID-19 crisis, it was the general consensus that steroids given too early in the disease process might suppress the immune system’s ability to fight the infection and reduce viral replication. As noted above, antibodies are produced against ACTH during SARS-CoV-2 infection. These antibodies interfere with ACTH’s normal signaling to trigger cortisol production as part of the stress response. Lower cortisol levels then provide feedback to the hypothalamus and pituitary to increase the production of ACTH to release more cortisol. Instead, increased ACTH production increases ACTH antibodies that do nothing to fight the viral infection. It is proposed by both Siejka and Wheatland that if corticosteroids are administered early, shortly after the start of the infection, ACTH production and therefore antibody production toward ACTH would decrease, freeing up the immune system’s antibody response to fight against the virus rather than ACTH [1, 2]. The increase in exogenously-administered corticosteroids may also help fine-tune the inflammatory response early, which would keep tissue damage under control. Early intervention with lower potency steroids like hydrocortisone, may act as a replacement for what is missing due to the interference of cortisol production by the virus. Perhaps this proves the adage that, “an ounce of prevention is worth a pound of cure.” Studies Related to SARS and Adrenal Insufficiency One small study on 28 hospital patients demonstrated that adrenal response to infection with SARS-CoV-2 was unexpectedly decreased – patients had low plasma cortisol and ACTH levels consistent with central adrenal insufficiency. Lower plasma cortisol and ACTH levels were consistent with higher disease severity, suggesting a direct link between COVID-19 and impaired glucocorticoid response [3]. Interestingly, ACE2 receptors, the gateway for SARS-CoV-2 entry into cells, are expressed in the hypothalamus, pituitary and adrenal glands, allowing the virus to enter these tissues. Autopsy studies on patients who died from the SARS-CoV-1 infection showed evidence of the viral genome in hypothalamic tissue. In a recent case study, a 51-year-old male presented to the emergency department complaining of two episodes of vomiting. He had received a positive COVID-19 test via polymerase chain reaction testing 10 days prior but was asymptomatic with stable vital signs and a normal chest X-ray at the time of diagnosis. No laboratory studies were done, and he was instructed to quarantine at home. When he presented to the ER, he was hypotensive with multiple electrolyte derangements that could not be substantiated by only two episodes of vomiting. Adrenal insufficiency was confirmed by low morning cortisol levels and an ACTH stimulation test. The patient was started on 20 mg of prednisolone daily with subsequent improvement in blood pressure and sodium levels [5]. In another case study, a 47-year-old male with a recent diagnosis of COVID-19, developed new onset central hypocortisolism in the convalescent phase of a mild case of COVID-19. He was sent to an isolation facility but returned to the hospital one week later due to a new onset seizure. The patient’s vital signs were normal, and he was well-oxygenated on room air. His bloodwork revealed elevated eosinophils and he complained of new onset persistent dyspepsia. Hypocortisolism was suspected and confirmed with a serum cortisol of 19 (normal range = 133-537 nmol/L) and an ACTH of 7.1 (normal range = 10.0-60.0 ng/L). He also presented with elevated thyroxine and thyroid stimulating hormone (TSH). This led his physicians to believe that the hypocortisolism was due to effects within the hypothalamic-pituitary pathways, affecting both adrenal and thyroid function [6]. SARS-Induced Endocrinopathy The deleterious impact of SARS-CoV-2 on the various organs within the endocrine system are becoming clearer as further research reveals the far-reaching health consequences of the virus. As we develop an understanding of the extent of these effects, we can better intervene with appropriate therapy. We understand from current research that SARS-CoV-2 can induce new onset or worsen existing conditions, such as diabetes mellitus, trigger hypocortisolism, and contribute to thyroid and reproductive aberrations [7]. The available data suggest that effects on endocrine tissues can occur either from direct viral damage or from immune-mediated mechanisms on endocrine tissues precipitated by the SARS-CoV-2 virus [7]. Diabetes mellitus increases the risk for the development of COVID-19 complications and adverse outcomes. In reviewing the effects of SARS-CoV-1, it was suggested that the virus could directly damage pancreatic cells that express ACE2 receptors, leading to a state of hyperglycemia, which reduces immune response and increases organ damage and systemic complications [8]. In a recent article in Endocrine, Mongioi et al hypothesized that patients with COVID-19 may be subject to virus-mediated pancreatic damage, resulting in the development of diabetes. It is uncertain at this point if the onset of diabetes is permanent or a transient effect of the virus that will eventually resolve with recovery from the infection [8]. Little is known about the effects of SARS-CoV-2 on thyroid function; however, some research has revealed a relationship between SARS-CoV-1 and central hypothyroidism secondary to hypothalamic-pituitary dysfunction resulting in low TSH. In secondary hypothyroidism, if the thyroid is not receiving the message from TSH to stimulate the production of thyroid hormones, T3 and T4 will also be low. SARS-CoV-1 did not directly invade the thyroid; however, tissue studies revealed injury to the follicular epithelium with an increase in cell apoptosis, suggesting that the damage was likely mediated by an immune response against the thyroid [8]. Direct damage to thyroid tissue could result in impaired function and a decrease in thyroid hormones and calcitonin levels as compared to controls. It appears that both primary and secondary hypothyroidism may be caused by the virus. The effects of COVID-19 on thyroid function appear to be transient and resolve shortly after recovery from the viral infection [7]. Though no evidence exists that SARS-CoV-2 infects the ovaries, increases in serum prolactin, follicle-stimulating hormone, and luteinizing hormone with a reduction in estradiol and progesterone levels was noted in SARS patients as compared to controls. We do know that ACE2 is highly expressed in testicular tissue and past studies have found tissue damage indicative of orchitis on autopsy of six patients who died with SARS-CoV-1. Tissue effects may also be representative of immune-mediated damage triggered by the presence of the virus [8]. Some researchers suspect that testicular tissue provides an additional site of infection and may increase viral load in males as compared to females. The hypothalamic and pituitary tissue also have ACE2 receptors and can be sites of SARS-CoV-2 infection if the virus enters the brain. As previously mentioned, it is suspected that SARS-CoV-2 can enter the brain via the olfactory pathway where it gains access to the brain across the porous cribriform plate. The virus can then enter the hypothalamus fairly easily as the blood-brain barrier is permeable near this structure. Infection of the hypothalamus may result in hypophysitis (inflammation of the hypothalamus) and would have broad effects across the entire endocrine system. Long COVID and Adrenal Insufficiency Adrenal insufficiency tends to develop in COVID-19 patients during the late stage of the disease and appears to be secondary to hypophysitis or direct damage to the hypothalamus from the SARS-CoV-2 virus. In 2005, Leow et al explored the function of the HPA axis in 61 SARS-CoV-1 survivors by evaluating serum electrolytes, cortisol, ACTH levels, and 24-hour urinary-free cortisol three months after the acute infection. Adrenal insufficiency was defined as cortisol values <550 nmol/L 30 minutes after an ACTH stimulation test. Nearly 40% of patients tested had hypocortisolism and among them 83% had central adrenal insufficiency, which is secondary to ACTH deficiency [9]. Of those with hypocortisolism, 62.5% recovered within one year paralleled by the resolution of orthostatic hypotension and an overall improved sense of well-being. The majority of the patients in the study exhibited cortisol dynamics analogous to patterns seen in chronic fatigue syndrome, post-traumatic stress disorder, and fibromyalgia [9]. It is important to note that patients may also experience hypocortisolism due to treatment with dexamethasone to reduce inflammation during active infection. Treatment of COVID-19 with potent steroids to address the immunoinflammatory response to the infection may result in short-term adrenal insufficiency that may require evaluation and supportive care. In the 2005 study by Leow et al referenced above, the majority of the patients studied had not been treated with steroids during the course of their illness. Four of the six who had received high-dose parenteral glucocorticoids did not develop post-SARS hypocortisolism as demonstrated by the lack of prolonged suppression of the HPA axis as revealed in serial ACTH stimulation tests [9]. Addressing Long COVID through HPA Axis Support Many of the symptoms of post-viral syndromes interfere with our ability to thrive, which indicates involvement of the autonomic nervous system (ANS), leaving us with orthostatic intolerance, cognitive dysfunction, muscle weakness, fatigue, dizziness, and heart rate abnormalities. Although isolating where some of these symptoms may be coming from is a starting point to treatment, it is necessary to consider the contribution of other organ systems to each dysfunction. Many of the symptoms associated with autonomic dysfunction may be related to the ability of the mitochondria to make energy and support metabolic processes. Involvement of the HPA axis with the sympathetic branch of the ANS contributes to maintaining adequate blood sugar and blood pressure, as well as inhibiting inflammation and supporting a balanced immune system response. An appropriate response of the HPA axis during an acute stressor is necessary for survival, but frequent and prolonged activation can alter the functional tone of the stress response reducing the ability of the HPA axis to respond efficiently and effectively [10]. Post-viral illness is difficult to address in that it cannot be cured by treating only one symptom or one system. Genetic susceptibility, nutritional status, and state of health prior to infection will likely play a role in the development of long COVID, and the supportive care to pull through the long-term sequelae of this virus will require a multi-pronged approach. Our ability to respond to stressors involves the sympathoadrenal system and the HPA axis, and interactions between these two systems play a central role in adaptation. Healthy function of the HPA axis is dependent on healthy mitochondria for steroid hormone conversion and an intact ANS to support a normal stress response. Long-term changes to the HPA axis may occur in response to the stress of an acute illness that has altered the metabolism of cortisol, leading to a reduced capacity to respond to stress [4]. To address the oncoming tidal wave of COVID-19 survivors who have ongoing symptoms, supporting the HPA axis through nutrition, supplementation, adaptogenic herbs, glandulars, and hydrocortisone if needed, will likely offer some relief. Options for support of the nervous system, immune system, and mitochondria have been outlined in parts one through three of this series. Testing the HPA Axis Aside from infection with the SARS-CoV-2 virus, the stress of the pandemic itself has been extensive. Fear of infection, lockdowns, social isolation, financial instability, and emotional distress have taken a toll on our collective psyche. The extraordinary amount of stress that we have been under can certainly have lasting consequences in chronic activation of the stress response systems, leading to ongoing dysfunction of the HPA axis. For those who have been infected with the virus, early testing of the HPA axis offers another opportunity for intervention and recovery from COVID-19 and can be easily done at home through a multi-point salivary test measuring cortisol output throughout the day. As the above-referenced studies indicate, developing hypocortisolism is a real possibility after the infection with SARS-CoV-2 and may likely be a major contributor to the symptoms of long COVID. Testing for and addressing this issue is key to a full recovery. In addition to multi-point cortisol measurements, our clinic can also provide testing to assess melatonin levels, dehydroepiandrosterone sulfate (DHEA-S), high-sensitivity C-reactive protein (hsCRP), vitamin D, sex hormones, thyroid hormones, and neurotransmitters. Melatonin increases in response to darkness but may be compromised due to dysregulation within the circadian rhythm. In addition to regulating sleep, melatonin is a potent antioxidant that can help to neutralize reactive oxygen species produced during inflammation. DHEA-S functions in the brain and nervous system as a neurosteroid, is a potent immune-modulating hormone and functions 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, and antioxidant and anti-inflammatory effects. Measuring sex hormones and thyroid markers can 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. hsCRP can be readily measured in a dried blood spot (DBS) sample alongside other cardiovascular and metabolic markers. Healthy vitamin D levels are associated with a robust and balanced immune response and can also be measured in DBS. Our clinic can also provide testing to assess neurotransmitters that impact mood, cognitive ability, and sleep. Neurotransmitters are responsible for functionally integrating the immune and endocrine systems, indicating that neurotransmitter imbalances often reach beyond the brain. As we face the burgeoning issue of long COVID, the approach to treatment will involve addressing inflammation and dysregulation within the central nervous system, autoimmune issues, mitochondrial function, and hormone and HPA axis dysregulation. We have a long road ahead of us and there will likely be many who suffer from the long-term consequences of this pandemic – those who acquired the infection and those who simply lived through it. Our personal timelines may be forever referred to by pre-COVID and post-COVID events. My hope is that through the efforts of the many brilliant minds in medical research and through the practice of preventive and interventional therapies, we have learned how to better prepare for and respond to a novel virus. Early treatment for viral infections and immune system support are still important as coming up with new vaccines for each novel virus may not be practical, timely or safe. We may not be able to prevent infection, but by investing in our health every day, we may effectively support our recovery. References 1. Siejka A, Barabutis N. Adrenal insufficiency in the COVID-19 era. Am J Physiol Endocrinol Metab. 2021;320(4):E784-E785. 2. Wheatland R. Molecular mimicry of ACTH in SARS – implications for corticosteroid treatment and prophylaxis. Med Hypotheses. 2004;63(5):855-862. 3. Alzahrani AS, Mukhtar N, Aljomaiah A, et al. The impact of COVID-19 viral infection on the hypothalamic-pituitary-adrenal axis. Endocr Pract. 2021;27(2):83-89. 4. Annane D, Pastores SM, Arlt W, et al. Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a multispecialty task force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Intensive Care Med. 2017;43(12):1781-1792. 5. Hashim M, Athar A, Gaba WH. New onset adrenal insufficiency in a patient with COVID-19. BMJ Case Rep. 2021;14(1):e237690. 6. Chua MWJ, Chua MPW. Delayed onset of central hypocortisolism in a patient recovering from COVID-19. AACE Clin Case Rep. 2021;7(1):2-5. 7. Kothandaraman N, Rengaraj A, Xue B, et al. COVID-19 endocrinopathy with hindsight from SARS. Am J Physiol Endocrinol Metab. 2021;320(1):E139-E150. 8. Mongioì LM, Barbagallo F, Condorelli RA, et al. Possible long-term endocrine-metabolic complications in COVID-19: lesson from the SARS model. Endocrine. 2020;68(3):467-470. 9. Leow MK‐S, Kwek DS-K, Ng AW-K, et al. Hypocortisolism in survivors of severe acute respiratory syndrome (SARS). Clin Endocrinol (Oxf). 2005;63(2):197-202. 10. Steenblock C, Todorov V, Kanczkowski W, et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the neuroendocrine stress axis. Mol Psychiatry. 2020;25(8):1611-1617.

In parts one and two of this series, we looked at the issues related to long COVID and its impact on the nervous and the immune systems. The effects of COVID-19 on the nervous system can present as localized effects such as loss of smell and taste to chronic fatigue, headaches, postural orthostatic tachycardia syndrome, and cognitive issues. The potential to trigger an autoimmune reaction is a very real possibility with any infection and is stimulated by molecular mimicry, bystander activation, and viral persistence. The presence of a healthy and diverse gut and lung microbiome helps to regulate the immune system and supports a robust and balanced innate immune response. The most common reported symptom of long COVID is fatigue and the overall symptom picture resembles that of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is often triggered by a viral infection. Fatigue can be described as lack of energy; and when we think of energy production, we think of the mitochondria. In addition to being the powerhouses of the cell, mitochondria are also involved in maintaining cell immunity, homeostasis, cell survival, and cell death. Mitochondria also play a role in cell apoptosis (programmed cell death), calcium signaling, regulation of cellular membrane potential, and steroid synthesis [1]. SARS-CoV-2 hijacks the mitochondria and uses it for protection and viral replication, diverting resources from supporting normal cellular function to now serving as a viral factory. Decreased mitochondrial function means less cellular energy, resulting in generalized fatigue, muscle weakness, and brain fog on a broader scale. In part three of this series, we will explore the effect of viral infection on mitochondrial function, how SARS-CoV-2 specifically affects mitochondria, resulting in symptoms of long COVID and what we can do to support mitochondrial function to prevent the long-term effects of COVID-19. Basic Overview of Mitochondrial Function Mitochondria are responsible for the majority of energy production in the form of adenosine triphosphate (ATP), which is readily used by cells as a source of chemical energy. Cellular respiration is the process by which mitochondria produce chemical energy from glucose. Through the process of glycolysis, one molecule of glucose is converted to two molecules of pyruvate, two molecules of nicotinamide adenine dinucleotide (NADH) and two molecules of ATP. The pyruvate enters the mitochondria where it is converted into acetyl-coenzyme-A, which enters the tricarboxylic acid (TCA or Krebs) cycle and produces two additional molecules of ATP. The energy-rich products of the TCA cycle, NADH and flavin adenine dinucleotide, undergo oxidative phosphorylation (OXPHOS) via the electron transport chain (ETC), producing water and 32 additional molecules of ATP. The entire process of cellular respiration results in approximately 36 molecules of ATP to support cellular energy needs [2]. The process of glycolysis, which is the first step in cellular respiration, occurs in the cytosol of the cell. If there is enough oxygen available for cellular respiration, the process of energy production will advance to the TCA cycle and OXPHOS along the ETC. However, if oxygen is low, glycolysis results in the production of two molecules of ATP and lactic acid. Anaerobic glycolysis can occur for quick energy production during extreme exercise or illness where oxygen delivery to cells is deficient. The reliance on anaerobic glycolysis as a means of energy production can result in fatigue and muscle pain due to the buildup of lactic acid [2]. Another form of energy production is through aerobic glycolysis also known as the Warburg effect. Once thought to occur solely in cancer cells, aerobic glycolysis may occur in specific immune cells in response to signaling events and the physiological environment. In the field of immunometabolism, it has been observed that metabolic shifts in immune cells may occur to facilitate specific immune responses, and many viruses induce metabolic reprogramming in host cells similar to the Warburg effect observed in cancer cells to produce a quick and readily available source of energy [3, 4]. Viral Influence on Mitochondrial Function Under the influence of a viral infection, mitochondria experience a loss of integrity in structure and function and can trigger an immune response that activates the production of inflammasomes, which may contribute to autoimmunity and ongoing inflammatory reactions [5]. Inflammasomes are intracellular proteins that trigger the activation of inflammatory cytokines. Mitochondria play a central role in the host response to viral infection and immunity, and function as a platform for immune signaling by engaging the interferon system, which operates as a liaison between the innate and adaptive immune systems [6]. SARS-CoV-2 has the ability to disable the initial immune response by inhibiting the production of interferons. Reduced interferon production delays the release of natural killer cells and stagnates T cell response. Hepatitis C, hepatitis B, adenoviruses, herpes simplex virus-I, Epstein Barr virus, cytomegalovirus, influenza A and coronaviruses have adaptations that allow them to inhibit the interferon pathway to prolong survival and evade the immune system, leaving them with a greater chance to replicate and spread [6]. Viral influence on mitochondrial activities can lead to altered energy levels by changing mitochondrial density and function, resulting in suboptimal energy output [7]. Mitochondria also produce reactive oxygen species (ROS) as a by-product of the process of oxidative phosphorylation. Once thought to have only harmful effects, it is now known that ROS function as signaling molecules, which increase the production of antioxidants, promote apoptosis, and trigger the production of new mitochondria. Mitochondrial ROS also induce mitochondrial anti-viral signaling (MAVS), resulting in induction of type I interferons, heralded as key regulators of antiviral activity [5]. ROS are a normal product of oxidative phosphorylation and can be neutralized through adequate availability of antioxidants; however, this process can become overwhelmed during infection, when ROS production increases beyond the body’s ability to control the oxidative stress. Infection can also interfere with the energy-producing pathway of the mitochondria, leaving cells and tissues with an energy deficit and an excess of ROS. S ARS-CoV-2 Hijacks Mitochondrial Function Host response against viral infections depends on optimal mitochondrial function but the presence of SARS-CoV-2 can cause structural and metabolic changes within the mitochondria, interfering with an appropriate immune response. Host cell metabolism and activation of signaling pathways is reprogrammed by SARS-CoV-2 viral proteins [4]. SARS-CoV-2 uses its spike glycoprotein, assisted by host transmembrane serine protease 2 (TMPRSS2), to gain access to cells via the angiotensin-converting enzyme-2 (ACE2) receptor on the host cell. Binding of this receptor by the virus decreases the production of ACE2, which has a regulatory effect on mitochondrial function. Less ACE2 results in less ATP production [6]. Once the virus has entered the cell, viral RNA, RNA transcriptase, and viral open-reading frames (ORFs) enter the mitochondria to hijack and manipulate function. ORFs are segments of DNA or RNA from the virus that code for particular proteins. Viral ORFs interact with mitochondrial proteins to directly manipulate mitochondrial function to evade host cell immunity, suppress immune response, and support viral replication [6]. The presence of the virus also creates stress within the mitochondria, leading to the formation of double-walled vesicles, which give the virus a place to hide and replicate. These vesicles function like portable organelles, taking viral information to the endoplasmic reticulum to further aid in viral replication [6]. SARS-CoV-2 also promotes a metabolic shift to aerobic glycolysis to facilitate viral replication and survival. The Warburg effect appears to be involved in several processes during COVID-19 infection [4]. In response to hypoxia, the Warburg effect is induced in lung endothelial cells, which in the presence of atherosclerosis, can lead to vasoconstriction and thrombosis. Initially, aerobic glycolysis supports the activation of pro-inflammatory pathways that are needed to mobilize defenses against infections; however, a subsequent shift to the OXPHOS pathway is also needed to promote anti-inflammatory pathways that are reparative. Aging, cardiovascular disease, metabolic syndrome, type II diabetes, obesity, hypertension, and chronic kidney disease along with mitochondrial senescence contribute to a state of chronic inflammation, which promotes the Warburg effect and prevents the metabolic transition to OXPHOS to decrease inflammation and initiate repair mechanisms [4]. Aging, Comorbidities, and Mitochondrial Function Factors that favorably contribute to the takeover of mitochondrial function by the SARS-CoV-2 virus are aging, chronic inflammation, and genetic susceptibility. The aging process results in less mitochondria and lower production of ATP with a decrease in autophagy of mitochondria, which contributes to unregulated inflammasome activity leading to chronic inflammation. The process of aging is marked by the progressive decline in cellular function, which increases susceptibility to age-related morbidity and mortality [6]. One of the hallmarks of aging is mitochondrial dysfunction, which induces senescence and contributes to the process of inflammaging. Senescence occurs when cells lose the power to divide and grow, and inflammaging is the increase in systemic inflammation as one ages. The overall effect reduces mitochondrial capacity by about 50%, resulting in fatigue and muscle weakness [6]. Many of the conditions that are considered comorbidities for SARS-CoV-2 contribute to a state of chronic inflammation. Diabetes, heart disease, obesity, and metabolic diseases are commonly present with mitochondrial dysfunction. Mitochondrial genetic mutations may also be a contributing factor in determining the severity of post-viral sequelae related to mitochondrial function. While there are no studies on the long-term effects of SARS-COV-2 on mitochondrial function, past studies on ME/CFS strongly implicate mitochondrial dysfunction as a central cause of ME/CFS symptoms [8, 9]. A renewed interest in the causes of post-viral syndromes will likely be forthcoming as we progress through this pandemic. Mitochondrial Issues in Post-Viral Syndromes and ME/CFS Although no single cause has been associated with ME/CFS, viral infections have often been cited to trigger the onset of this disorder. In the case of SARS-CoV-2 and other viruses, there may be a direct impact on mitochondrial function from the virus itself [10]. The oxidative stress that occurs during an infection can leave mitochondria in a state of dysfunction. The mitochondria of our cells are responsible for the production of ATP and produce 90-95% of the body’s total energy [11]. ATP drives all the necessary chemical reactions in the body and if there is a shortage of ATP production, basic biochemical reactions may not be optimized. As a point of comparison, mitochondrial diseases associated with genetic mutations manifest as fatigue, muscle weakness, and cognitive decline along with waxing and waning energy patterns typical of ME/CFS. While there are no definitive markers to identify ME/CFS specifically, there are a range of different markers that can be used to assess mitochondrial function including mitochondrial proteins, production of ATP, and oxygen consumption of live plated cells. The earliest evidence of the relationship between ME/CFS and mitochondrial issues was seen in structural changes of skeletal muscle cell mitochondria in peripheral blood mononuclear cells. Also noted was the decrease in OXPHOS and an increase in aerobic glycolysis, resulting in less ATP production in ME/CFS patients as compared to controls. As reported by the Journal of Translational Medicine, Sweetman et al concluded that mitochondrial dysfunction can happen via oxidative damage as might occur during an extreme inflammatory reaction to an infection [12]. In a 2019 article in Mitochondrion, Robert Naviaux, MD, PhD, discusses the cell danger response (CDR) and its connection to environmental health, mitochondrial function, and chronic illness. The CDR is a universal response to environmental threat, stress, infection or injury, and it is the mitochondria that sense and respond to changes in the cellular environment and mediate the regulators of the CDR that signal safety or danger within the cell. Once initiated, the CDR cannot be turned off and must cycle through to completion to effectively resolve the danger response. If the CDR persists abnormally, whole body metabolism, the gut microbiome, and multiple organ systems become impaired and chronic disease can emerge. Previous illness, stress, environmental toxins, chronic inflammatory illnesses, hormonal imbalances, autoimmune disorders, and allergies can impede the process of resolution of the CDR [13]. As much of the CDR is mediated by the mitochondria, supporting mitochondrial function, and employing general habits of good health can support a healthy CDR and potentially resolve chronic illness. Mitochondrial Support To offset the production of ROS within the mitochondria, enzymes, and coenzymes such as vitamin E and CoQ10 (ubiquinone) help to remove ROS to prevent damage. If essential nutrients, such as vitamin E and CoQ10 are deficient, removal of the ROS is impaired and damage through oxidative stress occurs. CoQ10 is the only lipid-soluble antioxidant that is produced endogenously in humans [11]. Ubiquinol is the reduced form of CoQ10 and acts as an antioxidant by reducing ROS and regenerating other antioxidants. It is also found in the highest concentration in the most metabolically active tissues such as the heart, liver, and muscle. Deficiencies of CoQ10 can occur with less endogenous production as we age and can be depleted with certain medications like statins to reduce cholesterol. CoQ10 deficiency may also be associated with dysfunctional OXPHOS, which can occur in ME/CFS. A study of 58 ME/CFS participants and 22 healthy controls, showed that the ME/CFS participants had lower overall levels of CoQ10, and their degree of fatigue was associated with a lower concentration of CoQ10 in plasma. It was also noted that ATP levels were significantly decreased while lipid peroxidation was increased, indicating mitochondrial dysfunction [11]. In a study out of Spain, Castro-Marrero et al evaluated the effects of CoQ10 and reduced NADH supplementation on the symptoms associated with ME/CFS. Seventy-three female participants were randomized to either the CoQ10+NADH or placebo group. In addition to improvements in fatigue according to the Fatigue Impact Scale, after eight weeks supplementing with 200 mg of CoQ10 and 20 mg of NADH, participants in the supplement group showed a decrease in oxidative damage, improvement in mitochondrial function, and enhanced energy [14]. CoQ10 and NADH can stimulate energy production by replenishing depleted cellular stores of ATP, and together they can act as free radical scavengers that can reduce lipid peroxidation and DNA damage caused by oxidative stress. Mitochondria are very susceptible to environmental toxins, nutrient deficiencies, and oxidative stress [15]. Additional support for mitochondrial function includes acetyl-L-carnitine, pyrroloquinoline quinone, vitamin C, choline, α-lipoic acid, α-ketoglutaric acid, resveratrol, N-acetyl cysteine, magnesium, and a quality multivitamin and mineral complex. Several professional product lines have mitochondrial support products that include most of the above-listed nutrients. In Summary Age and health status prior to infection can be a predictor of outcomes and may help us to determine who will develop long COVID. Metabolic issues associated with aging, obesity, and a sedentary lifestyle are not supportive of mitochondrial health. Viruses can manipulate the energy-producing pathway of the mitochondria to favor glycolysis over OXPHOS. If the mitochondria are already in a state of dysfunction due to preexisting health issues and oxidative stress from low-level inflammation, their ability to keep up with energy demands becomes severely compromised [10]. The hijacking of the mitochondria to serve the needs of the virus structurally and functionally changes the mitochondria, resulting in ongoing inflammation and a reduced ability to support the energy needs of cells. Symptoms such as fatigue and weakness, are often the result of these cellular changes. COVID-19 long-haulers may experience excessive oxidative damage in response to extreme inflammation generated by the infection; however, poor mitochondrial status and deficiencies in nutrients that are needed to quench ROS may also be prevalent among those who experienced only mild to moderate illness. This might explain why the severity of COVID-19 does not seem to predict who experiences post-viral syndrome or long COVID. Having less metabolic reserve due to stress, inadequate sleep, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, poor diet, chronic inflammation, a constant low level of oxidative stress, and the existence of comorbidities may lead to the development of long COVID even if the acute infection is mild to moderate. References 1. Rogers K. Mitochondrion. Definition, function, structure & facts. Encyclopedia Britannica. https://www.britannica.com/science/mitochondrion. Accessed April 30, 2021. 2. BD Editors. Mitochondria. Biology Dictionary. https://biologydictionary.net/mitochondria/. Accessed April 30, 2021. 3. Jones W, Bianchi K. Aerobic glycolysis: beyond proliferation. Front Immunol. 2015;6:227. 4. Icard P, Lincet H, Wu Z, et al. The key role of Warburg effect in SARS-CoV-2 replication and associated inflammatory response. Biochimie. 2021;180:169-177. 5. Iwasaki Y, Takeshima Y, Fujio K. Basic mechanism of immune system activation by mitochondria. Immunol Med. 2020;43(4):142-147. 6. Singh KK, Chaubey G, Chen JY, et al. Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis. Am J Physiol Cell Physiol. 2020;319(2):C258-C267. 7. Ganji R, Reddy PH. Impact of COVID-19 on mitochondrial-based immunity in aging and age-related diseases. Front Aging Neurosci. 2021;12:614650. 8. Booth NE, Myhill S, McLaren-Howard J. Mitochondrial dysfunction and the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Int J Clin Exp Med. 2012;5(3):208-220. 9. Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009;2(1):1-16. 10. Nunn AVW, Guy GW, Brysch W, et al. SARS-CoV-2 and mitochondrial health: implications of lifestyle and ageing. Immune Ageing. 2020;17(1):3 3. 11. Wood E, Hall KH, Tate W. Role of mitochondria, oxidative stress and the response to antioxidants in myalgic encephalomyelitis/chronic fatigue syndrome: a possible approach to SARS-CoV-2 ‘long-haulers’? Chronic Dis Transl Med. 2021;17(1):14-26. 12. Sweetman E, Kleffmann T, Edgar C, et al. A SWATH-MS analysis of myalgic encephalomyelitis/chronic fatigue syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction. J Transl Med. 2020;18(1):365. 13. Naviaux RK. Perspective: cell danger response biology—the new science that connects environmental health with mitochondria and the rising tide of chronic illness. Mitochondrion. 2020;51:40–45. 14. Castro-Marrero J, Cordero MD, Segundo MJ, et al. Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? Antioxid Redox Signal. 2015;22(8):679-685. 15. Pizzorno J. Mitochondria—fundamental to life and health. Integr Med (Encinitas). 2014;13(2 ):8-15.

SARS-CoV-2 has been circulating in the global population for over a year. According to Worldometer, at the time of this writing, 185 million people have been infected with the virus, 4 million have died, and 169 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 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. Brio Functional Medicine 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. Our clinic 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, which can be combined with other cardiovascular and metabolic markers. Lastly, healthy vitamin D levels are associated with a robust and balanced immune response. 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. References 1. Moldofsky H, Patcai J. Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study. BMC Neurol. 2011;11:37. 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.

In a perfect wold, the master stress hormone cortisol should be in sync with the master sleep hormone melatonin. Each hormone counter-balances the other in a precise rhythm - when cortisol is high melatonin should be low, and when melatonin is high cortisol should be low. For many, this rhythm is out of balance. With an estimated 60 million Americans suffering from some degree of sleep loss, it's surprising that many are still unaware of the connection between hormones and sleep. The Downside of Chronic Sleep Loss According to the Department of Health and Human Services, over a third of U.S. adults report daytime sleepiness so severe it interferes with work, decision making and social functioning. In fact, depression, obesity and diabetes are just three of the long term consequences of sleep deprivation - defines as six or fewer hours per night. Common hormone-related causes of sleep loss often involve the following scenarios: High Cortisol Results in insomnia, anxiety, sugar cravings, feeling tired but wired and increased belly fat. Low Melatonin Results in excessive fatigue, depression, anxiety and insomnia Neurotransmitter Imbalance Changes in sex steroid hormone levels during menopause can impact neurotransmitter levels, leading to recurring sleep issues.

Unraveling the Confusion over Saliva, Blood Spot, Serum & Urine Testing for Steroid Hormone Levels

As January's Thyroid Awareness Month winds down, now is the time to practice all we've learned about the care and feeding of our master metabolism. We have zeroed in on the enemies of a healthy thyroid. Now we will help you fend them off to protect the health of your thyroid gland with the following key action steps. Reverse Estrogen Dominance An imbalance of high estrogen/low progesterone can suppress activation of thyroid hormones that drive metabolism. Your best defense: If testing detects a problem, consider supplementing with natural (bioidentical) progesterone to re-balance estrogens and keep them in check. Avoid xenoestrogens, the environmental toxins found in everything from soup cans to shampoos that increase the body's estrogen burden. Take it easy on soy products that raise estrogens. Boost Androgen (Testosterone & DHEA) Levels Deficiencies of these anabolic hormones that build bone and muscle can implode the metabolic rate to slow calorie burning and cause weight gain. Your best defense: Exercise, particularly strength training, increases lean muscle mass to boost androgens. supplementing DHEA in physiologic amounts (e.g. levels naturally produced in the body), or androgen therapy with physician guidance, can lift low levels. Stress Busting High cortisols run interference on that all-important conversion of T4 to T3, the active thyroid hormone. Your best defense: Turn down the volume. Are you over-worked, over- booked, over-caff einated? Non-stop stressors keep cortisol levels elevated and thyroid defl ated. Obviously we can't avoid all stress, but we can develop strategies to limit the damage. Think meditation. Yoga. Walking. Creative pursuits. Junk the junk food. Cut back on caff eine. Don't take your iPhone to bed. Any or all of these actions can reduce stress overload and rev up your thyroid. Rule Out iodine Deficiency The enzymes that make conversion of thyroid hormone happen depend on adequate essential materials. Iodine in particular is a key component of T3 and T4, so when it's too low the thyroid gland cannot make enough hormone to direct the metabolic process. Your best defense: If testing shows a deficiency, consider thyroid hormone and/or iodine therapy. Dietary shifts away from iodine-rich foods and vegan diets have led to lower iodine consumption over time. Good food sources are sea vegetables (kelp, kombu), organic yogurt, cranberries, strawberries, navy beans, potato (with skin) and Himalayan gray salt. Rule Out Selenium Deficiency Though found in minute amounts in the body, a deficiency of this essential mineral (due to denatured soil, poor absorption, and heavy metal exposure), disrupts thyroid hormone synthesis and action. Your best defense: If testing reveals a deficiency, consider supplementing adequate selenium (200-400 mcg) for improved thyroid synthesis. Good food sources of selenium are brazil nuts, beef, cod, turkey and whole wheat bread. Essential Vitamins Deficiencies of C,D,A,E and B12 vitamins are generally lower in individuals suffering from thyroid disorders. Your best defense: Take your vitamins and eat a diet well balanced in proteins, fiber, bruits, and vegetables. Optimal nutrition goes a long way towards improving an impaired thyroid. Remove Heavy Metal Toxicity The elements, arsenic and mercury in particular, when present at high levels, severely deplete iodine and selenium levels. Your best defense: Test arsenic and mercury levels for exposure. Supplemental selenium (200-400 mcg) can reduce heavy metal damage by binding tightly to mercury - thus removing it from circulation. As an anti-oxidant selenium counteracts the bad effects of prolonged heavy metal exposure. If you have dental amalgams which are strongly associated with mercury toxicity, consider having them removed. If you drink well water, have it tested for contamination. Avoid Xenoestrogens These environmental toxins disrupt hormone operating systems and stimulate accumulation of estrogen that block thyroid. Your best defense: Look for "hormone - free" food products. Switch to glass or ceramic versus plastic for heating/storing food. Use stainless steel or BPA-free water/baby bottles. Go for "green" house hold, garden, and personal care products. Eat cruciferous* vegetables (cabbage, brussels sprouts, cauliflower, broccoli, kale) or supplement with the active extract DIM, to rid the body of toxic xeno buildup. *Moderate intake of crucifers (especially in cooked forms) is not known to compromise thryoid function*