More Than Sick of Salt

All Posts in Category: Autonomic Dysfunction

Do I Have Mast Cell Activation Syndrome (MCAS)?

Click here to download this post 

Mast Cell Activation Syndrome (MCAS) is a disorder where components of the blood stream, namely mast cells, secrete various substances which can be involved in an allergic reaction or inflammatory reactions.  However, before discussing MCAS, we need to understand what the mast cell is and where it comes from.

What is Mast Cell?

Mast cells come from more undifferentiated-type cells in the bone marrow.  They usually mature in various tissues.  Mast cells are important reactionary cells in allergic reactions and in inflammatory reactions.

They secrete substances, such as Histamine, Prostaglandins, Leukotrienes, various enzymes which can break up other substances known as Proteolytic  enzymes and Cytokines, such Interleukins 6, 18 and 13.  Also, Tumor Necrosis Factor (TNF) and Vascular Endothelial Growth Factor (VEGF) may be secreted.  These substances may cause inflammation and also activate the immune system in various circumstances. 

Normally, mast cells do not spontaneously secrete these substances but in disorders such as MCAS they can.  Common triggers for mast cells to secrete these substances include IgE and antigens during an allergic reaction, anaphylatoxins, Cytokines, hormones, and substances such as Substance P (SP).  In fact, SP may be the main trigger in many skin disorders such Contact Dermatitis, a disorder in which mast cells are activated and secrete many of the substances named above.  In addition to Contact Dermatitis, Mast cells are very importantly involved in many other skin abnormalities, immunological responses, gastrointestinal responses, and may, interact and affect virtually every organ in the body.

What is Mast Cell Activation Syndrome

MCAS is a chronic condition involving multiple organs in which normal mast cell activation leads to the inflammation and allergic symptoms that may occur episodically in patients.  Gastrointestinal symptoms are common including Irritable Bowel Syndrome

Recently, the term mast cell activation syndrome disease (MCAD) has been defined.  This is the major heading for MCAD with two main categories. 

One is known as Systemic Mastocytosis (SM) and MCAS. 

Both of these disorders may have similar symptoms and systemic manifestations.  Usually with SM and its subclass, Mast Cell Leukemia (which is very rare), there is a genetic or clonal abnormality and there is usually an abundance of mast cells produced or a higher quantity exists; whereas, in MCAS, the number of mast cells are not increased, they are only hyperactive.   It is not known if MCAS can be transferred over time into the rare neoplastic or malignant states of SM and Mast Cell Leukemia.

What Causes Mast Cell Activation Syndrome

The triggers of MCAD include stress, food, alcohol, and various medications including possibly aspirin, infections, air pollution, heat, mold, chemicals, and changes in our intestinal microbiome.  The latter may be affected by antibiotics or stress.

What is the definition of MCAD?  Over the last ten years, much has been devoted towards establishing a clear definition for this disorder. 

Criteria have been proposed, and three criteria are specifically agreed upon.  It is important to satisfy all three criteria before concluding that the given patients’ symptoms are due to mast cell activation. 

It should be recognized that idiopathic anaphylaxis is a specific entity within the MCAS.  A patient may, however, experience urticaria or hives or gastrointestinal symptoms after exposure to a possible trigger allergen.

Mast Cell Activation Syndrome Symptoms

While many of the symptoms of MCAS (see below) are nonspecific in nature, again, there are specific criteria that must be fulfilled before one can diagnosis a patient as having MCAS.  There have been many criteria, but the ones most commonly used require symptoms consistent with chronic recurrent mast cell release.  These include:

  1. Recurrent abdominal pain, diarrhea, flushing, itching, nasal congestion, coughing, chest tightness, wheezing, lightheadedness, or a combination of some of these.
  2. Laboratory evidence of a mast cell mediator (elevated Serum Tryptase) whether at baseline or with provocation or during an attack, N-methylhistamine, Prostaglandin D2, or 11-Beta-prostaglandin F2 alpha, Leukotriene E4 and other mediators as determined by various laboratory measurement that pertain to mast cells.
  3. Improvement in symptoms with the use of medications that block or-treat elevations in these mediators, specifically Histamine blockers and other mast cell stabilizers.

Sources of MCAS Symptoms

Symptoms of MCAS can derive from any organ system and one usually needs two organ systems or comorbidities of at least two organ systems to fulfill criteria #1 above.

In regard to constitutional symptoms, fatigue and weakness, heat and cold sensitivities and sleep deprivation are commonly identified.

Dry eyes, red itchy and red burning, runny nose, and inflammation ulcers of the mouth may be seen in the head and neck organ system.

In regard to the chest and heart, chest discomfort, rapid heartbeats, redness, flushing of the skin, sudden dizziness, hot flashes, and blood pressure surges may be seen.  Also, syncope and presyncope.

In regard to the pulmonary system, dry cough that occurs repeatedly, shortness of breath, difficulty taking a deep breath, and episodic asthma and wheezing-like complaints can be present.

For the gastrointestinal system, abdominal symptoms are common to include pain, crampy or spastic discomfort oftentimes associated with diarrhea, abdominal bloating and distention, and symptoms of irritable bowel syndrome and diarrhea is also noted.  Swallowing difficulties and throat tightness are also noted.

In regard to the urinary tract and pelvis, bladder and pelvic pain as applies to both men and women may be present.  There may be painful, frequent and urgent urination or pain during sex.  The disorder of Interstitial Cystitis has been described where it is believed mast cells are very operative in its presentation and where an individual has significant urinary tract symptoms and discomfort, but does not have a documented urinary tract infection.

Neurological symptoms may occur with headaches, brain fog and neuropathic leg or arm pain.

The skin is one of the most affected organ systems by mast cells.  Hives, itching, swelling of the lips, cheeks, eyelids, reddish-brown spots under the skin and occasional hemangiomas are noted.  One may see reddish or pale complexion, itchiness with a burning feeling, and Dermatographism is common.

In regard to the hematologic system, one can see bruising and unusual nose bleeds.

In regard to the bones, patients can demonstrate bone pain.

Also, immune system involvement can be noted.  There have been immunological disorders, such as Common Variable Immunodeficiency Syndromes associated with MCAS.  One needs to determine if they get head colds or upper respiratory infections frequently and if they turn into bacterial infections, such as bronchitis and sinus infection which are common, and do these infections come on with attacks episodically that are related to mast cell activation.

How is Mast Cell Activation Syndrome Diagnosed

Various physicians will order different tests to determine if there is an increase in mast cell mediators. 

Various Mast Cell Mediators

Oftentimes all of these tests can come back negative for MCAS, but during attacks if these mediators, specifically Serum Tryptase, are tested during the first 1-4 hours, we can see a rise above baseline and can confirm objective data to support their diagnosis. 

Serum Tryptase

As mentioned, Serum Tryptase is an important mediator, and during an attack one likes to see at least a two-fold plus 20% increase in this value to consider that significant.  At times, Tryptase will be elevated at rest, and if it is above six (6.0), one may have to look towards a genetic enzyme abnormality. 

Histamine

Histamine can be measured in the plasma and its metabolite N-methylhistamine can be measured in the urine, and plasma histamine in the blood.  We often like to see this number more than 10 times the upper limit of normal, but any elevation is important. 

Prostaglandin D2

Prostaglandin D2 in the plasma is also measured as Heparin or Factor 8.  Chromogranin A, which is nonspecific and can be seen in neuroendocrine tumors and other gastrointestinal disorders or can be elevated in renal failure. 

If increased, it is very suspicious for MCAS in patients who do not have the former disorders.  The Leukotriene E4 in urine is also an important mediator to test for. 

Another important mediator to test for in the urine is PG-D2 or 11β PG F2α.  In addition, many times a biopsy is taken of the skin or the GI tract during endoscopy or colonoscopy. 

Other Tests for MCAS

If focal or disseminated infiltrates or morphologically inconspicuous mast cells are seen, or a mast cell collection, or a morphology of spindle shaped mast cells or if they are specially stained for CD25-positive mast cells, this gives significant strength to the diagnosis of MCAS.

One has to exclude other disorders which may mimic MCAS to make sure the symptoms are not due to Diabetes, Porphyria, Thyroid diseases, Amyloidosis, Hepatitis, Gallbladder disease, infectious Enteritis, Carcinoid tumors, Pheochromocytoma, (a tumor of the adrenal gland which can elevate blood pressure), pancreatic endocrine tumors, Eosinophilic Syndrome abnormalities, hereditary Angioedema, Vasculitis and rarely, intestinal Lymphomas.

Mast Cell Activation Syndrome Treatment

Treatment of MCAS or suspected MCAS is important because a response fulfils one of the criteria above.  Usually we begin with H1-antihistamines, such as Cetirizine (Zyrtec*), Ketotifen (Zaditor), or Fexofenadine (Allegra) or Loratadine (Claritin). 

H2-histamines, such as Famotidine (Pepcid*) or Ranitidine (Zantac) are added on.  This is usually first-line treatment using both an H1 and an H2 agent.  If the response is not complete, we often go to Antileukotrienes, such as Montelukast (Singulair) or Zileuton (Zyflo). 

Some people use natural products, such as Curcumin or St. John’s wart.  If not contraindicated, or not determined to be a triggering agent, a nonsteroidal anti-inflammatory (NSAID) agent and aspirin can be helpful in reducing inflammation in some of the patients. 

Oftentimes, we will tailor the therapy if a certain mediator is tested for and is elevated in the urine or blood.  For example, Prostaglandin elevation may influence us to use nonsteroidals or aspirin earlier. 

Disodium Cromoglycate (Cromolyn), is a mast cell stabilizer that is used in cases of MCAS that have not responded to the above treatment with antihistamines and Leukotriene inhibitors.  It can be given as a liquid four times day or even inhaled.  Biological agents are usually used only in severe cases that are refractory to treatment and beyond the scope of this review.

One should note that there is also a natural substance which has been found to occasionally be effective as a mast cell stabilizer and may be more effective than Disodium Cromoglycate (Cromolyn).  This is Quercetin, which is a Flavonoid.  On cultured human mast cells, Quercetin has been shown to inhibit the secretion of Histamine in PGD2.   In addition to inhibiting Histamine, Leukotrienes and PGD2 from primary human cord blood-derived cultured mast cells stimulated by IgE/anti-IgE.  In fact, it has been shown in tissue cultures to be more important than Cromolyn as a mast cell stabilizer.

If too many mediators are spilled into one system they may experience anaphylaxis, which includes difficulty breathing, itchy hives, flushing, pale skin, a warm feeling, weakness, and rapid pulse, low blood pressure, nausea, vomiting, diarrhea, and dizziness.  With low blood pressure, one can have syncope or fainting. 

Hypermobile Ehlers-Danlos Syndrome, POTS And MCAS

There has been a relation between hypermobile Ehlers-Danlos syndrome (hEDS), Postural Orthostatic Tachycardia Syndrome (POTS) and MCAS.  To date, it has not been proven unequivocally that there is a cause and effect relationship between these entities. 

Many believe that the pathophysiology of POTS can involve a mast cell activation etiology which can overlap with other types of etiology, such as hyperadrenergic, hypovolemic, neuropathic, and so forth.  The problem is that there are vague overlapping symptoms that one sees with POTS and hEDS. 

Many autonomic dysfunction  symptoms can be seen in people with MCAS, such as lightheadedness, dizziness, fainting, rapid heartbeat, blood pressure changes and so forth, and there may not be as close an association as is often thought.

Many patients present with symptoms that are suggestive of MCAS and significant skin abnormalities, such episodic rashes, hives, and generalized itching. 

If two organ systems are involved with symptoms, one should begin to think that they may have an MCAS problem.  Appropriate laboratory testing should be done. 

As the laboratory testing takes some time to be sent back to the physician’s office, empiric treatment should be started with antihistamines and H1 and H2 blockers. 

Many patients will have a significant response.  This is very suggestive.  However, a third criteria really needs to be fulfilled for a precise diagnosis, and if the urine and blood testing comes back negative, one could presume that the patient has MCAS, but it still does not meet all three criteria.  We will often have a patient repeat the blood test during an acute episode to see if the Tryptase, Histamine or any of the blood components rise significantly.  There has been some suggestion that the Mayo Clinic has developed a spot-urine test to also be taken.

We see many of our patients tested in the autonomic laboratory that have both EDS and MCAS.  We believe this is a strong interrelationship and not just an association of commonly found problems that occur frequently in people. 

While MCAS is becoming more frequently recognized now that we have diagnostic criteria, it is still not that common of a disorder to be aggregated with Ehlers-Danlos syndrome (which can be found in up to 5% of people) or autonomic dysfunction (orthostatic intolerance is becoming more commonly recognized in our population).

 

Read More
Mind Body Wellness Chart

COVID-19 Involves Oxidative Stress and Inflammation: Antioxidants Are Possibly Therapeutic and Preventative

Click here to download this post

SARS-COV-2 (COVID-19 or Coronavirus) is a severe, acute, respiratory syndrome infection that involves the lungs and the immune system.  The major clinical feature is Respiratory Distress Syndrome, and one key complication is Acute Cardiac Injury [1].  COVID-19 is a self-limiting infection and the strength of the immune and respiratory systems is critical in overcoming the infection and surviving the potential morbidity and mortality risks associated with the infection. Several comorbidities have been reported as risk factors for unfavorable prognosis in patients with COVID-19.  The most common comorbidities that influence the outcome of COVID-19 patients are Cardiovascular Disease (CVD), Diabetes Mellitus type 2 (DMT2), Hypertension, Malignancy and Chronic Obstructive Pulmonary Disease (COPD), among others, especially pulmonary disorders.  Smoking and other factors that may compromise the lungs have also emerged as risk factors associated with a worse outcome.  For example, China, which is one of the hardest-hit countries, has the vast majority of its population living in densely populated cities in which there have been significant amounts of construction, and the majority of their heat and electricity comes from burning fossil fuels, especially coal.  This has been the condition for a number of years.  On a visit to a number of their larger cities over a number of weeks in 2014, many of its citizens, especially the younger adult population, were already wearing masks to protect themselves from the heavy particulate pollution.  In other words, by the time of the COVID-19 outbreak, it is reasonable to assume that the population of China was already respiratory-compromised to some degree.

As commented [2], it has been shown that oxidative stress is associated with the same diseases (including CVD and DMT2 [3]) that increase the risk of a severe outcome from COVID-19.  Oxidative stress is a condition of imbalance between the release of Reactive Oxygen Species (ROS) and the endogenous antioxidant capacity of an individual’s system.  It is also well known that smoking can induce cellular oxidative stress while it depletes antioxidants through various mechanisms [4],[5].  Studies have shown that antioxidant deficiency leads to increased sensitivity to even mild oxidative stress, while altered activity and levels of antioxidants have been recognized as markers of inflammation [6].  For example, and specifically for the Respiratory System, dysregulation of Glucose 6-Phosphate Dehydrogenase leads to a greater risk for protein glycosylation [7], a process that plays an essential role in promoting viral pathogenesis, including COVID-19 [8,[9],[10].  This example suggests that antioxidant therapy may help to treat, and perhaps prevent, SARS infections, including COVID-19, as well as Influenza.

It has been demonstrated [11] that human lung epithelial A549 cells with lower G6PD activity (via RNA interference) have a 12-fold higher viral production when infected with human coronavirus 229E, which shares a sequence similarity with COVID-19 and clinically resembles it, compared to control cells [11,[12].  Antioxidants may at least provide heart protection for COVID-19-infected individuals, based on the oxidative stress theory [13].  According to recent clinical reports, the therapeutic time for COVID-19 infection is much longer than 14 days, but long-time viral stimulation is prone to suddenly elicit intensive immunological reactions, cytokine storm, and immune-cell infiltration.  However, some immunocytes, especially Macrophages and Neutrophils, can produce numerous Reactive Oxygen Species (ROS) [13,[14],[15].

A certain level of ROS is important for regulating immunological responses, clearing viruses, and general health.  It is part of the first line of defense by the immune system.  Together with fever, Oxidants (like ROS) are used to “burn” the invading “trash” (i.e., foreign or excessive bacteria, molds, mildews, viruses, etc.) that enters your body every moment.  The immune system collects the Oxidants and dumps them on the invading trash to kill them by oxidizing cellular proteins, membrane lipids, Mitochondria, and even DNA and RNA, etc.  Meanwhile, the body brings in the Antioxidants to “put out the fire” once the “trash” is burned to protect the healthy tissue.  However, excessive ROS (such as with illness, cancer, or Psychosocial stresses – including mental and physical stresses) will cause excessive oxidative stress, overwhelming the body’s reserve of Antioxidants, resulting in sickness and, in the extreme, death.  This is why, in general, it is good to have a healthy Antioxidant reserve, and this is best built up through exercise and diet and, in those at risk, with additional nutraceuticals to supplement.

Oxidative stress may quickly destroy not only virus-infected cells, but also normal cells in the lungs, heart, nerves, and kidneys, resulting in multiple organ failure.  Lungs are susceptible because they are constantly exposed to the outside.  The heart and nerves are susceptible because they contain the greatest number of Mitochondria of all the cell-types in the body.  Ironically, Mitochondria (the power plants of the body) are the greatest natural producers of ROS in the body (think of ROS and oxidants as the “pollution” from the power plants, however, in the case of the body these “pollutants” are used for good, to help the body, under normal conditions).  The kidneys are susceptible because their job is to filter out the toxins from the blood, therefore, they exist in a highly toxic environment.  Thus, a healthy Antioxidant reserve helps to prevent illness and, if ill, helps to treat illness, just like with colds, when people consume additional amounts of Vitamin C, a well-known antioxidant, to help rid themselves of the virus that caused the cold.

Thus, a potential antioxidant therapy could be proposed to alleviate the respiratory, cardiogenic, and other casualties caused by COVID-19.  For example, inexpensive medicinal Antioxidants include Vitamin C (Ascorbic Acid) and Vitamin E.  These work through their reductive Hydrogen atoms react with ROS and then produce nontoxic water [16].  Plant-derived molecules (similar to ancient Chinese medicine), such as Curcumin (aka., Turmeric), may have potential antioxidant efficacy. These well-known Antioxidants and others (e.g., Vitamin A, Glutathione, Resveratrol, Omega-3 Fatty Acids, proper daily intake of water – 48 to 46 oz, etc.) are known to be made more potent through recycling with either Alpha-Lipoic Acid (ALA) or Co-Enzyme Q10 (CoQ10).  While ALA and CoQ10 are arguably the most powerful Antioxidants the body naturally makes, they increase their strength and the strength of the other Antioxidants by redirecting them away from the kidneys for another pass through the body.  ALA tends to be specific for nerves, helping to protect the Mitochondria in the nerves to prevent the nerves from weakening, thereby preventing or relieving the neurological symptoms of illnesses, including viruses, like lightheadedness, malaise, cognitive and memory difficulties, fatigue, etc.  CoQ10 tends to be specific for the heart, helping to protect the Mitochondria in the heart to prevent the heart from weakening, thereby preventing or relieving the cardiological symptoms of illnesses, including viruses, like low blood pressure, lightheadedness, fatigue, etc.

These Antioxidants also help to reduce chronic inflammation [6] which serves to exacerbate the effects of viruses, especially in the lungs as with SARS viruses (including COVID and Influenza).  These Antioxidants are helped with Nitrates (dietary and supplemental) to boost the production of Nitric Oxide in the body.  Nitric Oxide performs multiple functions in the body, including as an Antioxidant and an Anti-inflammatory, and it helps to prevent or relieve Atherosclerosis to improve heart health.  Nitric Oxide also helps to detoxify the body, reducing the prevalence of Oxidants, including ROS.  Nitric Oxide may be supplemented through L-arginine (which is limited by the body’s needs to produce it), L-Citrulline and L-Carnitine (which help the body to produce L-Arginine, and therefore is limited), and dietary Nitrates (the most well-known supplement at this time is Beet Root Extract Powder[1], and there are others).  Dietary Nitrates are not limited and help to produce as much Nitric Oxide as is possible from the amount ingested.  A healthy diet, like the Mediterranean Diet with multiple servings of fresh vegetables and fruits, helps to provide all of the above.  The typical American Diet does not and may be contributing to Americans being more susceptible to illness, including COVID-19.

An optimal immune response depends on an adequate diet and nutrition in order to keep infection at bay [17].  For example, sufficient protein intake is crucial for optimal antibody production.  Low micronutrient status, such as of vitamin A or Zinc, has been associated with increased infection risk.  Frequently, poor nutrient status is associated with inflammation and oxidative stress.  Dietary constituents with especially high anti-inflammatory and antioxidant capacity include vitamin C, vitamin E, and phytochemicals such as carotenoids and polyphenols (i.e., Resveratrol) and sources of other antioxidants (e.g., Glutathione, CoQ10 and ALA), as well as Nitrates and Amino Acids that support proper levels of Nitric Oxide production. Several of these can interact with transcription factors such as NF-kB and Nrf-2, related to anti-inflammatory and Antioxidant effects, respectively. Vitamin D in particular may perturb viral cellular infection via interacting with cell entry receptors such as Angiotensin Converting Enzyme 2 receptors (ACE2).  Dietary fiber, fermented by the gut microbiota into short-chain fatty acids, and other sources of healthy Fatty Acids (e.g., Extra Virgin Olive Oil), have also been shown to produce anti-inflammatory effects, among other benefits for example, to help keep cell membranes pliable and resilient to infection.  These and more are the benefits of a healthy diet with fresh, ripe produce (including extra helpings of dark green leafy vegetables – raw or lightly cooked, they still need to be green; not gray) and well-balanced proteins and fats which reduce inflammation and oxidative stress, thereby strengthening the immune system during any infection, including the COVID-19 crisis.

With all of the above regarding Antioxidants being said, arguably the most powerful and universal Antioxidant is EXERCISE [6,[18]].  Just one example is fever.  As mentioned above, fever is part of the body’s first-line defense against illness and invading pathogens (viruses, bacteria, molds, mildews, allergens, etc.).  While healthy human cells may survive between the temperatures of 98 and 104 °F, pathogens tend to be killed above 101.1 °F.  Mild to moderate exercise for 40 minutes or more a day at least three times per week will simulate a fever (raise body core temperature to above 101.1 °F for at least 20 minutes).  The simulated fever will help the body to eliminate any invading pathogens before they acquire a “foot-hold.” Read that: potentially kill off any COVID-19, Influenza, or other viruses, if exposed, before the pathogens (including the viruses) have a chance to infect you and make you sick.  By mild to moderate exercise, we mean walking, gardening, playing with children, housework, calisthenics, or any activity that raises your heart rate and blood pressure above resting for a continuous 40 minutes and makes you sweat for at least 20 minutes.  Of course, if you are healthy and fit, more strenuous exercise is also helpful to simulate fever.  Exercise will also provide a number of other benefits, including:  happier moods, reduced pain, better sleep quality, improved concentration and creativity, reduced stress levels and anxiety, maintained mental fitness, improved parasympathetic and sympathetic nervous systems function, stress reduction, improved heart and vascular health, improved neuroendocrine health, weight control (loss), reduced risk of DMT2 and metabolic syndrome, reduced cancer risk, stronger bones and muscles, reduced arthritis and other joint disorders, and promoted longevity (promotes living longer) [6].[2]

Exercise is demonstrate to have both short and long term effects by increasing aerobic capacity thereby increasing the function and strength of immune and respiratory systems, particularly those essential for overcoming COVID-19 infections and associated disorders. [18].  Exercise that increases aerobic capacity produces safe improvements in the function of immune and respiratory systems, particularly those specific for COVID-19 infections.  These improvements are mediated through:  (1) improved immunity by increasing the level and function of immune cells and immunoglobulins, regulating CRP levels, and decreasing anxiety and depression; (2) improved respiratory system functions by acting as an Antibiotic, Antioxidant, and Antimycotic[3], restoring normal lung tissue elasticity and strength; and (3) reducing the effects of risk factors such as DMT2,  Hypertension, and CVD, Obesity, and aging, to decrease COVID-19 risk factors, which helps to decrease the incidence and progression of the virus.  To punctuate the issue, a recent review article [19] highlights the impact of “sedentarism” due to the COVID-19 home confinement.  Even a few days of sedentary lifestyle are sufficient to induce muscle loss, neuromuscular junction damage and fiber denervation, insulin resistance, decreased aerobic capacity, fat deposition and low-grade systemic inflammation.  Regular moderate exercise, together with a 15-25% reduction in caloric intake, are recommended for preserving neuromuscular, cardiovascular, metabolic and endocrine health, important in reducing the effects of the virus.

 

A proper dose of Antioxidants may ameliorate respiratory, cardiac, and other system injuries of critically ill COVID-19-infected patients

 

Even after a serious infection, like from COVID-19, if the Antioxidant system was over taxed, the virus or infection will leave behind oxidative stress – at the cellular level.  We emphasize “at the cellular level” because often times, the systems seem normal and healthy and all of the tests that most physicians order return normal, yet there are lingering symptoms and even disability, both mental and physical.  The problem is two-fold.  First, while the individual cells themselves are dysfunctional, the net sum total of their functioning still meets the minimum standards for “normal.”  Second, the typical patient’s problem is not at rest (which is when most tests are performed – sitting or lying down) but when active.  It is like a car with a full fuel tank, which idles just fine, but, due to a clogged fuel filter, cannot accelerate when needed.  They look normal at rest, but are quickly fatigued when required to do work, either mental or physical.  Again, Antioxidants, especially ALA, CoQ10, and EXERCISE, will help to relieve the oxidative stress and thereby relieve the fatigue and other lingering symptoms.

Currently, there is a lack of evidence regarding the exact role that Antioxidants play in COVID-19 infection. High-dose supplementation with Antioxidants, when given at an early stage of the infection, may prevent the spread of the virus in the body, thereby providing protective effects and reducing the severity of disease.  This is proven to help in the other well-known SARS viruses including Influenza.  To that end, traditional medicine products, supplements and nutraceuticals that are Antioxidants and anti-inflammatories are amongst the various additive treatments for COVID-19 under investigation [20].

ENDNOTES

[1] Not the portion of the beet that is typically eaten, the tuber, but the little root below the tuber.

[2] However, as always, an exercise regimen should be started under close physician supervision.  The wrong types of exercise may do more harm than good, including increasing body fat (and thereby weight), fatigue, and pain due to the fact that the body is programmed to over-react to stresses.  Under these conditions, the body sees exercise as stress and works to protect itself against the stress. 

[3] An agent that is used against fungal infections.

 

REFERENCES

____________________

[1] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Lancet 395 (2020) 497–506.

[2] Wang JZ, Zhang RY, Bai J.  An anti-oxidative therapy for ameliorating cardiac injuries of critically ill COVID-19-infected patients.  Int J Cardiol. 2020 Apr 6.  doi: 10.1016/j.ijcard.2020.04.009 (Epub ahead of print).

[3] Moldogazieva NT, Mokhosoev IM, Mel’nikova TI, et al. Oxidativestress and advanced lipoxidation and glycation end products (ALEsand AGEs) in aging and age-related diseases. Oxid Med Cell Longev2019;2019:3085756.

[4] Niemann B, Rohrbach S, Miller MR, et al. Oxidative stress and cardio-vascular risk: obesity, diabetes, smoking, and pollution: part 3 of a 3-part series. J Am Coll Cardiol 2017;70:230e251.

[5] Wenham C, Smith J, Morgan R. Gender and COVID-19 WorkingGroup. COVID-19: the gendered impacts of the outbreak. Lancet2020;395:846e848.

[6] DePace NL, Colombo J.  Autonomic and Mitochondrial Dysfunction in Clinical Diseases:  Diagnostic, Prevention, and Therapy.  Springer Science + Business Media, New York, NY, 2019.

[7] Jain SK. Glutathione and glucose-6-phosphate dehydrogenase defi-ciency can increase protein glycosylation. Free Radic Biol Med 1998;24:197e201.

[8] Watanabe Y, Bowden TA, Wilson IA, et al. Exploitation of glycosyl-ation in enveloped virus pathobiology. Biochim Biophys Acta GenSubj 2019;1863:1480e1497.

[9] Lan J, Ge J, Yu J, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020;581:215e220.

[10] Gumustekin K, Cifttci M, Coban A, et al. Effects of nicotine and vitaminE on glucose 6-phosphate dehydrogenase activity in some rat tissuesin vivo and in vitro. J Enzyme Inhib Med Chem 2005;20:497e502.

[11] Wu YH, Tseng CP, Cheng ML, et al. Glucose-6-phosphate dehydroge-nase deficiency enhances human coronavirus 229E infection. J InfectDis 2008;197:812e816.

[12] Li Y, Liu B, Cui J, et al. Similarities and evolutionary relationships ofCOVID-19 and related viruses. arXiv 2020;2003. 05580 [q-bio.PE].

[13] Loffredo L, Martino F, Zicari AM, Carnevale R, Battaglia S, Martino E, et al., Enhanced NOX-2 derived oxidative stress in offspring of patients with early myocardial infarction, Int. J. Cardiol. 293 (2019) 56–59.

[14] Perrone LA, Belser JA, Wadford DA, Katz JM, Tumpey TM, Inducible nitric oxide contributes to viral pathogenesis following highly pathogenic influenza virus infection in mice, J. Infect. Dis. 207 (2013) 1576–1584.

[15] Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van Loo G, et al., Identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury, Cell 133 (2008) 235–249.

[16] Erol N, Saglam L, Saglam YS, Erol HS, Altun S, Aktas MS, et al., The protection potential of antioxidant vitamins against acute respiratory distress syndrome: a rat trial, Inflammation 42 (2019) 1585–1594.

[17] Iddir M, Brito A, Dingeo G, Fernandez Del Campo SS, Samouda H, La Frano MR, Bohn T. Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis. Nutrients. 2020 May 27;12(6):E1562. doi: 10.3390/nu12061562. PMID: 32471251.

[18] Mohamed AA, Alawna M. Role of increasing the aerobic capacity on improving the function of immune and respiratory systems in patients with coronavirus (COVID-19): A review.  Diabetes Metab Syndr. 2020 Apr 28; 14(4): 489‐496.  Published online ahead of print,

[19] Narici M, De Vito G, Franchi M, Paoli A, Moro T, Marcolin G, Grassi B, Baldassarre G, Zuccarelli L, Biolo G, di Girolamo FG, Fiotti N, Dela F, Greenhaff P, Maganaris C. Impact of sedentarism due to the COVID-19 home confinement on neuromuscular, cardiovascular and metabolic health: Physiological and pathophysiological implications and recommendations for physical and nutritional countermeasures. Eur J Sport Sci. 2020 May 12:1-22. doi: 10.1080/17461391.2020.1761076. Epub ahead of print. PMID: 32394816.

[20] Fauci AS, Lane HC, Redfield RR. Covid-19: Navigating the uncharted. N Engl J Med 2020;382:1268e1269.

Read More
Mind Body Wellness

COVID-19 (Coronavirus) and Exercise, Diet, and Antioxidants

Click here to download this post

COVID-19 Prevention Tips: Exercise And Nutrition

COVID-19, the Coronavirus, like the flu (e.g., the Influenza virus) and similar to colds, may be prevented or mitigated, and are often treated, by the combination of a healthy diet and exercise, and perhaps additional antioxidant; the most common being Vitamin C in some form:  fresh, ripe fruits and vegetables are preferable, and supplements are also good.

In fact, many typically healthy people have contracted COVID-19 and have recovered.  Many more have contracted it and may have even had mild symptoms, but never knew they had it until after having recovered from COVID-19.  This is similar to cases with the Influenza virus or the flu.  So like, the flu, those at risk need to protect themselves and take necessary precautions to stay healthy.  Again, the major contribution to health, even if you are at risk, is a healthy diet full of fresh fruits and vegetables and exercise.

  EXERCISE

Please, EXERCISE IS NOT A DIRTY WORD!  It does not have to be drudgery.  We are not talking about going to the gym and beating yourself up for hours.  Perhaps a better description is “ACTIVE LIFESTYLE,” which may include exercise (in the sense of the current vernacular), but it should reflect the lifestyle of people before automobiles, elevators, television remotes, and cell phones.  It can be a single (preferably daily) acute bout of physical exertion or muscular activity that expends energy above one’s basal or resting level – frequent movement of some sort.  It is true, siting has become the “new smoking.”  For those who are old enough, we are referring to a time before electronics, when play was not sitting around with computer games getting strong thumbs and weak bodies and communicating with someone was not done electronically developing stronger thumbs.  People walked places or rode their bikes, children were outside walking, skipping, running, jumping, breathing fresh air and soaking in sunshine for their daily dose of Vitamin D.  Adults would do house work, garden, yard-work, walk to the corner store, walk over to the neighbors to check on the children, or have a cup of coffee or tea and catch up on the news of the neighborhood, or simply play with the children at home, take the stairs or shop, etc.  Life was not sedentary.  Life included what we mean by exercise.

The physiologic and psychologic benefits of exercise are numerous.  It is better than any supplement or pill available, and what we mean by exercise is infinitely less expensive.  Again, it is probably better than any combination of supplements or pills or possibly even pharmacological agents available.  In fact, exercise with supplements, etc., including diet which supports exercise, is the best combination for minimizing the risk of illness, including flu conditions, like COVID-19.  Exercise optimizes quality and continuation of life, and minimizes mortality risk, which optimizes longevity and minimizes the impact of disease if and when it happens.  While the diet fuels exercise and provides the nutrients needed for good health, exercise provides many health benefits, like simulated fever and being (arguably) the strongest antioxidant available.  The list of benefits includes:

Wards-off Viruses and other pathogens trying to invade your body by simulating fever.  Exercise raises your core body temperature.  Most pathogens are killed by elevated temperatures (like above 101°F).  Our recommended 40 minute walk at 2 mph typically reaches this core body temperature goal and helps to prevent viruses and other pathogens from gaining a foothold in your body.  In effect the higher temperatures help to “burn-out” the invaders, including viruses.

Happier Moods from the release of endorphins in the brain, and other brain chemicals that elevate mood.  Regular physical activity (3 to 5 times a week for 30 to 60 minutes each time) reduces risk of depression.

Immune Health from two aspects of exercise as mentioned above:  1) Exercise (physical activity) raises the body’s core temperature, simulating a fever (20 minutes or more of exercise, three or more times per week helps to prevent disease before is starts); 2) Exercise is arguably the strongest antioxidant available and provides all of the benefits of antioxidants (like Vitamin C), including defeating (promoting the oxidation of) all types of infections:  viral, bacterial, fungal, etc.

Reduced Pain.  Endorphins are natural pain killers and can help to provide temporary pain relief.

(The brief explanations of the rest of these benefits are available at the end of this document.)

Better Sleep Quality.[1]

Improved Concentration & Creativity.[2]

Reduce Stress Levels & Anxiety.[3]

Maintain Mental Fitness.[4]

Parasympathetic and Sympathetic (P&S) Nervous Systems.[5]

Stress Reduction.[6]

Heart & Vascular Health.[7]

Neuroendocrine Health.[8]

Weight Control (Loss).[9]

Reduced Risk of Type 2 Diabetes and Metabolic Syndrome.[10]

Reduced Cancer Risk.[11]

Strengthen Bones and Muscles.[12]

Promotes Longevity (promotes living longer).[13]

CAUTION:  As always, an exercise regimen should be started under close physician supervision.  The wrong types of exercise may do more harm than good, including increasing body fat (and thereby weight), fatigue, and pain due to the fact that the body is programmed to over-react to stresses.  Under these conditions, the body sees exercise as stress and works to protect itself against the stress.  With certain diseases (e.g., some arrhythmias, diabetes, stroke or aneurysm risk, or heart disease), the wrong type of exercise may also lead to heart attack, stroke, or sudden death.  It is best to start slow and build up and always listen to your body.  Until endurance built, recommended goals may not be reached for a while.  This is not bad; keep at it until the goals are reached.  The health benefits of physical activity far outweigh the risks of getting hurt.

As with a pure Mediterranean diet, strict compliance with the recommended 150 minutes of exercise per week is not required to get beneficial effects.  Smaller amounts of exercise are helpful, just not as much.

ANTIOXIDANTS

Again, exercise is the strongest antioxidant possible.  Less than healthy people, especially those at most risk, because of age or illness have fewer naturally available antioxidants made by their bodies.  Either (1) aging slows the production or (2) the disease is causing the immune system to use them faster than normal and out-pacing the body’s production.  Alpha-Lipoic Acid (ALA, specifically (r)ALA*) and CoQ10 are arguably the two most powerful antioxidants your body makes, and they are made more powerful by the fact that they recycle other antioxidants (like Vitamin C, as well as Vitamins A & E, and Glutathione). The fact that (1) exercise is arguably the most powerful antioxidant of all and (2) healthy youngsters are more active (exercise more) and are making more ALA and CoQ10 naturally than older or sicker folks, goes a long way to explaining the difference in the reaction of healthy youngsters versus healthy older folks.  It also explains why the more active older folks we know that have contracted COVID-19 have all survived.

In addition to helping the immune system, antioxidants also help keep Mitochondria healthy, especially ALA (in the nerves) and CoQ10 in the heart muscle. Again, exercise enhances this as well, as well as releases the endorphins, which helps to minimize depression and anxiety. By elevating mood, illness is minimized or prevented. The cascade goes on. There is a lot of this in the second book we wrote.[14]

IMMNUNE RESPONSES

Some doctors and scientists are reporting that an immune system gone haywire may be doing more damage than the coronavirus itself in patients with the severest forms of COVID-19.  Exercise, Antioxidants and a proper diet help to stabilize the immune system and keep it stable.  In the case of Severe Acute Respiratory (SAR) type viruses, the out-of-control immune response eventually causes the patients’ lungs to stop delivering oxygen to the body leading to respiratory failure.  It may also cause excessive inflammation that adds to fluid generation in the lungs.  It may also weaken blood vessels adding more fluid in the lungs further exacerbating respiratory failure and, in some cases, may cause death. In this way, the malfunctioning (overactive) immune system may be driving the rapid decline in lung function experienced by some patients.

We have found that the immune system is controlled and coordinated by the Parasympathetic Nervous System.  Further, we have found that an over-active immune system is associated with an over-active Parasympathetic Nervous System, and the opposite is true as well.  We have labeled an over-active Parasympathetic Nervous System as Parasympathetic Excess, or PE.  For example, brain trauma patients with PE are found to have a higher incidence of life threatening pneumonia than those brain trauma patient s without PE.  We have also found that normalizing PE helps to stabilize the immune system and reduces mortality and morbidity risk.

[*] There are two isomers of Alpha-Lipoic Acid, (r) and (s).  Only (r) is used by the body.  The (s) isomer is used for filler and less expensive products.

 

To slow or stop this process, some are being prescribed standard courses of anti-inflammatories, including steroids, including high dose steroids.  Some believe, high dose steroid is also accepted treatment for COVID-19, therefore if administered prior to detection of COVID-19 may mask COVID-19 in these patients until late in the progression of the disease.  Excessive amounts of steroids may also suppress the immune system which of course would have a negative effect.  Having experienced this, we strongly recommend that patients on high dose steroids be screen for COVID-19, as a precaution.

ANGIOTENSIN RECEPTORS

In a similar vein, evidence suggests that COVID-19 gains entry into cells through the ACE2 receptor.  ACE stands for Angiotensin Converting Enzyme.  ACE-Inhibitors (ACE-Is) and Angiotensin Receptor Blockers (ARBs) are commonly prescribed to patients with high blood pressure (Cardiovascular disease patients and patients with Diabetes).  Of course, the connection has caused concern within these communities.  However, the Cardiology communities (ACC & AHA) have stated that ACE-Is and ARBs are still considered safe and, perhaps, without these medications, those patients would be more at risk for infection (COVID-19 or other).  The concern is that by taking ACE-Is or ARBs, the number of ACE2 receptors in the body will increase, which they will, and that this increase may provide more entry points for the virus.  However, the latter is not likely.  In Angiotensin-mediated Hypertension (HTN), the number of ACE2 receptors is already elevated.  That had already contributed to the HTN.  ACE-Is and ARBs are designed to block the excess receptors to begin with and even block some of the original receptors to ensure lower blood pressure.  If these receptors are already blocked to limit their use for raising blood pressure, then it is not likely that COVID-19 will be able to use them either.  Think of a lock and a key.  Once a key is inserted into the lock, another key cannot be inserted.  The ACE-I or ARB is the first key.  COVID-19 is the second key and is also blocked.

While ACE-Is and ARBs may help those patients to whom they are prescribed have lower risk to COVID-19, they are not being recommended for patients who do not qualify under the guidelines for those medications.  Remember, the patients who are prescribed ACE-Is and ARBs were already at risk due to the HTN.  If you are already prescribed an ACE-I or ARB do not stop it.  If you are not already prescribed an ACE-I or ARB do not start it without physician permission.  As always, never take medication without consulting your physician first.

OXIDATIVE STRESS

There is another aspect to the Coronavirus (COVID-19).  The Coronavirus like other viruses and significant infections cause oxidative stress.  Oxidative stress is a stress to the cells of your body.  It is the result of something, in this case COVID-19, attacking the cells’ energy production processes.  The primary component (organelle) responsible for energy production is the Mitochondria.  Mitochondria are like power plants in many ways.  They produce energy.  They also produce waste.  However, in the case of cells, the waste is not considered pollution, it is actually used, and under healthy conditions, all of it used; nothing is wasted.

The waste products are oxidants.  Yes, the very things that destroy cells, and we try to flood our systems with their opposites – antioxidants – are the very things that the Mitochondria make as waste products.  Again, under healthy conditions these oxidants are not “pollutants.”  They are used by a healthy immune system to “burn the trash.”  Pathogens (things invading our bodies and trying to make us sick) enter our bodies every moment.  As long as we are in familiar places, our bodies already have developed a defense mechanism against all of these pathogens, and in addition to fever, another first line of defense is to use the oxidants to burn the trash.  However, once the trash pile is burned, the fire must be extinguished.  The antioxidants are the fire extinguishers, or buckets of water if you will, to put out the fire before it burns healthy tissue.  Therefore, a small amount of oxidant production is healthy, as long as there is an ample supply of antioxidant on hand as well.

Again, as we age or are ill for long periods of time, the natural production of antioxidants declines, and again, fortunately, they may be supplemented.  However, if they are not supplemented sufficiently, the virus may leave behind oxidative stress.  Unfortunately, oxidative stress only reduces the functioning of cells.  This is unfortunate because the organs remain largely functional, and structurally, remain within normal limits.  Therefore, at rest (which is when most doctors assess their patients – sitting or lying down), these patients seem normal.  Yet they complain of fatigue (sometimes debilitating fatigue), lightheadedness or dizziness, poor sleep, brain-fog, memory and cognitive difficulties, sex dysfunction, GI upset (both upper and lower), sensory and temperature hypersensitivity, headache or migraine, depression or anxiety, generalized pain, and more. While it is difficult to measure oxidative stress, we are now able to directly measure its effects, especially on the Parasympathetic and Sympathetic (P&S) nervous systems.

P&S Monitoring helps to document the effects of any serious illness, including oxidative stress due to viruses, including COVID-19, which may leave significant oxidative stress behind.  Since oxidative stress does not do overt damage to the organ system, affecting primarily the mitochondria, cells’ function is sub-par, these patients are affected when they attempt to be active.  It is like having a clogged fuel filter on your car.  Your car will start and idle just fine, but as soon as you hit the gas the engine begins to choke and you are unable to move or move very fast.  Oxidative stress primarily affects the Parasympathetic nervous system, causing it to be more active.  If the Parasympathetics are already overactive (PE) due to immune system excesses, this additional Parasympathetic activation only serves to exacerbate the whole problem and these patients rapidly deteriorate into disability claims, yet they appear healthy.  With no specific disorder, unless the P&S nervous systems are measured independently and simultaneously (as only the technology that we have can – P&S Monitoring), patients will go from doctor to doctor for years and perhaps decades, including recommendations for psychological evaluation, before they find someone with P&S Monitoring, if ever.  In the meantime, they are disabled, out of work, have very poor qualities of life, and are at higher risk for infections such as COVID-19.

CASE IN POINT

A recent patient was admitted to hospital with Inflammatory Myopathy, a large group of potentially treatable myopathies in both children and adults [15].  They represent a heterogeneous group of disorders which include the Dermatomyositis, Polymyositis, Immune-Mediated Necrotizing Myopathy (IMNM), and Inclusion Body Myositis.  There are various strategies for treating Inflammatory Myopathies especially IMNM.  IMNM accounts for approximately one-fifth of all Inflammatory Myopathies and present with severe muscle weakness and high creatinine levels.  They are often seen after viral infections, malignancies (cancer) or connective tissue disorder such as Rheumatoid Arthritis, Lupus and Scleroderma, but can be seen in patients taking statins.

Many of these patients have resistance to conventional immunosuppressive therapy [16].  IMNM is distinguished by the absence of primary inflammation on muscle biopsy and may be associated with myositis-specific autoantibodies.  Prompt treatment is important especially in patients who develop acute or progressive swallowing or breathing abnormalities from difficulty with skeletal muscle function.  Prednisone is first-line treatment, but is oftentimes ineffective and second-line treatment needs to be employed.  Second-line treatment may include disease-modifying agents, such as Methotrexate, Azathioprine or Mycophenolate Mofetil.  Additional second-line treatment includes Intravenous Immunoglobulin (IVIG).  Recent research has suggested a high rate of response to Rituximab in patients with autoimmune myopathies [17].

Immunosuppressive therapy increases the risk of infection including Aspiration Pneumonia [17,18].  Pneumococcal vaccine and yearly Influenza vaccinations are recommended.  Before starting second-line treatment, it has also been recommended to screen for Tuberculosis and Hepatitis B and C.  There are no consensus guidelines for Pneumocystis Pneumonia (PCP).

With the emergence and spread of the 2019 novel Coronavirus (COVID-19) it has become imperative to consider this virus when beginning patients on immunosuppressive therapies.  The virus originated in bats and was transmitted to humans through unknown intermediary animals in Wuhan-Hubei Province, China, in December 2019.  Patients present with fever, cough, sore throat, breathlessness, fatigue, malaise and other symptoms.  This is predominately an upper respiratory infection.  However, a large subset of patients may be asymptomatic [19].  In February 2020, the World Health Organization (WHO) designated the disease COVID-19, which stands for Coronavirus Disease 2019 [20].  The virus that caused COVID-19 is designated as Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2).

This was a case of acute relapsing, remitting IMNM, with progressive severe life-threatening Dysphagia that required enteral feeding and aggressive immunosuppressive treatment.  The patient had no significant symptoms consistent with acute Coronavirus infection and underwent first IVIG treatment, Mycophenolate Mofetil, and subsequently plasma exchange treatment.  After just beginning plasma exchange treatment the patient became acutely Hypoxemic and Hypotensive and sustained a fatal cardiorespiratory arrest.  Postmortem reporting of respiratory secretions at the time of the cardiac arrest disclosed what was positive for COVID-19.  We now propose that even in asymptomatic rheumatological patients with rheumatological disease who are starting advanced immunosuppressive therapy that they be screened for COVID-19 in addition to Tuberculosis and viral Hepatitis.

This is an unfortunate case of a patient with a five-year history of IMNM who, on presentation, initially responded to IVIG, but with the most recent acute flare-up did not have a good response.  Despite high-dose intravenous steroids, IVIG, Mycophenolate (CellCept) and subsequent plasma exchange, the patient did not respond and had an acute deterioration with Hypoxemia, Hypotension, and Cardiorespiratory Arrest, all of which occurred suddenly.  Microbiology disclosed COVID-19.  Pre-mortem, prior to the patient’s Cardiopulmonary arrest, this infection was not suspected.  He had no fever or salient cough.  His shortness of breath appeared to be related to volume overload due to diastolic dysfunction, which responded to diuretics.  He had no significant radiographic infiltrates and no signs of elevated inflammatory markers.  The patient was, however, on high-dose steroids which may have suppressed fever and an inflammatory response.

Among subsets of patients at high risk of developing severe infections are patients with Rheumatic diseases including Lupus, Rheumatoid Arthritis, Scleroderma, Inflammatory Myopathies, and Vasculitis [17, 21]. The European League Against Rheumatism released guidance for patients with rheumatic and musculoskeletal diseases receiving immunosuppressive therapy, including biological agents and disease-modifying anti-rheumatic drugs [22].

COVID-19 can cause viral Pneumonia.  This patient showed no evidence of Radiographic Viral Pneumonia or increased biomarkers.  In addition, COVID-19 can cause myocardial damage and Myocarditis.  This patient’s echocardiogram showed no evidence of myocardial impairment and Troponins and BNP were negative for myocardial injury during the patient’s hospital course.  Also, acute viral infections can be responsible for Acute Coronary Syndrome, and plaque rupture can trigger and precipitate Acute Coronary Syndromes and plaque rupture, but this was not demonstrated in this case [23].  It appears the patient developed an abrupt, overwhelming, acute Respiratory Distress Syndrome, which came on precipitously as a result of the virus in a very immunocompromised host.

 

Figure: A recent JAMA Cardiology article published the above chart indicating the potential mechanisms for acute effects of viral infections on the Cardiovascular system [23, JAMA Cardiol. Published online March 27, 2020. doi:10.1001/jamacardio.2020.1286]. The pathway outlined in red represents the patient in this case study.

 

CONCLUSIONS:

We believe this to be a landmark case and we discuss recommendations for expanded guidelines.  To this end we present a patient with IMNM who required aggressive immunosuppressive therapy because of acute relapse and significant progression of dysphagia.  Unexpectedly, the patient had an acute cardio-hypoxemic episode with cardiopulmonary arrest which was terminal.  He had no significant symptoms or radiographic consistent with COVID-19 acute infection.  He may have developed the infection while in the hospital, but this is uncertain.  We propose that rheumatological patients, even when asymptomatic, be tested for COVID-19 prior to initiating second-line immunosuppressive therapy treatment.

 

 

REFERENCES

__________

[1] Five or six hours after workout, the decreased body core temperature signals the body to sleep, promoting less time to fall asleep and sounder sleep cycles, resulting in more restorative sleep and less daytime drowsiness.  Also, since Exercise helps to reduce body weight (see below), less weight may mean less risk of Sleep Apnea and snoring.

[2] Exercise increases circulation, thereby increasing tissue oxygenation and removal of wastes from throughout the body (detoxifies).  In the brain, this improves function, including concentration, creativity, and productivity.  In addition to an improved cardiovascular system, the endorphins released stimulate the mind for more creative thoughts.

[3]  “Too busy” is a logical excuse to skip a work out, but physical activity actually helps alleviate stress and promotes productivity.  Exercise increases the body’s ability to handle stress.  It produces higher levels of norepinephrine, a chemical that regulates areas of the brain that send stress signals.  The more the body is trained with the healthy physical stresses of mild to moderate exercise, the better the body responds to emotional and mental (as well as physical) stresses.

[4]  Through aging, brainpower decreases and the brain actually grows smaller.  Mental decline can start as early as 24 years of age.  The elderly who exercise show less brain shrinkage than those who do not.  Therefore, exercise may also reverse brain shrinkage.  Regular physical activity (3 to 5 times a week for 30 to 60 minutes) helps maintain or sharpen thinking, learning, and judgment skills with age, and increases memory by increasing the volume of gray matter in the brain.

[5]  The P&S (autonomic) nervous systems control and coordinate all of the organs and “involuntary” functions of the body.  A proper balance is needed, both at rest and during activity.  Note, sleeping is an activity and so is sitting at a desk and working, but sitting watching television is not.  Exercise by itself can balance the P&S nervous systems better than any supplement or diet alone.  Again, the best is when exercise and diet and the rest of the Mind-Body Wellness Program are taken together!  Establishing and maintaining P&S balance should always be a goal, and mild to moderate exercise (at a minimum) is an excellent adjunct to pharmacology and other lifestyle measures, including diet in this regard.

[6] Exercise reduces stress, reducing cortisol levels (as mentioned above), psycho-social stress, anxiety, depression (as mentioned above), and fatigue.  It reduces oxidative stress, improving endothelial function, increasing nitric oxide production, and the numbers of mitochondria for more energy.

[7] Physical activity engages the entire body, and a healthier cardiovascular system means the heart is better able to circulate blood to all parts of the body, including in older individuals.  Heart disease and stroke are two of the leading causes of death in the United States.  Following physician recommendations and getting at least 150 minutes a week (2½ hours) of moderate-intensity activity reduces the risk for these diseases.  The more (mild to moderate) exercise, the more that risk is reduced.  Regular physical activity improves almost all cardiac risk factors, including by increasing HDL cholesterol, lowering LDL cholesterol (clears arteries), lowering blood pressure, increasing cardiovascular fitness, and making the blood less prone to thrombosis or clotting, not only around the heart but also in the brain.  Greater blood flow to the brain underlies the brain function improvements mentioned above, including:  restorative sleep, improves mood, reduces depression, helps clear “brain fog,” improves cognitive abilities, and perhaps memory.

[8] Exercise reduces cortisol release for better neuroendocrine balance.  It helps to keep insulin levels healthy and increases insulin sensitivity.  It boosts sex hormones.  It helps to maintain healthy thyroid and hypothyroid hormone levels, including levels of growth hormones, which in adults helps with healing and repair.

[9] Diet and physical activity play a critical role in weight management.  Weight gain occurs when the calories burned, including those burned during physical activity, are less than the calories consumed.  The amount of physical activity required for weight management varies greatly, depending on metabolism (genetics), age (including stage of development), environment, and more.  Physical activity can help with weight loss as well as weight maintenance.  Establishing and maintaining a healthy weight requires both regular physical activity and a healthy eating plan.

[10] Regular physical activity reduces risk of developing type 2 Diabetes and Metabolic Syndrome.  Metabolic Syndrome includes a combination of (1) too much fat around the waist, (2) high blood pressure, (3) low HDL cholesterol, (4) high triglycerides, or (5) high blood sugar.  Lower rates of these conditions are seen with 120 to 150 minutes (2 to 2½ hours) a week of mild to moderate-intensity aerobic activity.  The more exercise, the more the risk is reduced (to a limit – see your doctor).  Regular physical activity also helps control blood glucose levels and can reverse type 2 Diabetes and Metabolic Syndrome.

[11]  Regular physical activity reduces risk of cancers as compared with people who do not exercise regularly.  Physically active people have a lower risk of colon cancer.  Physically active women have a lower risk of breast cancer.  Regular physical activity reduces risk of endometrial and lung cancer.  Improve quality of life.  Cancer survivors who exercise regularly have improved quality of life and physical fitness over those who do not.

[12] Bones and joints, as well as muscles, change with activity level and age.  They also need more protection with age.  Physical activity strengthens them, which protects bones and joints.  Strong and healthy bones, joints, and muscles promote an active lifestyle.  Adding a proper diet ensures the necessary micronutrients to maintain bone, joint, and muscle health.  Physical activity of at least a moderately-intense level slows the loss of bone density that comes with age.  Altogether, exercise helps to reduce the risk of falling in elderly, either due to fewer leg bone fractures or improved muscle strength.  Hip fracture is a serious health condition that often negatively affects quality of life, especially for older adults (e.g., climbing stairs, grocery shopping, or playing with the children or grandchildren).  However, 2 to 5 hours of at least moderate-intensity aerobic activity each week lowers risk of hip fracture.

Regular physical activity reduces risk of developing, and helps to manage, arthritis and other joint disorders.  For arthritis, 2 to 2½ hours a week of moderate-intensity, low-impact activity improves the ability to manage pain and do everyday tasks, and improves quality of life, not just from the pain, but also in terms of range of motion.

Muscle-strengthening activities help increase or maintain muscle mass and strength.  Gradually increasing the amount of weight and number of repetitions provides even more benefits, including endurance, no matter the age.  Regular physical activity helps to return and improve quality of life, reduces morbidity risk (including dizziness and lightheadedness, thereby reducing fall risk), and mortality risk, at any age.

[13] Exercise alone has never been proven to increase longevity.  However, by reducing mortality risk, increasing the antioxidant milieu, boosting immune activity, reducing stress (including pain), and maintaining nervous system and cardiovascular health (establishing and maintaining P&S balance and Mitochondrial health in support of wellness), a patient’s natural longevity is promoted or preserved.  Only a few lifestyle choices have as large an impact on health as physical activity.  People who are physically active for about 7 hours a week have a 40% lower risk of dying early than those who are active for less than 30 minutes a week; and this activity does not have to be vigorous; moderate-intensity is sufficient.  Everyone may gain the health benefits of physical activity.  Age, ethnicity, shape, or size does not matter.  One hundred and fifty minutes of moderate exercise per week (approximately 21 minutes per day) is routinely advocated for patients.

[14] DePace NL, Colombo J.  Autonomic and Mitochondrial Dysfunction in Clinical Diseases:  Diagnostic, Prevention, and Therapy.  Springer Science + Business Media, New York, NY, 2019.

[15] Dalakas MC.  Inflammatory Muscle Diseases.  N Engl J Med. 2015 Jul 23; 373(4): 393-4. doi: 10.1056/NEJMc1506827.

[16] Basharat P, Christopher-Stine L.  Immune-Mediated Necrotizing Myopathy: Update on Diagnosis and Management.  Curr Rheumatol Rep. 2015 Dec;17(12):72. doi: 10.1007/s11926-015-0548-6.

[17] McGrath ER, Doughty CT, Amato AA.  Autoimmune Myopathies: Updates on Evaluation and Treatment.  Neurotherapeutics. 2018 Oct;15(4):976-994. doi: 10.1007/s13311-018-00676-2.

[18] Marie I, Ménard JF, Hachulla E, et al. Infectious complications in polymyositis and dermatomyositis: A series of 279 patients.  Semin Arthritis Rheum. 2011; 41(1): 48–60. doi: 10.1016/j.semarthrit.2010.08.003. Epub 2010 Nov 2.

[19] Singhal T.  A Review of Coronavirus Disease-2019 (COVID-19).  Indian J Pediatr. 2020 Apr; 87(4): 281-286. doi: 10.1007/s12098-020-03263-6. Epub 2020 Mar 13.

[20] McIntosh K.  Coronavirus disease 2019 (COVID-19) – Update.  March 2020; https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19.

[21] Hospital for Special Surgery: What to know about Rheumatic Diseases and the COVID-19 coronavirus, published March 11, 2020, access March 13, 2020, https://www.hss.edu/conditions_ rheumatic-disease-and-COVID-19-coronavirus. asp

[22] European League Against Rheumatism (EULAR).  EULAR Guidance for patient’s COVID-19 outbreak. Accessed March 13, 2020 www.eular.org/eular_guidance_for_patients_covid19_outbreak.cfm.

[23] Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O.  Potential Effects of Coronaviruses on the Cardiovascular System:  A Review.  JAMA Cardiol.  Published online March 27, 2020. doi:10.1001/jamacardio.2020.1286

Read More
Autonomic_Changes_With_Age: Diabetic Patients

Biological Aging and Anti-Aging Mechanisms

Click here to download this post

The main risk factor for atherosclerosis or hardening of the arteries is usually aging.  The older one gets the more likely they are to have atherosclerosis or hardening of the arteries and complications, such as stroke and heart attack.  In addition, in regard to the nervous system, specifically the Autonomic Nervous System (ANS), there is also a significant risk factor for malfunction with degeneration of nerve fibers; including due to a lack of a proper blood supply to the very delicate fibers.  This is a delicate interaction.  The ANS, specifically the Sympathetic branch of the ANS, controls the vasculature and thereby proper blood profusion of the various tissues.  It is the Parasympathetic branch of the ANS that senses tissue perfusion and drives the Sympathetics to that end.  Normal, natural aging processes cause declines in the Parasympathetic and Sympathetic (P&S) Nervous Systems.  Chronic disease and other chronic condition that cause oxidative stress, accelerate these declines.  Reduced P&S activity to the vasculature reduces blood perfusion, which accelerates the aging of the nerves and tissues, which further reduces blood perfusion, and so goes the circle.  Unfortunately, this is asymptomatic for up to two decades before patients feel it; at which time it is very late in the progression.

See the figure below comparing 300 healthy subjects over time and 500 chronic disease subjects over the same time.  Notice that the upper curves show a gradual decline over time in the healthy subjects.  The lower curves show a more rapid decline in the chronic subjects, then the decline virtually stops once the patients comply with therapy.  Note, however, that the virtual stop occurs just above the horizontal broken line that indicates Cardiovascular Autonomic Neuropathy (CAN) which is end stage autonomic dysfunction and increased mortality risk (a 50% greater chance of heart attack or stroke in the next two years as compared with age-matched patients not demonstrating CAN).  Note, DAN is the abbreviation for Diabetic Autonomic Neuropathy (also known as Advanced Autonomic Dysfunction in non-Diabetics).  DAN is the precursor to CAN.

Eventually, age catches up with the chronic subjects and their decline parallels the healthy subjects with one important difference.  For the healthy subjects the Parasympathetics are a little higher than the Sympathetics.  This is reversed in the chronic subjects.  A little more Parasympathetic activity in the geriatric population is known to be cardio-protective and is associated with lower morbidity and mortality risks.  The more Sympathetic activity in the older chronic patients is associated with greater numbers of co-morbidities (25% more), prescribed pharmaceuticals (37% more), and life-threatening risks (e.g., Major Cardiovascular Adverse Events, or MACE, 18% more).  In addition, with aging we see more small fiber inflammation and subsequent decrease in density of small fibers, which carry sensory pain and autonomic impulses.  For both P&S decline and small fiber decline, early intervention often slows, significantly, the decline of nerve function (see figure below).  In the case of the P&S Nervous Systems, early interventions may return a patient to the normal path and perhaps buy back up to 20 years.

Vascular aging causes degeneration and hardening of the arteries and degeneration of the nerve fibers which ultimately affect every organ creating end-organ changes; particularly, the heart, brain and kidneys are very susceptible.  In general, age dependent injury to the vasculature and the nerve fibers becomes more manifested in the fifth or sixth decade of life.  However, some people develop this more prematurely, such as diabetics or individuals with high genetic lipid disorders, or other genetic disorders.  Some individuals have aging of their fibers and blood vessels more rapidly than other and, therefore, their biological age progresses faster than their chronological age.

There are certain noninvasive tests and blood test and biomarkers that can assess how the aging process is progressing.  Perhaps, the most well known is the length of the telomeres.  Telomeres are repetitions of DNA sequences that protect the end of chromosomes.  With each cell division, the telomere is shortened and at such a point when they get below a critical length cells will be susceptible to death.  As a telomere is shortened, one can get a higher incidence of heart disease, coronary artery disease, and cerebral vascular disease.

Other mechanisms, such as DNA methylation and low-grade inflammation may accelerate the aging process.  The most common inflammation marker that we measure is C-reactive protein.  Interleukin-6 is also another factor, which can be measure and be reflective of increased biological aging.  However, there is no one blood test that can indicate whether an individual’s nervous system or vascular system is aging prematurely or more rapidly.

Recently, the leaky gut disorder has become a very popular topic and has been associated with many changes in the ANS and malfunction and degeneration of the ANS.  Gut or gastrointestinal dysbiosis (microbial imbalance) has been linked to increase mortality risk and to disease.  Increased gut permeability alters the microbiotic composition; that is the composition of one’s intrinsic bacteria in their GI tract.  Toxic metabolites, if they leak through the cell junctions, can enter the blood stream and cause significant damage to blood vessels and nerves in the long term.  Breath tests and various urine tests after ingesting specific compounds can detect Chronic Intestinal Bacterial Overgrowth (CIBO) syndromes which if not corrected can be detrimental to vascular and neural structures.

Many noninvasive tests can assess whether one’s vascular system or neural system is prematurely aging.  We particularly like to assess HRV testing modalities especially coupled with respiration to assess Parasympathetic and Sympathetic power.  Sudomotor testing can assess small fiber integrity, inflammation and deficiency.  Carotid intimal thickness measures the thickness inside the carotid arteries and can also assess plaque burden, volume and density, which can be a surrogate for atherosclerosis and vascular aging.  Endothelial dysfunction, which can be derived from measures of ultrasound flow-mediated dilatation, or other similarly noninvasive techniques, which are easily available to clinicians in a laboratory and can demonstrate a malfunction of the small cells lining the arteries as one ages.  Calcium phosphate crystals deposited in the inner layer of the artery or the arterial intima, which is related to atherosclerosis, can be assessed with various tests.  Commonly used is a CT scan of the heart in which one calculates your Coronary Artery Calcium Score (CACS).  These are tests that can be obtained quite inexpensively and give a scoring system and assess the risk of future cardiac events and your degrees of potential atherosclerotic burden.  This test correlates well with coronary artery plaque burden.

Tests that measure arterial stiffness and velocity in the arteries, such as carotid-to-femoral pulse wave velocity or brachial-to-ankle pulse wave velocity can give an indication of how stiff the arteries are and how they are aging.  A high pulse wave velocity increases risk of cardiovascular disease and mortality from other causes.  Hypertension can promote arterial aging and rigidity as can high cholesterol, sedentary lifestyle and poor diet, such as high meats and saturated fats, high salt intake and high refined sugars.  Cigarette smoking is also a major culprit.  While alcohol in low quantities may be protective for vascular endothelium, high quantities can be deleterious and can accelerate vascular aging.  Sleep habits are also important in regard to aging of the blood vessels and nerves in the body.

We strongly promote a Mediterranean diet with high fruits and vegetables, nuts, seeds and legumes, and moderate alcohol consumption with flavonoids and antioxidants, such as with wine products, omega-3 intake with fish.  In fact, omega-3 and fish oils have been shown to potentially decrease telomere length shortening and may have significant anti-aging properties.

There are many natural behavioral and pharmacological strategies which have anti-aging potential on the nerve fibers and blood vessels.  Behavioral strategies include moderate alcohol consumption, exercise 150-200 minutes a week, weight reduction, diet high in antioxidant contents such as the Mediterranean diet and even supplements with antioxidant properties such as Alpha Lipoic Acid, which is extremely beneficial to nerve fibers, specifically autonomic nervous system fibers, or small C fibers.  Cofactors with methylfolate and B vitamins are extremely beneficial also in preserving small fibers and even regenerating growth of them when they are deficient.

We have used Beetroot, L-arginine and L-citrulline as nitric oxide-producing compounds to better enhance endothelial function and preserve endothelial integrity and keep the blood vessels healthy.  These produce nitric oxide by various mechanisms.  As one ages, nitric oxide declines in a linear fashion, which is detrimental to the blood vessels.  High vegetable and fruit intake is also associated with improving endothelial function and decreased arterial stiffness and decreased blood pressure.

Other studies have shown arterial function is less stiff and improves with flavonoids and cocoa, tea, coffee and wine, also in fermented dairy products, nut, seeds and vegetables.  Olive oil and monosaturated fat has been shown to be extremely beneficial as an anti-inflammatory agent and endothelial-improving agent.

Key pathways to be regulated in the aging process that should be targeted are the mechanistic target of Rapamycin (mTOR) and Adenosine Monophosphate Activated Protein Kinase (AMPK).  By inhibiting the mTOR and activating the AMPK, arterial stiffness can improve and blood pressure control can become better.

Regular moderate exercise to strengthen bone helps to keep calcium in the bone and reduce the calcium in arteries which reduces atherosclerosis, thereby reducing arterial stiffness.  Vitamin K2 (not ‘K’ but ‘K2’) is a new consideration in the anti-aging process.  Vitamin K2 works to redirect calcium from the soft tissue (e.g., arteries) to hard tissue (e.g., bones).  However, you must check with your physician to ensure that you are not at risk for blood clots.  Vitamin K2 may increase the risk of blood clots.

Metformin is one of the most prescribed medicines for diabetes.  It has antioxidant effects in addition.  Besides increasing insulin sensitivity, Metformin beneficially activates AMPK and beneficially inhibits mTOR.  Endothelial function, vascular stiffness and carotid artery calcium have been improved with Metformin.  Metformin has cardiovascular mortality benefits independent of its blood sugar lowering results.  In addition, there has been data to suggest it can prevent certain types of cancer such as colon cancer.  Perhaps the best agent to prevent cancers is the Mediterranean diet which has been purported to reduce at least 16 types of cancer.  Resveratrol is a polyphenol naturally present in grapes and berries and especially red wines.  It also activates AMPK and inhibits the mTOR pathways and has been very beneficial in protecting blood vessels and with antioxidant effects protecting nerve fibers.  In animal substances, Nicotinamide Adenine Dinucleotide has been shown to have anti-aging effects on the blood vessels.

Anti-inflammatory agents are being developed to beneficially affect nerve fibers and blood vessels.  More research is needed in that area.  One of the most unappreciated anti-inflammatory agents are Omega-3 fatty acids, such as from or fish or krill oils; especially the compound Eicosapentaenoic Acid (EPA) in fish oils can reduce heart attacks and strokes, up to 25% as found in one study; even on top of statin therapy.

Gut dysbiosis contributes to inflammation and abnormalities of the ANS and the vascular system.  Probiotics have been suggested as being useful in regulating gut dysbiosis as has certain antibiotics.

Risk reduction medicines used in heart disease, such as Aspirin, Statins, and Renin Angiotensin System blockers may have additional anti-aging potential.

Stress reduction and good sleep habits have significant effects on reducing oxidative stress and improving nerve fiber function and reducing degeneration of nerve fibers and improving blood pressure, endothelial function and arterial stiffness.  Relaxation techniques, such as meditation and yoga have been found to be extremely important in this regard.

We specifically use what we consider therapeutic quantities of Alpha Lipoic Acid, L-carnitine, and Co-enzyme Q10 in treating many of our patients with autonomic dysfunction and have found improvement in autonomic neuropathy testing parameters over a period of six months in these patients in our laboratory.  By combining these antioxidants, which we consider a Mitochondrial cocktail, as they produce more ATP energy molecules in addition to being good antioxidants, with Nitric Oxide producing compounds in appropriate concentrations (L-arginine, L-citrulline and Beetroot Extract), we believe we keep both the nerve fibers and arterial/vascular vessels from degenerating and aging.  By lowering LDL cholesterol below 70 and by keeping LDL molecules from being oxidized with the use of antioxidants, by exercising and weight reduction to raise beneficial HDL levels, the vacuum cleaner of the blood vessels, we believe that we can affect reversal of Atherosclerosis in many patient’s especially when anti-inflammatory agents, such as statins (Rosuvastatin) is added in selected instances.

One needs to discuss all of these ideas and concepts with their personal physician who knows their case in detail to recommend what lifestyle, dietary, and pharmacological supplement and other additions or alterations in their regimen need to be done.

Read More

Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)

Click here to download this post

ME/CFS is a common and very debilitating disease for which the origin, or etiology, is unknown. While there is some controversy about the exact cause or causes, much has been learned in the last 20 years.  One widely held theory is that patients with a genetic predisposition and abnormal bacteria colonization, or dysbiosis, experience a gradual development of lymphocytes which are known as B cell clones which are susceptible to autoreactivity.  Normally these B cells produce normal antibodies in the body.  However, during unusual circumstances a triggering event such as a viral or a bacterial infection can cause these B cells to become autoreactive and produce autoantibodies.  Therefore, there was some belief there may be an autoimmune mechanism which begins evolving and causes this disease process.

ME/CFS is a chronic disease that usually has lasted for more than six months.  The result is post-exertional fatigue, unrefreshing sleep, memory and cognitive disturbances (“Brain Fog”), and oftentimes Autonomic Nervous System dysfunction (typically involving Parasympathetic Excess, an abnormal increase in Parasympathetic activity in response to a Sympathetic challenge or stress).  Usually the stricken individual was very active prior to the onset of the disease.  The disease usually persists as a chronic condition.  Females are affected more than males.  As many as 8 million Americans may be affected.  While the cause of ME/CFS is unknown, many factors are through to contribute to the development of the illness, such as:  (1) bacterial or viral infections, or (2) physical or emotional trauma, including from an accident, concussion, immobilization, surgery, trauma, or even a significant emotional stress such as loss of a loved one.  Genetics may also contribute, and a genetic link with common environmental exposures, such as infectious or toxic has been postulated.  Identical twins have a higher incidence then fraternal twins.  Environmental factors, such as molds or toxins may also be a trigger to ME/CFS.  However, no one common cause has been identified.  This is because the population is heterogenous.  Patients are affected at different ages and have different presentations.

Dysfunctional energetics at the cellular level is believed to be a common mechanism.  Disturbed muscle function, metabolism, mitochondrial function, immunity, signaling, neurological, and adrenal and gut health are involved.  Specifically, abnormal metabolism regarding the mitochondria has been demonstrated.  Urea Cycle dysregulation, Tricyclic Carboxylic Acid (TCA) Cycle disturbances, and dysregulation of Amino Acid metabolism are also involved.  Also, gut microbiota disturbances have been identified.  In regard to Mitochondrial dysfunction, studies state that ATP8 levels have been both noted to be reduced and elevated, and resting ATP8 synthesis rates have been variable.  However, studies on isolated Peripheral Blood Mononuclear Cells have shown that under stress such as Hypoglycemia there is inefficient ATP8 production in Chronic Fatigue patients but not in normal controls.  This was demonstrated by Tomas and coworkers in 2017.  Therefore, while resting ATP studies show that production may not be significantly abnormal in ME/CFS patients as compared with controls, it appears that under stressful situations, such as Hypoglycemia, the situation is different when one analyzes peripheral blood mononuclear cell ATP production.  ATP is the energy molecule of the cell and of the body and is produced in the Mitochondria, which are the energy factories of the body.

Mitochondria are organelles, or components of cells, which are very active and contain their own DNA contents separate from the nucleus of the cell.  Elevated oxidative stress has also been demonstrated in many subpopulations of patients with ME/CFS.  Increasing oxidative stress has been demonstrated with testing products which are the result of oxidative stress, which include increased isoprostane, increased oxidized LDL levels, and increased iso-prostaglandin F2 levels. Also, reduced protective antioxidants, such as glutathione levels have been reduced in populations of patients with ME/CFS.  Oxidative stress is produced when free radicals are produced in the mitochondria of cells in abundance during stressful situation and in essence cause a chemical burning reaction in damaged tissues.

Figure Legend: Schematic diagram showing various viral pathogens potentially associated with ME/CFS and possible molecular mechanisms altered by these pathogens that can contribute to ME/CFS development [[i]].

Plioplys and coworkers demonstrated lower levels of serum total Carnitine, free Carnitine, and Acetylcarnitine compared to healthy controls, and the lower level correlated with the more severe disease and ME/CFS patients.  Carnitine is an important natural component in transporting Fatty Acids across the Mitochondria cell membrane to continue the process of fatty acid oxidation, which also produces ATP molecules.

In regard to ATP molecules, Mayhill and coworkers measured Mitochondria function and ATP production in Neutrophils and developed an ATP profile test.  More elements of the ATP profile are abnormal in patients with ME/CFS.  Again, this reinforces the fact that there are abnormal energetics occurring within the Mitochondria of cells.  They state “our observations strongly implicate Mitochondrial dysfunction as the immediate cause of chronic fatigue symptoms.  However, we cannot tell whether the damage to Mitochondria function is a primary effect or a secondary effect to one or more of a number of comorbidities, for example, cellular hypoxia or oxidative stress, including excessive peroxynitrates.”

[i] Rasa S, Nora-Krukle Z, Henning N, Eliassen E, Shikova E, Harrer T, Scheibenbogen C, Murovska M, and Prusty BK.  Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).  J Translational Med.  2018; 16: 268, doi:10.1186/s12967-018-1644-y.

 

Figure Legend:  Main stages and location of energy metabolism in a human cell (left), and simplified details of a mitochondrion showing the main metabolic cycles and the oxidative phosphorylation respiratory chain (right). The outer mitochondrial membrane is highly permeable whereas the inner membrane is permeable only to water and gases. Special carrier and Translocator proteins pass reactants through it. At the top are the proteins involved in the respiratory electron transfer chain (ETC) and in the transfer of ATP and ADP between the cytosol and mitochondrion. ADP and Pi are combined by ATP synthase to make ATP. The ADP/ATP Translocator opens OUT to transfer ADP into the matrix and opens IN to transfer ATP to the cytosol. Nicotinamide adenine dinucleotide plays a key role in its oxidized form NAD+ and its reduced form NADH + H+ in carrying and transferring protons (H+) and electrons (e) [[i]].

Key reports on ME/CFS have shown abnormal metabolites produced which demonstrate disturbed Amino Acid metabolism, dysregulated lipid metabolism with possible glycolysis impairment, possible Pyruvate Dehydrogenase (PDH) impairment, Urea Cycle dysregulation and overall TCA cycle substrates provision deficiency and reliance these cells for alternate fuel sources.  As noted, Mitochondria function has been shown to be abnormal and the Electron Transport Chain, specifically if Complex IV is inefficiently compensated for the up-regulation of supporting pathways.

[i] Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction.  Int J Clin Exp Med. 2009; 2(1): 1–16. 

Abnormalities in B cells have been linked to mitochondrial disturbances and as gut microbiota and physiology.  Autoimmunity has been little researched but has been performed on a subtype that is especially comorbid with Irritable Bowel Syndrome, which is seen in many Chronic Fatigue patients.   Autoimmune evidence has been strengthened by the fact that there is a decrease in the natural killer cell cytotoxicity in patients with ME/CFS.  Natural killer cells are Granular Lymphocytes which attack viruses and bacteria foreign to the body.  In addition, the autoimmune evidence is supported by autoantibodies which have been noted against various transmitter receptors, both Muscarinic receptors and Beta receptors.  A high incidence of these receptors has also been found in patients with Postural Orthostatic Tachycardia.  Specifically, autoantibodies against the Muscarinic and Cholinergic receptors #3 (M3) and autoantibodies against the Muscarinic and Cholinergic receptor #4 M4) are elevated in 20-30% of all patients suffering from ME/CFS.  Other studies have shown Beta-1 Adrenergic Receptor Autoantibodies and Beta-2 Adrenergic Receptor Autoantibodies along with Alpha-1 Adrenergic Receptor Autoantibodies, the same autoantibodies which we find in a significant number of patients with Postural Orthostatic Tachycardia Syndrome.

Testing for these autoantibodies is expensive, and it is not proven that immunomodulating therapy or steroids may be effective in these patients although there is some data that low-dose Hydrocortisone does improve patients with ME/CFS.  There is also data that B lymphocyte cell depletion with a drug known as Rituximab can result in clinical benefit also.  Also, an immunoabsorption technique which removes Beta 2 receptors and depletes them has been shown to be effective.  This supports a cause and effect relationship with autoantibodies against receptors and removing them as a clinical response.  This improvement in patients has been seen with Chronic Fatigue.  In one study, immunoabsorption removed Beta 2 Adrenergic Receptor Antibodies in patients with ME/CFS and showed clinical improvement in memory in symptoms. Some of these patients had long-lasting improvements, while others had short lasting improvements.  These are only pilot studies and more research is needed.  Other studies have also shown higher autoantibody levels against M1, M3 and M4 Acetylcholine receptors and Beta 2 Adrenergic receptors compared to controls.

Impairments of the Hypothalamic-Pituitary-Adrenal system (considered a portion of the Autonomic Nervous System) have also been reported.  There has been noted decrease in Adrenocorticotropic Hormone sensitivity of Adrenal cells expression of negative feedback mechanisms.  Some patients with ME/CFS have low Cortisol levels and improvement with low-dose Hydrocortisone has been shown in these patients.  In and to hormonal dysregulation, Autonomic dysregulation shows a strong association with ME/CFS.  Some studies have shown that more than 90% of patients with ME/CFS have Orthostatic Intolerance.  This is strengthened by the fact that many patients with Postural Orthostatic Tachycardia Syndrome (POTS) have similar autoantibodies to patients with ME/CFS.  Blood pressure or heart rate regulation abnormalities are seen particularly in adolescents with ME/CFS and many experience symptoms of Orthostatic Intolerance as noted.  These patients have worsening symptoms when they get upright posture and improvement when they lie down.

The association of Ehlers-Danlos Syndrome and Autonomic Dysfunction with high frequency of ME/CFS has been intriguing.  We believe that there is a genetic predisposition to patients with Ehlers-Danlos Syndrome and Hypermobility spectrum disorders, and they are susceptible to develop Autonomic Dysfunction and Chronic Fatigue after exposure to certain triggers, such as viruses, bacterial infections, emotional stress, trauma, and concussions.  Indices of inflammation are also noted to be increased in the populations of patients with ME/CFS.  Increased production of various proinflammatory cytokines produce symptoms of fatigue, fevers, adenopathy, myalgias, and arthralgias, sleep disturbances, cognitive impairment and mood disturbances.  Infections can trigger or initiate an autoreactive process affecting brain and energy metabolism in people genetically predisposed and patients with abnormal dysbiosis.  Patients experience a gradual development of a B cell clone prone to autoregulation, and this may lead to autoimmunity.

Some patients have abnormalities of levels of immunoglobulins.  Increased levels of IgA and in some cases, IgM have been noted, and these have been directed against endotoxin components of gram negative bacteria and may be the cause of increased gut permeability noted in many people with ME/CFS.

Exercise is the hallmark treatment for improving patients with ME/CFS.  Given that Parasympathetic Excess is a typical Autonomic Dysfunction, usually “low-and-slow” exercise is recommended.  Some experts in the field feel patients should exercise no more than two to five minutes at a time followed by five minutes of rest so not to damage skeletal muscle.  However, “low-and-slow” exercise, such as walking slowly at no more than 2 mph for 40 minutes, every day for 6 months.  No running or jogging or weight lifting or anything else that would raise heart rate too fast.  Even if biking or rowing, the motion is still as if walking at no more than 2 mph.  This is to re-train the Parasympathetic nervous system to accept small stresses, then larger stresses may be (re-)introduced.  For some patients, this is still too stressful.  For those days in which a patient simply cannot lift their head off the pillow, supine exercises are recommended, see figure below.

Antimitochondrial cocktails with antioxidants, such as Alpha Lipoic Acid, Coenzyme Q10 and L-carnitine have also been proposed by many experts and some patients are significantly benefited by these cocktails.

In regard to inflammation within the Central Nervous System, there is a glial activation or microglia activation which induces Nitric Oxide and superoxide production of free radicals.  These cause neural excitation and neurodegeneration of tissue.  Glial activation causes the chronic pain and allodynia in hyperalgesia via the impact a bidirectional signaling mechanism.

In regard to the unrefreshing sleep, we have already discussed the Hypothalamic-Pituitary-Adrenal Axis and the Hypocortisolism.  Two meta-analyses have shown an attenuated Cortisol awakening response which may contribute to this morning feeling of non-refreshing sleep.

In addition to exercise and antioxidants, a ketogenic diet, which is high fat and low carbohydrate and limits calorie restriction, or a fasting diet has been recommended.  This form of diet has variable results.

Recently from Stanford, a new blood test which produces a stressful environment to white blood cells, in this case mononuclear cells, was developed by Dr. Davis.  It appears that patients with ME/CFS have a very high abnormal gradient or electrical charge when exposed to a salt stress environment then cells from normal individuals.  Researchers are working arduously to develop these types of test, so we have more objective and easy ways to diagnose ME/CFS.  ME/CFS must be differentiated from other entities that have other symptoms which are active participants in causing a malaise, such as collagen vascular disease, cancer, anemia, depression, thyroid disease, drug or pharmacological effects, and other metabolic and infectious diseases.

We believe that mitochondrial mutations or chromosomal mutations in susceptible people may cause ME/CFS.  We believe that an autoimmune mechanism may be operative, where in some cases infections induce a normal immune response, but the pathogens may be close enough to our own receptors to cause them to be similarly attacked.  After this, additional infections or physical or psychological stress can intensify both the mitochondrial energy deficits and the autoimmunity, and this can create a vicious cycle of fatigue.  Patients can present with pain, brain fog, disability and poor exercise tolerance.  These are direct or indirect symptoms of Parasympathetic Excess.  The association of autoantibodies with similar autoantibodies with POTS and autonomic dysfunction syndrome in ME/CFS patients is not simply coincidence.  Note, the Parasympathetic nervous system controls and coordinates the immune system.  It may be possible that Parasympathetic Excess causes overactive and persistent immune responses that may lead to autoimmunity.  Studies have shown that positive autoimmune tests also show mutations in Mitochondria genes that play an important role in the five mitochondrial respiratory complexes (I, II, III, C & IV; see figure above) in the Electron Transport Chain that produces 90% of the body’s energy with ATP.

The overlap with Hypermobility syndrome, Chronic Fatigue and Autonomic Dysfunction with Orthostatic Intolerance or Parasympathetic Excess states leads us to believe that there is mechanism at the cellular level, which causes an acquired Mitochondria Dysfunction with abnormal energetics producing energy from the body, and that the insulting agents that trigger this are in may cases infectious or inflammatory and can be worsened by emotional stress or trauma stress.  They produce a state of inflammation known as oxidative stress which produces energy depleting agents (including oxidants) similar to autoimmunity.  Authors have shown that oxidation of critical parts, for example, the Pyruvate Kinase Enzyme System can affectively block the transition of Glycolysis to Aerobic Metabolism, and this demonstrates a biochemical feasibility mechanism.  Therefore, the autoimmune model involving the oxidative stress and acquired Mitochondria Dysfunction appear to have significant overlapping features when one looks at all of the studies that have been done on these populations of patients with ME/CFS.

What does this mean in terms of helping the patient?  More studies need to be done in terms of using immunomodulating agents in trials, such as IVIG, Corticosteroids and B cell depleting therapies.  More work is required assessing the types of exercise programs that are most effective, along with the types of diets that are more effective.  The typical American Diet, highly processed foods, full of chemicals, together with the high levels of Psychosocial stress in the American lifestyle may be more of a cause of Chronic Fatigue, than anything else.  More is required to study the components and dosages of Mitochondria cocktails that utilize antioxidant agents to see which are most valuable.  More work needs to be done to stratify the ME/CFS patients into different phenotypes or categories, as this is a heterogenous group of patients.  These patients have different presenting symptoms with different organ systems being more dysfunctional than others.

 

REFERENCES

1 Rasa S, Nora-Krukle Z, Henning N, Eliassen E, Shikova E, Harrer T, Scheibenbogen C, Murovska M, and Prusty BK.  Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).  J Translational Med.  2018; 16: 268, doi:10.1186/s12967-018-1644-y.

2 Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction.  Int J Clin Exp Med. 2009; 2(1): 1–16. 

Read More