Click Here to Download this Blog Post – Long COVID and Multi-Organ Disorder

Here we provide a definition for this syndrome and discuss the organs that are involved. The involvement of multiple organs is due to that fact that angiotensin converting enzyme-2 receptors (the entry points for the virus), inflammation and oxidative stress (the immediate effects of the virus) effect all systems of the body. We suggest that this is then perpetuated by a resulting autonomic dysfunction. Since the autonomic dysfunction also effects all systems of the body, the initial infection is compounded and perpetuated by the resulting autonomic dysfunction underlying the Long-COVID Syndrome. We discuss the symptoms and suggest therapies that target the underlying autonomic dysfunction to relieve the symptoms, rather than merely treating symptoms. In addition to treating the autonomic dysfunction, the therapy also treats chronic inflammation and oxidative stress. To fully document the autonomic dysfunction, a full assessment of the autonomic nervous system is recommended, including Cardio-Respiratory Monitoring. Specific measurements of Parasympathetic and Sympathetic activity, both at rest and in response to challenges, connects all symptoms of Long-COVID to the documented autonomic dysfunction(s).

Citation: Nicholas L DePace, Joe Colombo (2022) Long-Covid Syndrome: A Multi-Organ Disorder. Cardio Open, 7(1): 213-224 

History   

COVID-19 was reported in Wuhan, China in December 2019. It is caused by a small novel coronavirus. The acute phase of COVID-19 infected patients has been well described and may a have varying number of symptoms and intensity. The majority of patients have fever, sore throat, cough, shortness of breath, and chest pain. Although, multiorgan involvement may become extensive. COVID symptoms may be identified in six clusters [1]. These include: 1. Flu-like with no fever, which consist of headache, loss of smell or taste, cough, muscle pains, sore throat, chest pains. 2. Flu-like with fever, which consists of headache, loss of smell or taste, cough, sore throat, hoarseness, fever, loss of appetite. 3. Gastrointestinal, which consists of headache, loss of smell or taste, loss of appetite, diarrhea, sore throat, chest pain, but no cough. 4. Severe level one, fatigue with headache, loss of smell or taste, cough, fever, hoarseness, chest pain. 5. Severe level two, which consists of confusion with head ache, loss of smell, loss of appetite, cough and fever, hoarse ness, sore throat, chest pain, fatigue, and muscle pain. 6. Severe level three, which is abdominal and respiratory dysfunction with headache, loss of smell or taste, loss of appetite, cough, fever, hoarseness, chest pain, fatigue, sore throat, confusion, muscle pain, diarrhea, shortness of breath and abdominal pain. The recovery from COVID-19 usually occurs at seven to ten days after the onset of symptoms in mild disease but could take up to six weeks in severe or critical illness. It is for this reason that mild cases are usually quarantined for between 7-10 days, and severe illnesses are for a more extended period of time. However, it is believed that even when one is ill for 3-6 weeks, they are probably not actively contagious. Some studies have shown that active coughing is indicative of continuing contagiousness. This has not been clarified. Studies have shown that household cases support the highest incidences of contagious ness and that rational for masks appears to be most beneficial with close contacts for prevention. The most common feature of acute illness is interstitial pneumonia, which may in some cases be complicated by the serious acute respiratory distress syndrome where individuals require high doses of oxygen. This has a high mortality particularly in elderly people who have comorbidities. The cough is usually dry. Laboratory abnormalities may be present and include low lymphocyte counts, elevated inflammatory markers, such as Sed Rate, C-reactive protein, Ferritin, Interleukin 1 and 6, and Tu mor Necrosis Factor abnormalities, and others, which will be discussed later. Coagulation system abnormalities may occur (to be discussed later). Clots may form in the acute phase as well as in the subacute phase, especially if there is a history of clots.  

Click Here to Download this Blog Post – Long COVID and Mitochondrial Dysfunction

Excerpt from the Article “Long COVID and the Autonomic Nervous System: The Journey from Dysautonomia to Therapeutic Neuro-Modulation through the Retrospective Analysis of 152 Patients ” published in MDPI

The severity and prevalence of Post-Acute COVID-19 Sequela (PACS) or long-COVID syndrome (long COVID) should not be a surprise. SARS-CoV-2 targets diverse organs and tissues after entry into the human body.

Long-COVID syndrome is defined as persistent symptoms beyond 12 weeks after acute COVID-19 infection. Viruses, by inducing an inflammatory state, can damage tissue. At a cellular level, the mitochondria are susceptible to the effects of inflammation and oxidative stress. Given that nerve cells, including brain cells, and heart muscle cells contain significantly more mitochondria than other cells in the body, it is to be expected that they will be the most affected by oxidative stress.

The results of mitochondrial dysfunction includes primarily autonomic dysfunction (including both parasympathetic and sympathetic (P&S)) and cardiovascular dysfunction. Arguably, the first symptom of P&S dysfunction is orthostatic dysfunction [5,6]. Orthostatic dysfunction is a significant contributor to poor cardiac and cerebral perfusion (and, of course, all structures around and above the heart). Autonomic dysfunction is also induced as a result of the severity of the infection.

Furthermore, COVID-19 injures the lungs, reducing their ability to exchange oxygen, exacerbating the poor perfusion and resulting dysfunctions. The initial respiratory compromise, due to the COVID-19 virus, on the medullary respiratory control centers (including the pre-Bötzinger complex) may be so dramatic that P&S symptoms and signs are often overlooked or misunderstood. Respiratory pacing from the pre-Bötzinger complex involves (1) vagus nerve afferents, among other brainstem structures; (2) feedback from the COVID-19-damaged lung; (3) aortic and carotid chemo-, baro-, and vagal receptors; and (4) medullary chemoreceptors. All involving P&S nerves.

Brainstem cardiorespiratory centers (e.g., the Nucleus Tractus Solitarius, Dorsal Vagal Motor Nucleus, and Nucleus Ambiguus, all of which are autonomic nuclei) are also implicated in COVID-19 infection. Furthermore, sympathetic involvement in cytokine storms and the angiotensin system, and parasympathetic involvement in immune function, provides further evidence of P&S compromise in COVID-19 infections.

Any resulting damage to these nerves further implicates P&S dysfunction in long-COVID syndrome. Long-COVID symptoms may be explained by a pro-inflammatory state with oxidative stress and P&S dysfunction. This study presents the data obtained from autonomic dysfunction patients who were P&S tested and treated prior to COVID-19 infection due to other causes of autonomic dysfunction. Then, they were P&S tested and treated after surviving COVID-19 infection. Long-COVID symptoms may be explained by a pro-inflammatory state with oxidative stress and P&S dysfunction. This is hypothesis generating. Long COVID is characterized by parasympathetic excess and alpha-sympathetic withdrawal. Anti-cholinergic therapy may relieve post-COVID-19 symptoms associated with parasympathetic excess. This is hypothesis generating and further trials are needed.

Long COVID and Autonomic Nervous System Imbalance

By Joseph Colombo, Michael I. Weintraub, Ramona Munoz, Ashish Verma, Ghufran Ahmad, Karolina Kaczmarski, Luis Santos, Nicholas L. DePace

Excerpt from Long COVID and the Autonomic Nervous System article published in MDPI

Introduction

COVID-19 is documented to adversely affect the autonomic nervous system. In many patients, the lingering effect on the autonomic nervous system results in what has been termed long COVID. Long COVID is well documented to involve the autonomic nervous system.

Autonomic Dysfunction in Long COVID

Autonomic dysfunctions may be peripheral or central. In central cases, autonomic dysfunctions may be related to microglial hyperactivation inside the brainstem autonomic centers. Microglial hyperactivation is associated with PE. Autonomic dysfunctions may also be highly influenced by psychological factors.

Parasympathetic Excess and Sympathetic Withdrawal in Long COVID

In our findings, Long COVID is largely characterized by parasympathetic excess and sympathetic withdrawal, both potentially contributing to hypoperfusion of the brain and all structures above and around the heart. Pre-COVID-19 infection, patients presented to the clinics with more sympathetic withdrawal (45.7%) than parasympathetic excess (27.0%). Post-COVID-19 infection, these patients presented with that ratio reversed (36.2% and 46.7%, respectively). The etiology of this is not well known; however, parasympathetic excess may be more prominent post-COVID-19, due to an over-active immune system, which the parasympathetics help to control and coordinate and leads to parasympathetic excess.

Role of the Parasympathetic Nervous System in Immune Response

Given that the parasympathetic nervous system controls and coordinates the immune system, severe infections lead to excessive and prolonged parasympathetic activation in response to challenges or stressors (known as parasympathetic excess), which exacerbates autonomic and cardiovascular dysfunctions.

Orthostatic Dysfunction and COVID-19

A common, and perhaps first cause of autonomic dysfunction, due to mitochondrial dysfunction and associated oxidative stress, is orthostatic dysfunction, resulting in poor cardiac and cerebral perfusions (and, of course, all the structures around and above the heart). Orthostatic dysfunction is caused by poor vasoconstriction due to alpha-adrenergic (sympathetic) dysfunction, known as sympathetic withdrawal. Poor perfusion and dysfunction are exacerbated by the effect of COVID-19 on the lungs. Both parasympathetic excess and sympathetic withdrawal are separate and treatable dysfunctions.

Pharmaceutical Treatment of Autonomic Dysfunction

As in this study, parasympathetic excess was treated, pharmaceutically, with anti-cholinergics (e.g., Nortriptyline, see the Methods Section) and sympathetic withdrawal was treated, pharmaceutically, with oral vasoactives (e.g., Midodrine, see the Methods Section). Our findings demonstrate an initial worsening of autonomic dysfunction and symptoms associated with COVID-19 infection, and then, with autonomic treatment, these dysfunctions and symptoms may again be relieved.

Sympathovagal Balance and Post-COVID-19 Syndrome

Traditionally, upon COVID-19 infection, there is a marked increase in the resting sympathetic activity and a decrease in anti-inflammatory resting parasympathetic activity, causing a high (resting) sympathovagal balance in all patients. However, in post-COVID-19 syndrome patients, after 12 weeks or more, our data shows that there is a significant percentage of patients that develop a parasympathetic dominance as indicated by the low (resting) sympathovagal balance. This is also indicative of increasing and prolonged parasympathetic activity.

Protective Role and Complications of Parasympathetic Activation

Parasympathetic activation is meant to be protective; including, since the parasympathetics are anti-inflammatory. However, prolonged and increased parasympathetic activity, especially in response to stressors, seems to exaggerate sympathetic inflammatory activity. Within this cohort, and anecdotally with the vast majority of our patients, anti-cholinergic therapy relieves parasympathetic excess. Further studies are required to elaborate whether anti-cholinergic therapy may relieve post-COVID-19 symptoms.

Symptoms of Long COVID Linked to Oxidative Stress and P&S Dysfunction

All symptoms of long COVID may be explained by oxidative stress and P&S dysfunction. For example, P&S dysfunction leading to orthostatic dysfunction underlies poor cerebral (including all structures above the heart) perfusion, which causes fatigue, brain-fog, cognitive and memory difficulties, sleep difficulties, and other depression-like symptoms, including “coat-hanger” pain, headaches and migraines; cranial nerve dysfunctions, including visual and auditory effects (including tinnitus), taste and smell deficits, and facial sensations due to trigeminal nerve dysfunction.

Blood Pressure and Cerebral Perfusion Compensatory Mechanisms

P&S dysfunction may also increase BP (and may eventually lead to hypertension) as a compensatory mechanism to promote cerebral perfusion. Further decreases in cerebral perfusion may lead to “adrenaline storms”, which cycle anxiety-like symptoms, including shortness of breath and palpitations which may cause chest pressure or chest pain. The effects of sympathetic withdrawal and orthostatic dysfunction are exacerbated by parasympathetic excess, which may limit or decrease the heart rate and blood pressure, reducing cerebral perfusion. The decrease in BP is also associated with excessive vasodilation from parasympathetic excess.

Prolonged Parasympathetic Excess in Long COVID

If the parasympathetics increase in response to a stress (known as parasympathetic excess), the result is a secondary sympathetic excess. Our findings of prolonged parasympathetic excess in long-COVID patients appears to prolong sympathetic excess responses causing more and chronic symptoms, suggesting that this may be a mechanism contributing to long-COVID syndrome.

Conclusion and Need for Further Research

Pharmaceutical therapy for P&S dysfunction (anti-cholinergics for parasympathetic excess and oral vasoactives for sympathetic withdrawal) needs to be very low to prevent additional symptoms, thereby exacerbating P&S dysfunction. From Table 3, COVID-19 significantly increases autonomic dysfunctions and the associated symptoms, and autonomic therapy significantly reduces autonomic dysfunctions and the associated symptoms. Further studies are needed, including blinded, controlled studies.

Long COVID and the Autonomic Nervous System: The Journey from Dysautonomia to Therapeutic Neuro-Modulation through the Retrospective Analysis of 152 Patients Joseph Colombo 1,*, Michael I. Weintraub 2,*, Ramona Munoz 1 , Ashish Verma 1 , Ghufran Ahmad 1 , Karolina Kaczmarski 1 , Luis Santos 3 and Nicholas L. DePace 1 1 Franklin Cardiovascular, Autonomic Dysfunction and POTS Center, Sicklerville, NJ 08081,USA;  rmunoz@franklincardio.com (R.M.); ashish@ashishverma.com (A.V.); ghufran.kmc@gmail.com (G.A.); kikaczmarski@gmail.com (K.K.); dovetech@erols.com (N.L.D.) 2 Department Neurology and Medicine, New York Medical College, Valhalla, NY 10595, USA 3 New Jersey Heart, Sicklerville, NJ 08081, USA; drlou214@icloud.com * Correspondence: jcolombo@physiops.com (J.C.); miwneuro@gmail.com (M.I.W.)

NeuroSci 2022, 3, 300–310. https://doi.org/10.3390/neurosci3020021