Click Here to Download this Blog Post –  Long COVID Syndrome and the Cardiovascular System: A Review of Neuroradiologic Effects on Multiple Systems

Nicholas L. DePace · Joe Colombo

© The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature 2022 

Abstract 

Purpose of Review Long-COVID syndrome is a multi-organ disorder that persists beyond 12 weeks post-acute SARS-CoV-2  infection (COVID-19). Here, we provide a definition for this syndrome and discuss neuro-cardiology involvement due to the  effects of angiotensin-converting enzyme 2 receptors (the entry points for the virus), inflammation, and (3) oxidative  stress (the resultant effects of the virus). 

Recent Findings These effects may produce a spectrum of cardio-neuro effects (e.g., myocardial injury, primary arrhythmia,  and cardiac symptoms due to autonomic dysfunction) which may affect all systems of the body. 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.  Together with a full noninvasive cardiac workup, a full assessment of the autonomic nervous system, specifying parasympathetic and sympathetic (P&S) activity, both at rest and in response to challenges, is recommended. Cardiac symptoms must be  treated directly. Cardiac treatment is often facilitated by treating the P&S dysfunction. Cardiac symptoms of dyspnea, chest  pain, and palpitations, for example, need to be assessed objectively to differentiate cardiac from neural (autonomic) etiology.

Summary Long-term myocardial injury commonly involves P&S dysfunction. P&S assessment usually connects symptoms  of Long-COVID to the documented autonomic dysfunction(s).

Click Here to Download this Blog Post – History of Long COVID

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.

Long-Covid Syndrome: A Multi-Organ Disorder Research Article 1 Franklin Cardiovascular Assoc., PA and Autonomic Dysfunction and POTS Center, Sicklerville, NJ, USA 2 Pennsylvania Hospital of the University of Pennsylvania Health System, Philadelphia, PA, USA 3 Neuro-Cardiology Research Corporation, LLC, Wilmington, DE, USA 4 CTO and Sr. Medical Director, Physio PS, Inc., Atlanta, GA, USA Nicholas L DePace1,2,3, Joe Colombo1,3,4* * Corresponding author Joe Colombo, Franklin Cardiovascular Assoc., PA and Autonomic Dysfunction and POTS Center, Sicklerville, NJ and Neuro-Cardiology Research Corporation, LLC, Wilmington, DE, CTO and Sr. Medical Director, Physio PS, Inc., Atlanta, GA, USA. Submitted: 04 Mar 2022; Accepted: 14 Mar 2022; Published: 23 Mar 2022

Copyright: ©2022 Joe Colombo. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Click Here to Download this Blog Post – Long-Covid Syndrome: A Multi-Organ Disorder Research Article 1

SARS-CoV-2 Infection COVID-19 is a major pandemic that is worldwide and causing significant mortality and morbidity. About 80% have mild to moderate disease. However, among the 20% with severe disease, 5% develop a critical illness. There is a subset of patients, however, who will have lingering, persistent or prolonged symptoms for weeks or month afterwards, which we termed “Post-Acute Sequelae of SARS-CoV-2 infection” syndrome or simply the “Post-Acute COVID-19 Syndrome” or “Long COVID-19” or just “Long COVID” or “Long Haulers COVID-19” or simply “Long Haulers” or “Post-Covid Syn drome.”

This has extended the significant worldwide morbidity from this pandemic. It is estimated that about 10% of patients who tested positive for SARS-COVID-19 will remain ill beyond three weeks and a smaller proportion for months. This is a sub set that constitutes the Long-COVID syndrome. Globally, there are estimated over 200 million confirmed cases of COVID-19. Although the majority of infected individuals recover, we still do not know the exact percentage that will continue to experience symptoms or complications after the acute phase of the illness is over.

This prolonged phase with morbidity and ongoing symptoms creates significant burden to the patient and burden to the health care system and is not completely understood. To complicate matters, not only do the long-term effects of those infected by the virus remain largely unknown, but there are also reports highlighting that sustained transmission and emergent variants continue to cause challenges to healthcare providers throughout the world, and therefore we do not know when the pandemic will cease. While it is estimated that 10% will develop a chronic syndrome, or symptoms that are persistent, this statistic may actually increase. Since this is a new illness, we do not know the cause or characteristics of the long-term sequelae of someone who has recovered from acute COVID, not just the quality of life, including mental health, but the employment and productivity issues become paramount when the acute phase of COVID, the subacute, and the chronic phases occur. In our experience, approximately 20% of people will exhibit symptoms for more than five weeks and 10% will have symptoms for more than 12 weeks.

Franklin Cardiovascular Assoc., PA and Autonomic Dysfunction and POTS Center, Sicklerville, NJ, USA 2 Pennsylvania Hospital of the University of Pennsylvania Health System, Philadelphia, PA, USA 3 Neuro-Cardiology Research Corporation, LLC, Wilmington, DE, USA 4 CTO and Sr. Medical Director, Physio PS, Inc., Atlanta, GA

Click Here to Download this Blog Post – Long COVID Adversely Affects the Autonomic Nervous System

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 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. 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.

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. 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. 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.

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. 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. 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. 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. 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. 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.