Abstract. SARS-CoV-2 is the cause of COVID-19 and is responsible for 270,000,000 confirmed cases and 5,200,000 deaths worldwide (January 1, 2022). Most persons who contract COVID-19 survive their illness, but up to 70% of survivors have one or more symptoms lasting for 3 months or greater. Cough, fatigue, resting tachycardia, dyspnea (difficulty breathing), post-exercise exhaustion, sleep disturbance, brain fog, and anxiety are common, lingering symptoms—symptoms which could only be explained by a multi-factor cause. The Gerson Institute of Āyurvedic Medicine’s Post COVID Āyurvedic Care Program has been developed to meet the needs of this new potential epidemic.

As everyone knows by now, coronavirus disease 2019 (COVID-19) is caused by an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients infected with SARS-CoV-2 exhibit a wide spectrum of clinical manifestations, ranging from asymptomatic to severe, during the acute phase of illness. Symptoms may appear 2-14 days after exposure to the virus with the average being 4-5 days. The most common symptoms of acute mild to moderate COVID-19 include:

Fever or chills
Cough
Shortness of breath or difficulty breathing
Fatigue
Muscle or body aches
Headache
New loss of taste or smell
Sore throat
Congestion or runny nose
Nausea or vomiting
Diarrhea

As of January 1, 2022, more than 270 million confirmed cases of COVID-19 worldwide and more than 5.2 million deaths have been reported. The disease has now been found in every one of the 195 countries on earth. The United States has reported the most cases with over fifty-two million cases and more than 820,00 deaths as of this writing (January 3, 2022). Ninety-eight percent of new COVID cases in the U.S. are from the Omicron variant.

However, the natural history, clinical course, and long-term consequences of this new disease are still not completely understood. Most people with COVID-19 return to their baseline state of health after acute infection with SARS-CoV-2 in 2-4 weeks, but a significant proportion report persistent life-altering health problems. The exact number of people affected with these late sequelae after the acute COVID-19 episode remains unknown but a good estimate would be 50-70%. Given the sheer number of acute cases, these “long-covid” or “long haul” cases represents the next pandemic just around the corner.

Unfortunately, a similar post-viral syndrome has been seen with prior human coronavirus diseases. For example, symptoms of fatigue, shortness of breath, myalgia, and psychiatric impairments have affected survivors of Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) for up to four years. Even at 7-year and 15-year follow-ups, pulmonary and bone radiological complications were still evident among a proportion of SARS survivors who were mostly younger than 40 years. This is rather disturbing as it raises the possibility that long covid, if not properly addressed, may extend beyond just a few months to years.

It’s difficult to predict who will experience long covid. Persistent symptoms seem to be more prevalent in women and be linearly related to age. Long covid can occur irrespective of the initial severity of infection, and often affects multiple organ systems. Long covid can cause impairment in the heart, lungs, kidneys, liver, pancreas, or spleen. Many individuals have more than one organ affected and it is unclear how and when these chronic symptoms will resolve. Persistent symptoms as well as remitting and relapsing patterns do also occur. As is commonly the case for modern biomedical research seeking a marker or protein to detect and measure a disease, studying long covid syndrome is especially difficult because there is such a wide range of health issues involved -- from shortness of breath to “brain fog” to fatigue to insomnia to cardiovascular problems to polyneuropathies to depression and even rare cases of psychosis -- and there’s no consensus on how to define, diagnose or measure this syndrome using modern medical technology.

Pathophysiology of Long Covid

The cellular entry point for SARS-CoV-2 is the angiotensin converting enzyme 2 (ACE2) receptor (see Figure 1). Normally, a protein called angiotensin II (ANG II) binds to this receptor, which breaks down angiotensin II into molecules that in turn counteract its harmful effects. So normally, angiotensin II is ingeniously self-regulated. But if the SARS-CoV-2 virus is occupying these receptors, angiotensin II cannot attach and be broken down. Attachment of the virus by its “spike protein” to the ACE2 receptor is therefore associated with increased levels of angiotensin II leading to inflammation, vasoconstriction, and thrombosis. In addition to the ACE2 receptor, SARS-CoV-2 requires a protease to prime the spike protein before the virus can enter the cell. ACE2 receptor and the required protease are both expressed in lung, nose, heart, gut smooth muscle, liver, kidney, neurons, and immune cells, which provide an explanation for the diverse symptomatology of COVID-19.

Figure 1. The ACE-2 Receptor (ACE2) Binding Spike Protein Allowing Intracellular Entry of SARS-CoV-2

We do not precisely know all the intricacies of the pathological mechanisms of Long Covid and likely never will. One thing that is clear in any case is that it is multifactorial and observed not to be identical in all persons, which is consistent with Āyurvedic concepts of doshic specific vulnerability. Mechanisms considered likely are: 1) long-term tissue damage, 2) a persistence of viruses or at least virus components, and 3) chronic (hyper-/auto-) inflammation. We do know that one of the earliest ultra-structural pathology in Covid infection is the break in the continuity of the alveolar epithelium in the lung tissue. There is actual destruction of both type 1 and type 2 alveolar cells. This allows extracellular fluids and proteins to enter the alveolar air space and create edema. The edematous fluids quickly lead to the formation of an abnormal hyaline membrane along the alveolar epithelium (see Figure 2). This membrane consists of cellular debris, denatured proteins, and surfactant particles. Both the edema (fluid) and hyaline membrane interfere with oxygen and C02 exchange and the result is hypoxia and respiratory distress.

Figure 2. Pathologic Hyaline Membrane Formation: An Early Result of SARS-CoV-2.

Simple Schematic Illustration of alveolar hyaline membrane

Detailed Schematic Illustration of alveolar hyaline membrane

Microphotograph (magnification 200x)
[Green arrow: hyaline membrane]

The good news is that is stage of the disease usually heals. Yes! The alveolar epithelium is re-populated with type 2 alveolar cells (80%) which differentiate into type 1 cells (20%). The new type 2’s pump the edema fluid back out into the extracellular spaces and the remaining cellular debris is eventually cleared. However…sometimes not all the debris, collagen, and protein gets cleared resulting in various degrees of permanent (?) fibrosis and connective tissue changes. This results in diminished elasticity of the lung tissue, decreased pulmonary vital capacity, and reduced ventilatory function (diffusion capacity). This is what can often happen in Long Covid. Some patients with SARS-CoV-1 which occurred in 2003-2004, which is similar to SARS-CoV-2 (the infection that causes COVID-19), have experienced impaired pulmonary function up to 15 years after infection.

Neurologic Sequelae

While the coronavirus is primarily a respiratory virus, increasing evidence of neurologic involvement has emerged. Many studies have confirmed the neurotropism and replication capacity of SARS-CoV-2 in neuronal tissues. Resulting neurologic symptoms range from mild, such as headache, nausea, anosmia (loss of smell), ageusia (loss of taste), altered consciousness, “brain fog” to more severe such as hemorrhage, syncope, seizure, stroke, meningoencephalitis, Guillain-Barre syndrome, and demyelinating disease. The exact pathologic basis for these neurologic symptoms is not currently known in modern medicine, despite an abundance of published investigations. Again, initial COVID-19 severity plays little role in predicting these brain diseases. Several possible mechanisms for neurologic involvement include (1) direct viral invasion, (2) a “Trojan horse” mechanism where the virus accesses the brain through the blood-brain barrier via circulating lymphocytes, (3) a systemic inflammatory response and (4) coagulopathy-induced prothrombotic state. Several studies have now documented that the S1 subunit of the “spike protein”, many copies of which are shed during the infection, can readily cross the blood brain barrier and lodge in the gray matter of the brain. This toxic spike protein subunits also enter the spleen, liver and kidneys (Rhea, E.M., Logsdon, A.F., Hansen, K.M. et al. The S1 protein of SARS-CoV-2 crosses the blood–brain barrier in mice. Nat Neurosci 24, 368–378 (2021). https://doi.org/10.1038/s41593-020-00771-8).

Cardiac Sequelae

Evidence of cardiac injury in long COVID is also mounting. Many studies of previously confirmed Covid-19 cases have found cardiac abnormalities and myocardial inflammation in between 60-80% of participants, respectively, which were not associated with initial COVID-19 severity. The most frequently observed cardiac symptoms include: chest pain, heart palpitations, and tachycardia which commonly persist among COVID-19 survivors for 6-12 months or longer, suggesting substantial cardiac sequelae. COVID-19 can also affect the autonomic nervous system. Affected individuals may display orthostatic hypotension along with tachycardia in response to position changes. I have personally documented several cases of this in my clinic. Individuals with this condition are at risk for vasovagal syncope.

Gastrointestinal, Renal, and Musculoskeletal Sequelae

The gastrointestinal system may also be affected. Complaints of abdominal pain, gastrointestinal bleeding, nausea and vomiting, diarrhea, hepatitis, and pancreatitis may be experienced by long-haulers. Long-haulers who experienced kidney dysfunction during the acute illness period are more likely to have continued kidney dysfunction as time passes. The development of acute kidney injury is associated with worse long-term outcomes in many other diseases, but we are uncertain how this will affect COVID-19 long-haulers. The musculoskeletal symptoms of myalgias and arthralgias are also very common complaints among long-haulers and often misdiagnosed as fibromyalgia.

Skin Sequelae

Skin lesions may develop up to 2 weeks after acute COVID-19 infection and normally resolve within 4 to 8 weeks, but can persist. Common cutaneous manifestations of COVID-19 include morbilliform rash (“measles-like”) and chilblain-like acral lesions, “COVID toes.” Dermatologic findings may occasionally be the only symptom associated with COVID-19 infection.

Immunity Sequelae

Some people who have recovered from COVID-19 are left with a weakened immune system. Many other viruses are thought to do this. We know from 2003 that SARS, for instance, is known to decrease immune-system activity by reducing the production of interferons and other signaling molecules. The virus can also have the opposite effect, causing parts of the immune system to become overactive and trigger harmful uncontrolled inflammation throughout the body. This is well-documented in the acute phase of the illness and could affect some people to a lesser extent long-term. When people recover from Covid, we simply do not know how long it takes the immune system to regain balance and normalcy.

A study of over 40,000 COVID-19 patients found increased risks of new respiratory, diabetes, and cardiovascular diseases occurring within the subsequent six months compared to controls (Ayoubkhani D, Khunti K, Nafilyan V, et al. . Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study. BMJ. 2021;372:n693). Therefore, we need to be vigilant for possible extrapulmonary and multi-organ involvement that may be initially less obvious. It should also be noted that our notion of long-term consequences, at this point in time, is only ∼2 years and the potential for longer term effects remains to be determined.

*Part 2 of this article briefly outlines the Āyurvedic treatment approach to long COVID. Click here to view Part 2: The GIAM Post COVID Āyurvedic Care Program.

For more information or to inquire about receiving GIAM Post-Covid Āyurvedic Care, please call 727-371-1000 or email giam@gersonayurveda.com.

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The Āyurvedic Approach to Long Covid, Part 1: Symptoms and Pathophysiology, By Dr. Scott Gerson, M.D., Ph.D. (Ayu)