10 min|Dr. Maya Kuczma

What Now: POST COVID-19 Syndrome, Long Haulers & Multi-System Inflammatory Syndrome (MIS)

Wellness, Education, Immune Health

Following the initial outbreak of the novel coronavirus SARS-CoV-2, much of the global effort aimed to control the acute effects of the pandemic, particularly with regards to preventing and treating COVID-19.

One year later, the emergence of long-term complications of COVID-19 has led many researchers to shift their attention in an attempt to gain a better understanding of these lingering effects, known as Post-COVID Syndrome, or ‘long COVID’. Initial research suggests that 90% of people recovering from COVID-19 experience persistent symptoms 60 days after diagnosis. (1)

It appears that people experiencing long-term effects of COVID-19, or ‘long-haulers’, can be separated into two groups:

Those with permanent damage to the heart, lungs, kidneys, or brains, as a result of COVID-19
Those with no detectable permanent damage to these organs, who still experience debilitating symptoms (2)

Since the virus enters human cells via angiotensin-II-converting enzyme (ACE2), a component found on various tissues within the body (such as the oral and nasal mucosa, spleen, heart, lungs, blood vessels, kidneys, gastrointestinal tract), SARS-CoV-2 infection can create a wide range of symptoms.(3) Long-term effects of COVID-19 have been reported in many of these tissues.

Lung Damage following COVID-19 Infection

SARS-CoV-2 infection appears to begin in the upper respiratory tract following exposure to respiratory droplets. (4) Both oral epithelial cells and cells of the respiratory tract have high expression of ACE2, allowing for viral entry. (5) The lungs are another site rich in ACE2; if the virus spreads into the lungs, it can bind, enter cells, and replicate further, creating the hallmark symptoms of COVID-19: cough, pneumonia, lung damage, and/or acute respiratory distress syndrome. (6)

For some patients, the damage to the lungs remains long after recovery from acute effects of the virus. In a California-based study, one-third of patients previously hospitalized for COVID-19 had scarring over a month later. (7) A study of COVID-19 patients in Austria found that for some, lung damage decreased over time - 88% of patients had visible lung damage 6 weeks after being discharged; by 12 weeks, that number dropped to 56%. (8) Risk of lung damage, and likelihood of recovery, is thought to be related to initial disease severity, health status prior to infection (such as the presence of existing health conditions), how quickly the patient received treatment, and what kind of care they received. (6) However, large questions still loom regarding best practices to prevent lung damage, the reversibility of COVID-19 lung damage, and how to ensure COVID-19 survivors have access to necessary pulmonary rehabilitation.

Long Term Cardiovascular Effects of COVID-19

SARS-CoV-2 infection has been associated with a variety of cardiovascular complications, including inflammation of the heart, increased blood clotting, and sudden cardiac death. (9) Cardiovascular involvement is thought to be triggered by direct SARS-CoV-2 binding to ACE2 on endothelial cells of the blood vessels and cardiomyocytes; (10) increased blood pressure and inflammation as a result of decreased degradation of angiotensin-II; (10) increased inflammatory cytokines; (11) and/or acute myocardial injury as the result of a clot. (9) Similar to lung damage, recent studies suggest many survivors of COVID-19 have persistent heart damage, particularly inflammation of the heart muscle (known as myocarditis). (12)

Myocarditis can put patients at risk of further cardiovascular complications, such as heart failure. Damage to the cardiovascular system is not necessarily correlated to severity of COVID-19 symptoms; initial reports suggest even patients not hospitalized could experience cardiac injury. (13) Additionally, there is overlap within symptoms of lung and heart damage; for example, shortness of breath occurring post COVID could be due to lung or heart damage. This overlap illustrates why patients experiencing Post Covid Syndrome require a detailed work-up to establish organ involvement.

Research is ongoing to evaluate cardiovascular implications of COVID-19, both acutely and following infection. For example, the CAPACITY registry has been set-up within the UK to collect data regarding cardiovascular history and cardiovascular complications of COVID-19 patients. (14) Many doctors are recommending such registries, along with long-term trials, to develop understanding of long-term cardiovascular sequelae of COVID-19 which they have described as ‘post-COVID-19 cardiac syndrome’. (15)

MIS: A Heightened Immune System Response

Multi-system inflammatory syndrome in children (MIS-C) is a serious condition that appears to be associated with SARS-CoV-2 infection. (16) For reasons that so far remain unknown, following SARS-CoV-2 infection, some children experience severe inflammation in organs and tissues, such as the heart, blood vessels, kidneys, brain, lungs, skin, or eyes. (17) Some adults experience a similar syndrome following SARS-CoV-2 infection, known as multisystem inflammatory syndrome in adults (MIS-A). (18) Both MIS-C and MIS-A are considered rare, and research is ongoing to determine risk factors for both syndromes. (17)

In cases of MIS-C and MIS-A, testing for current infection of SARS-CoV-2, as well as antibody evidence of historical infection, may be helpful for diagnosis. Symptoms of MIS-C include fever; vomiting; diarrhea; stomach pain; skin rash; fatigue; rapid heart rate; rapid breathing; red eyes; redness or swelling of the lips and tongue; redness or swelling of the hands or feet; headache; dizziness; lightheadedness; and enlarged lymph nodes. (17) Manifestations of MIS-A are widespread, and may include cardiovascular, gastrointestinal, dermatologic, and neurologic signs and symptoms. (19) Both MIS-C and MIS-A are thought to be the result of an excessive immune response triggered by SARS-CoV-2, but it is not yet understood why a small number of adults and children experience such a response. (17)

Post COVID-19 Chronic Fatigue

One of the most common symptoms reported in COVID-19 survivors is fatigue. (20) In a study completed in Dublin, more than half of recovered COVID-19 patients experienced post-viral fatigue syndrome, regardless of the severity of their initial COVID-19 symptoms. (21) Fatigue, along with many other symptoms of Post COVID syndrome, resemble Chronic Fatigue Syndrome, also known as Myalgic Encephalitis (ME), a chronic condition characterized by at least 6 months of fatigue, in addition to other symptoms such as sore throat, headache, muscle pain, joint pain, post-exertional fatigue, sleep disruption, cognitive disturbance (or ‘brain fog’), and secondary anxiety or depression. (22,23) CFS/ME has long been misunderstood, but recent research suggests viral-mediated neuroinflammation, (24) reduced ability for cells to utilize ATP, a small molecule that provides energy to our cells; (25) and viral-mediated gene up regulation may be play a role in pathogenesis. (26) Many patients diagnosed with CFS/ME report that their illness began following a bout of an acute infectious disease, often mononucleosis or the flu. (27)

Chronic fatigue following a viral infection is not unheard of; studies of SARS-CoV-1 patients reported chronic fatigue for years following infection. (28, 29) Persistent fatigue has also been noted following cases of H1N1, (30) and the West Nile virus. (31) Although this link has been made, the mechanism remains murky. But CFS/ME may hold the key to understanding Post COVID syndrome, particularly with respect to lymphatic involvement. Lymphatic drainage from the brain occurs via a space surrounding the olfactory nerves, through the cribriform plate, into the nasal mucosa. (32) A proposed component of the pathogenesis of CFS/ME is a disturbance in lymph drainage along this pathway, and subsequent build-up of pro-inflammatory cytokines within the central nervous system.(33, 34) Without adequate drainage, various molecules can accumulate within the brain.

If these molecules are pro-inflammatory, chronic inflammation within the nervous system can ensue, leading to detrimental effects on the nervous system. SARS-CoV-2 is suspected to penetrate the nervous system via the neuro-mucosal interface of olfactory mucosa, which may explain the anosmia (loss of smell) associated with COVID-19. (35) As a result, SARS-CoV-2 may disrupt lymph drainage from the brain, leading to an accumulation of pro-inflammatory cytokines, similar to the proposed mechanism of CFS/ME. (36,37) Inflammation triggered by these cytokines could instigate short-term symptoms, such as fever, as well as long-term symptoms, such as chronic fatigue, altered sleep-wake cycle, and cognitive dysfunction, symptoms characteristic of Post COVID ‘long-haulers’. (36)

Unfortunately, symptoms of CFS/ME patients were initially believed to be psychosomatic when doctors first identified this condition more than 70 years ago, and this stigma remained until fairly recently. The lack of a formalized test to diagnose this condition hindered clinical progress, as diagnosis relied solely on self-reporting of symptoms. However, research connecting viruses as triggers for CFS/ME has helped begin the process of de-stigmatization. CFS/ME may provide the key to understanding Post COVID Syndrome. In turn, the attention Post COVID syndrome has garnered may finally provide solace for the CFS/ME community that was largely neglected by academia, or worse - told to ’try to exercise’ or go to psychotherapy, in order to feel better.(27, 38)

Who is More Likely to Become a Long-Hauler?

In cases where we can detect permanent organ damage, the mechanism of chronic symptoms is more well understood; for example, when scarring of the lungs is detected, it follows that a patient may experience reduced lung function. However, in Post COVID Syndrome patients with no detectable tissue damage, doctors cannot predict long-term consequences. Current research indicates no correlation between severity of COVID symptoms with likelihood of conversion into a ‘long-hauler’. (39) And until the pathogenesis of chronic fatigue and brain fog is better understood, we are left largely in the dark as to why some people experience these symptoms, and others do not.

Where Do We Go From Here?

Further research exploring lung, heart, immune system, nervous system, and systemic complications of COVID-19 is needed, and some has already begun. In the UK, the Post-Hospitalization COVID-19 study is following 10,000 patients for a year. (40) The Canadian COVID-19 Prospective Cohort Study (CANCOV) has been established to raise the standard of care for COVID-19 patients, establish clinical guidelines for policy makers, and track the various ways COVID-19 can affect the body. (41) St. Paul’s Hospital, in Vancouver, has established Canada’s first Post-COVID clinic to study, in real-time, the recovery of COVID-19 survivors. (42)

Unfortunately, the outcome of ongoing research will not be available to many ‘long-haulers’ any time soon. Currently, there are no official treatment guidelines for patients without detectable permanent organ damage, but who still experience chronic symptoms following COVID-19. However, due to similarities between Post COVID syndrome and CFS/ME, it may be prudent to invoke similar treatment strategies utilized in cases of CFS/ME for COVID-19 ‘long-haulers’.

A naturopathic approach to CFS/ME aims to reduce neuroinflammation, improve mitochondrial functioning, restore a healthy circadian rhythm, and resolve nutrient deficiencies. Additionally, we aim to treat historical health concerns, such as digestive conditions (IBS, SIBO, hypochlorhydria, etc) or hormonal dysregulation, based on the belief that these imbalances may have helped ’set the stage’ for the pathogenesis of CFS/ME. These therapeutic principles may prove fruitful for ‘long-haulers’, particularly while we wait for the results of long-term research. Additionally, although Post COVID Syndrome is not considered a psychosomatic condition, the effects of stress - or trauma - experienced as a result of COVID-19 could linger, and exacerbate symptoms.

Patients may benefit from therapy specifically targeted towards post-traumatic recovery. The acute symptoms of COVID-19 can be devastating, and lingering symptoms can turn this traumatic event into an ongoing struggle. While we continue to manage an ongoing pandemic, we cannot forget those who survived, yet continue to suffer.

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