Long COVID is defined as “the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection (the technical name for the COVID-19 virus), with these symptoms lasting for at least 2 months with no other explanation (WHO 2022).” There are over 200 possible symptoms of Long COVID, but the most common are fatigue, shortness of breath, fever, headaches and brain fog (NIH Long COVID).
Many with Long COVID are diagnosed with postural orthostatic tachycardia syndrome (POTS) and/or chronic fatigue syndrome/myalgic encephalomyelitis. The “silver lining” of the pandemic for these communities is that both awareness and government funding for research are increasing as millions of people globally are being diagnosed with Long COVID within a very short time. We hope that this new awareness and increased funding will lead to breakthrough treatments that will benefit all members of these chronic invisible illness communities.
Long COVID has been estimated to affect somewhere between 10 and 30% of all those infected with SARS-CoV-2 (Davis et al. 2023). 40% of adults in the US have had COVID-19 and 19% of those continue to have symptoms of Long COVID, which means that 7.5% of the US population is suffering with various degrees of the illness (CDC One in Five). A large metanalysis of 1.2 million people who had symptomatic SARS-COV-2 infection found the incidence of Long COVID was 6.2% at 3 months, with 3.7% having ongoing respiratory issues, 3.2% with persistent fatigue with body pain or mood swings, and 2.2% having ongoing cognitive problems (Global Burden of Disease Long COVID Collaborators 2022). These numbers may overestimate long-COVID prevalence, however, because they don’t account for asymptomatic COVID infections that went undetected.
Why Does Long COVID Occur?
The short answer is that we don’t know for sure. Many people in the POTS and CFS/ME communities developed their illnesses after infection (e.g., Epstein Barr virus, Lyme disease, influenza) so this is not a new phenomenon. There are several lines of thinking that are being explored to try to better understand why Long COVID occurs in some people.
The SARS-CoV-2 Virus Itself
This virus has several characteristics that make it particularly insidious. First the virus is neurotropic, which means that it has high affinity for the central nervous system. The virus is thought to enter the brain through the olfactory bulb located just above the nose and involved with the sense of smell. In addition, this virus infects individual host cells through the ACE2 receptor and then uses a lytic cycle (it replicates inside the cell and then lyses the cell, killing it) to cause damage to CNS neurons. Unfortunately, these ACE2 receptors are found throughout the body, including epithelial cells of the lung and lining of the gastrointestinal tract (Chadda et al. 2022).
There are 4 potential mechanisms that may cause an acute COVID infection to become chronic, or Long COVID.
- Persistent virus, viral antigens or RNA in host tissues that drive chronic inflammation
- Autoimmunity that is triggered by acute viral infection
- Dysbiosis of the gut microbiome
- Tissue damage from the initial infection which cannot be repaired (Merad et al. 2022).
It may be that all of these are involved in the tissue damage linked with Long COVID or that some combination of these mechanisms are involved. We need a lot more research before we know for sure. Understanding the underlying cause is important, as it will allow more targeted treatment options to prevent this damage in future COVID infections.
Abnormal Mast Cell Activation in Response to the Virus
About 17% of the general population is thought to carry genetics associated with potential for abnormal mast cell activation in which these cells respond excessively to a variety of triggers, potentially including the spike protein in acute and long COVID (Afrin et al. 2020). It is interesting that about the same percentage of the population, 19%, has Long COVID (Global Burden of Disease Long COVID Collaborators 2022). Mast cells are activated by SARS-CoV-2, release histamine and other inflammatory mediators and can cause hyperinflammation similar to what is seen in Long COVID (Afrin et al. 2020). The SARS-CoV-2 virus enter host cells, including mast cells, via the ACE2 receptors. Symptom profiles for Long COVID and MCAS are virtually identical (Weinstock et al. 2021). Long COVID may progress in association with the development of MCAS (Batiha et al. 2022).
How can the COVID-19 virus lead to POTS?
The ACE2 receptor (used by SARS-CoV-2 to enter the human cell) normally functions as part of the renin-angiotensin-aldosterone system that regulates both blood volume and blood pressure. One of the effects of the SARS-CoV-2 infection is that it downregulates the ACE2 receptor which can lead to hypovolemia or low blood volume (Chadda et al. 2022), a known problem for many people with POTS.
In addition, the longstanding inflammation that occurs during the acute COVID infection due to cytokine storms may cause chronic neural dysregulation. Remember that this virus is neurotropic – it loves to infect the central nervous system and can directly destroy infected neurons. In addition, the severity and duration of the cytokine storms can cause autoantibodies to develop that attack autonomic ganglia and further damage nervous tissue (Chadda et al. 2022). Fatigue and cognitive deficits are related to the presence of autoantibodies against β2 adrenoceptors, α1-adrenoceptors, AT1R, MAS receptors, muscarinic type 2 receptors, and nociceptin-like opioid receptors, leading to dysautonomia, POTS, and other neurological dysfunctions (Kharraziha et al. 2020).
Both of these, of course, could be correct, and there could be other mechanisms that lead to damage and long-term illness. It will take time and much more research to fully understand the complex relationship between SARS-CoV-2 infection, tissue damage, and the development of Long COVID and post-COVID POTS.
At Home Treatments at Onset of COVID-19 that Might Prevent Long COVID
Mast cell activation syndrome (MCAS) targeted medications upon suspicion of the onset of COVID-19 illness could decrease the severity of illness. Over-the-counter antihistamines (mast cell stabilizers) are both inexpensive and safe, and can be taken to decrease activation of mast cells at initial infection (Afrin et al. 2020). Specifically, histamine -1 (cetirizine, tradename Zyrtec) and -2 receptor (famotidine, tradename Pepcid AC) antagonists are available over-the-counter. Treatments of MCAS, including antihistamines, inhibition of synthesis of mediators, inhibition of mediator release, and inhibition of degranulation of mast cells may be helpful (Batiha et al. 2022).
- Cetirizine hydrochloride (10 mg BID) and famotidine (20 mg BID) can alleviate pulmonary symptoms in COVID-19 patients, possible by minimizing the histamine-mediated cytokine storm and decrease mortality and symptom progression, even in hospitalized patients (Hogan et al. 2020).
- Suggested doses of 40 to 80 mg of famotidine every eight hours ensures maximal antagonism of the H2 histamine receptor (Malone et al. 2021). Famotidine was safe and well tolerated in people with mild-moderate COVID-19 at doses of 80 mg TID for 14 days (Brennan et al. 2022).