Long COVID and POTS

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.

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.

1. Persistent virus, viral antigens or RNA in host tissues that drive chronic inflammation
2. Autoimmunity that is triggered by acute viral infection
3. Dysbiosis of the gut microbiome
4. 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).

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.

Long COVID often leads to orthostatic intolerance and POTS, in which the release of epinephrine and norepinephrine causes tachycardia, heart palpitations, breathlessness, and chest pain (Dani et al. 2021). In fact, 67% of Long COVID patients have moderate to severe autonomic dysfunction, regardless of the severity of their COVID-19 infection (Larsen et al. 2022). POTS is regarded as a distinct type of Long COVID and is characterized by sinus tachycardia, postural tachycardia, and inappropriate sinus tachycardia (Batiha et al. 2022).

Patients presenting with breathlessness, palpitations, fatigue, chest pain, presyncope or syncope after acute COVID infections should be tested carefully, including a standing test (Dani et al. 2021) in which the:

1. Patient lays supine for 10 minutes. Take pulse and blood pressure.

2. Patient stands upright without leaning or moving. Take pulse and blood pressure every 2 minutes for up to 10 minutes. 

Presence of chronic symptoms of orthostatic intolerance (≥ 3 months) accompanied by increased heart rate ≥ 30 beats per minute in adults and ≥ 40 beats per minute in ages 12-19 within 10 minutes of standing. This increased heart rate must be found in at least 2 measurements taken at least 1 minute apart and in the absence of classical orthostatic hypotension (prolonged decrease blood pressure >20/10 mmHg) (Raj et al. 2022). Morning assessments optimize diagnostic sensitivity of the standing test (Brewster et al. 2012).

In addition, other testing can be done to better understand the patient’s history and rule out other causes of orthostatic intolerance:

• Complete history and physical exam
  • Chronicity of condition
  • Possible causes of orthostatic tachycardia
  • Impact of daily activities
  • Potential triggers
  • Family history
  • POTS symptoms exacerbated by dehydration, heat, alcohol and exercise
  • Joint hypermobility (if Ehlers-Danlos syndrome is suspected)
• Tests to rule out potential cardiovascular or systemic etiology
  • 12-lead electrocardiogram
  • Hematocrit
  • 24-hour Holter monitor
  • Transthoracic echocardiogram
• Rule out other conditions that could cause orthostatic tachycardia (Raj et al. 2022).
  • Anemia
  • Anxiety (HR should not change with orthostasis in anxiety, but will in POTS!!)
  • Fever
  • Pain
  • Infection
  • Dehydration (acute hypovolemia)
  • Hyperthyroidism
  • Pheochromocytoma
  • Prolonged bed rest
  • Medications that increase heart rate (stimulants, diuretics, norepinephrine reuptake inhibitors)

Treatment of POTS-COVID POTS mirrors recommendations for POTS in general and includes blood volume expansion, abdominal and extremity compression, isometric and recumbent exercise and medications (Dani et al. 2021).

Non-pharmacologic options to consider

• Withdraw medications that might worsen symptoms like norepinephrine transport inhibitors (Wellbutrin, Strattera, Edronax, Qelbree)
• Increase blood volume with up to 10-12 grams of salt and 2-3 liters of fluid intake
• Reduce venous pooling with abdominal compression (binders, bike shorts) and compression hose (Bourne et al. 2021)
• Gradual rising from supine and sitting position
• Small, frequent and lower-carbohydrate meals instead of large meals
• Avoidance of prolonged standing, high ambient temperature and high humidity
• Physical counter-maneuvers (leg crossing, muscle tensing) during standing and prodromal symptoms (Fedorowski 2018)
• Structured, graduated, supervised exercise program beginning in recumbent position CHOP Modified POTS Exercise Program

Pharmacologic options to consider

Heart rate controlling agents (Raj et al. 2022 and Fedorowski 2018)

• Propranolol: If standing heart rate very high: 10-20 mg propranolol PO 4x per day, especially if palpitations present
• Ivabradine: If standing heart rate very high and β-blocker contraindicated: 5 mg (2.5-7.5 mg) ivabradine, 2 times per day slows sinus rates without impacting blood pressure
• Pyridostigmine: 30-60 mg PO up to three times daily. Best with suspected autonomic neuropathy, gastrointestinal dysfunction, and non-specific muscle weakness

Vasoactive and Volume-Expanding Agents

• Vasocontrictors  (Raj et al. 2022 and Fedorowski 2018)
  • Midodrine: If standing heart rate is not too high and blood pressure is low: Midodrine 5 mg (2.5-10 mg) PO every 4 hours, 3 times per day (8 am, noon, 4 pm)
• Sympatholytic drugs (Raj et al. 2022). Particularly helpful for those with hyperadrenergic POTS
  • Clonidine: 0.1-0.2 mg PO, 2-3 times daily or long-acting patch
  • Methyldopa: 125-250 mg PO, 2 times daily
• Blood volume expanders (Raj et al. 2022)
  • Fludrocortisone: 0.1-0.2 mg PO daily. Potassium supplements needed.
  • Desmopressin: 0.1-0.2 mg PO daily, as needed

• IV fluids for POTS patients that has shown positive results:
  • In hospital acute 1-2 L physiological saline infusion 3-5 consecutive days (Fedorowski 2018)
  • Initial treatments: 1 liter of IV normal saline infused over 1-2 hours weekly (Ruzieh et al., 2017)
  • Titrated dose depending on patient need
    • Up: 2 liters of IV normal saline per week
    • Down: 1 liter of IV normal saline every 2-4 weeks

You might also recommend the Pulmonary Wellness Foundation's COVID 19 Rehab & Recovery series to your patients.

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).