Ketotifen Eye Drops for long COVID
KETOTIFEN EYE DROPS
What is ketotifen?
Ketotifen is an antihistamine and mast cell stabilizer used as an eye drop to prevent and treat eye itching caused by allergies (also known as allergic conjunctivitis). An oral formulation of ketotifen is available to treat asthma and hives, but it is only available in the United States as an eye drop. It can be applied as one drop into the affected eye(s) twice daily every 8-12 hours and should not be used more than two applications daily.
How can ketotifen help alleviate certain long COVID symptoms?
Histamine is a chemical our immune system releases that causes allergy symptoms. Cells in our body called mast cells release histamine, and in some patients after COVID, they may release too much, leading to some of the symptoms of long COVID. Ketotifen prevents mast cells from releasing inflammatory mediators and blocks histamine in the body as a histamine type-1 blocker.
As an eye drop, ketotifen and similar products such as olopatadine (Pataday) can specifically relieve itchy eyes that certain COVID variants can cause. There have been some reports of the Omicron variant causing unusual symptoms such as itchy eyes or pink eye in some patients.1 While this is rarely reported outpatient, there may be up to 31.6% of hospitalized COVID patients experiencing conjunctivitis.2 If you are experiencing an isolated symptom of itchy eyes without other symptoms of COVID, however, it is likely not due to a COVID infection.
What evidence supports ketotifen’s use for long COVID?
The SARS-CoV-2 virus can cause extreme inflammatory outbreaks by activating mast cells in the respiratory tract and may cause an accumulation of mast cells. As a result, ketotifen has been studied to see if its mast cell stabilizer properties could be used for pulmonary inflammatory symptoms of COVID. Ketotifen has been found to reduce lung lesions in the early stages of an H5N1 infection and was studied to investigate its impact on a COVID infection.3, 4
While ketotifen was found to be useful for its anti-inflammatory and mast cell-stabilizing effects, it is important to note that these effects would only be significant enough in ketotifen taken orally, which is not currently available in the US. As an ophthalmic formulation, it is reserved for relieving conjunctivitis or itchy eyes due to COVID. More studies need to be conducted specifically on the use of ketotifen eye drops for long COVID symptoms.
What are some things to watch out for with ketotifen?
Ketotifen can cause some eye irritation or eye pain. Otherwise, it has minimal systemic absorption and relatively few side effects. If symptoms worsen or do not improve within three days, you should inform your provider and consider other options.
Additionally, soft contact lenses should be removed before using ketotifen. Ketotifen should not be used for irritation related to contact lenses. If you wear contact lenses, you should wait at least 10 minutes after using ketotifen before reinserting them.
References:
1) Korin M. Can Omicron cause itchy eyes? Experts explain. Prevention. Jan 20, 2022. Accessed October 31, 2023. https://www.prevention.com/health/a38830511/omicron-itchy-eyes/
Arginine for long COVID
ARGININE
What is arginine?
Arginine is an amino acid that possesses anti-inflammatory properties. Arginine plays a role in numerous biological processes [[1]]. Typically, our bodies make all the arginine we need. We
What does arginine do in the body?
Arginine works as a vasodilator, which means that it enlarges blood vessels to promote blood flow. It can treat angina, high blood pressure, and peripheral artery disease [[2]].
Arginine promotes nitric oxide formation, which increases blood flow and helps nerve cells talk to each other better [[3]]. Nitric oxide also serves as an antiviral agent with anti-inflammatory effects, may regulate endothelial and respiratory systems, protect cells, and exhibit anti-thrombotic properties [[1]], and reduces the activity of pro-inflammatory cytokines involved in the cytokine storm in severe COVID [[4]].
How can arginine help alleviate certain Long COVID symptoms and pathophysiology?
Research into Long COVID shows that long-hauler patients experience a variety of dysregulated cytokine processes long after the acute COVID-19 infection [[4]].
Severe COVID-19 patients taking oral arginine supplements with their regular treatment required less respiratory support and less time in the hospital. Arginine also modulates inflammation and supports endothelial function, so researchers believe it may also help improve Long COVID symptoms [[1]].
Together with the polyphenol hydroxytyrosol, arginine could prevent the formation of peroxy nitrate, a harmful substance involved in organ dysfunction in COVID-19 [[3]].
Is arginine safe for pregnancy and breastfeeding?
Arginine may cause complications during pregnancy, so it’s important to talk to your doctor to see if arginine supplementation could be right for you. It is also unclear whether arginine can be passed on to babies through breastmilk and what the effects might be [[5]].
Methylene Blue for long COVID
METHYLENE BLUE
What is methylene blue?
Methylene blue might be known for its vibrant blue color in high school chemistry labs, but it is also a medicine with many different uses. It can improve the body’s ability to take up oxygen and liver function, and it can also improve blood pressure and cardiac function in septic shock [[1]].
What does methylene blue do in the body?
Though methylene blue started as a textile dye, it has also been used for over a century as a medicinal compound. Methylene blue is low-cost and safe at low dosages [[2]]. Used to treat COVID-19, methylene blue can interact with the virus itself, blocking the viral replication process. Methylene in methylene blue can also interfere with pro-inflammatory cells and prevent the cytokine storm, which results from immune overreactivity, in the lungs [[2]]. Methylene blue is also a nitric oxide synthase inhibitor, which slows COVID-19 disease progression and increases oxygen saturation, improving COVID-19 outcomes [[2]].
How can methylene blue help alleviate certain Long COVID symptoms and pathophysiology?
Mitochondrial dysfunction plays a significant role in neurodegenerative disorders that involve inflammation and brain cell death. These disorders involve oxidative stress that contributes to inflammation of the endothelial tissues and disturbed metabolism, resulting from insult to the brain’s mitochondrial processes. Methylene blue protects mitochondria, whether in the context of stroke, neurodegeneration, or chemotherapy-induced neural injury. Therefore, methylene blue has attracted interest in reducing the cognitive and functional impairments in Long COVID. In a recent study, patients undergoing major surgery experienced a reduction in postoperative cognitive dysfunction when taking methylene blue, as opposed to controls [[3]]. These effects make methylene blue a promising therapeutic tool for improving cognition and brain metabolism processes in Long COVID and reducing inflammation, which is a feature of Long COVID
Cromolyn Sodium Nasal for long COVID
CROMOLYN SODIUM NASAL SPRAY
What is cromolyn sodium?
Cromolyn sodium is available as an over-the-counter nasal spray that can be used to prevent or treat seasonal or long-term allergy symptoms such as sneezing, wheezing, a stuffy or runny nose, and itching. It is a mast cell stabilizer that reduces inflammation in your nose. It can be applied as one spray in each nostril 3-4 times daily every 4-6 hours for up to 6 times daily. You can use it before exposure to allergens to prevent allergy symptoms. Cromolyn sodium should not be used to treat asthma, a sinus infection, or cold symptoms.
How can cromolyn sodium help alleviate certain long COVID symptoms?
Cells in our body called mast cells release histamine, a chemical that causes our allergy symptoms. With a COVID infection, mast cells can be overactivated and release excessive amounts of inflammatory mediators like histamine, leading to some of the symptoms of long COVID.1 Cromolyn sodium reduces the amount of histamine released from mast cells and blocks the release of other chemicals called cytokines that lead to inflammation. This allows it to be effective in decreasing the inflammatory effects of COVID.2
In addition, cromolyn may reduce neuroinflammation and improve cognitive function in long COVID patients. Inhaled cromolyn has been found to affect microglia directly (the brain’s primary immune cells) to reduce cytokine secretion, which may improve cognitive symptoms such as brain fog.2 It is important to note that the nasal formulation of cromolyn may not show the same effects as its oral or inhaled formulations because it has more of a local effect on the nasal passages.
What evidence supports cromolyn sodium’s use for long COVID?
It is unclear whether nasal cromolyn has enough systemic exposure to exhibit these neuro-inflammatory effects. Anecdotally, patients have reported improvement in post-COVID brain fog after using NasalCrom, but there are currently no studies specifically investigating the use of NasalCrom for cognitive symptoms of COVID.3
There is an ongoing Phase I trial of 10 patients studying the effects of adding cromolyn to the standard of care for hospitalized patients with COVID-19 pneumonia. Cromolyn will be given as a nebulized treatment four times a day for four days, followed by the intranasal spray for two weeks to assess its impact on symptom improvement.4
What should you be aware of when using cromolyn sodium?
Cromolyn can cause a burning or stinging sensation in the nose and sneezing. Less common side effects include headache, hoarseness, and post-nasal drip. Some may also experience an unpleasant aftertaste. If your symptoms do not improve within two weeks or if you are experiencing shortness of breath, wheezing, or chest tightness, you should stop using Cromolyn, as these symptoms may be due to another underlying condition.
References:
4) LongCovidPharmD. NasalCrom for Neuroinflammation? Studies, Surveys, & Supplements. November 23, 2022. Accessed October 31, 2023. https://pharmd.substack.com/p/nasalcrom-for-neuroinflammation
5) Michelson E. Cromolyn Sodium for Treatment of COVID-19 Pneumonia. ClinicalTrials.gov. February 14, 2023. Accessed October 31, 2023. https://clinicaltrials.gov/study/NCT05077917
Apheresis for long COVID
APHERESIS
What is apheresis?
Certain conditions can be caused by an abnormal cell or component in the blood that may need removal. Apheresis is a “blood-washing” procedure in which your blood is passed through a device that separates it into various components, discards cells or pathologic components that are thought to be causing a disease or condition, and returns the remaining blood along with replacement fluid and normal cells.
There are two main reasons why patients may undergo apheresis. Apheresis can be done on donated blood given to a recipient or be therapeutic for patients with certain conditions that impact their blood or components within their blood.
There are two types of therapeutic apheresis methods: plasmapheresis and cytapheresis.1 Plasmapheresis separates plasma (a light yellow liquid blood component containing proteins and antibodies) from the blood. In contrast, cytapheresis separates the blood into red blood cells, white blood cells, and platelets. Plasmapheresis typically removes autoantibodies or immune complexes, which the immune system makes in autoimmune disorders, infections, or certain cancers that target the body itself instead of a foreign invader. Cytapheresis is done to remove either excess components of cells or cells that are defective in some way. For instance, this can remove abnormally shaped red blood cells in patients with sickle cell disease.
How can apheresis help alleviate certain long COVID symptoms?
Proposed mechanisms behind the chronic fatigue and post-exertional malaise of long-COVID include reduced blood flow to tissues, inflammation in the brain and other organs, and reactivation of different infectious agents or components.2 Data has also shown that COVID can lead to the creation of autoantibodies and change components of the blood to make it more viscous and, thus, reduce blood flow.3 COVID can also cause a significant increase in lipid levels that can lead to long-term cardiovascular disease.
By removing these potential autoantibodies, lipids, and abnormal blood components, apheresis can improve blood flow and may, as a result, improve long-term COVID symptoms of chronic fatigue.
What evidence supports the use of apheresis for long COVID?
In a study done with patients in Germany who reported fatigue lasting for at least 12 months following COVID, 27 participants were treated with a therapeutic apheresis procedure that removed autoantibodies, inflammatory cytokines, certain lipids, and other molecules contributing to more viscous blood.2 Patients were treated twice within a three-week interval, with each treatment lasting 114 minutes. Biomarkers for inflammatory factors, autoantibodies, lipids, and clotting factors were measured before and after apheresis. About 15% of participants did not feel better after six months following apheresis; however, most participants reported no symptoms after treatment, and 11% reported moderate improvement. The study found a significant reduction in these biomarkers in patients who reported a substantial improvement in their symptoms.
Several case reports have also found relief of long-COVID symptoms such as muscle or chest pain, vision and hearing problems, insomnia, and general quality of life using HELP (heparin-induced extracorporeal LDL/fibrinogen precipitation) apheresis.4 HELP apheresis dissolves microclots in the blood and removes proteins in the body that can contribute to clots.5
There currently needs to be randomized control trials investigating the use of apheresis for long COVID patients. The evidence behind apheresis for long COVID should be discussed with a provider if being considered for treatment.
What should you be aware of with apheresis?
Patients may experience fatigue, nausea, low blood pressure, or an allergic reaction during apheresis. Some patients may also feel tingling or numbness that subsides when the treatment is completed.6 One session may take 2 to 5 hours, depending on the type of apheresis done. Apheresis can be a long and costly procedure, and some insurance plans may not cover the treatment for long COVID.
References:
1) Sarode R. Therapeutic Apheresis. Merck Manual. Sept 2022. Accessed November 5, 2023. https://www.merckmanuals.com/professional/hematology-and-oncology/transfusion-medicine/therapeutic-apheresis
Active Clinical Trials: Long COVID, apheresis | Card Results | ClinicalTrials.gov
Astaxanthin for long COVID
ASTAXANTHIN
What is astaxanthin?
Astaxanthin is a red pigment belonging to the carotenoid family. It is found in algae and creates the pinkish-red color seen in salmon [[1]]. Astaxanthin can be obtained through dietary sources or as a supplement. Natural sources of astaxanthin include algae, yeast, salmon, trout, krill, shrimp, and crayfish [[2]].
What does astaxanthin do in the body?
The benefits of astaxanthin are vast, supporting skin condition, eye health, cardiovascular function, the nervous system, exercise performance, and the immune system. Astaxanthin may also benefit intestinal flora and perform anti-diabetes functions [[3]].
In terms of immune function, astaxanthin is an antioxidant and immunomodulator. It suppresses cytokines and regulates the production of chemicals that maintain the inflammatory response. Astaxanthin prevents oxidative damage and reduces the inflammatory response [[1]].
How can astaxanthin help alleviate certain Long COVID symptoms and pathophysiology?
Astaxanthin can help protect the organs and immune system from COVID-19’s chronic inflammation and severe complications. Scientists believe it may reduce complications of COVID-19 and even have preventative functions against SARS-CoV-2, the virus that causes COVID-19 [[4]].
Astaxanthin can reduce inflammation generated by the COVID-19 cytokine storm, linked to Long COVID. Given that one consequence of COVID-19’s cytokine storm is cell death and that astaxanthin can prevent this cell death, this has become of interest to prevent multi-organ damage in COVID-19, potentially both in the acute and post-COVID-19 phases [[1]].
Vitamin D for long COVID
VITAMIN D
What is vitamin D?
Vitamin D can be found in foods, and our bodies can make it from sunlight. It is a fat-soluble vitamin [[1]]. Globally, over 1 billion people have a vitamin D deficiency, which is why the vitamin is often added to fortified foods such as cereals [[2]].
What does vitamin D do in the body?
Vitamin D is important in bone health due to its role in calcium metabolism. Relevant to Long COVID, Vitamin D’s role in immune function is well-established. It plays a role not only in innate and acquired immunity but also in the immune response to viruses [[3]]. Vitamin D is linked to a lower risk of unchecked inflammation and cytokine storm in older patients with COVID-19 [[4]].
How can vitamin D help alleviate certain Long COVID symptoms and pathophysiology?
Vitamin D has multiple effects on biochemical pathways involved in Long COVID. It reduces inflammation, and in people with a vitamin D deficiency, supplementation can reduce fatigue [[4]]. However, a study of Long COVID patients did not find a link between persistent fatigue, exercise tolerance, and vitamin D levels [[5]].
In patients with COVID-19, vitamin D deficiency is also related to the severity of the disease, including respiratory failure and mortality. A study of Long COVID patients and vitamin D found that vitamin D deficiency is associated with delayed recovery [[6]]. The study also found that a combination of zinc and vitamin D deficiency, but not a zinc deficiency without a vitamin D deficiency, was associated with Long COVID in patients under 65. However, older people with Long COVID also stand to benefit from the health benefits of proper vitamin D supplementation.
Desloratadine for long COVID
DESLORATADINE
What is desloratadine?
Desloratadine is a second-generation antihistamine that relieves seasonal or year-round allergy symptoms such as sneezing, runny nose, red, itchy eyes, hay fever, and hives. Unlike other first-generation antihistamines, it is non-drowsy and usually taken daily. Desloratadine is typically taken at 5 mg once daily. For people with liver or kidney impairment, it may be recommended to take 5 mg every other day.
Desloratadine is the active metabolite of the over-the-counter medication loratadine (Claritin). This allows the medication to have very similar effects to loratadine, but desloratadine is considered to be more potent.
How can desloratadine help alleviate certain long COVID symptoms?
Histamine is a chemical our immune system releases that causes our allergy symptoms. Cells in our body called mast cells release histamine, and in some patients, after COVID, they may release too much and lead to a prolonged inflammatory response. Long COVID is believed to be caused by a persistent hyper-inflammatory state that results in symptoms such as fatigue, arthralgia, myalgia, shortness of breath, chest pain, and rash. Two types of drugs can block histamine in the body, which we call our H1- and H2-antihistamines.
Desloratadine is an H1-antihistamine that reduces the inflammatory symptoms caused by excess histamine. It is suggested that it has other functions outside of its effect on histamine, such as inhibiting the generation and release of inflammatory mediators.1 With its anti-histamine and anti-inflammatory effects, it is believed to help relieve long-term COVID symptoms.
What evidence supports desloratadine’s use for long COVID?
In vitro, desloratadine and loratadine were found to have the most potent antiviral activity out of eight tested agents against the SARS-CoV-2 virus in both monkey cells and human nasal epithelium cells.2 Desloratadine has also been shown to have a stronger binding affinity to ACE2 receptors compared to loratadine, which can inhibit the virus from entering ACE2 cells.3 However, desloratadine should not be used to treat or prevent an acute COVID infection.
While there is currently a lack of studies investigating the use of desloratadine for long COVID, loratadine has been studied in combination with an H2-antihistamine with demonstrated beneficial effects in long COVID patients. A study with 49 long COVID patients found that a combination of an H1- and H2-antihistamine like loratadine 10 mg twice a day with famotidine 40 mg once daily taken for a minimum of 4 weeks showed an average reduction of about half of their symptoms. Symptoms that were most improved included neurologic symptoms such as brain fog and headaches, chest pain, and fatigue. Only the symptoms of postural tachycardia or an abnormal increase in heart rate when a person stands up were not improved.4 Because of its structural similarity to loratadine, desloratadine can be hypothesized to have similar effects on long COVID patients.
What should I be aware of when taking desloratadine?
Some side effects of desloratadine include dry mouth, headache, nausea, and dizziness.
References:
Levocetirizine for long COVID
LEVOCETIRIZINE
What is levocetirizine?
Levocetirizine is an antihistamine medication that relieves allergy symptoms such as a runny nose, sneezing, redness, and itchiness of the eyes caused by hay fever and hives. The recommended dose is typically 5 mg once daily or 2.5 mg once daily for children ages six to 11. It is very similar to cetirizine in its chemical structure but may cause less drowsiness.
How can levocetirizine help alleviate certain long COVID symptoms?
Histamine is a chemical our immune system releases that causes allergy symptoms. Cells in our body called mast cells release histamine, and in some patients, after COVID, they may release too much, leading to a prolonged inflammatory response.
Long COVID is believed to be caused by a persistent hyper-inflammatory state that results in symptoms such as fatigue, arthralgia, myalgia, shortness of breath, chest pain, and rash. Two types of drugs can block histamine in the body: H1- and H2-antihistamines. Levocetirizine is an H1-antihistamine that is believed to reduce the inflammatory effects associated with long COVID.
Montelukast, a leukotriene receptor antagonist commonly used for seasonal allergies and asthma, is believed to have a synergistic effect when combined with levocetirizine. Montelukast works by blocking substances in the body that cause inflammation and allergic diseases. The combination of levocetirizine can result in a more robust anti-inflammatory response.1
What evidence supports levocetirizine’s use for long COVID?
While studies have shown improvement in long COVID symptoms with other antihistamine combinations, few studies have looked at the efficacy of levocetirizine alone for long COVID symptoms. For an active COVID infection, a study with 53 COVID patients ranging from mild to severe infection who were given levocetirizine 5 mg and montelukast 10 mg daily for 14 days in combination with standard care found that most patients experienced symptom resolution within seven days. In addition, no patients exhibited long COVID symptoms greater than three months.1
Cetirizine has also been studied in hospitalized COVID patients and was found to reduce inpatient mortality and progression of pulmonary symptoms.2 Levocetirizine may have similar effects based on their chemical similarity. More studies are needed to determine the benefit of long COVID.
What should you be aware of when taking levocetirizine?
Because it is less sedating and a newer drug on the market, levocetirizine can be more expensive than over-the-counter cetirizine. Both medications share very similar side effect profiles. Levocetirizine can cause fatigue, diarrhea, drowsiness, and constipation. For those with reduced kidney function, half (2.5 mg) of the typical dose is suggested.
References:
Vitamin B12 in long COVID
VITAMIN B12
What is vitamin B12?
Vitamin B12 belongs to the B family of vitamins. It is sometimes referred to as cobalamin.
What does vitamin B12 do in the body?
Vitamin B12 is a cofactor in chemical reactions related to cell metabolism and DNA in the body. Deficiencies in vitamin B12 can, therefore, be very consequential and severe. Causes of vitamin B12 deficiency can include low dietary intake, autoimmune conditions, malabsorption, surgery, contraceptive and hormone use, pregnancy, genetic causes, or drug interactions (metformin, proton pump inhibitors, and histamine H2 receptor agonists) [[1]].
Symptoms of vitamin b12 deficiency include fatigue, lack of energy, nervous system issues, and psychological dysfunction [[2]]. Slow thinking, confusion, changes in memory, depression, and acute psychotic states may be psychiatric symptoms attributed to vitamin B12 deficiency [[3]].
How can vitamin B12 help alleviate certain Long COVID symptoms and pathophysiology?
Long COVID patients should ensure that they receive adequate vitamin B12 supplementation. Vitamin B12, a member of the B vitamin family, plays a crucial role in the functioning of the nervous system. Therefore, it is imperative for Long COVID patients experiencing neurological symptoms such as “brain fog” to maintain sufficient levels of vitamin B12 [[4]]. Additionally, vitamin B12 supplementation may aid in alleviating depressive symptoms and fatigue, both of which are associated with Long COVID [[5]].
Research suggests that vitamin B12 deficiency may be common in Long COVID, similar to other chronic conditions such as chronic fatigue syndrome (CFS) and postural orthostatic tachycardia syndrome (POTS). Individuals with autoimmune disorders are also susceptible to vitamin B12 deficiency.
Moreover, vitamin B12 deficiency is correlated with elevated homocysteine levels, a marker of inflammation that can lead to arterial damage. Considering the potential existing inflammation in the arteries of Long COVID patients, it is essential to ensure adequate vitamin B12 levels to mitigate this risk [[4]].
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