Special Wellness Rx Report: Long COVID.  

-Written by Mackenzie Quirk, M.S. in Pharmaceutical Sciences & Pharmacy Intern

It has been over three years since the COVID-19 Pandemic was officially announced as a health crisis, and while the world yearns to return to the normalcy of pre-COVID life, there are remaining complications that have yet to be fully addressed. One major concern for many patients and providers is the impact of Long COVID. Long COVID is known by many names according to the CDC and may also be referred to as: Post-COVID condition, Long-Haul COVID, Post-Acute Sequelae of SARS CoV-2 Infection (PASC), and Chronic COVID.(1) The most recent data suggests that 15-20% of individuals with a COVID infection will develop Long COVID. (1-3) The aim of this article is to provide a general understanding of what Long COVID is, whether it is preventable, and potential options and resources for someone who may have Long COVID.

What is Long COVID? 

The WHO defines Long COVID as the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation. It is important to note that there is a wide range of symptoms and severity for sufferers of Long COVID. The most common complaints, however, include fatigue, weakness, arthralgias, cognitive impairment, difficulty concentrating, chest pain, palpitations, and reduced effort tolerance. (4)

(3)

What causes Long COVID?

The exact cause of Long COVID is unknown and likely varies to some degree based on each individual. Nevertheless, there are several main theories that are currently accepted, all of which involve the presence of persistent inflammation. Infections such as COVID-19 trigger a cascade of inflammatory and autoimmune responses, especially as it becomes more spread into multiple organs and tissues. Studies have demonstrated that COVID-19 can infect and affect your brain and central nervous system through multiple proposed mechanisms, leading to inflammation in the brain. This inflammation is believed to be the cause of the majority of Long COVID symptoms most bothersome to patients, including fatigue, difficulty concentrating, issues with memory, and increased risk of depression and/or anxiety. 

Other causes of chronic inflammation induced by COVID-19 infection include the potential for inducing autoimmune conditions, in which your body is attacking itself and causing inappropriate inflammation, or the actual persistent presence of COVID-19 virus in your body despite testing negative for the disease. Viral persistence presents a challenge to your body where your immune system is trying to get rid of all of the virus, but is unsuccessful, leading to chronic inflammation and essentially the burn out of your immune system. Chronic inflammation exhausts your body and causes damage on a cellular level, particularly to your mitochondria. Mitochondria are colloquially known as the “powerhouse” of our cells, and proper mitochondrial function is imperative to our energy metabolism and overall immune support. (3, 5 – 8) 

Who is at the greatest risk for Long COVID?

Evidence for those at greatest risk is mixed, although current literature suggests that age between 50 - 59, female gender, obesity, having underlying conditions such as COPD or diabetes, and >2 symptoms one month after the initial infection all increased risk of having symptoms 1-year post-infection. (3, 9) 

Can Long COVID be prevented? 

As with many disease states and infections, the best way to avoid complications is to prevent infection through vaccination when available. While initial studies are difficult to compare because the different measuring methods and diagnosis of Long COVID, data is still consistent in demonstrating a reduced risk of Long COVID in those who are vaccinated. In fact, a prospective cohort study published in March, 2023 demonstrated that non-vaccinated patients were almost seven times more likely to develop Long COVID symptoms compared to vaccinated patients. (10)

In a study published by the Department of Veterans Affairs, Paxlovid was shown to reduce the incidence of Long COVID by 25% when given to COVID-positive patients who qualified for antiviral treatment. (11) Briefly, Paxlovid (nirmatrelvir and ritonavir) is an anti-viral medication authorized for emergency use by the US Food and Drug Administration (FDA) for the treatment of mild to moderate COVID-19 in adults and pediatric patients (aged 12 years above a certain weight) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19. Paxlovid should be started within 5 days of symptom onset for the best response. (12)

What treatment options currently exist for patients with confirmed or suspected Long COVID? Unfortunately, there is no single treatment or cure for Long COVID. On a positive note, however, many studies are ongoing to address this health concern and should impact standards of care once more information is published. Currently, the main goal is to help treat the specific symptoms a person is feeling. Many patients with Long COVID appear to develop symptoms consistent with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome). (1)

Growing evidence for possible development of ME/CFS post COVID-19 is emerging, and a large barrier that is being met is provider education and appropriate diagnosis. ME/CFS is a complex illness that is characterized by excessive fatigue that is not made better by rest, is often exacerbated by any emotional, mental, or physical effort, and still being tired despite adequate hours of sleep. People with ME/CFS often have impaired memory or ability to concentrate, and/or may feel lightheaded or dizzy when standing up.  (13, 14) These symptoms are often consistent with the fatigue, “brain fog,” tiredness, and discomfort that many patients with Long COVID experience. 

Some articles have suggested that this inflammation in the brain is similar to other conditions, such as concussions and chronic Lyme disease. (15, 16) The good news is that perhaps these similarities will allow us to borrow from treatment options used to help other conditions. For example, if someone suffers from a concussion, there is evidence that they will benefit from brain rehabilitation and physical therapy to help them get back to normal activities of daily living. Similarly, studies have found that exercise interventions and physical therapy are correlated to significant improvements in quality of life for those suffering with Long COVID. (17) Cognitive-behavioral therapy and counseling are valuable tools to help patients cope with feelings of depression and establish healthy sleeping patterns. Finally, maintaining hydration is a simple yet important component to overall health and is recommended to help with feelings of dizziness or lightheadedness. (18)

Patients suffering from Lyme disease that has crossed the blood-brain-barrier often experience fatigue, changes in mood, decreased attention span, and other complications secondary to chronic inflammation. Dr. Jack Lambert, MD and PhD infectious disease specialist from Dublin, recommends that clinicians test and aggressively treat COVID infections in addition to using therapeutics aimed at reducing inflammation in order to prevent and lessen these complications that mirror the complications of chronic Lyme disease. (16)

One option being investigated is the use of antihistamines for acute and chronic COVID symptoms possibly due to inflammation. Famotidine (brand name Pepcid) is an antihistamine that has demonstrated reduction in symptom severity and duration for acute covid by preventing the virus from replicating. Some providers may try a combination of antihistamines that act on different histamine receptors, such as Benadryl (diphenhydramine) and Pepcid (famotidine) to reduce your body’s over-inflammatory and immune response. (19, 20) These medications generally provide a low-risk option especially if used short term. However, long-term studies are currently lacking therefore the role of antihistamines in the treatment of Long COVID is not yet clear.

Natural supplements have also been of interest when considering treatment options for Long COVID, particularly for their antioxidant and anti-inflammatory properties. Vitamin C has demonstrated considerable promise in improving post-COVID fatigue without significant side effects when dosed appropriately (500 – 2000 mg daily). Additional data has emerged to support the use of nutraceuticals, in other words depleting your body of vital nutrients, to reduce the chronic inflammatory and immune response post-COVID infection. Literature supports the idea that antioxidants such as Vitamin C, selenium, zinc, and curcumin could be viable and safe options for patients looking to relieve certain Long COVID symptoms. (21, 22) Theoretically, by supplementing with anti-inflammatory and antioxidant compounds, you are supporting your mitochondrial and immune system health, thereby reducing some of the symptoms associated with chronic inflammation such as pain and fatigue. 

Additional evidence to support supplementation with melatonin exists. Melatonin is thought to act as an NRF2 agonist. NRF2 inhibits pathways that cause significant inflammation; therefore, melatonin may theoretically be acting as an anti-inflammatory. Several studies have suggested benefits when taking melatonin 1 – 5 mg nightly to help with symptoms of chronic fatigue with or without supplementation of zinc 10 mg daily. (22 – 24) Additional benefits of melatonin include helping patients who have difficulty falling asleep and is overall a well-tolerated supplement. 

There are hundreds of ongoing clinical trials currently investigating potential options to address Long COVID, including homeopathic regimens, traditional medications, novel agents, and non-pharmacological therapy. Several pharmacotherapeutic agents of interest include Montelukast, Melatonin, Deupirfenidone, Nicotinamide riboside, Leronlimab, Adaptogens (such as extracts of Eleutherococcus senticosus root, Schisandra chinensis berry, and Rhodiola rosea root), Tocilizumab, and Probiotics are undergoing clinical trials. (25)

If you or someone you know is experiencing symptoms consistent with Long COVID, speak to your health care providers about potential pharmacological and nonpharmacological treatment options. 

What resources are available to people with Long COVID?

If you are or someone you know is suffering from Long COVID, please know that you are not alone. A recent publication estimates that at least 65 million individuals worldwide are dealing with Long COVID, and that the number of cases will continue to increase. (6) There are several support groups that have been started to connect people dealing with Long COVID symptoms and provide patients the opportunity to share their stories, what has worked, and what has not worked in their fight to feel better. Links to additional resources and support groups may be found below:

• https://www.facebook.com/groups/longcovid/
• https://acl.gov/covid19/resources-people-experiencing-long-covid 
• https://www.covid.gov/longcovid 
• https://www.survivorcorps.com/ 
• https://connect.mayoclinic.org/group/post-covid-recovery-covid-19/ 
• https://www.health.ny.gov/diseases/long_covid/

If you are interested in participating in research for the treatment of Long COVID, the National Institutes of Health has created the RECOVER initiative found here: https://recovercovid.org/. 

‍

References:

1. CDC. (2021). Long COVID or Post-COVID Conditions. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html 
2. CDC. (2022). Long COVID - Household Pulse Survey - COVID-19. Www.cdc.gov. https://www.cdc.gov/nchs/covid19/pulse/long-covid.htm 
3. Nalbandian, A., Desai, A. D., & Wan, E. Y. (2023). Post-COVID-19 Condition. Annual review of medicine, 74, 55–64. https://doi.org/10.1146/annurev-med-043021-030635 
4. https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-condition 
5. Davis, H. E., McCorkell, L., Vogel, J. M., & Topol, E. J. (2023). Long COVID: major findings, mechanisms and recommendations. Nature reviews. Microbiology, 21(3), 133–146. https://doi.org/10.1038/s41579-022-00846-2
6.  Liew, F., Efstathiou, C., & Openshaw, P. J. (2023). Long Covid: clues about causes. The European respiratory journal, 2300409. Advance online publication. https://doi.org/10.1183/13993003.00409-2023 
7. Chen, Y., Yang, W., Chen, F., & Cui, L. (2022). COVID-19 and cognitive impairment: neuroinvasive and blood‒brain barrier dysfunction. Journal of neuroinflammation, 19(1), 222. https://doi.org/10.1186/s12974-022-02579-8 
8. Monje, M., & Iwasaki, A. (2022). The neurobiology of long COVID. Neuron, 110(21), 3484–3496. https://doi.org/10.1016/j.neuron.2022.10.006
9. CDC. Nearly One in Five American Adults Who Have Had COVID-19 Still Have “Long COVID.” (2022, June 22). Www.cdc.gov. Available from: https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2022/20220622.htm
10. Abu Hamdh, B., & Nazzal, Z. (2023). A prospective cohort study assessing the relationship between long-COVID symptom incidence in COVID-19 patients and COVID-19 vaccination. Scientific reports, 13(1), 4896. https://doi.org/10.1038/s41598-023-30583-2 
11. Yan Xie, Taeyoung Choi, Ziyad Al-Aly. (2022) Nirmatrelvir and the Risk of Post-Acute Sequela of COVID-19. MedRxiv. doi: https://doi.org/10.1101/2022.11.03.22281783 
12. CDC. (2020, February 11). Underlying Medical Conditions Associated with High Risk for Severe COVID-19: Information for Healthcare Providers. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html 
13. CDC. (2019). What is ME/CFS? CDC. https://www.cdc.gov/me-cfs/about/index.html
14. Brennan, C. M., Nadella, S., Zhao, X., Dima, R. J., Jordan-Martin, N., Demestichas, B. R., Kleeman, S. O., Ferrer, M., von Gablenz, E. C., Mourikis, N., Rubin, M. E., Adnani, H., Lee, H., Ha, T., Prum, S., Schleicher, C. B., Fox, S. S., Ryan, M. G., Pili, C., Goldberg, G., … Janowitz, T. (2022). Oral famotidine versus placebo in non-hospitalised patients with COVID-19: a randomized, double-blind, data-intense, phase 2 clinical trial. Gut, 71(5), 879–888. https://doi.org/10.1136/gutjnl-2022-326952 
15. Alvarez, A. (2023, March 3). Long covid patients could benefit from concussion treatment, DU study finds. Axios. Retrieved April 5, 2023, from https://www.axios.com/local/denver/2023/03/03/long-covid-concussion-treatment-university-of-denver 
16. Dleland. (2022, September 28). Treatment strategies for long-haul covid and persistent lyme disease. LymeDisease.org. Retrieved April 5, 2023, from https://www.lymedisease.org/long-haul-covid-lyme-disease/
17. Jimeno-Almazán, A., Pallarés, J. G., Buendía-Romero, Á., Martínez-Cava, A., Franco-López, F., Sánchez-Alcaraz Martínez, B. J., Bernal-Morel, E., & Courel-Ibáñez, J. (2021). Post-COVID-19 Syndrome and the Potential Benefits of Exercise. International journal of environmental research and public health, 18(10), 5329. https://doi.org/10.3390/ijerph18105329
18. Jeannette Yeznach Wick, Rp. (2023). Fourteen Percent of Those Who Contracted COVID-19 Face Long-Term Challenges. Www.pharmacytimes.com, 89. https://www.pharmacytimes.com/view/fourteen-percent-of-those-who-contracted-covid-19-face-long-term-challenges
19. Ishola, A. A., Joshi, T., Abdulai, S. I., Tijjani, H., Pundir, H., & Chandra, S. (2022). Molecular basis for the repurposing of histamine H2-receptor antagonist to treat COVID-19. Journal of biomolecular structure & dynamics, 40(13), 5785–5802. https://doi.org/10.1080/07391102.2021.1873191 
20. Mashauri H. L. (2023). Covid-19 Histamine theory: Why antihistamines should be incorporated as the basic component in Covid-19 management?. Health science reports, 6(2), e1109. https://doi.org/10.1002/hsr2.1109 
21. Catalano, A., Iacopetta, D., Ceramella, J., Maio, A. C., Basile, G., Giuzio, F., Bonomo, M. G., Aquaro, S., Walsh, T. J., Sinicropi, M. S., Saturnino, C., Geronikaki, A., & Salzano, G. (2022). Are Nutraceuticals Effective in COVID-19 and Post-COVID Prevention and Treatment?. Foods (Basel, Switzerland), 11(18), 2884. https://doi.org/10.3390/foods11182884 
22. Tosato, M., Ciciarello, F., Zazzara, M. B., Pais, C., Savera, G., Picca, A., Galluzzo, V., Coelho-Júnior, H. J., Calvani, R., Marzetti, E., Landi, F., & Gemelli Against COVID-19 Post-Acute Care Team (2022). Nutraceuticals and Dietary Supplements for Older Adults with Long COVID-19. Clinics in geriatric medicine, 38(3), 565–591. https://doi.org/10.1016/j.cger.2022.04.004 
23. Castro-Marrero, J., Zaragozá, M. C., López-Vílchez, I., Galmés, J. L., Cordobilla, B., Maurel, S., Domingo, J. C., & Alegre-Martín, J. (2021). Effect of Melatonin Plus Zinc Supplementation on Fatigue Perception in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Antioxidants (Basel, Switzerland), 10(7), 1010. https://doi.org/10.3390/antiox10071010 
24. van Heukelom, R. O., Prins, J. B., Smits, M. G., & Bleijenberg, G. (2006). Influence of melatonin on fatigue severity in patients with chronic fatigue syndrome and late melatonin secretion. European journal of neurology, 13(1), 55–60. https://doi.org/10.1111/j.1468-1331.2006.01132.x 

Banerjee, I., Robinson, J., & Sathian, B. (2022). Treatment of Long COVID or Post COVID syndrome: A Pharmacological approach. Nepal journal of epidemiology, 12(3), 1220–1223. https://doi.org/10.3126/nje.v12i3.48532