The Untold Struggle: Long COVID and the Quest for Effective Treatment

From the beginning of the COVID-19 pandemic, people in the ME and CFS communities, including some researchers, predicted the development of a post-infectious syndrome (Komaroff & Bateman, 2021).

About 70% of people with ME and CFS became ill after an infection trigger, primarily viral. Why should SARS-CoV-2 be any different? Despite these early warnings, mainstream medicine seemed to be caught off guard when people started developing what is now called long COVID. As with all new conditions, long COVID goes by some other names, most commonly post-acute sequelae of SARS-CoV-2 (PASC), chronic COVID and long-haul COVID.

People with long COVID reported being dismissed by their medical practitioners and struggling to obtain useful guidance about how to manage their symptoms best—just like the ME, CFS community before them. They thought that given how common and serious long COVID is, the research community would rush to their aid and start searching for answers. As time passed, the long COVID community became angry at the lack of research funding directed toward understanding and solving their problems.

According to a recent feature article in the medical journal Nature, the 1.15 billion dollars invested in long COVID research so far by the National Institutes of Health (NIH) in the United States and the $515 million earmarked to be spent over the next four years are not being paid to research treatments that patients are reporting as beneficial (Fairbank, 2024). A quick search of the official clinical trials website reveals that most of the 500+ registered studies on long COVID are about

• identifying symptoms
• finding measurable abnormalities in function
• testing treatments that may improve symptoms but don’t get at root causes (e.g., physical rehabilitation, brain games, breathing exercises, etc.)

While these may be useful adjuncts, patients rightly want more research on interventions that might help shift their biology in meaningful ways so that they can get their lives back. There are very few studies underway on treatments that might shift root-cause biology.

In the gap left by governmental agencies, people with long COVID, especially those with scientific expertise, have pushed the agenda forward. It was patient groups who fought for the name long COVID and patients who collected valuable data about the symptoms of long COVID. Eric Topol and colleagues from The Patient Led Research Collaborative published this research in an influential paper. I relied heavily on that paper (Hannah E. Davis et al., 2021) for my November 2022 blog post, A Deep Dive into Long COVID.

The same group has published a comprehensive paper identifying the major findings about what is happening at the cellular level (H. E. Davis, McCorkell, Vogel, & Topol, 2023). I recommend this paper to anyone wanting to get up to speed on the current hypotheses, many of which suggest treatments that might be effective.

Three Exciting New Clinical Trials for Long COVID

Despite the overall dissatisfaction with the speed and direction of research, there are some bright spots on the long COVID research horizon. Although most of the symptoms of long COVID are related to mitochondrial dysfunction (e.g., brain fog, fatigue and low blood pressure are likely related to low cellular energy), chronic immune activation (inflammation) may be an upstream factor contributing to the mitochondria working below capacity.

Accordingly, all three studies I will share in this blog post involve modulating or resetting the immune system.

 
Can You Repair the Immune System After Long COVID With Baricitinib?

(Please note these fact boxes don’t include every piece of information. People who want to learn more are directed to the https://www.clinicaltrials.gov/ site.)

 This chart amalgamates information from the clinical trials.gov site and an interview on the Long COVID podcast with Dr. Ely, the lead investigator.

The baricitinib study is led by Dr. Wes Ely at Vanderbilt University in Tennessee. Baricitinib has been approved for the treatment of rheumatoid arthritis that has not responded to other treatments. It is in a class of drugs called Janus kinase inhibitors because it turns down some immune pathways controlled by Janus kinase molecules. An artificial intelligence search identified it as having a high probability of addressing the symptoms of long COVID.

The drug modulates the immune system by decreasing pro-inflammatory molecules like interleukins and interferons. It also has antiviral properties and has been shown to improve outcomes in people acutely ill with COVID-19 (Selvaraj et al., 2022). It is not clear whether acute and long COVID share similar biology. If not, they may not respond to the same treatments.

In the case of long COVID, there continues to be debate about the cause of persistent symptoms:

• ongoing presence of replicating (i.e., “live”) viruses that continue to activate the immune system, preventing it from returning to its normal low-gear surveillance function. This hypothesis is losing favor since no one has found evidence of full viruses in people with long COVID
• ongoing presence of viral particles like the notorious spike protein. Even though these particles don’t make more viruses, they may be recognized by the immune system and, therefore, be a cause of chronic inflammation
• an immune imbalance caused by the acute COVID infection, which in vulnerable individuals becomes chronic and the system can’t get back to normal—the so-called hit-and-run hypothesis

Notably, the same debate remains active in the ME, CFS community. At first, it was thought that chronic symptoms were due to the ongoing presence of infection. But this has pretty much been ruled out by extensive studies by reputable researchers like Dr. Ian Lipkin at Columbia and Dr. Ron Davis at Stanford. As a result of these “negative” studies, the belief that ongoing infection is the cause of chronic immune activation (inflammation) in ME and CFS was in the rearview mirror. However, more recently, people have found evidence of viral particles and antibodies in people with ME and CFS, and the persistence theory is back on the table (Rasa-Dzelzkaleja et al., 2023).

A drug like baricitinib, which could kill replicating viruses if present and decrease inflammation, is attractive.

Can You Reprogram the Immune System in Long COVID With Maraviroc + Atorvastatin?

(Since the protocol has not been published, I’m extrapolating from previous work and podcast interviews.)

Since the protocol has not been published, I’m extrapolating from previous work (Patterson et al., 2023) and a podcast interview with Dr. Mobeen Sayed.

Dr. Bruce Patterson, formerly of Stanford and currently leading a private company called IncellDX, proposes a very different immune approach. He hypothesizes that many of the symptoms of long COVID can be explained by chronic endotheliitis—an inflammation of the endothelial cells that line the blood vessels. He believes this inflammation is due to the persistence of the COVID spike protein hidden in cells called non-classical monocytes (Patterson, Francisco, et al., 2021). Normally, these cells live less than a week. In the case of long COVID, the usual cell death system (apoptosis) may be malfunctioning, allowing these inflammatory cells to persist for weeks to months and continue causing symptoms.

Non-classical monocytes have two types of receptors implicated in cardiovascular disease because they are found in large numbers on endothelial cells. Inflammation of the endothelial cells increases the risk of cholesterol plaques forming, causing blockages to blood flow. Both receptors, CC chemokine receptor 5 (CCR5) and fractalkine, can be targeted with relatively safe and already available pharmaceuticals.

Maraviroc was discovered in the 1990s and used to fight HIV aids. It is thought to reprogram and regulate inflammatory non-classical monocytes. Pravastatin is in the statin family of drugs usually used to lower cholesterol. However, like many drugs, it has multiple effects, one of which is to block fractalkine and decrease inflammation. Fractalkine blocks the normal process of cell death. If fractalkine receptors are blocked, the persistent inflammatory non-classical monocytes may die in the usual time frame, and the spike protein inside might be cleared, resolving the chronic inflammation.

Patterson and his team recently reported on a case series of 18 patients with long COVID who responded positively to their protocol (Patterson et al., 2023). They claim to have treated thousands of patients. The outcome of the two-drug protocol was measured by patient report of symptoms and laboratory evaluation of a blood panel that identifies immune markers claimed by Patterson’s team to be diagnostic of long COVID. On both subjective and objective measures, very significant improvements were reported after treatment compared to baseline.

Dr. Patterson’s team has developed a panel of 14 cytokines (immune markers) that they report differentiates among those who have acute COVID, long COVID, chronic Lyme disease and ME/CFS (Patterson, Guevara-Coto et al., 2021). If validated by other researchers, this could be the diagnostic test we have been waiting for. The test is gaining traction, is covered by many insurers in the US and is available in the UK and Europe.

Dr. Patterson has announced a placebo-controlled trial of the protocol is about to start. I have yet to see the study posted on the clinical trials website. Please do your due diligence regarding Dr. Patterson and his approach. An article in Mother Jones raises some red flags about Dr. Patterson’s business practices, and experts point out that his hypothesis may be too simple to explain everything that is going on with long COVID. It is worth noting that the group has developed its diagnostic test with private funding and plans to run the study of maraviroc and pravastatin with private funding.

Intravenous Immune Globulin (IVIG) Is Back!     Will It Help People With Long COVID RECOVER?

 I want to share one more study with you—one that excites me even though the results won’t be available until 2026 at the earliest. The over one billion dollars directed by the NIH towards long COVID research was invested in the RECOVER program. RECOVER divides the body into eight systems and researches each one in a silo (https://trials.recovercovid.org/design). This is a worrying shortcoming in my mind. I hope each program’s participant assessments are broad enough to pick up the unexpected. The study mentioned here is part of RECOVER-AUTONOMIC, which focuses on the autonomic nervous system (https://trials.recovercovid.org/autonomic).

Many cases of autonomic dysfunction, including orthostatic intolerance and postural orthostatic tachycardia syndrome (POTS), are thought to be caused by antibodies activating or inactivating critical autonomic receptors, preventing them from working as they should. For reasons that aren’t entirely clear, giving people exogenous antibodies from donated blood can decrease the symptoms of many autoimmune diseases, including some cases of autonomic dysfunction.

As an aside, IVIG is an accepted treatment for stiff-person syndrome, the condition that ended Celine Dion’s singing career. Dr. Carmen Scheibenbogen’s team from Berlin has reported improvements in patients with ME/CFS from plasmapheresis, a treatment to remove autoantibodies from the blood. This strengthens the evidence that autoantibodies are causing symptoms in at least a subset of patients with ME (Scheibenbogen et al., 2018).

Four randomized controlled trials of immune globulin therapy have been conducted in ME (Brownlie & Speight, 2021). The results were “mixed,” and as a result, IVIG never became widely accepted. Over the years, a few of my patients were able to access IVIG, and all benefited while they were on it. Unfortunately, the effects tend to wear off after treatment is stopped. Other experienced clinicians have also noted the benefits of IVIG, leading to it being recommended by the US ME/CFS Clinician Coalition and a recent influential publication on the diagnosis and management of ME/CFS (Bateman et al., 2021).

The lack of widespread acceptance of IVIG for ME is not only due to the mixed research results. IVIG is very expensive and difficult to access in most countries, even for accepted indications. Sadly, ME has never made that list. Immune globulin can also be given subcutaneously into the fat and intramuscularly, but the RECOVER study is sticking with the traditional method.

Since the four early studies mentioned above, we have learned that many patients with ME have autoantibodies against adrenergic receptors, and many have small fiber neuropathy, a condition often associated with autoantibodies. Since immune globulin is an effective treatment for many autoimmune conditions, and given some shortcomings in the early studies, there is renewed interest in immune globulin therapy, particularly as an option for the severely ill (Brownlie & Speight, 2021). 

Perhaps the RECOVER-AUTONOMIC study will provide more information about which people and symptoms are most likely to respond to IVIG. If the study is positive, access to this potentially helpful and safe drug will increase for people with long COVID and ME can ride on the coattails.

Conclusions

It is frustrating to watch people with long COVID go through much of the same frustration as people with ME/CFS have endured for years. Part of the problem is that good-quality research takes time—there just aren’t any shortcuts. The good news is several studies are underway uncovering root causes like immune activation. The three I mentioned in this blog post will tell us a lot about what is going on, whether positive or negative, with respect to effectiveness.

That’s the thing about research. If we knew the answer, we wouldn’t have to do the experiment. Every study results in more information and more questions to be tested. Although it is little consolation to those suffering now, if we look at the big picture, we have come a long way in understanding the impacts of SARS-CoV-2 on the body in a very short time.

Did you know that I host live sessions every other Thursday in which you can learn more about topics such as long COVID? The program is called Live! with Dr. Stein. These sessions provide no-to-low-cost strategies for people with complex chronic diseases. You will get science-based information and the chance to ask questions of me and my growing community of lifelong learners. Subscribers to Live! are granted free access to amazing experts on a wide variety of topics—The Expert Speaker Series is offered approximately once a month.

References

Bateman, L., Bested, A. C., Bonilla, H. F., Chheda, B. V., Chu, L., Curtin, J. M., . . . Yellman, B. P. (2021). Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management. Mayo Clinic Proceedings, 23, 23. doi: https://dx.doi.org/10.1016/j.mayocp.2021.07.004

Brownlie, H., & Speight, N. (2021). Back to the Future? Immunoglobulin Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Healthcare, 9(11). doi: https://dx.doi.org/10.3390/healthcare9111546

Davis, H. E., Assaf, G. S., McCorkell, L., Wei, H., Low, R. J., Re'em, Y., . . . Akrami, A. (2021). Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. eClinicalMedicine, 38. doi: https://dx.doi.org/10.1016/j.eclinm.2021.101019

Davis, H. E., McCorkell, L., Vogel, J. M., & Topol, E. J. (2023). Long COVID: major findings, mechanisms and recommendations. [Review]. 21(3), 133-146.

Fairbank, R. (2024). Long COVID still has no cure - so these patients are turning to research. Nature, 628(8006), 26-28. doi: https://dx.doi.org/10.1038/d41586-024-00901-3

Komaroff, A. L., & Bateman, L. (2021). Will COVID-19 Lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Frontiers in Medicine, 7. doi: https://dx.doi.org/10.3389/fmed.2020.606824

Patterson, B. K., Francisco, E. B., Yogendra, R., Long, E., Pise, A., Rodrigues, H., . . . Mora, J. (2021). Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) up to 15 Months Post-Infection. Frontiers in immunology, 12, 746021. doi: https://dx.doi.org/10.3389/fimmu.2021.746021

Patterson, B. K., Guevara-Coto, J., Yogendra, R., Francisco, E. B., Long, E., Pise, A., . . . Mora-Rodriguez, R. A. (2021). Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning. Frontiers in immunology, 12, 700782. doi: https://dx.doi.org/10.3389/fimmu.2021.700782

Patterson, B. K., Yogendra, R., Guevara-Coto, J., Mora-Rodriguez, R. A., Osgood, E., Bream, J., . . . Zgoda, M. (2023). Case series: Maraviroc and pravastatin as a therapeutic option to treat long COVID/Post-acute sequelae of COVID (PASC). Frontiers in Medicine, 10, 1122529. doi: https://dx.doi.org/10.3389/fmed.2023.1122529

Rasa-Dzelzkaleja, S., Krumina, A., Capenko, S., Nora-Krukle, Z., Gravelsina, S., Vilmane, A., . . . Murovska, M. (2023). The persistent viral infections in the development and severity of myalgic encephalomyelitis/chronic fatigue syndrome. Journal of Translational Medicine, 21(1), 33. doi: https://dx.doi.org/10.1186/s12967-023-03887-0

Scheibenbogen, C., Loebel, M., Freitag, H., Krueger, A., Bauer, S., Antelmann, M., . . . Grabowski, P. (2018). Immunoadsorption to remove s2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME. PLoS ONE [Electronic Resource], 13(3), e0193672. doi: https://dx.doi.org/10.1371/journal.pone.0193672

Selvaraj, V., Finn, A., Lal, A., Khan, M. S., Dapaah-Afriyie, K., & Carino, G. P. (2022). Baricitinib in hospitalised patients with COVID-19: A meta-analysis of randomised controlled trials. eClinicalMedicine, 49, 101489. doi:https://dx.doi.org/10.1016/j.eclinm.2022.101489