Every now and then my mouth gapes open with I read a paper. While the limitations of this paper must be noted – a small sample set involving three case reports – its conclusion – a very rapid return to health of people with severe long-term COVID – makes one sit up in one’s seat. Time, of course, will tell how this will all turn out
Oddly enough, the paper is heavy with authors who specialize in emergency medicine and rescue. They hail from the Florida and Texas Depts of Health Dept of Health, the Pebble Beach Fire Rescue, the Department of Emergency Medicine at an Oregon University, and an emergency management software company. But then there’s also Nancy Klimas (!) from the Institute of Neuroimmune Studies and the Veterans Administration to give us some comfort that all was done above board. (All, except for one author, were MD’s and PhD’s.)
God knows how they all got together but they were clearly determined to get the word out and so they did in a Journal they were apparently familiar with – the American Journal of Emergency Medicine (:)). Long COVID treatment papers are probably not common fare in that journal but it’s fitting in a way. With millions looking for answers, long COVID and its related diseases really ought to be on emergency status.
Three Severely Ill Long Patients – Three (VERY) Rapid Recoveries
The paper “Remission of severe forms of long COVID following monoclonal antibody (MCA) infusions: A report of signal index cases and call for targeted research” doesn’t say who these people but one suspects that the three “previously healthy, middle-aged, highly-functioning persons” were all involved with the emergency rescue departments.
Noting the lack of satisfactory treatments for long COVID, they offered up what they called their “compelling” observations of three patients in this paper.
Interestingly, no one expected the patients to get well – the treatment – a monoclonal antibody called casirivimab/imdevimab antibody cocktail (Regeneron™) – was simply done in an attempt to keep them from getting worse. The treatment was called “incidental” and “serendipitous” ; i.e. it appears to have been a shot in the dark.
The authors went to great lengths to make it clear that the placebo response could not have been involved. They stated that all three of the patients “had already come to terms that their respective diseases were likely untreatable and permanent conditions”. Nobody, not the “medical personnel, the patients, nor their families had anticipated improvements, let alone complete remissions.”
They are apparently not the only ones to respond either. The authors stated that the first three cases in which this drug was tried were published in order “to remain concise” but that they were only the first “among many others”; i.e. this drug has worked in others.
These were not mild cases of long COVID. All occurred prior to any of them being vaccinated.
Even mild exertion (climbing stairs or walking) caused severe fatigue in one formerly healthy 60-year-old woman. Along with that, she experienced “chest discomfort”, joint pain, shortness of breath, numbness and tingling, sleep issues, brain fog (difficulties reading, and performing simple math calculations), “nerve pain feeling like bee stings”, and frequent nightmares. All these symptoms were new to her. A Pfizer vaccination did not help.
Approximately a year after becoming ill she received the casirivimab/imdevimab antibody cocktail (Regeneron™). Within 4-5 days all her long COVID symptoms dissipated completely. Two years later she remains in good health.
A 43-year-old woman came down with COVID-19 in early 2021. After getting over that she developed severe fatigue, extremely poor exercise intolerance, severe muscle and joint aches, dyspnea, palpitations, dizziness while sitting and standing, and “profound difficulty” concentrating and remembering. She also experienced headaches, sensory symptoms, vivid dreams, and some alterations in taste and smell. A later Pfizer vaccination produced only some mild relief.
In September 2021, testing positive for COVID-19 she received the casirivimab/imdevimab As with the first patient all her COVID symptoms disappeared entirely within five days.
Despite getting infected with COVID again in the summer of 2022, she remains in normal health 2 years later.
The 3rd person was not in such good health. He was overweight and had type II diabetes but was a highly functional individual in good health with good exercise tolerance – until he met up with the coronavirus. After getting over the initial infection his health plummeted and he experienced severe fatigue, extremely poor exercise tolerance, severe muscle aches, dizziness upon standing, brain fog, etc..
Five months after his long COVID onset, he met up with the coronavirus again. This time doctors gave him the casirivimab/imdevimab MCA cocktail. Once again all his long COVID symptoms disappeared within a week and he remains completely healthy two years later.
Warning – The authors warned that because the antibody mixture was developed prior to the development of some of the coronavirus variants it’s not clear that it will work as well with those who have those variants. (Indeed, the casirivimab plus imdevimab infusions proved to be ineffective against the omicron variant and are no longer used today.) Since then other MCA products have, however, been produced, and the authors reported that “they have become aware of other MCA products having similar positive effects in long COVID patients who likely were infected with the more recent SARS-CoV-2 variants”.
Most importantly for many of us, though, they stated “ these cases also provide mechanistic implications for treating/managing other post-viral chronic conditions.”; i.e. they provide a possible template for treating other postviral diseases.
Using Arseneau’s assessment categories (credibility of the source/quality of the evidence/benefit-cost-risk) for determining whether or not to try a treatment we can say that with Dr. Klimas involved – the source has very high quality. The quality of the evidence – three case reports – is not high; i.e. it’s all anecdotal case reports which do not substitute for a placebo-controlled, randomized study, and, if you can get these drugs – and you probably can’t – the potential benefit is VERY high, the risk is probably more or less moderate, and I don’t know what the cost is but it’s probably quite high.
With only one of the criteria being met (excellent source) – monoclonal antibodies are a wait-and-see type treatment.
- This paper came from an obscure journal but boy was it exciting. While its limitations must be noted – a small sample set involving three case reports – its conclusion – a very rapid return to health of people with severe long-term COVID – makes one sit up in one’s seat.
- Nancy Klimas and others reported how shocked they were when a drug that they hoped might at best arrest a further drop in health in three long-term severely ill long COVID patients quickly returned them to health. Two had been ill with severe exercise intolerance and the rest for over two years. Within a week they were back exercising and have remained healthy since then.
- The drug used was casirivimab/imdevimab duo monoclonal antibody infusion. This drug was designed to neutralize the coronavirus by attaching itself to the spike protein the virus uses to enter the cell. The drug is actually no longer in use as it was not effective against later coronavirus variants but the authors reported that they know of more advance monoclonal antibody drugs which have had the same effect.
- The author proposed that the drug was either neutralizing whatever virus was left in the body, displacing detrimental autoantibodies, and/or enhancing the immune response.
- The authors didn’t speculate how a similar drug therapy might play out in diseases like ME/CFS, but ME/CFS was referred to throughout the paper. More to the point, they stated that “these cases also provide mechanistic implications for treating/managing other post-viral chronic conditions.” They also suggested that the drug could be helping to wipe out reservoirs of the Epstein-Barr virus (EBV) in the body.
- Finally, they noted the growing evidence that a “chronic, insidious infection” is present not just in long COVID but in people exposed to other ACE2-binding viruses. (ACE2 is the receptor through which the coronavirus enters cells and ACE2 dysregulation has been found in ME/CFS as well.)
- While the authors don’t mention it, the fact that a different coronavirus – one that causes the common cold but which can send people to the hospital – also enters cells through the ACE2 virus suggests it could conceivably be causing the ACE2 dysregulation in ME/CFS – and helping to trigger the disease.
- While the authors don’t mention it, the virus most commonly associated with ME/CFS
– the Epstein-Barr virus – also has a link to ACE2 dysregulation. Attempts to create a monoclonal antibody that attacks EBV are underway.
- Noting the “compelling” results and the severe impact long COVID has on patients and families the authors proposed that at a minimum a prospective observational study employing a “very large series of volunteer patients with severe long COVID” get underway. (One small study at UCSF is underway.)
- The ability of this treatment to quickly return 3 severely ill long COVID to health (and the authors hinted they knew of more) was stunning. Time will tell, though, whether MAB therapy is kind of a one-hit wonder or if provides something more fundamental.
The casirivimab/imdevimab duo monoclonal antibody (600 mg/600 mg) MCA infusion used was developed specifically to treat COVID-19. The antibody is designed to neutralize the coronavirus by attaching itself to the spike protein the virus uses to enter the cell. Laboratory studies indicated that each antibody was extremely effective (≥ 95%) at blocking the spike protein RBD from binding to the ACE2 receptor the virus uses to enter the cell.
It received emergency authorization to help prevent COVID-19 in at-risk patients in the US in Nov. 2020 and later in Canada, the EU, Japan, and the UK. It’s usually given in a single dose but can be given in subsequent doses to people who require further prevention.
Several different versions of the MCA infusion exist including a later one focused on more recent variants
Possible Pathways to Recovery
The authors hypothesized four ways the antibody infusion could be helping:
- Neutralization – The antibody infusion neutralized; e.g. stopped whatever coronavirus remained from replicating. Once the remaining coronavirus was fully eradicated the patient’s immune systems were able to return to homeostasis and they were well again.
- Displacement – The antibody infusion displaced auto-antibodies attached to Fc receptors that help drive B-cell response. Once those auto-antibodies were no longer able to turn on the immune response, the patients returned to health. Note that if #1 or #2 are occurring, IVIG becomes a possibility and the authors specifically mentioned ME/CFS in this regard.
- Enhancement – The monoclonal antibodies enhanced the immune response by attaching to sites (CD16) that activate the cytotoxic immune response – and thus were able to eliminate leftover viral particles or virus-infected cells, including, interestingly, viruses such as EBV.
- Combination – Any combination of any of these elements.
Ramifications for other Postviral Syndromes
Nancy Klimas’ influence (she was involved with the “conceptualization, methodology, resources, writing – review & editing” of the paper).is clear in the lengths the authors went to to associate long COVID with chronic fatigue syndrome (ME/CFS). Links to inflammation, autoimmunity, herpesvirus reactivation, brain fog, POTS, and endothelial (blood vessel) issues in both diseases are given.
Likewise, the first appendix proposes that the fatigue-dominated form of long COVID found in these case is analogous to ME/CFS cases featuring reactivated herpesviruses (cytomegalovirus (CMV), EBV, herpes type 6, herpes zoster). They propose that a low-grade endothelial (blood vessel) dysfunction in concert with a maladaptive immune response (involving INF-γ, CCL4, MIP-1 beta, or IL-6 or IL-10) may be causing widespread and severe mitochondrial dysfunction.
Other than stating that “these cases also provide mechanistic implications for treating/managing other post-viral chronic conditions.” and suggesting that the monoclonal antibodies could be helping to wipe out Epstein-Barr virus (EBV) reservoirs, the authors don’t speculate, however, about how this therapy could help diseases like ME/CFS, POTS, post-treatment Lyme disease and others.
The idea, though, that viral/bacterial remnants in hard-to-access reservoirs may be causing diseases like ME/CFS goes way back, however, and the authors specifically referred to EBV in conjunction with this idea. They proposed that these monoclonal antibody infusions may be able to reach places (gut, brain, prostate, eye) that the immune system (and antivirals) have trouble getting at.
If they are right then what may be needed in other post-viral disorders is to find a way to finally clear the initial infection. The good news is that a concerted effort is underway to assess the role viral reservoirs in the body may be contributing to long COVID.
Could a Common Coronavirus Cold Virus be Causing ME/CFS?
Finally, they noted the growing evidence that a “chronic, insidious infection” is present not just in long COVID but in people exposed to other ACE2-binding viruses.
The ACE2 receptor is so interesting because small ME/CFS and POTS studies have implicated it in those diseases as well. It was initially linked to the RAAS paradox and low blood volume in ME/CFS and POTS but it could be linked to increased sympathetic nervous system activation, blood vessel narrowing (vasoconstriction), inflammation, and oxidative stress.
Having ACE2 dysregulation show up in these three diseases has been bizarre, to say the least. Understanding its connection to long COVID is easy – the coronavirus enters cells through this receptor. How to explain its appearance in ME/CFS and POTS – two diseases that showed up long before the SARS-CoV-2 coronavirus appeared on the scene?
There is a way. It turns out that another coronavirus – the human coronavirus NL63 (HCoV-NL63) also enters cells through the ACE2 receptor. This virus was first identified in 2004 but is believed to have been circulating in humans for centuries. It’s a common respiratory virus; i.e. a cold virus that has been found worldwide – meaning that many of us may be been exposed to it.
Symptoms are usually mild but can put people into intensive care and it “provokes an eerily similar immune response to the SAR-CoV-2 coronavirus that causes long COVID. One wonders whether this common cold virus could be triggering ME/CFS and POTS (and dysregulating ACE2) in some people as well?
Monoclonal Antibodies Against EBV?
Or could EBV be the link between long COVID and ME/CFS? EBV does not enter cells through the ACE2 receptor but in a rather remarkable coincidence, it does impact that receptor. When EBV replicates it turns on the ACE2 enzyme which then facilitates entry of the coronavirus into the cell. Plus an ACE2 promoter also turns on EBV and helps it wake up from latency. EBV, then, enhances coronavirus infections and the coronavirus enhances EBV replication. It’s no wonder that the two have become closely linked.
If monoclonal antibodies directed against the coronavirus can help with long COVID what about monoclonal antibodies for EBV? Efforts to develop monoclonal antibodies against EBV are underway. Using X-ray crystallography and electron microscopy researchers recently uncovered “multiple sites of vulnerability” at the site where the virus attaches to cells that antibodies could attack. Mice studies suggested that a monoclonal antibody may be able to achieve “near complete” neutralization of the virus. This year another study used monoclonal antibodies to target a different part of EBV (glycoprotein 350 (gp350) on the EBV envelope).
Things are heating up in the EBV world. Recently a new high-throughput method that promises to better assess EBV antibodies and monoclonal antibodies was published and two new vaccine candidates, from the National Institutes of Health and Moderna, have entered or are about to enter clinical trials.
The authors suggested that the COVID-19 vaccines are at least somewhat preventative against long COVID either because they’re shifting the immune balance and displacing dysfunctional antibodies or they’re enhancing the ability of the immune system to clear the infection. If the coronavirus vaccines are able to shift the immune landscape and help prevent or ameliorate long COVID, could EBV vaccines help with ME/CFS as well?
The rapid recoveries were compelling indeed. Given the antibody mixtures “relative therapeutic safety” the authors proposed that at a minimum a prospective observational study employing a “very large series of volunteer patients with severe long COVID” get underway and that a registry of persons receiving therapy be established. (Prospective studies do not involve randomization or placebo but simply follow patients over time.).
One small trial is already underway. Michael Peluso’s “OutSmart” trial at UCSF (n=30) will use the AER002 monoclonal antibody in long COVID patients infected by a specific coronavirus variant.
We need to be careful. We already have comments indicating that this approach did not in others. Everyone should be aware that small studies produced wonderful results with antivirals and Rituximab in ME/CFS which were later overturned by larger, more rigorous studies. There’s obviously some potential here but it needs to be assessed by better studies before we have any solid ground.
In an appendix, the authors noted that “both patients and family members uniformly expressed that the disabilities had produced overwhelming, unremitting physical and psychological distress that affected work and family.” (No argument there!).
- Check out Health Rising’s Lives Interrupted program to get the many costs of these diseases.
The authors ended with this:
“With millions still debilitated by long COVID, this initiative should receive immediate attention, not only for the patients themselves, but also for the many millions of loved ones, employers, and healthcare professionals also impacted by long COVID.”
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