Remission of severe forms of Long Covid following monoclonal antibody (MCA) infusions: A report of signal index cases..., 2024, Scheppke, Klimas et al

[Andy]

Note: title change in final publication - see post below

Preprint
Pathophysiology and potential treatment of long COVID: A report of signal index cases and call for targeted research, 2023, Scheppke, Klimas et al

Objective
Long COVID has afflicted tens of millions globally leaving many previously-healthy persons severely and indefinitely debilitated. The objective here was to report cases of complete, rapid remission of severe forms of long COVID following certain monoclonal antibody (MCA) infusions and review the corresponding pathophysiological implications.

Design
Case histories of the first three index events (among others) are presented. Unaware of others with similar remissions, each subject independently completed personal narratives and standardized surveys regarding demographics/occupation, past history, and the presence and respective severity grading of 33 signs/symptoms associated with long COVID, comparing the presence/severity of those symptoms during the pre-COVID, long-COVID, post-vaccination, and post-MCA phases.

Setting
Patient interviews, e-mails and telephone conversations.

Subjects
Three previously healthy, middle-aged, highly-functioning persons, two women and one man (ages 60, 43, and 63 years respectively) who, post-acute COVID-19 infection, developed chronic, unrelenting fatigue and cognitive impairment along with other severe, disabling symptoms. Each then independently reported incidental and unanticipated complete remissions within days of MCA treatment.

Interventions
The casirivimab/imdevimab cocktail.

Measurements and main results
Irrespective of sex, age, vaccination status, or illness duration (18, 8 and 5 months, respectively), each subject experienced the same complete remission of their persistent disabling disease within a week of MCA infusion. Each rapidly returned to normal health and previous lifestyles/occupations with normalized exercise tolerance, still sustained to date nearly two years later.

Conclusions
These index cases provide compelling clinical signals that MCA infusions may be capable of treating long COVID in certain cases, including those with severe debilitation. While the complete and sustained remissions observed here may only apply to long COVID resulting from pre-Delta variants and the specific MCA infused, the striking rapid and complete remissions observed in these cases also provide mechanistic implications for treating/managing other post-viral chronic conditions and long COVID from other variants.

Key points

• Question: Considering that long COVID-19 has been devastating for many millions worldwide, what is the proposed pathophysiology and are there any effective treatments?
  
  
• Findings: Previously-healthy middle-aged persons who had developed persistent debilitating post-acute SARS-CoV-2 sequelae, each experienced complete remission their symptoms within days of receiving a specific monoclonal anti-body infusion despite relative differences in sex, age, vaccination status, and long COVID duration.
  
  
• Meaning: Certain monoclonal antibody infusions may be capable of reversing severe long COVID. Beyond providing an effective potential treatment for long COVID, these findings have mechanistic implications for treating other post-viral chronic conditions, including future long COVID variants.

Paywall, https://www.sciencedirect.com/science/article/abs/pii/S073567572300534X

 

[Jaybee00]

Long Covid
Long Bio
TLDR

https://useagles.org/teammembers/paul-e-pepe/

 

[Trish]

Interventions
The casirivimab/imdevimab cocktail.

That's not a treatment patients casually try on their own, it has to be prescribed and administered by clinicians. I assume those clinicians didn't choose to give this treatment randomly, and only to 3 patients. If so, why single out these 3 to write a paper about. Why not do a proper pilot study and report on all included patients.

I hope a better pilot study will be done with proper controls, outcome measures and reporting.

 

[Jaybee00]

Why not do a proper pilot study and report on all included patients

Probably because of funding. I’m fine with them publishing a case study. Now they have something that they can cite for developing a larger proposal.

 

[Trish]

Probably because of funding. I’m fine with them publishing a case study. Now they have something that they can cite for developing a larger proposal.

I agree, I was just questioning whether they only treated 3 people. If not they should have said what happened to the rest of the people treated, not just picked the 3 that recovered. Unfortunately it's paywalled so I don't know what they did. If they treated and hundred people and 3 recovered, given the short duration of their LC, that's not so surprising - people with short duration LC are recovering all the time. if they only treated a few people and 3 recovered, that looks worth studying further.

 

[EndME]

I agree, I was just questioning whether they only treated 3 people. If not they should have said what happened to the rest of the people treated, not just picked the 3 that recovered. Unfortunately it's paywalled so I don't know what they did. If they treated and hundred people and 3 recovered, given the short duration of their LC, that's not so surprising - people with short duration LC are recovering all the time. if they only treated a few people and 3 recovered, that looks worth studying further.

Indeed the monoclonal antibodies were adminstered in October and September 2021. The price of the drug doesn't seem to be too high either (at least compared to some other things) at roughly $1000 per person, from what I calculated. One would think they would have tried this on more patients by now given the phenomenal results they achieved 2 years ago. They do mention though that these 3 patients received the drug on the basis of a very recent Covid-19 reinfection (there are also some anecdotal stories where a reinfection seemed to cure Long Covid) rather than being Long Covid related.

The journal pre-proof mentions "Among other cases being followed by the investigators, MCA infusions did not improve long COVID patients with isolated (but persistent) anosmia/dysgeusia.", but I don't have access to the paper either.

 

[Jonathan Edwards]

The objective here was to report cases of complete, rapid remission of severe forms of long COVID following certain monoclonal antibody (MCA) infusions and review the corresponding pathophysiological implications.

This is a pretty weird statement. It seems that the 'objective' was to report the ones that did brilliantly, with no mention of anyone who didn't.

This is not how you do preliminary or pilot studies. Been there, done that.

 

[SNT Gatchaman]

Noting: "We also express our sincere gratefulness to those various members of the Centers for Disease Control and Prevention (CDC) who provided the investigators with tremendous guidance regarding these findings in the early phases of the project."

This is a summary case series. The summary seems to be that 3 patients with established LC received Regen-Cov2 (casirivimab/imdevimab) as an anti-spike monoclonal-antibody "cocktail" due to repeat (or significant exposure to) acute Covid that was thought to significantly risk worsening of their symptoms.

the first three index cases (among many others) are being used because, by themselves, each persuasively illustrate this serendipitous observation. In all three cases, long COVID symptoms had been severely debilitating and unrelenting (for 18 months in one case), yet each person had the same complete (and sustained) rapid remission within 5- 7 days of MCA administration regardless of age, sex or duration of long COVID.

These complete remissions were corroborated by loved ones. Each verified that the sudden reversal of the chronic condition was indeed dramatic, and unanticipated after so many months of unrelenting severe debilitation that had come to be accepted as a permanent condition. Accordingly, these additional interviews provided a broader perspective of the treatment outcomes. Long COVID is not only life-changing for patients, but also family members, employers, and others who have to adapt, make accommodations, or provide direct support to these previously healthy persons. Consequently, they were witnesses with pivotal attestations to these apparent “cures”, but also provided broader reasons for identifying treatments.

 

[Trish]

the first three index cases (among many others) are being used because, by themselves, each persuasively illustrate this serendipitous observation.

Index cases, I understand, usually means the first recorded cases of a new disease. In this case it seems to be they are claiming them the first recorded cases of sudden recovery from LC after this treatment.

Does it say how many other people with LC were also treated with this drug intended for acute Covid whose LC didn't resolve or even got worse?
The sentence is ambiguous, do they mean among many others treated, or among many others recovered?

 

[SNT Gatchaman]

The case reports all read very similarly and I've summarised below. Note case 2 did not re-enter LC despite repeat infection post recovery. If nothing else, this at least confirms that:
1. It is possible to recover completely
2. Any effect of deconditioning is rapidly reversed on resuming normal life and exercise

And suggests that:
There may be a stochastic effect - even with a documented predisposition to LC, repeat infection does not mandate return to pathological state (variant viral infections being noted of course)

[60F] in good health, developed acute COVID-19 infection (March 2020) characterized in the peak phase by a transient but moderately-severe respiratory malady with some dyspnea, cough, and intermittent fever that resolved within two weeks.
She soon developed an insidious systemic syndrome [...] mostly severe fatigue, even with mild exertion[...] joint pain, paresthesia, significant memory difficulties, new-onset sleep disturbance and intermittent low-grade evening fevers [...] new-onset frequent nightmares with realistic terrors.[...] Pfizer BioNTech vaccinations 11- months later without diminishment of her long COVID.
Following new potential exposure [...] she received casirivimab/imdevimab antibody cocktail (Regeneron™) 10/10/2021. Despite some transient worsening of chronic chest discomfort, all long COVID symptoms dissipated, entirely, within 4-5 days. Low muscle tone developing during long COVID remained but rapidly-improved after resuming routine exercise. She sustained complete remission and remains in good health 21 months later

[43F] [...] in good health except “mild chronic anemia” developed COVID-19 on 01/04/2021. [...] progressively developed severe fatigue, extremely poor exercise intolerance, severe muscle and joint aches, dyspnea, palpitations [...], significant “dizziness” (both postural and resting), and profound difficulty concentrating [...] significant headaches [...] Pfizer BioNTech vaccinations, two-months after long COVID onset [...] no symptom diminishment [...] In September 2021, testing positive for COVID-19 [...] medical team recommended infusion of casirivimab/imdevimab MCA cocktail [...] all long COVID symptoms disappeared entirely within five days of receiving MCA. Again, low muscle tone acquired during long COVID, significantly improved after resuming normal physical activity.
[...] in remission to date, nearly 2-years later, even though, during Summer 2022, this patient developed mild upper respiratory illness, testing positive for COVID-19

[63M] (self-reported “overweight” man with history of adult-onset diabetes and hypertension) [...] acute COVID-19 (May 2021). [...] persistent severe fatigue, extremely poor exercise tolerance, and severe muscle aches [...] experienced significant postural dizziness, severe difficulty with memory, concentrating and “thinking clearly”[... ]become profound and debilitating. [...] never vaccinated.
Five months after long COVID onset, he was re-exposed to COVID-19. Medical professionals referred him for casirivimab/imdevimab MCA cocktail infusion. Again, all long COVID symptoms fully-reversed within 7 days and remain absent, 21 months later. Low muscle tone issues also developed during long COVID, but completely resolved after resuming routine exercise.

 

[SNT Gatchaman]

Does it say how many other people with LC were also treated with this drug intended for acute Covid whose LC didn't resolve or even got worse?

Not that I can see.

The sentence is ambiguous, do they mean among many others treated, or among many others recovered?

I read that as "recovered".

Edit: correct my last word.

 

[SNT Gatchaman]

Though somewhat rudimentary explanations for this complex disease entity, one could surmise four theoretical pathways through which the MCA infusion created the sudden, complete remissions:

1) The MCA provided a direct neutralizing attack on persistent SARS-CoV- 2 harboring in tissues not sampled or detected by routine nucleic acid amplification tests; this created enough reductions in persistent viral particles that the host could return to baseline immune balance and overall homeostasis.

2) MCA infusion displaced auto-antibodies attached to Fc receptors, facilitating clearance and removal of those factors.

3) The Fc portion of monoclonal antibodies attached to FcγRIII (CD16) sites that activate antibody-dependent-cytotoxicity pathways; the infused MCA cocktail eliminated residual viral particles or virus-infected cells, including reactivation viruses such as EBV.

4) Any combination of these elements.

 

[SNT Gatchaman]

From Appendix B (original emphasis) —

The patients reported in this brief report were chosen because: 1) they were the first three index cases reported to the investigators (among many others now) with complete remissions and they are, simultaneously, concrete examples of how these remissions were truly complete and sustained recoveries; 2) each individual case was remarkable in itself, but the similarities between all three were also striking, particularly the abrupt termination of a lengthy severe illness thought to be the permanent; 3) they included a pre-and a postmenopausal woman and a man with immunomodulating conditions thought to predispose persons to COVID-19, who also was not vaccinated; 4) the investigators were also confident that these first index cases had not been biased by any other word of mouth or knowledge of such an effect; and 5) all of them had already come to terms that their respective diseases were likely untreatable and permanent conditions. In each case, they had been advised to take the MCA simply to prevent their severe conditions from getting any worse.

 

[SNT Gatchaman]

Also from supplementary materials: Appendix B —

The authors have since 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, again indicating that the underlying pathogenesis of some long COVID-19 cases may be a persistent, ongoing antigen stimulation by SARS-CoV-2.

Most encouraging about this report is that both patients and family members uniformly expressed that the disabilities had produced overwhelming, unremitting physical and psychological distress that affected work and family. In that respect, long COVID also impacts the many other millions of persons related to or working with long COVID patients. Not only did MCA infusions reverse the physical disabilities, but also greatly improved those persons’ social, psychological, interpersonal, and economic well-being -- as well as the well-being of those around them.

 

[Hutan]

So, if I'm understanding things right, the authors of the paper were told about these recoveries. And these three people are the first three they were told about, but there have been others they have been told about since. The authors weren't the ones who administered the treatment, which was, in any case, not administered to cure Long Covid.

So, I guess one question is, how reliable are these reports? Had these people been physically assessed by the authors recently before the treatment? Were they physically assessed by the authors after the treatment? Given the timing of the treatment administration, probably not. What indications are given in the paper that these really are credible reports?

The abstract refers to 'interviews, emails and telephone conversations' and there's a reference to the cases filling out retrospective surveys.

It is interesting, for sure, but this:

Indeed the monoclonal antibodies were adminstered in October and September 2021. The price of the drug doesn't seem to be too high either (at least compared to some other things) at roughly $1000 per person, from what I calculated. One would think they would have tried this on more patients by now given the phenomenal results they achieved 2 years ago.

 

[Hutan]

From wikipedia

Casirivimab/imdevimab, sold under the brand name REGEN‑COV among others,[8][10] is a combination medicine used for the treatment and prevention of COVID‑19.[10] It consists of two human monoclonal antibodies, casirivimab and imdevimab that must be mixed together and administered as an infusion or subcutaneous injection.[12][8][10] The combination of two antibodies is intended to prevent mutational escape.[13] It is also available as a co-formulated product.[12] It was developed by the American biotechnology company Regeneron Pharmaceuticals.[14][15]

The most common side effects include allergic reactions, which include infusion related reactions, injection site reactions,[10] brief pain, weakness and others.[16]

The combination is approved under the brand name Ronapreve for medical use in Japan, the United Kingdom, the European Union, and Australia.[1][7][10][11][17][18]

REGEN‑COV is manufactured at the Regeneron's manufacturing facility in Rensselaer, New York.[20] In September 2020, to free up manufacturing capacity for REGEN‑COV, Regeneron began to shift production of its existing products from Rensselaer to the Irish city of Limerick.[21]
Regeneron has a deal in place with Roche (Genentech)[22] to manufacture and market REGEN‑COV outside the United States.[23][24]

So, Regeneron, an American company, are the treatment developers and they must have made squillions from it in a very short time.

In January 2021, the United States agreed to purchase 1.25 million doses of the drug for $2.625 billion, at $2,100 per dose.[28][29] On 14 September, another 1.4 million doses were purchased for the same price, totaling $2.94 billion.[30]

In January 2021, the German government purchased 200,000 doses for €400 million at €2,000 per dose.[31]

In May 2021, Roche India and Cipla announced that the medicine would be available in India for Rs 59,750 ($808.31) per dose.[32]

In September 2021, the World Health Organization urged producers and governments to address the drug's high cost and called for technology sharing to enable the manufacture of biosimilar versions. The WHO also said that Unitaid is negotiating with Roche for lower prices and equitable distribution, especially in low- and middle income countries.[33]

In October 2020 when U.S. President Donald Trump was infected with COVID-19 and taken to Walter Reed National Military Medical Center in Bethesda, Maryland, he was administered REGN-COV2.[21] His doctors obtained it from Regeneron via a compassionate use request (as clinical trials had not yet been completed and the drug had not yet been approved by the US Food and Drug Administration (FDA)).[22] On October 7, Trump posted a five-minute video to Twitter reasserting that this drug should be "free."[23] That same day, Regeneron filed with the FDA for emergency use authorization. In the filing, it specified that it currently had 50,000 doses and that it expected to reach a total of 300,000 doses "within the next few months."[24] The FDA granted approval for emergency use authorization in November 2020.[25]

But, the treatment doesn't seem to work against the Omicron variant, so that's a problem, including for Regeneron. Presumably they have the technology to tweak the antibodies.

In January 2022, the U.S. Food and Drug Administration (FDA) revised the authorizations for two monoclonal antibody treatments – bamlanivimab/etesevimab (administered together) and casirivimab/imdevimab – to limit their use to only when the recipients are likely to have been infected with or exposed to a variant that is susceptible to these treatments because data show these treatments are highly unlikely to be active against the omicron variant.[19]

It would be relatively easy to narrow down the options for how the treatment might be working, if it actually is, by giving it to people who could not have been exposed to earlier variants and who have developed Long Covid from the Omicron variant, as well as people with Long Covid from earlier variants.

The idea that the treatment could work against Long Covid, even if it is just Long Covid from the early variants, or even the rumour of that, would be another huge windfall for Regeneron and possibly for holders of Regeneron stocks. That's one reason why reports of seemingly miraculous recoveries need to be really solid.

Hopefully someone has a good trial of the treatment underway.

 

[Hutan]

There's a trial in ClinicalTrials: NCT05181683
COVID-19 Study Assessing the Safety and Tolerability of Co-Formulated Anti-Spike (S) SARS-CoV-2 Monoclonal Antibodies (Casirivimab+Imdevimab) in Adult Volunteers

It's a Phase 1 trial and it ran from 7 Jan 2022 to 3 Jun 2022. 45 people were enrolled. No results have been posted but its status is 'Completed'. It seems to be assessing the safety of injections and infusions of the antibody cocktail. The trial is being done by Regeneron Pharmaceuticals. Interestingly, it is being done run Florida, which of course is where Klimas and some of the other authors of this paper are.

The criteria for inclusion in the trial were people who were either healthy or with a stable chronic medical condition, and testing negative to Covid-19.

So, in Miami, giving a treatment for active SARS-CoV-2 infections to people who aren't testing positive to SARS-CoV-2 and who might have a chronic medical condition. That does look a bit curious, especially at a time when the treatment seems less relevant to current infections.

There are a couple of other Regeneron studies related to this treatment in ClinicalTrials, they are pediatric and targeting children with Covid-19, at risk or already with severe disease. They were both terminated due to 'Emerging SARS-CoV-2 variants impacting susceptivity to study drug'.

 

[Sean]

If nothing else, this at least confirms...

Three is a small number to be calling it confirmed. Though I agree that both degree of change and the close match in the patients' experience provides good support for it.

1. It is possible to recover completely
2. Any effect of deconditioning is rapidly reversed on resuming normal life and exercise

Excellent news, if the findings hold up, even if only for some.

Not only did MCA infusions reverse the physical disabilities, but also greatly improved those persons’ social, psychological, interpersonal, and economic well-being -- as well as the well-being of those around them.

How much, if any, prompting or rehabilitating did they require in returning to their pre-illness lives? Did they naturally do so of their own volition and management as soon as their bodies allowed them?

 

[SNT Gatchaman]

How much, if any, prompting or rehabilitating did they require in returning to their pre-illness lives? Did they naturally do so of their own volition and management as soon as their bodies allowed them?

None, as far as I can tell. All cases read as having been self-driven return to prior activity and normal life, without any need for rehabilitation (as would seem to have been consistently reported for decades by ME patients who have recovered.)

A 60-year-old woman, average height/weight, in good health [...] Low muscle tone developing during long COVID remained but rapidly-improved after resuming routine exercise

A 43-year-old woman (average height/weight, in good health except “mild chronic anemia”) [...] she progressively developed severe fatigue, extremely poor exercise intolerance [...] low muscle tone acquired during long COVID, significantly improved after resuming normal physical activity.

A 63-year-old (self-reported “overweight” man with history of adult-onset diabetes and hypertension) was a highly-functional individual in good health with good exercise tolerance [...] Low muscle tone issues also developed during long COVID, but completely resolved after resuming routine exercise.

 

[Trish]

Those descriptions of recovery sound very like my recovery from what was diagnosed as glandular fever which put me to bed for 6 months. I remember needing to crawl upstairs. I just recovered naturally and resumed normal activity and soon returned to normal fitness. No need for any therapy.

This sort of spontaneous recovery happens to a lot of people with glandular fever and is happening to some with Long Covid. I think we need to be wary about retrospective attribution of recovery to a specific treatment.