Deep Phenotyping of Neurologic Postacute Sequelae of SARS-CoV-2 Infection, Mina, Nath et al, 2023

Neurology, Neuroimmunology & Neuroinflammation
Deep Phenotyping of Neurologic Postacute Sequelae of SARS-CoV-2 Infection

Abstract
Background and Objectives SARS-CoV-2 infection has been associated with a syndrome of long-term neurologic sequelae that is poorly characterized. We aimed to describe and characterize in-depth features of neurologic postacute sequelae of SARS-CoV-2 infection (neuro-PASC).

Methods Between October 2020 and April 2021, 12 participants were seen at the NIH Clinical Center under an observational study to characterize ongoing neurologic abnormalities after SARS-CoV-2 infection. Autonomic function and CSF immunophenotypic analysis were compared with healthy volunteers (HVs) without prior SARS-CoV-2 infection tested using the same methodology.

Results Participants were mostly female (83%), with a mean age of 45 ± 11 years. The median time of evaluation was 9 months after COVID-19 (range 3–12 months), and most (11/12, 92%) had a history of only a mild infection. The most common neuro-PASC symptoms were cognitive difficulties and fatigue, and there was evidence for mild cognitive impairment in half of the patients (MoCA score <26). The majority (83%) had a very disabling disease, with Karnofsky Performance Status ≤80. Smell testing demonstrated different degrees of microsmia in 8 participants (66%). Brain MRI scans were normal, except 1 patient with bilateral olfactory bulb hypoplasia that was likely congenital. CSF analysis showed evidence of unique intrathecal oligoclonal bands in 3 cases (25%). Immunophenotyping of CSF compared with HVs showed that patients with neuro-PASC had lower frequencies of effector memory phenotype both for CD4+ T cells (p < 0.0001) and for CD8+ T cells (p = 0.002), an increased frequency of antibody-secreting B cells (p = 0.009), and increased frequency of cells expressing immune checkpoint molecules. On autonomic testing, there was evidence for decreased baroreflex-cardiovagal gain (p = 0.009) and an increased peripheral resistance during tilt-table testing (p < 0.0001) compared with HVs, without excessive plasma catecholamine responses.

Discussion CSF immune dysregulation and neurocirculatory abnormalities after SARS-CoV-2 infection in the setting of disabling neuro-PASC call for further evaluation to confirm these changes and explore immunomodulatory treatments in the context of clinical trials.

 

NIH News Release
NIH study identifies features of Long COVID neurological symptoms

quote:

The results showed that people with Long COVID had lower levels of CD4+ and CD8+ T cells—immune cells involved in coordinating the immune system’s response to viruses—compared to healthy controls. Researchers also found increases in the numbers of B cells and other types of immune cells, suggesting that immune dysregulation may play a role in mediating Long COVID.

Consistent with recent studies, people with Long COVID also had problems with their autonomic nervous system, which controls unconscious functions of the body such as breathing, heart rate, and blood pressure.

 

I wonder whether we'll see a broadly similar methodology ± findings as part of the upcoming NIH ME/CFS study reports (absent the olfactory bulb specifics).

Suggesting immune dysregulation, but not neuroinflammation — or at least not from direct SARS infection.

Small numbers, but this seems to be pointing to some people (and especially females) having a vulnerability in their immune system that predisposes to different forms of post-infection chronic illness, that may resolve but can then recur following a different infective agent.

If the majority of this group (58%) had a history of depression/anxiety, that could simply mean they were incorrectly diagnosed with those conditions previously ( fatiguing illness = "depression", dysautonomia = "anxiety" etc). But it could also indicate that this sort of immune dysregulation mechanism might underlie a number of neuropsychiatric conditions.

 

That is really disappointing. It would be more understandable if a smallish patient charity couldn't justify the processing costs for another 12 people until they knew whether it was a worthwhile avenue, but the NIH?

 

This is what I said in the other thread. There was initial enthusiasm, but then the momentum quickly came to a halt as a significant portion of people inside NIH think ME is a BPS disorder that doesn't really deserve quality science, just some psychological help for those "stubborn" bedbound patients. People expressed skepticism towards this idea but it seems pretty obvious to me - i mean look at the science and efforts that happens in other neurological diseases, it's a totally different thing.

There are patients who interact with NIH directly, and they say they don't think the people there think we have a fake disease. I respect their experience, but i have experience too and I've seen that over the years doctors have gotten really good at dealing with these kind of patients - they have no issue lying and deceiving you like a politician would do. It's in their interest, after all, to tell you that you have a biological illness so you will stop harassing and badmouthing them. I have seen doctors who really seemed to be by our side show their true colors.

I remain firmly of the opinion that actions speak louder than words.

 

I attended one of the IiME Conferences, Vicky Whittemore gave a presentation. I recall her saying that recently they'd identified the gene responsible for a rare disease she was "involved" in. So they could now develop treatments --- ME/CFS was not yet in that position ---cause was unknown --- no way in i.e. to identify biomarkers, develop diagnostic tests, drugs (treatments) ---.

We now have the Chris Ponting GWAS study and we've had news of a new GWAS in Holland -- in Dementia larger GWAS were required, or rather the combination of multiple studies i.e. to find genes and thereby help to target research. I'm hopeful that e.g. Chris will work to enable the further studies that are likely necessary---

Perhaps Vicky would be a good target i.e. to promote a US GWAS study funded by NIH ---?

So, if Vicky had written her memoir a few years ago then it may have been along the lines ---ME/CFS -- no way in i.e. to identify biomarkers, develop diagnostic tests, drugs (treatments) ---. Perhaps if she does write it then it may e.g. highlight the way in e.g. GWAS --- Nath's intensive study of a small number of patients with ME/CFS ---.

 

I don’t think the high prevalence of depression/anxiety/psychotropic meds in this study is surprising considering the demographic group in question. There was a chart floating around on Twitter the other day showing, I don’t know how accurately, that a quarter of middle aged white women in the US have taken antidepressants. The control group in this study is not presented in Table 1 which is highly unusual and makes me think they don’t want to show how poorly matched the groups are.

I’m surprised by what gets through review these days. I’m dreading their upcoming ME/CFS papers. 1980s-early 1990s horrific NIH papers from the Incline Village era buried ME/CFS in the psychosomatic dumpster for two generations.

 

Well I think she [edit - may] be able to highlight that they put together a research program to try to address the issue --- here's the reply to my email:
"
Thank you for your email. We are currently in the process of developing an ME/CFS Research Roadmap and Genomics/Genetics are one of the topic areas under discussion. We are aware of the studies you mentioned, and Chris [Ponting] is involved in the group that is discussing genomic/genetic research on ME/CFS. There will be a series of webinars open to the public in the coming months that will provide perspectives from experts in the field regarding research priorities for ME/CFS. If you are not already, you should sign up for the NIH email listserv so you receive notices of the webinar series; go to: https://www.nih.gov/mecfs


Thanks again, and best wishes,


Vicky"

 

The controls were from the intramural ME/CFS study, as the paper notes.

 

(fairly unrelated) Just wanted to state that Dr. Whittemore (along with Dr. Koroshetz) is aiming to try to attend the May 11th Millions Missing event with the Minnesota ME/CFS Alliance & patient community

I thought even in attempting in *wanting* to be present at that was a somewhat nice gesture, given how far the gap is with other NIH leaders & the ME community (historically).

 

Sure, using people who recovered completely after acute covid would've been the ideal control group. But it was very difficult to bring healthy people into the Clinical Center at that time. Basically impossible from what I've heard. And each healthy control in the intramural study took about 7-10 days to run through the protocol, so another dozen people would've been 2-3 months.

 

The restrictions on healthy inpatient volunteers was an NIH Clinical Center-wide policy. It had nothing to do with any specific study.

"In March 2020, the NIH Clinical Center implemented visitor restrictions, including limiting the admission of healthy volunteers to clinical research studies. Only patients who needed medical treatment or individuals participating in COVID-19-related research studies were allowed to enter the facility. The restrictions were put in place to limit the potential spread of COVID-19 to vulnerable patients and healthcare workers."