Persistent Autonomic and Immunologic Abnormalities in Neurologic Post-Acute Sequelae of SARS-CoV2 Infection, 2024, Goldstein, Walitt, Nath+

[SNT Gatchaman]

Persistent Autonomic and Immunologic Abnormalities in Neurologic Post-Acute Sequelae of SARS-CoV2 Infection
David S. Goldstein, MD, PhD, Yair Mina, MD, Brian Walitt, MD, MPH, Patti Sullivan, CMT, Yoshimi Enose-Akahata, PhD, Steven Jacobson, PhD, My-Le Nguyen, MD, Stanislav Sidenko, BA, RCS, Amanda Wiebold, RN, Bryan Smith, MD, Janna Gelsomino, RN, Risa Isonaka, PhD, Sarah Moore, CRNP, and Avindra Nath, MD

OBJECTIVES
After acute coronavirus disease-2019 (COVID-19), people often experience fatigue, “brain fog,” or other central neurologic symptoms (neuro–post-acute SARS-CoV2, or “NeuroPASC”). In this observational study we evaluated whether abnormalities noted on initial evaluation persist after at least another year.

METHODS
Neuro-PASC research participants who had undergone comprehensive inpatient testing at the NIH Clinical Center returned after at least 1 year for follow-up assessments including symptoms rating scales, MRI, lumbar puncture for tests of the CSF, physiologic recordings during the Valsalva maneuver and head-up tilting (with serial plasma catechols and cardiac Doppler ultrasound during the tilting), blood volume measurement, skin biopsies to examine sympathetic innervation, and blood sampling for neuroendocrine and immunologic measures.

RESULTS
7 patients with Neuro-PASC (6 women, age range 42–63 years) underwent follow-up testing. 71% of initially abnormal test results remained abnormal at follow-up, including the pattern of CSF and serum oligoclonal bands, CSF indices of central catecholamine deficiency, baroreflexcardiovagal dysfunction, the occurrence of tilt-evoked sudden hypotension, white matter hyperintensities on MRI, and adaptive responses in CSF.

DISCUSSION
In Neuro-PASC most of the autonomic and immunologic abnormalities found initially are still present after more than a year.

Link | PDF (Neurology) [Open Access]

 

[Hutan]

I approached this paper with trepidation, wondering what fresh hell Walitt was visiting upon us. Perhaps he didn't get the right to decide the wording this time. The study only had 7 participants, and so far it doesn't look as though they found one thing that might explain the long Covid pathology across all, or even just most of the participants. Still, they looked at a lot of things, and there are interesting things to note.

The frequencies and types of abnormalities observed in the patients varied substantially across individuals.

Blood volume was measured by the unit dose 131I-albumin technique (Daxor Corporation, Oak Ridge, TN).

None of the patients was hypovolemic.

None of the patients had persistently increased IL-6.

A total of 6 patients had evidence for decreased baroreflex-cardiovagal function. Low heart rate variability might be a consequence of COVID-19 rather than of a preexisting abnormality.10-13

Plasma EPI levels were persistently low in 3 patients; 2 others had low plasma EPI at follow-up. Low plasma EPI in antecubital venous blood might reflect forearm vasoconstriction, which increases the efficiency of extraction of circulating catecholamines in passage through tissues of the forearm and hand.14

I do see some evidence of Walitt in the paper e.g.
In the discussion:

Sympathoadrenal imbalance might underlie the tendency to fainting or presyncope.3

appears without qualification, but, only one of the 7 was found to have that, whatever it actually means

and 1 had sympathoadrenal imbalance

I don't know what the following really means

A total of 5 patients had elevated copeptin levels, raising the possibility of increased activity of neurons in the paraventricular nucleus of the hypothalamus, a major source of the releasing factors leading to pituitary secretion of AVP and a key area in the central autonomic network and central stress system.2 AVP inhibits barosensitive neurons in the nucleus of the solitary tract.15

But with 5 out of the 7 participants having elevated copeptin levels, that looks like something worth exploring.


The final section 'Perspective' seems to suggest something about stress, but it's quite vague so I guess people can read into it whatever they want:

Further application of the EAS concept may provide a framework for delineating integrated mechanisms of persistent allostatic states in a variety of postinfectious, multisystem disorders of regulation.

EAS=Extended autonomic system


So, based on a skim read, the paper doesn't seem to be traumatising and is worth looking at in detail, keeping in mind, this is just for 7 participants. Thank you to the participants for their effort.

 

[SNT Gatchaman]

Hutan beat me to it, but yes, no need for the big breath I and no doubt she took when opening! No evidence of low blood volume sounds useful info (small numbers).

 

[Hutan]

Copeptin?
the following is mostly from Wikipedia

Copeptin is a peptide that is released in the blood in response to stress and is used as a biomarker in diagnosing acute myocardial infarction (AMI), although it lacks specificity and can be elevated in other conditions such as sepsis, trauma, and shock.

Copeptin (also known as CT-proAVP) is a 39-amino acid-long peptidederived from the C-terminus of pre-pro-hormone of arginine vasopressin, neurophysin II and copeptin. Arginine vasopressin (AVP), also known as the antidiuretic hormone (ADH), is encoded by the AVP gene and is involved in multiple cardiovascular and renal pathways and abnormal level of AVP are associated with various diseases. Hence measurement of AVP would be useful, but is not commonly carried out in clinical practice because of its very short half-life making it difficult to quantify. In contrast, copeptin can be immunologically tested with ease and therefore can be used as a vasopressin surrogate marker.

The concentration of copeptin in the blood circulation ranges from 1 to 12 pmol/L in healthy individuals.[6] The levels of copeptin are slightly higher in men than in women[6] and are not influenced by age.[6] In response to serum osmolalityfluctuations, the kinetics of copeptin are comparable to those of vasopressin.[6][7]

High concentrations of vasopressin during cardiogenic shock have been widely described.[18][19] It has been shown that the kinetics of copeptin are similar to vasopressin in that context.[20]

The prognostic value of vasopressin for prediction of outcome in patients with heart failure has been known since the 1990s. Patients presenting with high levels of vasopressin have a worsened outcome.[21][22] Recently, a similar interest has been demonstrated for copeptin in heart failure.[10][23][24][25]

I've gone on about how I routinely get a high shock index and how, for me, a higher shock index correlates with symptom load. I don't know why it isn't measured and reported in ME/CFS and Long Covid.

 

[Hutan]

From eAppendix 3:

In general, scores on fatigue and cognitive dysfunction scales were about the same at follow-up as initially. In all 7 participants, PROMIS fatigue scores at follow-up were above normal, and PROMIS cognitive scores were below normal.

This paper gives us detailed Tables 1 and 2 (telling us how many tests were the same or different at the first and the follow up visits. But, that's almost meaningless. What we really need is the actual data.

For instance I want to see the actual copeptin data. eAppendix 3 Figure 3 is a table with cells for each measure for each participant for each visit. They could have given us actual data there. But, instead they just coloured the cells to indicate high, low or normal values. I haven't found any figure that provides actual copeptin data.

 

[Jonathan Edwards]

Seems like a rag-bag of tests on a small number of people with presumably no information on what those tests showed before Covid or whether their occurrence was due to Covid or coincidence. Since we do not have any clear evidence of relation of Covid to any specific neurological abnormality, other than loss of smell and residues from strokes, it all seems a bit hard to interpret.

It seems more as if these 'neurologic post-acute sequelae' are more along the lines of ME/CFS type symptoms (OI etc). If there were 100 subjects with the same sort of abnormality that would be interesting. Otherwise this sort of 'deep-dive' study of a handful seems pretty pointless.

 

[EndME]

One of the possibly more interesting findings in the intramural study, were the catecholamine findings. They don't report differences in norepinephrine here, but quote the intramural study findings with

"Decreased CSF DOPA, DHPG, and DOPAC in a patient sug- gested decreased central catecholamine biosynthesis, a pattern resembling that in postinfectious myalgic encephalomyelitis/ chronic fatigue syndrome.8"

It seems valuable that they report

Individual values for CSF levels of catechols initially and at follow-up were highly correlated (eFigure 4 in eAppendix 3).

More stability and follow-ups within LC studies will certainly be helpful to separate the more acute from the post-acute phenomena from the normal noise. But at such a small sample size it seems rather useless. I don't think we really need more of these studies.

Could be interesting to have a look at some of the actual data, but I'm certain they will have already compared it to the intramural study data.

It does seem like they report no elevated incidence of markers of neurological injury, like GFAP or NFL, which many other studies have reported which, depending on depending on patient selection, might be a valuable null result (but sample size might have been to small to detect anything in the first place?).

 

[MSEsperanza]

Patient sample is the remainder of 12 patients in the initial study:

Deep Phenotyping of Neurologic Postacute Sequelae of SARS-CoV-2 Infection

https://www.neurology.org/doi/10.1212/NXI.0000000000200097

Clinical Characteristics
"Between October 2020 and March 2021, 12 participants were recruited from a cohort of 173 individuals (see Figure 1A for flowchart of inclusion in the study). Demographics and clinical characteristics of these patients are detailed in Table 1. Participants were all White and mostly female (83%), with a mean age of 45 ± 11 years. The majority of participants had a history of depression/anxiety before COVID-19 (n = 7, 58%). A third of the patients (n = 4) had a prior history of resolved long-term disability after an infectious disease (infectious mononucleosis, Lyme disease, amoebiasis due to Entamoeba histolytica, and severe sepsis due to group A Streptococcus)."

Didn't read the articles nor checked the first study on how they selected the participants from the larger cohort and whether investigators did cognitive testing to have some objective symptom correlates or looked for an ME/CFS subgroup, but thought that sample looks a bit 'special'?

As others said, sample size too small anyway, but in addition I thought it's disappointing that at least in the follow-up study from skimming it seems they weren't interested in PEM, cognitive tests and objective measures on activity / movement patterns (no use of activity trackers or accelerometers)

 

[V.R.T.]

What on earth is the point of these miniscule cohorts? I know its not the kind of study where you'd want hundreds of patients but 7? It makes the ME intramural study look jam packed.

 

[Jaybee00]

What on earth is the point of these miniscule cohorts?

I think it’s better than nothing. If something is really out of whack, it will show up even in a small sample.

 

[V.R.T.]

I think it’s better than nothing. If something is really out of whack, it will show up even in a small sample.

True. But it's the NIH not some tiny funding starved researcher in an obscure university. Why couldn't they have studied more patients?