A multi-omics based anti-inflammatory immune signature characterizes long COVID-19 syndrome, 2022, Kovarik et al

Will read shortly, but: multi-omics in healthy/vaccinated vs Covid-recovered vs long Covid - Hallelujah!

 

(EPA is eicosapentaenoic acid and DHA is docosahexaenoic acid).

 

One week is not nearly enough to compare omega-3 levels to someone who has been supplementing regularly, blood levels can increase for weeks after starting supplementation. I would have given them supplementation at least a month, and might even have increased the dose to 3 g/day not a bit under 2 g/day.

Edit: There are also obviously individual differences and 10 people isn't a lot.

 

A few points from a recent review article: Vitamin D Binding Protein: A Historic Overview (2020)

It developed early in evolution and is conserved.

Two major functions —

Its plasma concentration is stable and independent of many factors, including vitamin D levels.

Concentration is increased in females.

Concentration is increased with infection.

It binds extracellular actin and is involved in clearance of fibrillar actin.

May effect macrophage function.

See also Vitamin D-binding protein as a biomarker to confirm specific clinical diagnoses (2019)

 

A team entirely from Vienna, Austria:

There's acknowledgement that LC isn't just anxiety and stress. There's a good list of symptoms, although 'lack of physical fitness' would have been better replaced with 'post exertion malaise and easy fatiguability'. The severity of the disease is noted. Although LC is described as 'novel', they go on to recognise the similarity with CFS in general and MERS and SARS in particular. This is not the first paper to suggest that long term symptoms following SARS1 has been observed 'for up to two years'. I'm sure that the persistence of symptoms from MERS and SARS have been much longer than that - there must surely be a reference that records that. But, overall, I thought it was a really good start.

 

There are four groups:
H - healthy, vaccinated at least 3 months ago, no covid 19 infection - 13 people

HL - healthy, no covid 19 infection, given tablets containing 870mg Omega-3 (420 mg EPA and 330 mg DHA) twice a day for one week - 10 people

R - recovered from a Covid-19 infection at least 3 months ago - 13 people

LCS - had a Covid-19 infection at least 3 months ago and have lingering symptoms (notably fatigue (9/13) and/or cognitive difficulties (10/13), dyspnoea (9/13)) - 13 people

They describe this study as an exploratory study - the sample sizes are small at 13 people in each group. From the listed symptoms of the LCS group, I don't think they would all qualify for an ME/CFS diagnosis, although perhaps if they were assessed by a clinician who routinely diagnoses ME/CFS, the description of symptoms would be different.

The samples look fairly well matched in terms of gender and age, although the inclusion of people with significant health conditions is a bit odd (e.g. the LCS group includes a person with multiple sclerosis and a person with autoimmune thyroiditis).

 

They make quite a lot of IL-18 levels being lower in the LCS group, but there's a lot of overlap with the other two groups- I'm not convinced there is a real difference in IL-18.



But, some of the the LCS group do look different from the healthy groups - look at the PCA and volcano plot. They just aren't presenting as a particularly well-characterised group - individuals in the LCS group seems to be fairly different from each other as well as different from the healthy groups, which isn't very helpful.



Serpina5 looks really interesting - the LCS are nicely clustered with lower levels. The clustering of BTD (biotinidase) in the LCS is nice, but there's a lot of overlap with the healthy groups, so, not so interesting. GC (inexplicably to me at the moment, 'GC' is actually Vitamin D binding protein) levels are statistically different between the recovered and Long Covid groups, but there is plenty of overlap between the Long Covid group and the healthy groups, so it's not looking very important to me.

 

GC was its old name ("group-specific component") which reflected —

(from the review article linked above)

 

Here's something about Serpina 5 - I'm posting it at least partly because I like the title:
Cell penetrating SERPINA5 (Protein C inhibitor, PCI): More questions than answers
A 2016 paper, perhaps coincidentally by two people also based in Vienna.

SERPINA5 binds glycosaminoglycans, phospholipids, and retinoic acid. Glycosaminoglycans and certain phospholipids can modulate its inhibitory activity and specificity. Studies suggest that SERPINA5 may play a role in hemostasis*, in male reproduction, in host defense, and as a tumor suppressor. However, its biological role has not yet been defined. So far SERPINA5 deficiency has not been described in man.

SERPINA5 can be internalized by cells and translocated to the nucleus. The internalization is dependent on the phospholipidphosphatidylethanolamine and on the intact N-terminus of SERPINA5, which functions as a cell penetrating peptide. Further functional analysis of intracellular SERPINA5 will contribute to our understanding of the biological role of this molecule.

*hemostasis:
Hemostasis is a complex network of cellular and humoral systems, involving the platelet system, the coagulation process, the anticoagulant, and the fibrinolytic pathways)

Edited to add: the authors of the paper that is the subject of this thread had this to say about SERPINA5:

 

It looks like the same research, so the thread heading and opening post have been amended. The first section is called 'summary' rather than abstract.

Summary
To investigate long COVID-19 syndrome (LCS) pathophysiology, we performed an exploratory study with blood plasma derived from three groups: 1) healthy vaccinated individuals without SARS-CoV-2 exposure; 2) asymptomatic recovered patients at least three months after SARS-CoV-2 infection and; 3) symptomatic patients at least 3 months after SARS-CoV-2 infection with chronic fatigue syndrome or similar symptoms, here designated as patients with long COVID-19 syndrome (LCS).

Multiplex cytokine profiling indicated slightly elevated pro-inflammatory cytokine levels in recovered individuals in contrast to patients with LCS. Plasma proteomics demonstrated low levels of acute phase proteins and macrophage-derived secreted proteins in LCS. High levels of anti-inflammatory oxylipins including omega-3 fatty acids in LCS were detected by eicosadomics, whereas targeted metabolic profiling indicated high levels of anti-inflammatory osmolytes taurine and hypaphorine, but low amino acid and triglyceride levels and deregulated acylcarnitines.

A model considering alternatively polarized macrophages as a major contributor to these molecular alterations is presented.
________________

 

Skim-reading this paper, the latest version of it now, there's a lot in it.

There is the issue with the selection of the Long Covid cohort - the definition seems to be chronic fatigue or cognitive dysfunction following Covid-19, plus one further chronic symptom including breathlessness, coughing or loss of the ability to smell. That has likely resulted in a bit of a heterogeneous LC cohort. Also the sample sizes are small.

Nevertheless, I still think this is an interesting study. I hope that replication of the key differential findings is underway in a more tightly characterised and larger sample.

I think it's an intriguing idea that levels of some molecules in LC people look like levels in healthy people who haven't had an infection, but quite different to levels of people who are functioning normally but are recovering from a Covid-19 infection. What if we aren't properly mounting healthy inflammatory responses, not even to minor challenges like exercise?

Thank you to the researchers and the funders.