Clinical relevance of circulating blood microaggregates and reactivation of Epstein Barr Virus in long-term Post-CoVID syndrome patients, 2026, Wick+

[forestglip]

Clinical relevance of circulating blood microaggregates and reactivation of Epstein Barr Virus in long-term Post-CoVID syndrome patients

Spoiler: Authors

Wick, Nikolaus; Hermann, M.; Lisch, Christoph; Gerth, Regine; Wick, Georg; Untersmayr, Eva; Marth, Tatjana; Bachler, Mirjam; Fries, Dietmar

Abstract
Chronic persistence of systemic symptoms after recovery from active CoVID-19 has become a significant disease burden, named post-CoVID syndrome. Among many pathophysiological hypotheses we focus on impaired hemostasis as well as reactivation of latent Epstein-Barr virus.

We now introduce a novel diagnostic morphological approach for visualizing microaggregates circulating in peripheral venous blood, which are large enough to impede capillary blood flow. In addition, secretion of interferon gamma by mononuclear leukocytes in response to peptides of Epstein-Barr virus is increased in these patients.

As a promising therapeutic approach, we provide retrospective data on the effect of anti-thrombotic and virostatic drugs, respectively. In a large number of patients, clinical improvement was observed after platelet inhibition, particularly when EBV was also treated with antiviral therapy.

Web | DOI | PDF | Scientific Reports | Open Access

 

[Murph]

Not sure about the retrospective patient analysis nor the EBV stuff, but the blood microscopy looks like a good contribution to step-by-step science, they clearly describe what they did and what they saw. Allowing anyone else to see if they can replicate.

As described previously, we performed live
confocal fluorescence microscopy of native, i.e., unfixed, blood samples to detect free-floating
cellular aggregates under unperturbed conditions (Fig. 1A, [23]). We could observe globular
structures of 100-200 μm diameter that contained leukocytes and acellular material staining
positively for carbohydrate residues, as visualized by the N-acetylglucosamine and N-
acetylneuraminic acid (sialic acid) residues binding lectin wheat germ agglutinin (WGA). As
proven by nuclear fluorescent staining, leukocytes were mainly granulocytes with polymorphic
nuclear shapes, in addition to mononuclear cells. Microaggregates were stable upon overnight
incubation. Regularly, microaggregates attached firmly to the plate surface (video as Online
Resource 1). Importantly, microaggregates also included thrombocytes with a tendency to build
a coverage on the microaggregate surface

Having these aggregates floating around might become a marker for a subset and help define what we are looking at.

 

[Jonathan Edwards]

I would be wary that this is another artifact. If aggregates of this sort really occur and are responsible for 'impeding capillary blood flow' then there should be clinical signs - spinter haemorrhages and other petechiae. Something of this size would completely block an arteriole rather than get to a capillary. I have not seen any reports of splinter haemorrhage Post-Covid.

 

[SNT Gatchaman]

This follows from the case report Circulating microaggregates as biomarkers for the Post‐COVID syndrome (2024, IDCases)

Speculating on capillary diffusion disturbances as one possible cause of fatigue due to diminished blood supply, we were interested in morphologically demonstrable alterations in blood samples taken from peripheral veins. As described previously, we performed live confocal fluorescence microscopy of native, i.e., unfixed, blood samples to detect free-floating cellular aggregates under unperturbed conditions. We could observe globular structures of 100-200 µm diameter that contained leukocytes and acellular material staining positively for carbohydrate residues

As proven by nuclear fluorescent staining, leukocytes were mainly granulocytes with polymorphic nuclear shapes, in addition to mononuclear cells. Microaggregates were stable upon overnight incubation. Regularly, microaggregates attached firmly to the plate surface (video as Online Resource 1). Importantly, microaggregates also included thrombocytes with a tendency to build a coverage on the microaggregate surface.

(The video is not yet available with the early access paper.)

While our results suggest an adhesive capacity of thrombocytic microaggregates to negatively charged surfaces, like those of microtiter plates, we were surprised to find primarily floating globular aggregates that were covered by thrombocytes around a so far undefined core of glyco-rich amorphic material. Critically, as described previously, the aggregates detected with our protocol did not contain mature fibrin. Consequently, we put the cellular composition of the structures in the focus our interest, motivating us to use the term micro-aggregates instead of micro-clots or micro-thrombi.

it is important to mention that both polymorphic and mononuclear leukocytes are intermingled on the surface of the microaggregates, supporting the concept of a localized immune reaction. For example, we observe an enrichment in eosinophilic granulocytes that might expel DNA to form neutrophilic extracellular traps, which we see in severely affected patients. Also, we follow incidental observations of blood capillaries with signs of endothelial activation and perivascular chronic inflammatory infiltrates of skin biopsies taken for the confirmation of small fibre neuropathies

In thinking of a broader application of these tests in diagnostic routine, several improvements have to be considered. First, single circulating microaggregates can be detected in healthy persons as well, albeit at a significantly lower number, implying the need for setting clear cutoffs of these structures in a well-defined volume.