Thread by @ZdenekVrozina

A new long COVID paper suggests that, in a subset of patients, the picture may involve circulating microaggregates, impaired capillary flow, and - EBV-related immune activation🧵

A study describes a subgroup of patients who had so called microaggregates in blood, along with stronger T-cell responses to EBV.
The main idea is that, in some patients, long COVID may involve a mix of impaired microcirculation and immune activation linked to latent herpesviruses.

So what are these microaggregates?
The authors describe them as spherical structures around 100-200µm diameter, containing leukocytes and an amorphous core rich in carbohydrate residues. Platelets were also found on their surface.

An important point. The authors deliberately do not call them microclots or microthrombi. Based on their methods, these structures did not contain mature fibrin, so they interpret them more as cellular/platelet aggregates than as classic blood clots.

That makes this a bit different from some earlier LC literature focused on fibrin microclots. So this is not a completely new concept in the broad sense, but rather a specific version of the finding, described differently by this group.

The paper itself also references earlier work on platelet-leukocyte aggregates, microclots, and their own 2024 paper on circulating microaggregates.

One of the study’s central claims is that these microaggregates may be large enough to impair capillary blood flow. The study shows a morphological finding and a biologically plausible mechanism, not direct proof in vivo.

Their composition is also interesting. The surface of the microaggregates contained both polymorphonuclear and mononuclear cells, and the authors also mention enrichment in eosinophils.

They interpret this as a sign of a possible localized immune reaction, not just a purely clotting-related event. They even speculate about a link to extracellular traps.

The second major axis of the paper is EBV. Using EliSpot, they report that 80% of patients with microaggregates had a positive T-cell response to EBV peptides above their chosen cutoff. Elsewhere in the paper, they say that in an unselected group of patients with post-COVID symptoms, about 50% showed IFN-γ responses to EBV.

This does not mean EBV directly causes the microaggregates.
The authors think SARS2 may have disrupted immune regulation, which could contribute to derepression of latent EBV, while platelet/hemostatic activation is happening in parallel. They propose a combined model, not a simple EBV explains everything story.

The authors themselves point out that most adults carry EBV, and that some low level immune reactivity to EBV is common. They also say that individual microaggregates can be found in healthy people too, just in much lower numbers.

The paper also includes a treatment section. In a small retrospective cohort, they compared patients treated with antiplatelet/antithrombotic therapy plus valacyclovir against patients treated with antithrombotic therapy alone.

Both groups had a similar reduction in symptom count, but the combination group showed better Bell score improvement and better subjective recovery.

In another small exploratory analysis, ASA + heparin + valacyclovir performed better than clopidogrel + heparin + valacyclovir @HarrySpoelstra. Larger symptom reduction, greater Bell improvement, and a higher rate of return to work or sport. Interesting signal, but the numbers were tiny. 16 vs 4 patients.

The authors also make an important admission - they cannot exclude that any apparent effect of valacyclovir may have involved not only EBV, but also other herpesviruses sensitive to valacyclovir.

That matters, because it weakens any overly simple interpretation like they found EBV, gave an antiviral, so EBV must be the cause.

Last important reality check. According to the authors, this subgroup represented about 40% of their patients with suspected post COVID syndrome. So they are not claiming this explains all of long COVID. In fact, they explicitly mention other possible mechanisms, including SARS-CoV-2 persistence and mast cell activation.

This is a retrospective observational study, small groups, no randomization, no blinding, incomplete longitudinal data. It is also still an Article in Press.

This paper is interesting because it tries to connect microcirculation, platelets, immune cells, and EBV into one possible biological subtype of long COVID.

Wick at al., Clinical relevance of circulating blood microaggregates and reactivation of Epstein Barr Virus in long-term Post-CoVID syndrome patients. nature.com/articles/s4159…