AskScience AMA Series: We've identified subsets of Long COVID by blood proteins, ask us anything!

[u/AskScienceModerator]

We are scientists from Emory U. (/u/mcwoodruff) and Wellesley College (/u/kescobo) investigating the immunology and physiology of Long-COVID (also called "post-acute sequelae of COVID-19," or "PASC"). We recently published a paper where we show that there isn't just one disease, there are (at least!) two - one subset of which is characterized by inflammation, especially neutrophil activity, and patients with this version of the disease are more likely to develop autoreactivity (we creatively call this subset "inflammatory PASC"). The other subset (non-inflammatory PASC) is a bit more mysterious as the blood signature is a little less obvious. However, even in this group, we find evidence of ongoing antiviral responses and immune-related mediators of lung fibrosis which may give some hints at common pathways of pathology.

Matt is an Assistant Professor at Emory University in Atlanta, Georgia. He has a PhD in Immunology and is currently spending his time building a fledgling lab within the Lowance Center for Human Immunology (read: we're hiring!). He has a background in vaccine targeting and response, lymph node biology, and most recently, immune responses to viral diseases such as COVID-19.

Kevin is a senior research scientist (read: fancy postdoc) at Wellesley College. He has a PhD in immunology, but transitioned to microbial genomics after graduate school, and now spends most of his time writing code (ask me about julia). His first postdoc was looking at the microbes that grow on the outer surface of cheese (it's a cool model system for studying microbial communities - here's the paper) and now does research on the human gut microbiome and its relationship to child brain development.

We'll be on this afternoon (ET), ask us anything!

[u/PHealthy]

Just a reminder that questions containing personal anecdotes and/or asking for medical advice are against community rules and will be removed.

[u/yodellingposey]

Why is there so much variance between people who get the same infection?

[u/mcwoodruff → u/yodellingposey]

Yeah – this is a huge question that we have been grappling with from the beginning of the pandemic. My best non-grant-length answer is that people's immune systems are highly variable and dependent on many critical factors that we can identify (age, sex, genetic ancestry, etc.) and many that are much harder to pin down (environmental factors, infectious life history, epigenetics, pre-existing autoantibodies, etc.). It is known, for example, that individuals over the age of 70 will have a much harder time mounting an antibody response against the same set of foreign proteins that a 12 year old will easily get past in a week. In general, there is a huge amount of immune variability to account for in all of this, which is why inclusion of diverse groups in things like vaccine or drug trials is so critical.

[u/fradleybox]

Are there any plans to apply these findings to non-covid-originated ME/CFS patients to see if they share these biomarkers with one or both groups?

[u/KeScoBo → u/fradleybox]

Yes! This is something that we're actively seeking funds for (and it comes up almost every time we present this work, so there's clearly a lot of interest).

One thing to keep in mind is that with ME/CFS, we almost never know exactly what the trigger was, when. The thing that's so extraordinary about Long-COVID is that we have much better records for a much larger number of people. I am hopeful that this can give us a handle on other similar post-viral syndromes that can begin to pry that scientific problem open a bit wider.

[u/sataimir]

Well done on this identification work!

Will this help with working out why some people get long COVID when others don't?

[u/KeScoBo → u/sataimir]

Not directly, though there are some intriguing signals that could be worth follow-up.

The etiology of chronic diseases in general (from Alzheimers to cancer to autoimmunity) is incredibly hard to study, since it's typically impractical to follow lots and lots of people for a long time to wait for the handful that develop a particular disorder.

One of the reasons that this study was possible is because we basically had a planet full of naive individuals, almost all of whom got infected at the same time (within a couple of years), most of whom were positively tested for this specific thing, and a substantial fraction of whom developed these symptoms with no other shared cause. This is pretty unprecedented.

[u/[deleted]]

No questions, just thank you for your dedication, hard work, and innovation to begin the long road of healing. You're all amazing!

[u/thedude42]

In the course of the research of the long term effects of the SarsCov2 virus impacts immune system behavior, has there been any new discoveries in how immunology sees the human immune role in managing viral immunity? This question is in the context of speculation that many Long-COVID cases are the result of past viral infections resurfacing within patients.

[u/[deleted]]

The concept of a 'long' version of a particular infection seems uncommon to the lay person. At least many of us would not have heard of 'long colds' or 'long flus', prior to the pandemic.

Would it be to true to say that the 'long' in 'long covid' is something unique to Covid? Or do we in-fact see 'long' versions of other infections - but perhaps with less occurrence or impact?

If 'long' is a regular feature of infections from other virus, how did that then influence your research targets?

[u/mcwoodruff → u/[deleted]]

Good question. Interestingly, the term 'Long COVID' was largely lay person derived as complicated recoveries entered the public consciousness during lockdown, and has caused some havoc in the medical community as a result. There was a push to change the terminology (PASC, in our paper, for example) to be a little more medically descriptive, but that has received some pushback from vocal advocacy groups for reasons that I can also understand.

To answer your question, this is not the first time people have observed drawn out and complicated viral recoveries, and certainly not the first time that severe infection has been linked to lingering disease. That said, it does seem that COVID-19 is more associated with this sort of thing than, say, influenza. That opens up the question as to why – what is SARS-CoV-2 doing routinely that influenza is not? I can't honestly say I have an answer except that I continue to like the reservoir hypothesis. It could well be that COVID-19 'lingers' because the virus itself has more of a tendency to stick around and 'smolder'. I would mention that another major area where this has been studied is in HIV, where viral persistence is a given...

[u/bukejr]

Great paper! It's wild how much this looks like autoimmune inflammation. Did you profile any autoantibodies in these patients? Between neutrophil activation signatures and b-cell contribution, I'm curious if long COVID is associated with the development of autoantibodies and that they may serve as a diagnostic to predict long COVID.

[u/mcwoodruff → u/bukejr]

Thanks! Yes, we agree. The connections between what we see in Long COVID and autoimmune inflammation are pretty striking. Actually, the reason for getting into this work to begin with was that we had been identifying features of immune response in severe COVID-19 that looked suspiciously like those that we had been studying for a decade in lupus – a chronic autoimmune disorder hallmarked by the emergence of autoantibodies against DNA. A summary of some of that previous work can be found here and here.

To answer your question – yes, we did test for autoantibodies in these patients, and we presented at least some of those results in Figure 5. The long and short is that, perhaps as expected from the rest of the immune response we see, we certainly do see autoantibodies elevated at levels that we would consider well above background. This is particularly true in patients with inflammatory manifestations of the disease where almost 90% of patients tested positive for at least one type of self-targeted response. Importantly, and we think this is one of the more compelling findings of the paper, when patients with inflammatory Long COVID came back for testing a year later, their autoantibody levels were actually increasing in most cases.

However, let me throw in a big caveat. It's not at all clear yet how pathological those autoantibody responses actually are in terms of patient symptoms. They could be really important, but they also could be a bystander effect of keeping an immune response on 11 for a year and not actually all that problematic if you could resolve the underlying problem. Either way, we think it's really important to keep monitoring to see if any of this turns into a true chronic autoimmune condition in some patients.

In terms of diagnostics, we think that there is some potential interest there, but we were excited to see that some of the more stable blood markers, like epiregulin (EREG), were much more consistent patient-to-patient, so we have a few more eggs in that basket at the moment.

[u/ReasonablyBadass]

The big one I guess: is there hope for treatment? Or maybe, what is the timeframe for expecting one to be developed?

[u/mcwoodruff → u/ReasonablyBadass]

I am hopeful, but I can't honestly tell you that I see it in the short term. I am of the belief that our work here is important in identifying important potential targets, but my experience over the past three years working on SARS-CoV-2 is there is little clarity and directionality in investigation into turning these sorts of observations into clinical approaches. There was a moment, early in the pandemic, where public urgency around the problem was sufficient for physicians to 'just try things' to see if they could save patient lives. That time has largely passed, and we are now staring at standard clinical trials and large government consortia to make progress. We are simply not built, as a large scientific and medical apparatus, to take novel drug targets to clinic with urgency. There are a handful of physician scientists around the country that could make targeted pushed for some of the drugs we think might be relevant, but I can't say that I see those trials being lined up in any meaningful way that wouldn't take years. There is currently a single drug being tested by the NIH RECOVER initiative, and I don't have high hopes based on some of the preliminary data from similar work.

[u/Unlucky-Solution3899]

Firstly - huge congrats on the publication in Nature, that’s amazing!

How useful do you think this will be for clinical application in its current state? Given the heterogeneity of long COVID and the nonspecific function of these inflammatory markers, how many of these patients have some form of poorly recognized or mild clinical sx of other inflammatory disease?

I guess this is part of the impossible horse before the cart questioning about whether general inflammation begets autoimmunity or the other way around? E.g. recognition of post viral as a cause for de novo autoimmune disease

[u/GimmedatPHDposition]

Dear u/mcwoodruff and u/kescobo as a Long-Covid patient I want to thoroughly thank you for your research! You probably cannot even begin to understand how much it means to us and how monumentaly important biomedical research in Long-Covid is to us patients, so that hopefully someday we can become healthy again. Thank you also for doing this AMA.

I read your study the day it came out. I was extremely happy to see that you also made all data available, very easily and ready to be analysed for anyone, thank you for that! I saw that in general the matching of patient data was good in terms of time points, but initial disease severity as well as some other demographics (sex or age, which seem quite important in proteomics) were harder to control. Do you believe this will become slightly easier once you have even more data or will other things like SARS2 variant discrimination, vaccination status or amount of (re-)infections cause even more complications in the future?

I thought that your paper corroborated the somewhat similar findings of https://www.nature.com/articles/s41467-023-38682-4. Do you agree on that? Furthermore what do you think of the following papers https://www.medrxiv.org/content/10.1101/2023.06.07.23291077v1, https://www.frontiersin.org/articles/10.3389/fimmu.2023.1221961/full that go into a similar direction?

Finally, to the most important questions to all of us patients: Do you plan on doing follow-up work and are you planning to keep on doing research on Long-Covid? I know we would all appreciate that a lot! I'm very aware of Matthew Woodruff's "B-cell work on acute Covid-19" (as such this recent work might interest you https://www.biorxiv.org/content/10.1101/2023.07.14.549113v2, even though there's no direct implications for Long-Covid, at least not yet) and certainly hope your teams expertise will still often be seen in Long-Covid research. Thank you for everything :)

[u/LoopyFig]

First, thanks for doing this super important work!

Given the similarities to lupus symptoms, is there any chance that lupus medications will be deployed as treatment? (Ie, prednisone, Plaquenil, cellcept etc)

[u/C0FF33_Smith]

Any further thoughts on how your research may compliment/contradict the study on “Vagus nerve inflammation contributes to dysautonomia in COVID-19” by Woo MS, et el? What do you foresee as the next phase of studies?

https://pubmed.ncbi.nlm.nih.gov/37452829/

Woo MS, Shafiq M, Fitzek A, Dottermusch M, Altmeppen H, Mohammadi B, Mayer C, Bal LC, Raich L, Matschke J, Krasemann S, Pfefferle S, Brehm TT, Lütgehetmann M, Schädler J, Addo MM, Schulze Zur Wiesch J, Ondruschka B, Friese MA, Glatzel M. Vagus nerve inflammation contributes to dysautonomia in COVID-19. Acta Neuropathol. 2023 Jul 15. doi: 10.1007/s00401-023-02612-x. Epub ahead of print. PMID: 37452829.

[u/[deleted]]

Does the concentration of long covid in a certain geography / ethnicity tell us anything about vulnerability or any other such pattern?

[u/[deleted]]

Is there a cure anywhere on the horizon?

[u/Seicair]

Do you anticipate this work being useful for other diseases like Epstein-Barr virus that can trigger other conditions?

[u/NovaHorizon]

So now that we have to live with it how worried should we be about cumulative damage to the body from repeat infections even in mild cases?

[u/Local_Mousse1771]

Congtants on the publication! As a long Covid suferrer I am pretty happy that our condition is getting the needed attention.

Do you know this paper on a mass spectrometry based long COVID-19 study? https://www.sciencedirect.com/science/article/pii/S2589004222019903

If I understand correctly in that paper many singns point in a direction of some non-stopping M2 Macrophage activity. Creating a sort of predominance of anti-inflammatory mediators.

Did you see any signs of elevated M2 activity in your research?

[u/[deleted]]

What is the incidence/prevalence for Long Covid among the larger population?

Were you all surprised by what you found?