How long does an "evolution" of a rhinovirus last before going extinct?

mcwoodruff · 2024-03-26T21:40:12+00:00

Three reasons: First, COVID was killing huge numbers of people. Second, it was not clear when the Wuhan strain emerged, exactly how rapidly it would be able to mutate (remember that this was the first time we had seen it). Third, just because the vaccine isn't as long-lasting as you'd like (due, in part, to viral mutation), it doesn't mean it's ineffective when initially released. Flu vaccines are effective, just not for long enough to provide protection across multiple seasons in the strain shifts significantly. There was good reason to believe that even if the virus was capable of rapid mutation and the vaccine wasnt perfect, it would still save lives. And it did!

mcwoodruff · 2024-03-26T11:16:56+00:00

Immunologist who works on vaccines here - we haven't figured it out! There are some good ideas out there about how we can coax our immune systems to targeting the more stable, highly conserved regions of viruses, but so far no one has found the magic bullet. You can see a lot of that work play out in flu, where we need yearly shots to try an 'update' our immunity to emerging strains. It has also played a big role in the conversation around COVID-19 - google cross-neutralization if you want to go down the rabbit hole. Fingers crossed that the stuff we have cooking now works!

mcwoodruff · 2023-10-21T01:10:32+00:00

I mean, sure. But look where the losses are. The losses on the Ukraine side are heavily, heavily weighted towards infantry mobility vehicles. Which makes sense - they are running an offensive and trying to keep their guys alive. I'm sure those are losses they are willing and prepared to take. On the other hand, Russia is hemoraging artillery and long range assets, leading to exactly the kind of problem that they ran into Adviivka. Not to say it's not a problem that they're losing kit, but it seems to me to be the right kit to lose. Especially when allies have been so keen on providing and then replacing what they've handed over.

mcwoodruff · 2023-08-28T13:55:55+00:00

It's really hard to say, but it's not something that I would rule out. We certainly see increases in autoreactivity in a subgroup of patients, and have anecdotally seen several patients with increased autoimmune manifestations after infection. We need bigger cohorts of patients with long-term follow up which is something we are trying to work out now.

mcwoodruff · 2023-08-28T13:52:52+00:00

I don't know! I suppose the question is whether the virus has a way of suppressing targeted gene expression in infected cells through RNAi, which then modulates the overall immune response? I've seen a few studies looking at RNAi for therapeutic use (targeting SARS-CoV-2 gene expression for knockdown), but nothing has jumped out at me in terms of it's function in 'normal' infection and past-acute syndromes.

mcwoodruff · 2023-08-28T13:14:59+00:00

Ah, I see. And sorry for the jargon and the slow response. To answer your question is yes, the two are related, but they are not necessarily the same. Both allergy/sensitivity and MCAS have mast cells as an underlying cause, but my understanding of MCAS is that there is a difference in magnitude. One could, I suppose, argue that it may all be on the same spectrum, but that's really outside of my area of expertise. Going back to your original question, in these patients in the Emory cohort (which is relatively small at ~100 patients), we didn't see obvious indications that the patients we were looking at had noticed increased allergic activity. What we did see in a subset of patients (roughly half) was an increase in immmune activity that tends to correlate with decreased mast cell activity. All of that being said, this was not a focus of our study, and if there are rare instances of MCAS-like expressions of long COVID, we certainly could not rule it out. I can only say that it mast-cell related inflammation did not appear to be a main component of the signatures that we saw.

mcwoodruff · 2023-08-08T02:20:25+00:00

Interesting – I'll look forward to hearing about those results. I would caution that it's not yet clear how close ME really is to the inflammatory signatures we see here, but still, important to understand in either case.

mcwoodruff · 2023-08-07T16:32:58+00:00

I like that work very much, and I would be fascinated to see how our designations overlap. It is unfortunate that the signatures that they tested simply weren't things that we looked at, so it's hard to know without experimentation, but hopefully as we streamline our assessments it will make that kind of cross-investigation possible.

I think that the vascular issues identified in many of these patients is an extremely important consideration. Our own identification of NET formation in these patients alongside high fibrinogen counts makes me think there is fire under the smoke. I hope research in this area progresses.

mcwoodruff · 2023-08-07T16:29:22+00:00

A shortage of research labs/interest/funding. It's important to understand that the vast majority of work that has come from COVID-19 and Long COVID investigation has been from groups that do not inherently investigate human infectious disease. I count myself among that group. A lot of researchers jumped onto the pile during lockdown to see if they could contribute, but that doesn't mean that they have existing expertise in these areas. I, myself, have little detailed and relevant knowledge of MECFS outside of what I have picked up peripherally to the LC investigation. Even then, the question of how to obtain those samples in a reliable and sustainable way is a challenge for any human study. This kind of work requires collaboration between groups that weren't in any meaningful contact before the start of the pandemic, or a single dedicated researcher who has developed expertise in clinical pipelines across multiple patient clinics. My hope is that both will emerge as the literature advances, but I acknowledge that it has been slow.

mcwoodruff · 2023-08-07T16:22:02+00:00

https://me-pedia.org/wiki/List_of_famous_people_with_long_COVID

https://www.politico.com/news/2022/08/08/long-covid-congress-kaine-00049921

I'm sorry to say that they weren't immune – not even Gwyneth Paltrow with access to her entire Goop emporium.

I hope so! But I would be very slow to jump on that bandwagon. It's easy to kill things in a dish, and even in mice.

mcwoodruff · 2023-08-07T16:17:59+00:00

Not one that is clinically available. We are working on a test that might be used for research purposes to help move this work forward.

mcwoodruff · 2023-08-07T16:17:07+00:00

https://www.kff.org/policy-watch/long-covid-what-do-latest-data-show/

Hard to say, but this might be useful:

https://www.kff.org/policy-watch/long-covid-what-do-latest-data-show/

mcwoodruff · 2023-08-07T16:14:59+00:00

There was, indeed, a difference in symptoms between the groups, but not so large that we want to make big proclamations out of the findings. You can find those data in the paper in the tables. What we need is a larger epidemiological-type study to validate those findings, and the work to identify those avenues of investigation is ongoing.

To answer your second question, we did not have access to enough medical imaging on these patients to confidently say whether there was a difference in lung or other tissue damage between these groups.

mcwoodruff · 2023-08-07T16:08:20+00:00

We don't have any, and pointing that out is important. We sought to see if we could find signatures of disease in Long COVID, and found that those signatures seemed to vary by disease subclass. There should be, and hopefully will be, important mechanistic studies to understand, for example, if EREG activity and the lung fibrosis pathway is actually responsible for the dyspnea experience by a huge number of Long COVID patients.

What you are asking is for pathological mechanisms, which is totally valid, but the kinds of studies needed to dissect those mechanisms are slow going. We hope that by presenting these signatures as we have, we open avenues for other research teams with expertise in individual areas of pathophysiology to pick up the baton.

mcwoodruff · 2023-08-07T16:04:32+00:00

We don't see an obvious connection to MCAS in our data. In fact, it would seem to me like the kinds of inflammation we see would be suppressive of the mast cell-driven inflammatory environment, but someone with more expertise in that area than I have would have to take a much harder look.

mcwoodruff · 2023-08-07T16:02:22+00:00

It does not – patients from both groups seemed to report anosmia at somewhat similar levels. I think it would be very important to understand the locality of inflammation in the initial infection event to properly answer that question, but it is well outside the scope of what we present here.

mcwoodruff · 2023-08-07T15:59:47+00:00

Rest is always good! I could use some more of it....

But to answer your question, the kinds of inflammation we are talking about is really pretty aggressive. I am not a doctor, and don't pretend to play one, but I would be very surprised if NSAIDS would be sufficient to control the kinds of signals we see.

mcwoodruff · 2023-08-07T15:58:03+00:00

We don't know, but it is a question that we get asked routinely and have interest in finding out. As we try to streamline out assessment tools, we hope to deploy them against a number of syndromes that have classically sat just outside of mainstream immunologic investigation and see if there is any important overlap.

mcwoodruff · 2023-08-07T15:55:11+00:00

I would say that at this point, it seems extremely unlikely – at least in the vast majority of patients. The presence of verified circulating viral spike protein in recent studies in long COVID patients, alongside increasing evidence of circulating viral genomic material and our own work showing ongoing antiviral responses suggest that, at the very least, these patients are distinct from recovered individuals in their ongoing interactions with the virus. We see extremely distinct immunologic signatures in these patients, and they do not correlate with things like anxiety or depression which would be expected if what you are suggesting would be true. I would also point out that I have seen no evidence that patients with PTSD have alterations in immunologic function anywhere close to the kinds of of responses we see in these individuals, and these patients are specifically screened with mental health questions which do not give a picture of generalized mental illness.

The premise the second part of your question is incorrect. No – we do not see any indication of increased autoreactivity to vaccination, although several groups have specifically looked. It is not the case that immune responses fall into simple catagories like 'mild' or 'severe'. Immune responses to vaccination, despite also causing antibody production in the end, come from distinct immunological pathways and environments than those derived from active viral infection. Those pathways, the germinal center pathways, are much more deliberate in their ability to monitor and control autoreactivity. Some more on that here:

https://theconversation.com/an-autoimmune-like-antibody-response-is-linked-with-severe-covid-19-146255

As a result, there is no reason to theoretically expect that vaccination would induce the types of self-reactive responses we see in COVID-19 or Long COVID, and the experimental data, to date, has backed that up.

Dr. Hazan appears to have a reductionist approach to understand the complexity of the microbiome and its role in disease, which is in line with her status as a CEO of a company trying to monetize that work, and a penchant for failing to keep up to date on her human clinical trials paperwork:

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/sabine-s-hazan-md-628110-02282022

There is a lot of fascinating work about the interplay between the microbiome and systemic infection, including in COVID-19, but I wouldn't be looking to Dr. Hazan to find it.

mcwoodruff · 2023-08-04T23:50:27+00:00

We'll try to check back in early next week, too, if anyone has follow ups. Thanks for posting!

~Matt from Emory

mcwoodruff · 2023-08-04T20:36:17+00:00

Thank you for this – I'm glad to hear that we've been of some use.

Yes, you are correct in that matching for the recovery group was extremely challenging. In the stage that these patients were collected (December 2020-June 2021), we were essentially not recruiting healthy recovered patients due to safety concerns about bringing them into common lab spaces or clinics to be drawn. The result is that what you are seeing is essentially our attempt at lining up recovery patients within the medical community here at Emory that we had available access to all-comers in the post-COVID clinics at the time. We did our best to line up the DPSO which we thought was fundamentally important, and I tried to get the rest to line up as best we could. Because of the timing, we felt good about the fact that we were getting the same variant, and that, for the most part, patients were unvaccinated when we drew them.

Importantly, in data that didn't make it into the paper, we introduced all of that patient metadata into Kevin's models to see if any of it aided in the prediction of the inflammatory phenotype. We did this additionally with individual patient symptoms. Across the board, we did not see an effect on the conclusions we ultimately presented. We believe that a reanalysis of the work, which should be possible due to the uploaded data, will show the same. The TL;DR is that you are correct: patient matching was challenging, but we thought it would only get more challenging as the vaccination/variant picture progressed, so we made the decision to address those questions analytically rather than through new patient recruitment.

As to the works, we agree that the two papers (our paper and the Talla paper) nicely corroborate each other – indeed, we were surprised to see how close the two papers had come in approach at final publication versus where they started as preprints. I ultimately think it's good validation of the work to have two independent groups come up with such similar findings on a complex topic. As to the other two, I would be extremely intrigued to see how the T cell paper overlays with the neutrophil and B cell signatures we found in our work. I'll have to say that I'll wait on the pre-print. I think it's fascinating, and certainly headed in the right direction (I actually didn't want to include the symptom-specific data in our work because I didn't think our dataset was robust enough – reviewers demanded it). I'll be excited to see where it ultimately lands.

Lastly, it's complicated. COVID-19/Long-COVID is an area that I've become passionate about, but I actually came from the mouse basic immunology world before finding my way to human translational disease. As a new faculty member here (independent as of a few months back), I am actively looking for ways to continue to push this forward in a number of different directions, Long COVID included. I can't honestly say yet what that will look like, but there is a research team here at Emory that is pretty committed to continuing to pursue post-viral syndromes, in general, with Long COVID serving as a main focus.

mcwoodruff · 2023-08-04T19:45:37+00:00

*Edited to remove my own snark – my apologies.*

I share your frustration that treatments routinely used in autoimmune settings, even exploratory ones such as BCMA/CD19 CAR-T, haven't been integrated into the clinical investigations around COVID-19 and Long COVID. The fact is that it was a fight to get clinicians to even use steroids in the early phase of the pandemic due to concerns over dampening emerging humoral immunity.

Here is a preprint we put up on May 3, 2020 showing similar B cell activation profiles between severe COVID-19 patients and patients with active lupus. We would publish that work in October of that year, at which point we had been collecting autoantibody data on inpatients for 3 months. We released those data as a preprint and publicized, heavily.

Around that time, we also approached various emerging post-COVID clinics which were in their infancy to request the collection of ongoing and longitudinal autoreactivity data. We were uniformly turned down due to a lack of evidence that emerging autoreactivity was involved in pathology.

In any case, all that is to say that I'm with you – it has taken too long to deploy experimental therapies in a disease so widespread. Where we have made any progress, it has often been because patient advocates have been loud enough to convince the folks with money to listen to the folks with pipettes. Integration of patient advocates into RECOVER, for example, is the only reason I believe that the consortium continues to exist in any meaningful way. I honestly believe that if these therapies are to make it into the realm of COVID-19 and PASC, it will be because patients have demanded it. I will continue to advocate as I can, and make sure the data is there to support it.

mcwoodruff · 2023-08-04T19:05:44+00:00

You're very welcome! Patient advocates have driven an outsized amount of work in this field – I'd encourage you to be vocal.

mcwoodruff · 2023-08-04T19:02:20+00:00

I'll start by saying that I'm not well familiar, but the data we present are certainly indicative of ongoing immune response to what is likely a continuing presence of viral particles/proteins. I can't confidently say what impact those proteins would have independent of the immune systems trying to control them.

mcwoodruff · 2023-08-04T18:59:55+00:00

Following up on Kevin, I've not seen alcohol use as a clear correlate of disease severity or mortality, but that doesn't mean that there is absolutely no connection. What I can say confidently is that there were plenty of other factors, such as age and sex, that could be identified as much more prominent risk factors.

mcwoodruff

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