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Oct 20, 2023 99 tweets 31 min read Read on X
The PolyBio Symposium starts shortly! We'll be live-tweeting through the day - follow this thread.

1/ #LongCovid
@microbeminded2 Over my head but very cool work on respiratory profiling, and work in endometriosis!

Really cool work planned in endometriosis, spinal ligaments, etc 14/
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@microbeminded2 Up next Dr. @MBVanElzakker: "Neuroinflammation and vasculature abnormalities in #LongCOVID and ME/CFS"

In looking at a brain, about half of cells are glial cells; have important functions, including immune function. 15/
@microbeminded2 @MBVanElzakker When they come in contact with pathogens or proteins from pathogens, they activate, release a protein called TSPO. TSPO is measurable with neuroimaging. 16/
@microbeminded2 @MBVanElzakker PET analysis in #LongCovid vs controls found neuroinflammation, which could implicate a bunch of things.

Really significant findings compared to controls! And not related to hospitalization or not (cohort was mostly non-hospitalized) 17/
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@microbeminded2 @MBVanElzakker Their hypothesis was that cytokines wouldn't correlate with neuroinflammation, but that vascular impacts & vascular health would, and this was true!

Multiple vascular markers were correlated with neuroinflammation (more than those just on this screen). 18/ #LongCovid Image
@microbeminded2 @MBVanElzakker Post-doc Mark Painter filling in for John Wherry for this talk on antigen-specific T & B cells as biosensors for viral persistence and reactivation in #LongCovid! 19/ Image
@microbeminded2 @MBVanElzakker Main two questions:

20/

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Can T & B cells be used as sensitive and specific biosensors for SARS-CoV-2?

Also looking for EBV, VZV, flu, CMV, and others

This helps understand virus-specific impacts 21/
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They hypothesized that not all #LongCovid patients would have these findings, but wanted to know if it was possible for them to identify subgroups with viral persistence. 22/ Image
They did not find evidence of COVID-specific viral persistence in all #longCovid patients, but in a subcohort (27%? unsure what that number refers to). They also found evidence of EBV and VZV in a minority of LC patients. 23/

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Next up, the amazing @VirusesImmunity!

She suggests 4 possible causes for #LongCovid:
viral reservoir, autoimmunity, tissue damage/dysfunction, latent virus reactivation.

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In autoimmune disease, patients are generating antibodies against ERV (endogenous retrovirus) 27/
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Next up: Dr. Alessio Fasano, "SARS-CoV-2 persistence in MIS-C & pediatric #LongCOVID".

Early in the pandemic, there was a misconception that kids were spared (despite never being seen before). Their team thought this was counterintuitive, started looking at impact on kids 28/ Image
Four hypotheses for #LongCovid, including persistence in the gut, chronic inflammation (including defect in zonulin-dependent barrier) (side note that MIS-C is driven by zonulin-dependent loss of gut mucosal barrier) 29/

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#LongCovid is associated with increase in zonulin and oxidized LDL 30/ Image
He suggests zonulin and oxidized-LDL could be potential biomarkers for #LongCovid. 31 Image
3rd and 4th hypotheses are autoimmunity and microclots 32/
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Next up is Dr. Locci, "Decoding Long COVID lymphoid tissue adaptive immune responses" 33/
(Hopping off, next tweeter will pick up shortly! -@ahandvanish)

34/
Hello all, @jannamoen here! Dr. Locci currently discussing her exciting approach using fine needle aspiration biopsies to study lymph tissue in #longCOVID Image
Her team found germinal center responses to SCoV2 appear to be more long-lasting in long COVID, suggesting immune dysregulation in the lymphatic system. /36 Image
Highlights from the Q&A:

Akiko Iwasaki was asked whether high spike antibody levels correlate with viral persistence. Neutralization assays from the lab suggest there may not be a strong correlation between anti-spike IgG and lymphocyte responses. /37
Next up - Gene S. Tan from UCSF presenting on identification of serological biomarkers that reflect immunological status and mechanisms of viral chronic disease /38
Early, low, non-neutralizing IgG responses were observed in people who progressed to severe acute COVID-19 ("progressors"). These antibodies lacked fucosylation, enhancing their affinity for their target receptors. This correlates with worse symptoms in C19 /38

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Now they are asking how antibody fucosylation is impacted in long COVID. LC phenotype is consistent with high inflammatory state without neutralization activity, not ideal for long-term health. /39 Image
Exosomes are an interesting target for the group - these are basically little envelopes released by cells that could shield the contents from detection. /40 Image
Next up - Dr. David Price discusses SARS-CoV-2 resevoirs in the lung as potential drivers of #longCOVID. His group found that peripheral virus-specific T cell frequencies were approximately the same between healthy controls and LC patients. /41 Image
This implies the immune response in #longCOVID patients may be blunted - specific T cell frequencies should be increased after encountering a virus. (Sorry, missed the screenshot for this slide!) /42
Prev slides were discussing frequency - but further analysis found the /behavior/ of SCoV2 specific T cells were also different. /43 Image
Activation of the alternative complement pathway, which is triggered by direct exposure to damaged cells and/or pathogens, is a predictive feature of long COVID. These data highlight ongoing tissue damage consistent with localized reservoirs of SCoV2 /43
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New study aims to elucidate the SCoV2 resevoir and related pathology in lung tissue with a variety of next-generation genomic technologies. Keep an eye out for this in the future! /44 Image
We are now hearing from Dr. Max Qian from J. Craig Venter Institute on the use of AI approaches to identify #longCOVID endotypes, a very popular methodological approach for discovery-driven research. /45
Machine learning is often applied in long COVID - it usually involves using an unsupervised process to split the population into clusters based on dimensionality reduction (or similar) methods. This can be paired with supervised learning classification /46 Image
Machine learning has been successfully applied to long COVID. Clustering can be done based on symptom group presentations. Current studies suggest at least 10 sub-phenotypes (probably not the correct phrase) in #longCOVID /47

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Ongoing work is being performed on semi-supervised topic modeling incorporating important events like vaccination and reinfection. These tools can help us understand divergent presentations and mechanisms in such a heterogeneous condition /48 Image
Some interesting data suggesting common demographic variables like race, BMI, smoking status, and sex are not correlated with #longCOVID - it impacts these groups equally. Variables that DID correlate with LC included HIV status, fatigue, and diabetes /49

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Next up is Dr. @resiapretorius discussing biofilms and endothelial debris contributions to #microclots.

Importantly, latest studies includes both LC and vaccine injury groups!

They have published a lot of work showing platelet hyperactivation in #longCOVID /50 Image
@resiapretorius Their first paper describing flow cytometry to systematically measure microclots was recently published and will hopefully facilitate microclots research around the world /51 Image
@resiapretorius More recent work in the lab is focused on novel methods to analyze and trace biofilms, amyloid microclots using fluorescent microscopy. These could easily be automated! /52
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@resiapretorius Final points - microclotting and endothelial damage point to heterogenous and complex disease pathology. Size, number of clots alone will not be enough to explain the pathology in #longCOVID, framework needs to include platelet activation and endothelialitis /53 Image
@resiapretorius Next on the podium is Dr. Marcelo Freire @drmfreire discussing immune, clotting, and infectious biomarkers of #longCOVID blood and saliva.

The mouth is a portal to the body, and the oral cavity can be an important site for pathogenesis of chronic diseases /54 Image
@resiapretorius @drmfreire Fun fact - your saliva contains a lot of immune cells, which are alive and active fighting off pathogens in your mouth. These leukocytes are highly heterogeneous and correspond to specific pathogens /55


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@resiapretorius @drmfreire Proteomics analysis found similar disruptions in protein expression from saliva compared with plasma (from blood). Saliva is a much easier sample to collect!

This indicates that salivary proteins could be used as biomarkers, and could also be driving pathology /56


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@resiapretorius @drmfreire Some very beautiful images showing transcriptional expression in situ (within tissue), in this case in samples from patients with diabetes. The goal is to apply this to #longCOVID /57 Image
@resiapretorius @drmfreire Now we have Dr. Annie Antar discussing evidence of SCoV2 persistence via evaluation of Long COVID B cell responses at Johns Hopkins

Measles is another RNA virus that causes post-acute sequelae, the most severe being paralyzing polio, which results from replication in the CSF /58
@resiapretorius @drmfreire Measles results in long-term disruptions of the adaptive immune system, this is previous work serves as inspiration for the SARS-CoV-2 studies /59 Image
@resiapretorius @drmfreire Cool study design - patients enroll at acute symptom onset, samples can then be correlated with reported long COVID symptoms. Delayed viral RNA clearance from nose/saliva was associated with brain fog, and elevated IL-6 associated with long COVID at 90 days /60
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@resiapretorius @drmfreire The survey team worked closely with @ahandvanish to ensure their questionairres accurately captured #longCOVID. Future studies include TCRseq - T-cell receptor sequencing /61 Image
@resiapretorius @drmfreire @ahandvanish Now is Dr. Maayan Levy discussing serotonin reduction and viral persistence in post-acute sequelae of viral infection. Serum metabolomics combined with machine learning identified several clusters, but serotonin reduction was strongest predictor /62
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@resiapretorius @drmfreire @ahandvanish Interestingly, serotonin reduction was not unique to SCoV2 - it was observed in mice following VSV, ARM, etc. By mimicking viral RNA with poly(I:C), they showed viral RNA activated interferon responses to reduce serotonin. This reduction is caused by disrupted gut absoption /63

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@resiapretorius @drmfreire @ahandvanish This study highlights the importance (and complexities) around serotonin signaling following viral infections! Image
Now we have Dr. Lael Yonker on her pediatric #longCOVID #longCOVIDkids work.

Multiple studies show SCoV2 in the gut, which causes zonulin release and can lead to MIS-C/PIMS in children. Can blocking zonulin release put the brakes on inflammation onset?
/65
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Open-label trial of zonulin receptor antagonist expedited the resolution of GI symptoms and spike clearance in children with MIS-C. Really promising results, currently in phase 2 DBPC trial! /66 Image
Can circulating spike act as a surrogate marker for larazotide? This is a case study showing several spikes and rebounds in CRP until given larazotide (zonulin receptor blocker), which quickly stabilized CRP and spike at low levels /67 Image
Alright, @jannamoen signing off! Tweets will continue below from other volunteers for the rest of the session! Thanks for tuning in. /68
@jannamoen @ahandvanish checking back in for the next few! 69/
@jannamoen @ahandvanish Next up is Dr. Tim Henrich "Total body PET imaging for T cell activity & deep tissue viral reservoirs in Long COVID".

There's lots of inflammation and immune dysregulation. "It's likely a tissue-based phenomenon." But tissue is hard to get!

#LongCovid 70/
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So new imaging - in this case non-invasive nuclear imaging - may be helpful.

They are using a tracer called F-ARG, which is taken up by T cells, so it's a marker for activated T cells. 71/ Image
Cohort was at a median of 195 days with #LongCovid, max was 2.5 years. Mostly non-hospitalized. Many had lost COVID antibodies!

Also had recovered COVID and pre-COVID healthy controls. 72/
Increased T cell activation in #longCovid patients compared to controls - curious places, cervical spine, thoracic spine, bone marrow, cauda equina. 73/
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Back to LIINC study - found spike RNA in some areas.

Plans to do whole-body imaging through immunoPET imaging of the spike protein! 74/
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A critical point - everyone having COVID just generally changes research baselines on inflammation, brain, cardiovascular health etc! 75/ Image
Next is Dr. Matthew Frank, "A multi-hit model of Long COVID development".

Successive inflammatory insults = neuroinflammatory and brain changes in #LongCovid. 76/
He is proposing that #LongCovid comes from two hits: first, the spike hit from COVID, and then a second inflammatory hit (could be bacterial, another virus, environmental hit. potentially reinfection?)

This second hit causes the neuro impacts on the brain 77/
They ran an experiment on this hypothesis with animals. NLRP3 (gatekeeper of neuroinflammation) became elevated 9 days after the initial infection. Wonder if this is why there is a delay in neurocog symptoms?

"There is a persistent cellular change in the brain" 78/
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Switching off to another volunteer now! 79/
VanElzakker in Q&A on questions about serotonin paper: underscores SSRIs are reuptake inhibitors; this is not the same as adding it or producing more of it
VanElzakker now summarizing research on detecting fibrin-based clots using radioligands; PolyBio interested in pursuing this in LC Image
VanElzakker discussing images of micro clots (notes amyloid here differs from amyloid in Alzheimer's). /81 Image
VanElzakker contrasting images of neutrophil movement in patients & controls/82 Image
"platelets and neutrophils are responding to the same thing" (image on left is neutrophils, right shows platelet overlay)/83 Image
the hope is this will lead to PET imaging that can provide information /84 Image
VanElzakker now onto a second study!/85 Image
Very interesting research drawing on CCI, instability, with potential to do vagus nerve stimulation in scanner to observe results/86 Image
Next up: Sara Cherry on tissue models in SARS-COV-2, especially viral persistence in the GI tract /87
Where we're at right now: approaches include direct acting antivirals and immunomodulators /88 Image
We know that antivirals can reduce viral load during acute infection, but what about viral persistence /89 Image
Cherry working here to ask questions about the difference between virus in airways during acute infection and in the gut later on/90 Image
Noting high and persistent levels of virus after acute phase of infection, but questions outstanding about when and how to dose antivirals /91 Image
Questions guiding Cherry's work / 92 Image
Next up: Steven Deeks on experimental medical studies for infection-associated chronic illnesses, including LC. Noting need to define a mechanism in which we can interest pharma, industry partners to invest/ 93
Deeks noting the pileup of multiple pathways, all of which are actionable / 94 Image
Deeks notes LIINC cohort shows emerging relationships between viral persistence and symptoms, though this research is ongoing / 95
One approach: antivirals targeting viral persistence (noting Stanford, Yale Paxlovid studies), but noting limits of antivirals that target replication of virus only / 96
Another approach: study of monoclonal antibodies that clear the viral reservoir itself / 97 Image
Other pathways to intervene: baricitinib (JAK inhibitor) / 98 Image
David Putrino up next on "how to be an innovator in the space of infection-associated chronic illnesses": noting that it takes 17 years to "go from bench to bedside" because funding rewards incremental research / 99
Putrino: hyperspecialization and siloing creates competition among departments, makes it difficult to approach infection-associated chronic illnesses b/c of the need for interdisciplinary knowledge and care / 100
Putrino: his work at Mount Sinai focused on adopting care models from pragmatic clinical trials. Importance of moving quickly, partnering with industry /101 Image
"Single guiding principle" for Putrino lab's work: "Never let a patient be told 'there's nothing more we can do'". But clinical adoption is the hard part: barriers in time, funding, difficulty of behavioral change / 102
Putrino's model: building a center to address infection-associated chronic conditions; essential to address and treat together / 103
Putrino: importance of studying multiple therapies, getting at combinations that work for different endotypes (noting that adaptive platform trials are "not your grandpa's monotherapy trials") / 104
Q. to Dr. Cherry: is the gut/lung primary source of viral persistence, but what about other sites? A: thinks other tissues are important and they are expanding to this, hoping for more primary samples / 105
Q. for Peluso: how is the monoclonal he's studying different from Regeneron or others used for acute COVID? A. This is an investigational monoclonal--was the last monoclonal standing at end of 2022.
Q. will these need to be combined with other drugs? A. combination therapeutics used in HIV to avoid resistance; interesting to look at multiple mechanisms contributing to resistance and target those. Cherry adds that combining multiples should be studied / 107
Q. to VanElzakker on vagus nerve and muscarinic receptors. A. Notes that the idea that the vagus nerve is infected is a hypothesis at this point, likely we need multi pronged approaches. Proal notes recent finding from autopsy study of SARS-COV-2 in vagus nerve / 108
Q. on sleep and reduced parasympathetic activity at night. A. VanElzakker: sleep one of multiple areas of dysfunction. They give a take-home wearable sleep device to study this in days prior to scans to capture data on this. Probs with sleep likely snowball w/other symptoms / 109
Q. on trial construction, being patient-centered, and including housebound patients. A. Iwasaki: now can enroll ppl across US (except Alaska/Hawaii) and deliver meds, take samples from home. Peluso notes PLRC input, patient advocates, community board / 110

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More from @patientled

Oct 2, 2024
We’re happy to announce a new @patientled preprint out today, on machine learning phenotypic with high-dimensional #LongCovid symptom data!

We used a dataset of 162 symptoms in 6,031 participants to explore making clusters of Long Covid patients. 1/
researchsquare.com/article/rs-490…
three clusters of Long Covid symptoms, showing inconsistent clusters across three machine learning methods
In sum, we used three different machine learning methods (a genetically optimized deep learning model, ensemble clustering, and probabilistic modeling).

We found that consistent clusters were *not* discovered across the three methods. 2/
This implies both that:

a) symptoms may not be the best way to create phenotypes of #LongCovid patients

b) studies that use fewer symptoms, fewer patients, or only use a single clustering methodology might be detecting phenotypes that are not robust or repeatable

3/
Read 7 tweets
Sep 24, 2024
We are thrilled to release a new preprint on reinfections today!

This paper details the impact of COVID-19 reinfections on both people with and without #LongCovid.

Overall, the odds of Long COVID increase with reinfections.

1/researchsquare.com/article/rs-490…
Those who had 2 COVID infections were 2.14 times more likely, and those who had 3 or more COVID infections were 3.75 times more likely, to report #LongCOVID than those with one infection.

2/
The odds of both severe fatigue and post-exertional malaise, two debilitating symptoms, increased with reinfections. 3/ #LongCovid pic of odds ratios showing higher fatigue and PEM
Read 14 tweets
Aug 30, 2024
New collaborative paper out! The paper looks at rates of #LongCovid in those with long-term disabilities.

Of people who got COVID, 40.6% of people with pre-existing disabilities got Long Covid, vs 18.9% of people without pre-existing disabilities.

1/ajph.aphapublications.org/doi/10.2105/AJ…
Population-wide, 10.4% of people with pre-existing disabilities had #LongCovid as of summer 2022, vs 7.5% without. 2/
The prevalence of #LongCovid was highest in those with chronic illness (diabetes, asthma) & lowest in those with sensory disabilities (deafness, blindness).

With the exception of sensory disabilities, all disability categories had higher LC rates than the general population. 3/
Read 7 tweets
Aug 22, 2024
We’ve released a new paper on designing & optimizing clinical trials for #LongCOVID!

Strong, high-impact trials are critical & most current ones are insufficient. The paper gives guidance on treatments, outcomes, design, participant inclusion, & more.

1/sciencedirect.com/science/articl…
It also gives an overview of the promising interventions being trialed (as of May 2024) for #LongCovid and their targets, including viral persistence, immune dysfunction, endothelial dysfunction, and symptom management. 2/ table of interventions being trialed for Long Covid, including monoclonal antibodies, truvada and maraviroc, IVIG, and others.
Some other key points:

-Trials should prioritize potentially curative interventions, including repurposed drugs and the development of new drugs.

-Combinations of therapies may be beneficial or necessary, which should be considered in clinical trial design. 3/
Read 11 tweets
Aug 9, 2024
We are happy to announce a new #LongCovid review out in Nature!

This was led by @zalaly, with co-authors @leticiasaurus @LisaAMcCorkell and @ahandvanish from PLRC, alongside @VirusesImmunity, @EricTopol, and @swulfie.



Some highlights:

1/nature.com/articles/s4159…
It puts the most conservative estimate of cumulative global incidence of #LongCovid in 2023 at around 400 million individuals.

As people have stopped testing and tests already had high inaccuracy rates to begin with, this is a low estimate, but still an enormous number. 2/ chart showing an estimated 409 million global Long Covid cases as of 2023
The economic impact of #LongCovid is at least $1 trillion *per year* - equivalent to 1% of the global GDP.

3/ impact of Long Covid on 8 countries, showing GDP loss due to Long Covid at -2.3% to -0.5%
Read 9 tweets
Aug 2, 2024
Today, we are thrilled to see the introduction of The Long COVID Research Moonshot Act by Senator Bernie Sanders (@SenSanders), co-sponsored by Senators @SenTimKaine, @SenDuckworth, @SenMarkey, @SenPeterWelch, and @SenTinaSmith!



#LongCovid 1/sanders.senate.gov/wp-content/upl…
9 months ago, our co-founder Lisa McCorkell (@LisaAMcCorkell) & Long COVID researcher Michael Peluso (@MichaelPelusoMD) called for a Moonshot for Long Covid - an investment of at least $1 billion yearly for 10 years into Long Covid research. 2/

#LongCovidnature.com/articles/d4158…
The Act is a historic piece of legislation. It includes $1 billion/yr for 10 years to NIH to establish & run a #LongCovid Research Program, led by a Director with expertise in Long COVID. Clinical trials & the development of new interventions would be prioritized & expedited. 3/
Read 14 tweets

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