@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/
@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/
@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
@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/
@microbeminded2 @MBVanElzakker Main two questions:
20/
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/
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/
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/
Next up, the amazing @VirusesImmunity!
She suggests 4 possible causes for #LongCovid:
viral reservoir, autoimmunity, tissue damage/dysfunction, latent virus reactivation.
24/
In autoimmune disease, patients are generating antibodies against ERV (endogenous retrovirus) 27/
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/
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/
#LongCovid is associated with increase in zonulin and oxidized LDL 30/
He suggests zonulin and oxidized-LDL could be potential biomarkers for #LongCovid. 31
3rd and 4th hypotheses are autoimmunity and microclots 32/
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
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
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
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
Exosomes are an interesting target for the group - these are basically little envelopes released by cells that could shield the contents from detection. /40
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
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
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
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
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
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
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
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
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
@resiapretorius Their first paper describing flow cytometry to systematically measure microclots was recently published and will hopefully facilitate microclots research around the world /51
@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
@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
@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
@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
@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
@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
@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
@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
@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
@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
@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
@resiapretorius @drmfreire @ahandvanish This study highlights the importance (and complexities) around serotonin signaling following viral infections!
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
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
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
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/
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/
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/
Back to LIINC study - found spike RNA in some areas.
Plans to do whole-body imaging through immunoPET imaging of the spike protein! 74/
A critical point - everyone having COVID just generally changes research baselines on inflammation, brain, cardiovascular health etc! 75/
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/
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
VanElzakker discussing images of micro clots (notes amyloid here differs from amyloid in Alzheimer's). /81
VanElzakker contrasting images of neutrophil movement in patients & controls/82
"platelets and neutrophils are responding to the same thing" (image on left is neutrophils, right shows platelet overlay)/83
the hope is this will lead to PET imaging that can provide information /84
VanElzakker now onto a second study!/85
Very interesting research drawing on CCI, instability, with potential to do vagus nerve stimulation in scanner to observe results/86
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
We know that antivirals can reduce viral load during acute infection, but what about viral persistence /89
Cherry working here to ask questions about the difference between virus in airways during acute infection and in the gut later on/90
Noting high and persistent levels of virus after acute phase of infection, but questions outstanding about when and how to dose antivirals /91
Questions guiding Cherry's work / 92
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
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
Other pathways to intervene: baricitinib (JAK inhibitor) / 98
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
"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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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…
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/
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
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/
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.
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/
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/
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.
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!
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/
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/