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Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
@NickAnderegg
Aug 6 • 30 tweets • 12 min read • Read on X
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THIS IS BIG. WOW. New paper in PLOS Pathogens has findings about:
- the effect of the SARS-CoV-2 spike protein on cardiac cells (and mitochondrial dysfunction!),
- a treatment to be investigated, and
- how this is NOT caused by mRNA vaccines!

Buckle up, we're diving in...

1/ Published August 5, 2024 in PLOS Pathogens: "SARS-CoV-2 spike-induced syncytia are senescent and contribute to exacerbated heart failure" "Author Summary In this paper, we directly linked SARS-2-S-triggered syncytium [fused cells] formation in the absence of infection with the ensuing induction of cellular senescence and its pathophysiological contribution to heart failure. We propose that both SARS-2-S expression and SARS-2-S protein internalization were sufficient to induce senescence in nonsenescent ACE2expressing cells. This is important because of the persistent existe...
[This paper is an uncorrected proof; it's been peer-reviewed, but not copyedited yet.]

A bit of background: syncytia (sin-sih-sha) are giant cells with multiple nuclei that form from the fusion of multiple cells. Viral infections are a common cause of syncytia.

2/
"Abstract SARS-CoV-2 spike protein (SARS-2-S) induced cell–cell fusion in uninfected cells may occur in long COVID-19 syndrome, as circulating SARS-2-S or extracellular vesicles containing SARS-2-S (S-EVs) were found to be prevalent in post-acute sequelae of COVID-19 (PASC) for up to 12 months after diagnosis. ... Here, we found that the senescent outcome of SARS-2-S induced syncytia exacerbated heart failure progression. We first demonstrated that syncytium formation in cells expressing SARS-2-S delivered by DNA plasmid or LNP-mRNA exhibits a senescence-like phenotype. Extracellular ...
NIH > National Library of Medicine Medical Subject Headings MeSH Descriptor Data 2024 Giant Cells (aka syncytia) Multinucleated masses produced by the fusion of many cells; often associated with viral infections. In AIDS, they are induced when the envelope glycoprotein of the HIV virus binds to the CD4 antigen of uninfected neighboring T4 cells. The resulting syncytium leads to cell death and thus may account for the cytopathic effect of the virus. Entry Term(s): Giant Cells, Multinucleated; Multinucleated Giant Cells; Polykaryocytes; Syncytia; Syncytium;
The authors had two motivations for this study:

1. Cardiac complications are a major feature of COVID.
2. Patients with heart failure tend to experience very poor outcomes from COVID.

Really, it hasn't been entirely clear *how* COVID leads to heart failure... until now?

3/ "Introduction ...Although symptoms resulting from infection typically resolve within weeks, some individuals experience persistent symptoms following the acute phase of COVID-19, the so-called post-acute sequelae of COVID-19 (PASC) or long COVID [2–4]. SARS-CoV-2 infection predominantly offends the respiratory system. Currently, evidence has suggested cardiac complications as one of the important pathogenic features of COVID-19 [5,6]. More importantly, compared with patients without heart failure, those with diagnosed heart failure experienced a longer length of hospital stay, increas...
Syncytia form when the spike protein present on the surface of one cell makes contact with another cell.

This study went a step further by looking at how *extracellular* vesicles containing the spike protein can fuse cells... *without* active infection.

4/ "SARS-CoV-2 syncytium constitutes a hallmark of COVID-19-associated pathology and may potentially contribute to pathology by facilitating viral dissemination, cytopathy, immune evasion, and the inflammatory response [12]. ... In addition to mediate viral-cell fusion, the presence of SARS-2-S on the cell surface is sufficient to mediate cell-cell fusion, a mechanism called fusion from within (FFWI)[14,15]. The fusogenic activity of SARS-2-S is potent, as even undetectable amounts of SARS-2-S can cause cell-cell fusion [14]. In addition to mediating FFWI, viruslike particles or lipid ves...
Why do syncytia matter?

They're a potential route for the spike protein to cause damage even AFTER an active infection has subsided.

Like some other viruses, SARS-CoV-2 can cause cell senescence—which is when the cell replication cycle stops, and the cells degrades.

5/ "SARS-CoV-2 elicits the senescence of infected cells, similar to other viruses (virus-induced senescence, VIS). Cellular senescence is a state of stable cell cycle arrest characterized by ... induction of the lysosomal enzyme senescence-associated β-galactosidase (SA-β-gal) and activation of the senescence-associated secretory phenotype (SASP). SARS-CoV-2 infection triggers paracrine senescence and can lead to a hyperinflammatory environment and the onset of acute respiratory disease syndrome. ... Interestingly, isolated recombinant SARS-2-S protein has been shown to increase the SASP...
So before we dive into results, what is the headline?

Although cytokine storm has long been thought the cause of COVID-related cardiac issues, this study found that the SARS-CoV-2 spike protein "led to profound cardiac fibrosis without affecting baseline cariac function."

6/ "Here, we recommend that rescue of cardiac metabolism dysfunction should be taken into consideration in individuals during the acute or post-acute stage of SARS-CoV-2 infection. It should be noted that SARS-CoV-2 infection also induces new onset of multiple cardiovascular diseases and causes long-term cardiovascular sequelae in PACS patients. Cytokine storm was suggested to be a point of convergence in the pathophysiologic process between COVID-19 and heart failure. Here we found that SARS-2-S led to profound cardiac fibrosis without affecting baseline cardiac function. Further studies...
Moreover, they found a drug target that may be able to prevent "the downregulation of mitochondrial metabolism," and it has shown potential promise in treating heart failure overall.

It would treat the "increased risk of developing heart failure and sudden cardiac death"!

7/ "Previous studies have shown that small-molecule inhibition of WNK1 prevents the downregulation of mitochondrial metabolism and improves RV function and survival in pulmonary arterial hypertension. We found that WNK1 inhibition alleviated SARS-2-Saggravated heart failure and reduced serum cTnT and IL-1ß levels. cTnT is released into circulation during injury to cardiac myocytes(51]. Individuals with higher cTnT levels are at an increased risk of developing heart failure and sudden cardiac death. Therefore, through its metabolism-rescue and anti-inflammatory properties, WNK463 may have ...
Let's dive in to the results! I'm going to jump around a bit, because this paper is EXTENSIVE.

First up, when they cultured cells expressing the spike (S) protein and the ACE2 receptor in a 1:1 ratio, the cells started fusing within four hours. Basic premise confirmed!

8/ "...To explore whether SARS-2-S expression was sufficient to induce senescence..., we cocultured SARS-2-S (Wuhan-Hu-1)-expressing A549 cells with ACE2-expressing A549 cells at a 1:1 ratio (S1A and S1B Fig). Syncytial cells rapidly appeared at 4 h post coculture (hpc) and gradually grew in size, as indicated by microscopic analysis (Fig 1A). Notably, SARS-2-S-expressing syncytia (hereafter referred to as SARS-2-S syncytia) with enhanced SA-B-gal staining began to appear at 12 hpc, and the percentage of SA-B-gal-positive syncytia among SARS-2-S syncytia gradually increased during the fus...
In the cultures with SARS-2-S syncytia, the cells secreted more senescence-related cytokines, including IL-6, IL-8, and IL-2, compared to the cells exposed to a mutant spike protein that can't cause senesense!

They found similar syncytia formation in other cell types.

9/ "Real-time PCR (RT-qPCR) revealed significant transcriptional upregulation of senescenceassociated genes (Fig 1B). The upregulation was fusion specific, as SNF , S, ACE2 and SNF +ACE2 cells did not exhibit such upregulation (S1G Fig). Consistently, the conditioned medium of SARS-2-S syncytia at 48 hpc contained significantly more SASP-related cytokines, such as IL-6, IL-8, and IL-2, than that at 0 hpc compared to SARS-2-S NF mutant (Fig 1D). We found that higher increased levels in secreted proteins than mRNA levels of IL-6 and IL-8. This may be due to the continued expression and secr...
They also tested the spike from four Omicron variants (BA.1, BA.5, BA.2.75, BA.2.75.2). Previous work has found BA.1 has a 5x reduction in ability to fuse cells (compared to wild-type), but the others have a 1.2-1.7x reduction.

All formed syncytia, just a bit more slowly.

10/ "We next compared the senescence potential of four Omicron variants, SARS-2-SBA.1 , SARS-2-SBA.5 , SARS-2-SBA.2.75 , and SARS-2-SBA.2.75.2 , with that of SARS-2-S (S1C Fig). As reported, the Omicron BA.1 variant showed significantly weaker fusogenic activity than SARS-2-S [26] (5× reduction). The fusogenic capacity of BA.5 (1.2× reduction), BA.2.75 (1.7× reduction), and BA.2.75.2 (1.7× reduction) was modestly lower than that of SARS-2-S [27,28]. Notably, the percentage of SA-β-gal-positive syncytia was comparable to that of SARS-2-S, although they formed more slowly (Fig 1F and 1G). .....
Here's where it gets REALLY concerning: Extracellular vesicles—little packets, emitted by cells, containing a protein or some other type of small molecule—have been found carrying the S protein in patients' blood long after initial infection...

11/ "SARS-2-S delivery by EVs or mRNA confers the ability to trigger syncytial senescence Since SARS-2-S was shown to be incorporated into extracellular vesicles circulating in patient blood [29], we then asked if SARS-2-S protein internalization by S-EVs has the ability to trigger syncytium formation and cell senescence in an FFWO-dependent manner. To this end, we first used ultracentrifugation to purify EVs from the supernatant of HeLa- or SARS-2-Sexpressing HeLa cells and confirmed their identity by probing for exosome markers and the EVs were normalized by NTA (S2A-S2C Fig). We next l...
...and they found that these extracellular vesicles, once taken up by a cell, can cause the cell to fuse to another ACE2-expressing cell.

The fused cells then showed signs of senescence (including increased transcription of TNF, IL6, IL8, and CDKN1A genes).

Not great!

12/ "SARS-2-S delivery by EVs or mRNA confers the ability to trigger syncytial senescence ... These cells fused with cells expressing ACE2 at 8 hpc, as indicated by the appearance of multinucleated cells (Fig 2A). Importantly, the fused cells exhibited enhanced SA-ß-gal and p21 staining, with increased transcription of the TNF, IL6, IL8 and CDKN1A genes (Fig 2B), features that are typical of senescence."
What about the mRNA vaccines—they produce a spike protein, so can they also cause this problem? Nope!

The spike design used in the vaccines has a couple of tweaks to make it more stable, and those changes prevent it the vaccine-based spike protein from causing cell fusion!

13/ "Since COVID-19 mRNA vaccines, including Pfizer and Moderna, express S protein antigen by delivering SARS-2-S mRNA, we next asked whether SARS-2-SwT and S-protein-based vaccine (SARS-2-Sv) delivered in the form of encoding mRNA would trigger syncytium formation and cell senescence (S3A Fig). Previous study indicated, compared to SARS-2-SwT, two prolines were added to stabilize the structure's prefusion shape of S-protein in COVID-19 vaccine, this mutation greatly reduces cell fusion of COVID-19 vaccine. ... ... We did not observe syncytial cells formation, signs of senescence and sign...
To be really sure that the S protein can cause this type of syncytial senescence to occur in real organs, they injected mice with a virus that causes them to express human ACE2 in their livers.

When injected with the wild S protein, it induced senescence in their livers!

14/ "Finally, we explored whether cell senescence related to SARS-2-S-mediated cell fusion would also occur in vivo. To this end, we injected AAV-hACE2 constructs into the tail veins of 8-week-old C57BL/6] mice to drive mainly hepatic hACE2 expression. Four weeks later, we intramuscularly administered a single dose of S-mRNA-LNP or LNP to hACE2-expressing mice and examined the induction of senescence. Immunohistochemical analysis revealed robust SARS-2-S expression and the increased appearance of multinucleated cells with at least four nuclei in the livers of S-mRNA-LNP-treated mice compar...
Next up, they looked at mitochondrial regulation.

Long story story, MAVS (mitochondrial antiviral signaling) proteins, which detect foreign double-stranded RNA, cause mitochondrial senescence in response to the SARS-2-S syncytia.

15/
"These data suggest the involvement of RIG-I, the primary sensor of nonself-derived dsRNA [this means it detects double-stranded RNA of a foreign-source (e.g. from a virus)], in functional MAVS aggregation in SARS-2-S syncytia." --- "SARS-2-S syncytia provoke the formation of functional MAVS aggregates ...We then focused on mitochondrial antiviral signalling adaptor protein (MAVS), a mitochondrial adaptor protein that links the cytoplasmic RNA sensor RIG-I to its downstream signalling molecules by forming well-ordered prion-like aggregates. .... Furthermore, MAVS aggregat...
"Fig 3. SARS-2-S syncytia induce the RIG-I-dependent formation of functional MAVS aggregates. Confocal microscopic images of MAVS and mitochondria in A549 cells infected with VSV or A549 cells cocultured for the indicated times. Red, MitoTracker staining for mitochondria; green, MAVS staining; blue, DAPI staining. A magnified view of the boxed region is also shown. Scale bars represent 10 um (whole image) and 1 um (magnified)."
Jumping ahead a bit, they found that "senescent SARS-2-S syncytia exhibit [shrunken] morphology, leading to the activation of WNK1," which is a molecule involved in regulating cell senesence.

It is activated by the fused cells losing their volume.

16/ "...Previous study indicated that with-no-lysine (WNK) kinasel is a molecular crowding sensor that undergoes cell shrinkage-dependent phase separation to restore cell volume, the shrinkage of senescent SARS-2-S syncytia made us wonder whether WNK1 was activated [41]. Notably, we observed a significant shift of WNK1 from a diffuse to punctate distribution in senescent SARS-2-S syncytia of A549 and AC16 cells (Fig 5E-5I), but not in those cells treated with palbociclib (Fig 5J-5M). This phase behaviour appeared as early as 12 hpc in AC16 cells (Fig 5E). Accordingly, WNK1-triggered SPAK p...
They found WNK1 activation led to significantly decreased "mitochondrial oxidative capacity of the cocultured cardiomyocyte"

But "inhibition of WNK1 via WNK463 [which prevents down-regulation of metabolic enzymes] was sufficient to rescue impaired mitochondrial respiration"

17/ "So, we try to study energy metabolism of cardiomyocytes syncytia whether dependent on WNK1 activation [42,43]. We next explored the possibility that senescent SARS-2-S syncytia in cardiomyocytes with WNK1 activation might contribute to impaired metabolism in the setting of heart dysfunction. Compared to non-fusion controls, the mitochondrial oxidative capacity of the cocultured cardiomyocytes was significantly decreased at 48 hpc as indicated by reduced basal respiration, ATP-linked respiration, spare respiratory, and maximal respiration (Fig 6A and 6B). In addition, these senescent c...
Jumping ahead again, we're getting to the headline experiments.

They administered the SARS-2-S protein to some mice that express the human ACE2 receptor, and syncytia formed, as expected.

18/ "Senescent SARS-2-S syncytia exacerbated heart failure To assess whether senescent SARS-2-S syncytium stimulates heart dysfunction in vivo, K18-hACE2 mice were administered with pseudovirus expressing BA.5 spike (SARS-2-Spp) intravenously. Mice were euthanized on the fifth day.... The results showed that the presence of cardiomyocyte syncytia in the hearts of mice infected with the SARS2-SpP. Additionally, fluorescence staining showed that cellular senescence in syncytia expressing the S protein. On the eighth day post administered, mice were performed heart function tests, then eutha...
They concluded that "SARS-2-S promotes fibrosis without causing baseline cardiac abnormalities," and in the mice with pre-existing heart failure, it "exacerbated heart failure progression"

"fibrosis without causing baseline cardiac abnormalities"... not great!

19/ "Functional analysis of hearts, including ejection fraction (EF), fractional shortening (FS), left ventricular internal dimension at end diastole (LVID;d), left ventricular internal dimension at end-systole (LVID;s), as well as serum brain natriuretic peptide (BNP) levels between the two groups were also comparable. Thus, SARS-2-S promotes fibrosis without causing baseline cardiac abnormalities during 7 observational days. We then repeated the above experiment with intraperitoneally (i.p.) injected isoproterenol (ISO) to assess the impact of SARS-2-Spp on cardiac function in mice with ...
Finally, they examined if WNK1 inhibition can "alleviate heart failure exacerbated by SARS-2-S through rescuing metabolic dysfunction." They found positive results, "further supporting the notion that senescent SARS-2-S syncytia contribute to exacerbated heart failure."

20/ "We then wanted to test if WNK1 inhibition by WNK463 can alleviate heart failure exacerbated by SARS-2-S through rescuing metabolic dysfunction. ... Therefore, WNK1 intervention can effectively protect the heart from exacerbated heart failure triggered by SARS-2-S. Additional, to further prove that senescence SARS-CoV-2 syncytia act as a central pathogenic principle provoking heart failure, we attempted to eliminate senescent cells or inhibit fusion by using the senolytic drug dasatinib or the anti-syncytial drug niclosamide. Intriguingly, the administration of dasatinib and niclosamid...
What do they conclude?

The S protein can contribute to heart failure. This is important for acute infections AND long-term complications, because the "persistence of circulating SARS-2-S protein ... increase the likelihood of cell-cell fusion in uninfected cells."

21/ "Discussion ... the SARS-2-S protein mediates fusion between the viral and cellular membranes during particle entry, fusion with uninfected cells and FFWO. ... Here, we directly linked SARS-2-S-triggered syncytium formation with ... its pathophysiological contribution to heart failure progression. We found that both SARS-2-S expression and SARS-2-S protein internalization were sufficient to induce senescence in non-senescent ACE2-expressing cells. In particular, mRNAs-SARS-2-S injection provoked pathways ... in vivo. This was not only important for acute SARS-CoV-2 infection, but the ...
They also note that syncytia expressed senescence-related cytokines, including TNF-alpha, IL-6, and IFN-gamma, among others, and these seem related to the metabolic regulation.

22/ "Nevertheless, we provide evidence of the contribution of RIG-I-MAVS to the regulation of SARS-2-S syncytium fate through TNFa. Using multiplex protein analysis, we identified a burst of SASP-related cytokines, including TNFa, IL-6, IFN-y, and others, in the hACE2 mouse model injected with SARS-2-S mRNA. Although the exact contribution of each cytokine to SARS-2-S syncytium survival and senescence remains unclear, we provide evidence that the central regulation of SARS-2-S syncytium survival and senescence may be dependent on TNFa. Previous studies reported that TNFR2 interacts with th...
And, importantly, the mRNA vaccines CANNOT cause cellular senescence using this mechanism, as they have a couple of mutations which "effectively inhibit the formation of syncytia, mitigate cellular senescence, and prevent the release of" senescence-relate signals.

23/ "Our results have also revealed that the S sequence derived from the COVID-19 mRNA vaccine which harbors mutations in two proline residues. These mutations effectively inhibit the formation of syncytia, mitigate cellular senescence, and prevent the release of SASP. This finding corroborates prior research, affirming that the unique design of the mRNA vaccine mitigates syncytia formation, thus enhancing its safety. Moreover, our findings emphasize the necessity of optimizing vaccine sequences to mitigate the risk of syncytia formation in vaccine design."
Because patients with heart failure show elevated ACE2 expression, while those with Long COVID exhibit "persistent circulating SARS-2-S and EVs harboring SARS-2-S," this combination "may increase the likelihood of syncytium formation."

24/ "With the progression of COVID-19, heart failure appears to be a potential hazard due to SARS-CoV-2 infection, chiefly in elderly patients with hypertension, ischaemic heart disease, and diabetes mellitus. Patients with basic heart failure disease showed elevated ACE2 expression, whereas patients with PACS exhibited persistent circulating SARS-2-S and EVs harbouring SARS-2-S. High ACE2 expression and long SARS-2-S duration may increase the likelihood of syncytium formation. Moreover, the pre-existing inflammatory environment with older age or with chronic disease, especially those with...
This is very much a basic research paper and doesn't have anything directly *usable* in clinical practice. However, it really illuminates the pathophysiology of cardiac complications of SARS-CoV-2 infection—EVEN ASYMPTOMATIC INFECTIONS.

Paper:

25/25journals.plos.org/plospathogens/…
AFAIK, it’s totally a non-issue with the non-mRNA vaccines, because they don’t even have a full spike protein.

And I think their statements about how mRNA vaccines with a different design could have more complications was a veiled reference to one of China’s vaccines

26/25
No idea what to do about denialism at this point, other than continuing to educate and hope it gets through!

That's the goal with my threads: Hopefully, they can help give people the knowledge and language they need to discuss the science directly!

27/25
At this point, it's a *potential* treatment that still needs further study, but it's a solid lead!

- Inhibiting the *WNK1 molecule* with a *WNK463 molecule* is the new option uncovered here
- Two existing preventative drugs should be investigated

28/25

WNK1 inhibition (using WNK463) is the potential new drug target to investigate. Other drugs to investigate include: • the anti-syncytial drug niclosamide • the senolytic (drug that may selectively kill senescent cells) dasatinib as a protective measure against heart failure exacerbation triggered by the SARS-2-S protein.
Glad you asked, because I was conflating previous vector vaccines with ones under development!

It seems that Novavax and Janssen use the same STABILIZED spike protein as Pfizer and Moderna:

But oddly enough...

29/25
pubs.acs.org/doi/10.1021/ac…

Janssen: "a stabilized variant of the SARS-CoV-2 spike (S) protein."
...it seems that a bunch of Russian viral vector vaccines—and AstraZeneca—used the regular spike protein!?

So that kind of explains the issues with the AstraZeneca vaccine! Weird.

30/25 ncbi.nlm.nih.gov/pmc/articles/P…

AstraZeneca: "containing S protein gene of coronavirus"
CanSino, Gam-COVID-Vac, and Sputnik Light: "the SARS-CoV-2 protein S gene"

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More from @NickAnderegg

Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Aug 4
New preprint on the PATHOGENICITY of H5N1 was published yesterday, and... it's not good news, but it's definitely not *terrible* news either!

The delayed, lackluster response to the current outbreak remains DEEPLY concerning.

Here's a summary for a general audience!

1/many
Preprint published August 3, 2024: "Enhanced replication of contemporary human highly pathogenic avian influenza H5N1 virus isolate in human lung organoids compared to bovine isolate" Abstract "We compared virus replication and host responses in human alveolar epithelium infected with highly pathogenic avian influenza (HPAI) H5N1 viruses. A/Vietnam/1203/2004 replicated most efficiently, followed by A/Texas/37/2024, then A/bovine/Ohio/B240SU342/2024. Induction of interferon-stimulated genes was lower with A/Texas/37/2024 and A/bovine/Ohio/B24OSU-342/2024, which may indicate ...
They test three H5N1 isolates. I'll refer to them as:

- Texas: Isolated from worker at Texas dairy farm (A/Texas/37/2024)
- Bovine: Isolated from dairy cow (A/bovine/Ohio/B24OSU-342/2024)
- Vietnam: Isolated from fatal 2004 human infection in Vietnam (A/Vietnam/1203/2004)

2/
"As of July 25, 2024, 13 human cases of HPAI H5N1 virus infection have been confirmed in the United States (3). Several of these cases are linked to exposure to infected cattle. However, recent outbreaks in Colorado have resulted in identification of additional human cases linked to infected poultry (3). Virus isolated from a worker at a Texas dairy farm (A/Texas/37/2024) was shown to be closely related to viruses circulating in cattle, and it is presumed that this case is a result of direct cow-to-human transmission (4). Reported symptoms included conjunctivitis, as well as mild respi...
"This is in stark contrast to prior cases of HPAI H5N1 virus infection in humans, which resulted in severe respiratory disease and mortality rates upwards of 50% (6). In order to assess the risk of developing severe disease following infection with contemporary HPAI H5N1 virus, we evaluated virus replication, host cell survival, and induction of innate immune responses in human alveolar epithelium infected with A/Texas/37/2024 or cattle isolate A/bovine/Ohio/B24OSU-342/2024, compared to a historical H5N1 isolate A/Vietnam/1203/2004, which was derived from a fatal human case (7)."
This study looked at pathogenicity, which is, basically, the ability of a virus to fuck up your cells, organs, or body, as determined by some measurable indicator of damage.

It's one of those concepts that's so broad that it's useful to include a formal definition:

3/
NIH > National Library of Medicine MeSH (Medical Subject Headings) Virulence (synonym-ish for "pathogenicity") The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenic capacity of an organism is determined by its VIRULENCE FACTORS.
NIH > National Library of Medicine MeSH (Medical Subject Headings) Virulence (Preferred): The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenic capacity of an organism is determined by its VIRULENCE FACTORS. Pathogenicity (Related): The capacity of a microorganism to cause disease.
Read 17 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Aug 4
This isn't a major paper, but it's an interesting jumping-off point for three different topics:

- Accuracy of RATs—in practice
- Understanding what descriptive (incl. Bayesian) statistics mean
- HOW rapid tests work

Here's a thread written for a general audience!

1/ Published Aug 2, 2024 in PLOS ONE: "Evaluation of COVID-19 rapid antigen test against polymerase chain reaction test in immunocompromised patients" Abstract: "... Patients with Ct value less than 20, had the highest detection rate which is consistent with other studies in the literature. The sensitivity and specificity of Panbio Rapid Antigen testing were of 69.9% and 100%, respectively. A correlation between age group and false negative results could not be made, but a correlation between Ct value and false negative result was noticed, Ct value was directly related to false...
This study was conducted from January 2020 to June 2021 using admission screening swabs from 556 oncology patients at a single hospital in Jerusalem.

The patients in this study were swabbed for both PCR and RAT, allowing for comparison of the detection ability.

2/ "Materials and methods Study design This prospective study was conducted on 556 patients evaluated at Augusta Victoria Hospital (AVH) between January 2020 and June 2021. Patients’ age range was from 1 month to 90 years of age with an average age of 41.8 years. Of the 556 patients, 481 (86.5%) were adult patients and 75 (13.5%) were pediatric patients. with an overall male to female ratio of 1:1.04. Patients arriving at AVH with any signs of respiratory symptoms, were simultaneously evaluated for the presence of SARS-CoV-2 antigens by Panbio TM COVID-19 Ag Rapid Test Device and for th...
The takeaway is simple: The Rapid Antigen Test (RAT) used here had a sensitivity of 69.6%.

Sensitivity is the *true positive* rate. This means that, out of the patients who tested positive for SARS-CoV-2 using qRT-PCR testing, only 69.6% were *also* positive on the RAT.

3/ "Results Panbio TM COVID-19 Test Device clinical sensitivity and specificity Of the 556 patient’s analyzed NPS, 112 (20.1%) samples were positive by the Allplex TM SARSCoV-2 Assay, while 78 (16.3%) were positive by the Panbio TM COVID-19 assay. Thirty-four samples were negative by Panbio TM COVID-19 Ag Rapid Test Device and positive by the Allplex TM SARS-CoV-2 Assay. Thus, the overall sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were, 69.6%, 100%, 100%, and 92.9%, respectively." --- Characteristics of Panbio Rapid Antigen Test ...
Read 25 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jul 29
Let me start by saying AAAAAAAAAAAAAAAAAAAAAA.

Turns out SARS-CoV-2 RAPIDLY infects the NERVOUS SYSTEM long BEFORE it even enters the bloodstream.

These findings have huge implications! Here's an analysis of the study, written for a general audience. (Sorry in advance!)

1/many Published July 28, 2024 in IJMS: "SARS-CoV-2 Rapidly Infects Peripheral Sensory and Autonomic Neurons, Contributing to Central Nervous System Neuroinvasion before Viremia" Abstract: "...little attention has been paid to susceptibility of the PNS to infection [by SARS-CoV-2] or to its contribution to CNS invasion. Here we show that sensory and autonomic neurons in the PNS are susceptible to productive infection with SARS-CoV-2 and outline physiological and molecular mechanisms mediating neuroinvasion. Our infection of K18-hACE2 mice, wild-type mice, and golden Syrian hamsters...
Overall, it's pretty extensive: They examined the productivity of neuronal infection in multiple animal models and multiple neuronal cell cultures, and found productive neuronal infection across the board.

It's also a long one, but we'll pick up the pace as we go!

2/ Figure 3. SARS-CoV-2 infection of the olfactory bulb and various brain regions in hACE2 and WT mice. SARS-CoV-2 RNA was detected in increasing concentrations from 3 to 6 dpi in the olfactory bulb (a), hippocampus (b), cortex (c), brainstem (d), and cerebellum (e) of hACE2 and WT mice in both inoculum groups.
So, as you may already know, neurological symptoms are actually VERY common when it comes to COVID, with several different types of neurological issues being notable features of Long COVID. There's seriously so much evidence beyond these 13 citations!

3/ "Up to 80% of people infected with SARS-CoV-2, the virus responsible for COVID-19, report neurological symptoms. ... including [with] sensory and autonomic systems [1–3]. Both central and peripheral symptoms, such as fatigue, memory issues, “brain fog”, hyper/hypoesthesia, and autonomic dysfunction, can persist as part of postCOVID-19 syndrome (“long COVID”) long after acute infection [4]. Detection of the virus, viral RNA, and antigens in the cerebrospinal fluid and brains of COVID-19 patients indicates SARS-CoV-2 is neuroinvasive, which has also been documented for common cold and ep...
Read 37 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jul 28
Big picture, these findings are bad for EVERYBODY, but ESPECIALLY for those still clinging to the fantasy of "natural immunity."

The takeaway? It's unclear if ANYONE has strong immunity to COVID infection!

Here's a deep analysis thread, written for a general audience!

1/many Published July 26, 2024 in Nature Medicine: "SARS-CoV-2 correlates of protection from infection against variants of concern" Abstract: "Serum neutralizing antibodies (nAbs) induced by vaccination have been linked to protection against symptomatic and severe COVID-19. However, much less is known about the efficacy of nAbs in preventing the acquisition of infection, especially in the context of natural immunity and against SARS-CoV-2 immune-escape variants. Here we conducted mediation analysis to assess serum nAbs induced by prior SARS-CoV-2 infections as potential correlates ...
The paper is fairly complex, but the takeaways are pretty straightforward, so I'll start with the highlights!

Method is robust, data collection was EXTENSIVE: It's a longitudinal study (follows the same individuals over time) with regular nasal swabs and blood draws!

2/ Figure 1: "Timing of cohort sample collections with respect to SARS-CoV-2 variants’ circulations in the two study sites. a, Timing of the blood draws with respect to the SARS-CoV-2 epidemic waves in the rural site (Agincourt) of the PHIRST-C cohort. The bar plot represents the weekly incidence (per 100,000 population) of SARS-CoV-2 cases from routine surveillance data collected from the Ehlanzeni district in the Mpumalanga province (where rural participants reside). The shaded areas represent the timing of the serum sample collections for the ten blood draws. Each curve within the shad...
Because they have blood draws from just before each wave, it's the perfect data to examine the immunity conferred by prior infections.

Because South Africa had a low vaccination rate at the beginning of Omicron, this is also great data for examining natural immunity!

3/ [Note: The 1st wave (Alpha) is referred to as D614G throughout the paper. The 4th wave (Omicron) is referred to as Omicron.] "This high-intensity sampling scheme allowed us to reconstruct the cohort participants’ SARS-CoV-2 infection histories with high fidelity, and to monitor infection-induced antibody responses over time. Blood samples collected immediately before Delta and Omicron waves offered a unique opportunity to investigate serum immune marker levels in close proximity to the next SARS-CoV-2 exposure. Furthermore, vaccine-derived immunity remained low at the onset of the Omi...
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Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jul 24
This preprint seems HUGE: It has CONCRETE DIAGNOSTIC CRITERIA for a specific subtype of LC!

The novel disease identified here is named "SARS-CoV-2 Persistent Intestinal* Epithelial Syndrome (SPIES)"!

Gastrointestinal LC has a new name! Thread, for a general audience...

1/20 Identification of SARS-CoV-2 Persistent Intestinal* Epithelial Syndrome (SPIES) as a Novel Disease Entity using Clinical, Histologic, and RNA Programmatic Data The "Infectious" in the title is a typo, as they use "Intestinal" in the rest of the paper. I guess they were also excited to get it posted!
I love this preprint because, not only does it make a specific subtype of LC into a tangible medical artifact, but it also identifies the way in which SPIES differs from similar conditions, like IBS!

2/
GI issues following a COVID infection have been known for a long time, and gastrointestinal Long COVID is one of the more prevelant issues among the total population.

Because there is the possibility of viral persistence, that's what they examined here.

3/ "... The impact of gastrointestinal LC has been substantial, and to date is relatively poorly understood. Prior work has identified a trend towards increasing pediatric inflammatory bowel disease (IBD) since the emergence of COVID', , the ability of SARS-CoV-2 to persist in the gut?, 3, as well as increased risk of liver disease, demonstrating capacity of this infection to induce durable gastrointestinal complications. Overall, 10-25% of patients report Gl symptoms (nausea, anorexia, weight loss, diarrhea, hematochezia) 6 months following infection'. Given previous work suggesting rate...
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Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jul 23
FIRST: This paper DOES NOT HAVE CLINICAL VALUE. It is NOT about treatment!

With that out of the way: WOW, WOW, WOOOW.

"After six years, 44.1% of the [ME/CFS patients treated with cyclophosphamide] scored an SF-36 PF of at least 70, and 17.6% of at least 90..."

Summary ⬇️

1/13 CAVEAT: These findings have NO practical use outside of a research setting! "Cyclophosphamide... should not be used for ME/CFS patients outside of clinical trials." Conclusions: "After six years, 44.1% of the cyclophosphamide group scored an SF-36 PF of at least 70, and 17.6% of at least 90, suggesting that cyclophosphamide in a subgroup may modulate the disease course in a beneficial way. However, cyclophosphamide carries toxicity concerns and should not be used for ME/CFS patients outside clinical trials. Rather, these data should encourage efforts to better understand th...
The clinical trials (conducted last decade) were based on the hypothesis that a subset of ME/CFS patients are experiencing an autoimmune condition; this study is the six-year follow-up!

The interesting result here is the impact of cyclophosphamide (from the CycloME trial)

2/ Six-year follow-up of participants in two clinical trials of rituximab or cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Abstract: "Objectives In this six-year follow-up study, we used patient-reported outcome measures (PROMs) to compare values at baseline, at 18 months, and at six-year follow up from the CycloME and the RituxiME trials. Methods Based on the hypothesis that ME/CFS in a subgroup of patients is a variant of an autoimmune disease, we performed two clinical trials between 2014 and 2017. The RituxVE trial was a randomized, double-blind and place...
Here's the major takeaway: "In the CycloME trial, mean SF-36 PF increased from 35.4 at baseline to 54.4 at 18 months, and 56.7 at six years."

At six years, 44% of the CycloME group had an SF-36 PF ≥ 70, and 18% had an SF-36 PF ≥ 80 "which is within normal range."

3/ Abstract: "Result Of the patients available after six years, 75.7% of RituxME and 94.4% of CycloME patients participated. In the RituxME rituximab group, the mean SF-36 PF scores were 32.9 at baseline, 42.4 at 18 months and 45.5 at six years. In the placebo group, the mean SF-36 PF scores were 32.3 at baseline, 45.5 at 18 months and 43.1 at six years. In the CycloME trial, mean SF-36 PF increased from 35.4 at baseline to 54.4 at 18 months, and 56.7 at six years. At six-year follow-up, 44.1% of cyclophosphamide-, 27.6% of rituximab- and 20.4% of placebo-treated patients had an SF-36...
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