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Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
@NickAnderegg
Jul 7 • 28 tweets • 10 min read • Read on X
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GUESS WHAT?! A new study has shown SARS-CoV-2 infection is DISTINCT from common respiratory viruses!

Unequivocally, COVID is NOT "just a cold."

These findings are HUGELY significant, for multiple reasons! Here's a breakdown of the study (written for a general audience)...
1/16 SARS-CoV-2 infections—both symptomatic and asymptomatic—produce distinct host immune responses compared to human rhinovirus infections (the common cold), influenza virus infections, and RSV infections. That is, SARS-CoV-2 induces a set of changes in gene expression with significantly higher magnitude of change compared to other common respiratory viruses. For each of the four viruses, the column on the left shows differential gene expression (relative to controls) for symptomatic infections, while the column on the right shows differential gene expression for asymptomatic infections. Note...
The paper is fairly complicated, so I'm going to start with the high-level takeaways before explaining everything in more detail.

Overall, they found a 3-gene signature that distinguishes SARS-CoV-2 infections from common viral infections—long before PCR test positivity!

2/ A T-Cell-Derived 3-Gene Signature Distinguishes SARS-CoV-2 from Common Respiratory Viruses Abstract: ..., we performed a multi-cohort analysis with integrated bioinformatics and machine learning. We collected 3730 blood samples from both asymptomatic and symptomatic individuals infected with SARS-CoV-2, seasonal human coronavirus (sHCoVs), influenza virus (IFV), respiratory syncytial virus (RSV), or human rhinovirus (HRV) across 15 cohorts. First, we identified an enhanced cellular immune response but limited interferon activities in SARS-CoV-2 infection, especially in asymptomatic cases. Se...
Because the signature:

1. is SPECIFIC to SARS-CoV-2,
2. is an EARLY indicator of infection,
3. is a DISTINCT pattern from other infections, and
4. even accurately identifies Omicron infections,

this discovery may be useful as a diagnostic tool AND a direction for treatment!

3/ "The 3-gene signature offered two major improvements to SARS-CoV-2 infection triage: specificity and early diagnostic power. ...showed superior diagnostic performance only in SARS-CoV-2 ... achieved excellent diagnostic performance in Omicron patients ... showed exceptional performance to identify SARS-CoV-2 infection before detectable viral RNA on RT-PCR testing.... ... The bioinformatics methods, including DEGs and WGCNA, provided biological insights into the stable SARS-CoV-2 specific candidate genes. The machine learning approaches on these candidates offered a better extrapolation po...
One of the major limitations of this study is that it's unknown how applicable this signature will be for immunocompromised individuals. Why?

Because T cells were the major source of this 3-gene signature being expressed! This is important, because...

4/ "Hence, we could not assess how the 3-gene signature would perform in patients with comorbidities, especially immune system-related disorders. Future studies validating the 3-gene signature should focus on addressing these limitations. In summary, our study aimed to uncover the unique pathogenesis of COVID-19 by investigating the differential host responses to prevalent viruses. We systematically identified a SARS-CoV-2-specific 3-gene signature that could independently distinguish asymptomatic and symptomatic individuals infected with SARS-CoV-2 from other respiratory viral infections. ...
This is YET ANOTHER study showing SARS-CoV-2 adversely impacts the immune system.

Monocyte abnormalities (decreases) were found in BOTH symptomatic and asymptomatic SARS-CoV-2 infections! Because monocytes INCREASE in normal immune response, this suggests monocyte infection!

5/ "In addition, the results of CIBERSORTx revealed a reduced level of monocytes in SARS-CoV2 infection, while other viruses introduced an elevated level of monocytes, especially in the symptomatic group (Figure 3A). SARS-CoV-2-related monocytic abnormalities have been observed in both symptomatic [53] and asymptomatic cases [17]. The possible mechanism might be that the monocytes could be directly infected with SARS-CoV-2, leading to pyroptosis [54]. Moreover, attention should be paid to the boosted levels of IFNG and TNF in COVID-19 (Figure 3B), as synergism of TNF-α and IFNG triggers i...
This study also found the same odd immune response patterns found by other studies: The immune system is STRONGLY activated (especially the inflammatory response), but the pathway responsible for signaling *targeted* attacks on infected cells is suppressed!

6/ "Host responses resulting in SARS-CoV-2 infection differed from several common respiratory viruses. These results were in line with previous in vitro studies [9] (Figure S5). Although part of ISGs (i.e., IFI27) were enhanced in SARS-CoV-2 infection (Figure 2A), moderate IFN responses have been a sign of COVID-19 (Figure 2C). The improved cellular immune response, such as strong T cell responses and high secretion of TNF, were observed, surprisingly in these asymptomatic subjects (Figures 2 and 3). It has been reported that asymptomatic SARS-CoV-2-infected individuals might develop an effi...
As shown in Figure 2C, BOTH symptomatic and asymptomatic SARS-CoV-2 activate identical cellular pathways, but with less inflammatory signaling for asymptomatic infections.

That is, even asymptomatic SARS-CoV-2 impacts processes usually unaffected by the other studied viruses!
7/ Figure 2C from the paper. This shows the pathways implicated by "differentially expressed genes" in symptomatic and asymptomatic cases of different viral infections. This shows that for both asymptomatic and symptomatic SARS-CoV-2 infections, there are many different cellular pathways that are strongly activated; there is usually much less activation of these pathways for HRV, IFV, and RSV in *symptomatic* infections than there is for SARS-CoV-2 in *asymptomatic* infections. This isn't good news. It suggests that the impacts of asymptomatic infections are likely similar to sympto...
This study strongly suggests that there are "distinct molecular mechanisms" at play during SARS-CoV-2 infections, relative to other common respiratory viruses.

It *unambiguously* shows, however, that even asymptomatic SARS-CoV-2 infections are NOT "just a cold."
8/ "Discovery and validation of SARS-CoV-2-specific host response genes have been calling [26]. To address this issue, an ideal dataset for biomarker discovery should include not only SARS-CoV-2 infections but also other respiratory infections (Figure 4). Therefore, we co-normalized datasets HRA000786 and GSE17156, which included both asymptomatic and symptomatic cases. With integrative bioinformatics and machine learning approaches, we identified that the combination of CLSPN, RBBP6, and CCDC91 was robustly associated with SARS-CoV-2 infection in both discovery and validation datasets. Col...
The authors validated their discovery with a longitudinal study that was able to detect even asymptomatic Omicron infections with high accuracy, long before a given patient is able to test positive with RT-PCR testing.

9/ "Research on the host responses to respiratory viruses could help develop effective interventions and therapies against the current and future pandemics from the host perspective. Here, we leveraged the substantial biological, clinical, and technical heterogeneity in publicly available respiratory virus datasets and identified a 3-gene (CLSPN, RBBP6, and CCDC91) host response signature for identifying the SARS-CoV-2 infection at either an asymptomatic or symptomatic stage. We validated this 3-gene signature in an independent longitudinal follow-up study and demonstrated that it performs ...
That's all the highlights! The study is Open Access and available at

The rest of this thread is going to be commentary/analysis of the details of the study...
10/16mdpi.com/1999-4915/16/7…
So what role do these genes play?

It seems to be a cascade that highjacks the innate and adaptive immune responses in a way that's advantageous for the SARS-CoV-2 virus itself. That's not to say that the virus *directly* increases expression of these genes...

11/ "We proposed that the upregulation of CLSPN, RBBP6, and CCDC91 by SARS-CoV-2 in T cells might create a cascade of effects that alter both the innate and adaptive immune responses. First, CLSPN plays a significant role in genomic stability during DNA replication [56]. ... CLSPN might help T cells manage the stress and damage induced by viral replication. Second, ... RBBP6 is involved in cell cycle regulation, apoptosis, and ubiquitination processes [58]. RBBP6 has been reported as a negative regulator of Ebola virus replication by mimicking the viral protein [59]. ... RBBP6 might preven...
Rather, these are the common product of the cascade of dysfunctional processes triggered by SARS-CoV-2 infection. This study identified a unique signature of *differentially expressed genes*, but there's not a 1:1 cause and effect for differential expression of a given gene!

12/ "Although there is limited specific information on the expression changes of CCDC91 in response to viral infections, CCDC50, a related gene to CCDC91, negatively regulated the type I IFN signaling pathway initiated by RIG-I-like receptors (RLRs), the sensors for RNA viruses [60]. Together, these genes may in concert with T cells not only respond to viral infections effectively through cellular immunity but also regulate the immune response to avoid excessive inflammation or autoimmunity. Further experimental validation and research would be essential to elucidate these proposed mechanisms...
The methods were thorough, in that they cross-validated all of their findings multiple ways to ensure they weren't picking up on some spurious signal in the data. Even if the genes turn out not to be meaningful for *pathogenesis*, they're VERY meaningful for *diagnosis*!

13/ Image
IMO, there's one big error. Figures 2A and 2B have slightly different Y-axes, likely because the graphs were generated separately, but it actually has the effect of shrinking a range that is *unexpectedly* larger.

I aligned the scales on Figures 2A and 2B here

14/ Image
When symptomatic and asymptomatic gene expression for each virus are put side by side, it's clear that SARS-CoV-2 has a wildly different pattern compared to the other viruses, and a vastly larger magnitude of effect.

Differential expression INCREASES in asymptomatic covid?!

15/ SARS-CoV-2 infections—both symptomatic and asymptomatic—produce distinct host immune responses compared to human rhinovirus infections (the common cold), influenza virus infections, and RSV infections. That is, SARS-CoV-2 induces a set of changes in gene expression with significantly higher magnitude of change compared to other common respiratory viruses. For each of the four viruses, the column on the left shows differential gene expression (relative to controls) for symptomatic infections, while the column on the right shows differential gene expression for asymptomatic infections. Note...
Most notably, T cells are the PRIMARY type of cell where the 3-gene signature is most differentially expressed... and it's specifically a pattern that will lead to T cell exhaustion through overactivation.

Say it with me: "COVID is airborne and exhausts T cells!"

16/end 3.4. T Cells Are the Primary Source of the 3-Gene Signature We used single-cell RNA sequencing (scRNA-seq) profiles of 15,639 cells from PBMC samples of 7 individuals (4 SARS-CoV-2 infections, 3 Controls) to identify the cell types that express the 3-gene signature. Visualization using UMAP illustrated the infection status (Figure 5A) followed by cell type (Figure 5B). T cells had the highest scores (Figure 5C), and 3-gene signature scores were significantly higher in T cells from patients with SARS-CoV-2 infection (Figure 5D), especially in activated CD4 T cells, mucosal-associated invarian...
Afterthought: The bit about “discovery should include not only SARS-CoV-2 infections but also other respiratory infections” is an echo of another paper about HCoV-OC43… from 1980! There, the author also complained about lack of dataset diversity



17/16
Discovery and validation of SARS-Co V-2-specific host response genes have been calling 26]. To address this issue, an ideal dataset for biomarker discovery should include not only SARS-CoV-2 infections but also other respiratory infections (Figure 4). Therefore, we co-normalized datasets HRA000786 and GSE17156, which included both asymptomatic and symptomatic cases. With integrative bioinformatics and machine learning approaches, we identified that the combination of CLSPN, RBBP6, and CCDC91 was robustly associated with SARS-CoV-2 infection in both discovery and validation datasets. Collect...
I’m not sure if it would, because at least one of the genes is involved in one type of cell entry, and there’s evidence that persistent infections may use *different* methods to move between cells that possibly wouldn’t engage that gene!

18/16
2. Lots of things can cause lymphopenia! () It's just usually *temporary* with most non-HIV causes.

1. Like the HIV patients on death's door in the 90s, who are alive today thanks to HAART, recovery may be possible

19/16
en.wikipedia.org/wiki/Lymphocyt…

The most common cause of temporary lymphocytopenia is a recent infection, such as the common cold.[citation needed] Lymphocytopenia, but not idiopathic CD4+ lymphocytopenia, is associated with corticosteroid use, infections with HIV and other viral, bacterial, and fungal agents, malnutrition, systemic lupus erythematosus,[3] severe stress,[4] intense or prolonged physical exercise (due to cortisol release),[5] rheumatoid arthritis, sarcoidosis,[6] multiple sclerosis,[7] and iatrogenic (caused by other medical treatments) conditions. Lymphocytopenia is a frequent, temporary result from man...
Simply put, if the cause of dysregulation is removed, the immune system can *likely* recover.

Time is the enemy, in this case! Cancer is a huge concern here, because without immune cells, cells with defective DNA will be ignored and grow into tumors
20/16
Opportunistic infections are the biggest concern with a compromised immune system (lack of defenses), but when an individual has effectively zero immune system, the body isn't able to perform basic janitorial tasks that clean up random defective processes!

21/16
Sure! Here's a meta-annotated version of the graph with simplified explanations of each element. The graph itself is fairly noisy, but the takeaways are simple!

tl;dr: larger graph = more intense response

[Quoted tweet was referring to the graph]
22/16

Image
Lack of symptoms may not even be because of immune system *destruction*! Symptoms of cold and flu are driven by interferon signaling, which SARS-CoV-2 suppresses.

But the end result is the same: lack of effective immune response!

23/16
The immune system has a vast range of functions spread across different systemic and cellular mechanisms.

It's likely that there are many people walking around with a compromised innate immune system, who don't realize it as leftover adaptive defenses fight infections

24/16
This discovery seems to have a clear path to commercialization, because this discovery is purely a new method of *analyzing* the results of existing types of Nucleic Acid Amplification Tests (NAAT), including RT-PCR and LAMP testing. It's software!

25/16
The advantage here is that, rather than requiring detection of a specific viral protein (which may be present in the body but not the swab location), it requires detection of elevated levels of HOST PROTEINS that indicate active viral infection!

26/16
Here's the entire thread about the article "A T-Cell-Derived 3-Gene Signature Distinguishes SARS-CoV-2 from Common Respiratory Viruses," on a single page for easier sharing:
readwise.io/reader/shared/…
[Caveat: This doesn’t apply to people trying supplements as *treatment*]

Supplements will have no effect. The deficiencies associated with severe covid/LC are likely a product of the infection itself, because the virus is dysregulating the production processes

27/16

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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...
Read 30 tweets
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...
Read 21 tweets
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...
Read 14 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jul 19
An interesting re-analysis was published today: "Remdesivir treatment does not reduce viral titers in patients with COVID-19"

Basically, remdesivir has no impact on *viral load* in acute COVID!

Here's a summary of the findings—and controversy—for a general audience!

1/12 Remdesivir treatment does not reduce viral titers in patients with COVID-19 "ABSTRACT The relationship (or lack thereof) between the clinical activity of remdesivir and its ability to reduce viral titers in patients with COVID-19 has not been fully delineated. There is a misconception that remdesivir was FDA-approved for COVID-19 due to its ability to reduce viral titers. Here, we analyze all clinical studies of remedesivir in COVID-19 that quantifed SARS-CoV-2 titers. As of 28 June 2024, we show there is no significant decrease in SARS-CoV-2 viral titers in patients treted with remd...
Initially, remdesivir received emergency FDA approval because in one NIH-sponsored trial, the remdesivir group recovered quicker than the control group. That's ALL.

It was trialed because it does seem to be a great drug in cell cultures in the lab!

2/
"Remdesivir (RDV) was the first FDA-approved treatment for COVID-19 based on results from the NIH-sponsored ACTT-1 trial demonstrating shorter time to recovery in patients with severe COVID-19 treated with remdesivir compared to placebo (10 vs 15 days, respectively) (1). While RDV demonstrated benefit in ACTT-1, its efficacy and clinical benefit have been marginal-to-ineffective in other contexts, making its FDA approval controversial. Several subsequent randomized controlled trials (RCTs) found no benefit with RDV treatment compared to placebo or the standard of care (SOC) (2-4), incl...
"Marginal clinical benefit with RDV treatment calls into question whether there is a relationship between the mechanism of viral load inhibition with RDV treatment and corresponding clinical outcomes. RDV is a prodrug of an ATP-analogue (GS-443902) that exhibits broad-spectrum antiviral activity (5). GS-443902 exhibits low Km for SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and cell-based assays have demonstrated low nanomolar EC50 values in SARS-CoV-2 infected cells treated with remdesivir (68)(9). Cells infected with SARS-CoV-2 and treated with remdesivir in vitro also show dose-de...
It SEEMED like it would be a great drug, because it does exactly what we want *in cell cultures*. Unfortunately, even in animal models, it seemingly had issues.

In particular, viral load was lower in fluid from the lungs, but not in nose, throat, or rectal swabs.

3/ "The preclinical pharmacodynamics of remdesivir have been extensively well-validated; it thus stands to reason that the observed decreases in viral load should translate in the clinic. If remdesivir demonstrates clinical benefit, it would stand to reason that there is a concomitant decrease in viral load associated with remdesivir treatment. However, this was not the case. Limited pharmacodynamic activity of RDV in humans was foreshadowed by the weak reductions in viral titers observed in rhesus macaque models of COVID-19 (11). Treatment with RDV lead to statistically significant decr...
Read 12 tweets
Nick #RespiratorsFilterPathogens😷 Anderegg Profile picture
Jul 18
NEW study in the Journal of Hospital Infection has found that, even from a purely economic perspective, the LACK OF MITIGATIONS currently present in healthcare settings MAKES NO SENSE!

Of course, preventative measures save LIVES, too.

Here's a quick analysis...

1/16 Admission screening testing of patients and staff N95 masks are cost-effective in reducing COVID-19 hospital acquired infections "Findings: Compared to no admission screening testing and staff surgical masks, all scenarios were cost saving with health gains. Staff N95s + RAT admission screening of patients was the cheapest, saving A$78.4M [95%UI 44.4M-135.3M] and preventing 1,543 [1,070-2,146] deaths state-wide per annum. Both interventions were individually beneficial: staff N95s in isolation saved A$54.7M and 854 deaths state-wide per annum, while RAT admission screening of patients...
This study is out of Australia, where patients who acquire COVID after their admission to the hospital are 50% more likely to die within 90 days.

When over 10% of the patients in the hospital are there BECAUSE of hospital-acquired infections, the problem is obvious.

2/ "... Hospital-acquired COVID-19 infections occur when patients admitted for non-COVID-19 reasons acquire COVID-19 following exposure to staff, other patients or visitors, and infection prevention and control measures are insufficient to prevent transmission. As well as being a patient safety risk, hospital-acquired infections carry significant costs to the health system [2-4]. [...] In the state of Victoria, 15-25% of patients in hospital with COVID-19 between June 2022-June 2023 acquired their infection after admission, with 90-day mortality of 18.9% compared to 12.3% among matched pa...
They used an established agent-based model—a model which simulates the interactions of individuals in a community—calibrated to actual local data.

Of course, it took a lot of work to get the appropriate data, because data collection was—surprise, surprise!—terrible.

3/ "Data on outbreaks occurring in Victorian acute care settings was aggregated from multiple sources, consisting of the outbreak size (number of patient and staff diagnoses), outbreak duration, and the corresponding demographic composition of each setting that recorded an outbreak (number of admissions, age distribution of admissions, distribution of length of stay, and staff:patient ratios).... ... Each of the outbreaks contained complete information about number of patient diagnoses, outbreak duration and demographic composition, however ~75% of outbreaks recorded zero staff diagnoses...
Read 16 tweets

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