The biology of coronavirus COVID-19 - including research and treatments

Science Magazine: Pepcid for COVID-19?:

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The heartburn remedy famotidine may disable a key enzyme that the new coronavirus uses to make copies (gold) of itself.

National Institutes of Health
New York clinical trial quietly tests heartburn remedy against coronavirus
By Brendan BorrellApr. 26, 2020 , 12:00 PM

The fast-growing list of possible treatments for the novel coronavirus includes an unlikely candidate: famotidine, the active compound in the over-the-counter heartburn drug Pepcid. On 7 April, the first COVID-19 patients at Northwell Health in the New York City area began to receive famotidine intravenously, at nine times the heartburn dose. Unlike other drugs the 23-hospital system is testing, including Regeneron’s sarilumab and Gilead Sciences’s remdesivir, Northwell kept the famotidine study under wraps to secure a research stockpile before other hospitals, or even the federal government, started to buy it. “If we talked about this to the wrong people or too soon, the drug supply would be gone,” says Kevin Tracey, a former neurosurgeon in charge of the hospital system’s research.

As of Saturday, 187 COVID-19 patients in critical status, including many on ventilators, have been enrolled in the trial, which aims for a total of 1174 people. Reports from China and molecular modeling results suggest the drug, which seems to bind to a key enzyme in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), could make a difference. But the hype surrounding hydroxychloroquine and chloroquine—the unproven antimalarial drugs touted by President Donald Trump and some physicians and scientists—has made Tracey wary of sparking premature enthusiasm. He is tight-lipped about famotidine’s prospects, at least until interim results from the first 391 patients are in. “If it does work, we’ll know in a few weeks,” he says.

A globe-trotting infectious disease doctor named Michael Callahan was the first to call attention to the drug in the United States. Callahan, who is based at Massachusetts General Hospital and has extensive connections in the biodefense world, has spent time in disease hot zones around the world, including the 2003 outbreak of another coronavirus disease, SARS, in Hong Kong. In mid-January, he was in Nanjing, China, working on an avian flu project. As the COVID-19 epidemic began to explode in Wuhan, he followed his Chinese colleagues to the increasingly desperate city.

The virus was killing as many as one out of five patients older than 80. Patients of all ages with hypertension and chronic obstructive pulmonary disease were faring poorly. Callahan and his Chinese colleagues got curious about why many of the survivors tended to be poor. “Why are these elderly peasants not dying?” he asks.

In reviewing 6212 COVID-19 patient records, the doctors noticed that many survivors had been suffering from chronic heartburn and were on famotidine rather than more-expensive omeprazole (Prilosec), the medicine of choice both in the United States and among wealthier Chinese. Hospitalized COVID-19 patients on famotidine appeared to be dying at a rate of about 14% compared with 27% for those not on the drug, although the analysis was crude and the result was not statistically significant.

But that was enough for Callahan to pursue the issue back home. After returning from Wuhan, he briefed Robert Kadlec, assistant secretary for preparedness and response at the Department of Health and Human Services, then checked in with Robert Malone, chief medical officer of Florida-based Alchem Laboratories, a contract manufacturing organization. Malone is part of a classified project called DOMANE that uses computer simulations, artificial intelligence, and other methods to rapidly identify U.S. Food and Drug Administration (FDA)-approved drugs and other safe compounds that can be repurposed against threats such as new viruses.

Malone had his eyes on a viral enzyme called the papainlike protease, which helps the pathogen replicate. To see whether famotidine binds to the protein, he would ordinarily need the enzyme’s 3D structure, but that would not be available for months. So Malone recruited computational chemist Joshua Pottel, president of Montreal-based Molecular Forecaster, to predict it from two crystal structures of the protease from the 2003 SARS coronavirus, combined with the new coronavirus’ RNA sequence.

It was hardly plug-and-play. Among other things, they compared the gene sequences of the new and old proteases to rule out crucial differences in structure. Pottel then tested how 2600 different compounds interact with the new protease. The modeling yielded several dozen promising hits that pharmaceutical chemists and other experts narrowed to three. Famotidine was one. (The compound has not popped up in in vitro screens of existing drug libraries for antiviral activity, however.)

With both the tantalizing Chinese data and the modeling pointing toward famotidine, a low-cost, generally safe drug, Callahan contacted Tracey about running a double-blind randomized study. COVID-19 patients with decreased kidney function would be excluded because high doses of famotidine can cause heart problems in them...
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Guardian: More cases of rare syndrome in children reported globally (link)

Doctors around the world have reported more cases of a rare but potentially lethal inflammatory syndrome in children that appears to be linked to coronavirus infections.

Nearly 100 cases of the unusual illness have emerged in at least six countries, with doctors in Britain, the US, France, Italy, Spain and Switzerland now reported to be investigating the condition.

The first cases came to light this week when the NHS issued an alert to paediatricians about a number of children admitted to intensive care units with a mix of toxic shock and a condition known as Kawasaki disease, an inflammatory disorder that affects the blood vessel, heart and other organs. So far 19 children have been affected in the UK and none have died.

The French health minister, Olivier Veran, said on Wednesday that the country had more than a dozen children with inflammation around the heart, and while there was insufficient evidence to prove a link with coronavirus, he said the cases were being taken “very seriously.”

Veran told Franceinfo news radio he had received an alert from Paris concerning “about 15 children of all ages”, adding that other cases had been reported in Spain, Italy and Switzerland. He listed the symptoms as fever, digestive problems and vascular inflammation.
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@Leila - and here in this thread @Michelle, as I just noticed again - posted that recently cases of the Kawaski Syndrom have slightly risen. I too saw it yesterday in TV. In England newborns displayed it. An association with corona comes to mind, but corona tests didn´t confirm it in that significance.

In case that it has to do with corona, directly or maybe indirectly, this article might especially be of importance:

Open Access Published: 10 November 2011
Association of Kawasaki disease with tropospheric wind patterns
Xavier Rodó et al, Scientific Reports volume 1, Article number: 152 (2011) Cite this articl


Abstract
The causal agent of Kawasaki disease (KD) remains unknown after more than 40 years of intensive research. The number of cases continues to rise in many parts of the world and KD is the most common cause of acquired heart disease in childhood in developed countries. Analyses of the three major KD epidemics in Japan, major non-epidemic interannual fluctuations of KD cases in Japan and San Diego and the seasonal variation of KD in Japan, Hawaii and San Diego, reveals a consistent pattern wherein KD cases are often linked to large-scale wind currents originating in central Asia and traversing the north Pacific. Results suggest that the environmental trigger for KD could be wind-borne. Efforts to isolate the causative agent of KD should focus on the microbiology of aerosols.
 
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Amw66 said:
Study of twins reveals genetic effect on Covid-19 symptoms
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Thank you, very interesting.

(Interestingly in our disease there has also been made - twice I think - an association between mt genetics and symptoms - but not with prevalence or onset. There is no inherent mitochondria dysfunction, everything could be fine again in this respect.)
 
This is worth a look. It reports on a small number of children who have developed an inflammatory condition that in many cases seems to have been triggered by COVID19:

https://www.theguardian.com/society...n-children-reported-globally?CMP=share_btn_tw
Some doctors suspect the syndrome is a “post-infection inflammatory response” where the immune system overreacts in the wake of an infection. This would suggest that in some children the disease has two phases – the initial infection and a secondary immune response that takes hold later.
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There are some interesting parallels to ME.
 
Woolie said:
This is worth a look. It reports on a small number of children who have developed an inflammatory condition that in many cases seems to have been triggered by COVID19:

https://www.theguardian.com/society...n-children-reported-globally?CMP=share_btn_tw

There are some interesting parallels to ME.
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Its interesting on TWiV Stanley Perlman suggested that the bad covid-19 response in the lungs may be due to a host response to the virus rather than the virus itself. That was a while ago and he didn't quote any evidence as far as I can remember.

Also it seems that the viral load in children is similar to that in adults



So it would perhaps seem like children aren't developing symptoms rather than not getting the virus.
 
New Scientist: What four coronaviruses from history can tell us about covid-19

Four coronaviruses cause around a quarter of all common colds, but each was probably deadly when it first made the leap to humans. We can learn a lot from what happened next

Israel G. Vargas

IN 1889, a disease outbreak in central Asia went global, igniting a pandemic that burned into the following year. It caused fever and fatigue, and killed an estimated 1 million people. The disease is generally blamed on influenza, and was dubbed “Russian flu“. But with no tissue samples to check for the flu virus, there is no conclusive proof.

Another possibility is that this “flu” was actually a coronavirus pandemic. The finger has been pointed at a virus first isolated in the 1960s, though today it causes nothing more serious than a common cold. In fact, there are four coronaviruses responsible for an estimated 20 to 30 per cent of colds. Only recently have virologists begun to dig into these seemingly humdrum pathogens and what they have found suggests the viruses have a far more deadly past. Researchers now believe that all four of these viruses began to infect humans in the past few centuries and, when they did, they probably sparked pandemics.

The parallels with our current crisis are obvious. And it turns out that our growing knowledge about these other coronaviruses could be vital in meeting the challenge of covid-19. Insights into the origins, trajectories and features of common cold coronaviruses can provide crucial clues about what to expect in the coming months and years. Understanding these relatively benign viruses may also help us avoid another pandemic.

Coronaviruses are a big family of viruses that are mainly known for causing diseases in livestock. Until recently, few virologists paid them much attention. “Human coronaviruses were recognised in the 1960s,” says Frank Esper at the …
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The rest is behind a paywall...
 
spinoza577 said:
@LeilaAnalyses of the three major KD epidemics in Japan, major non-epidemic interannual fluctuations of KD cases in Japan and San Diego and the seasonal variation of KD in Japan, Hawaii and San Diego, reveals a consistent pattern wherein KD cases are often linked to large-scale wind currents originating in central Asia and traversing the north Pacific. Results suggest that the environmental trigger for KD could be wind-borne. Efforts to isolate the causative agent of KD should focus on the microbiology of aerosols.
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https://books.google.de/books? "Diverging Paths of Developing in Central Asia." Edited by Özcan, 2017, page with Figure 7:
Pavlodar [a region in Kazakhstan, an oblast] aluminium plant had high air emission of manganese and vanadium metal, while steel and metallurgy complexes in Termitua (Karganda oblast) emitted phenols, dust, ammonia, carbon monoxide and nitric oxides (Simenenkov 2010).
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This might match up with NO2 -> lL-6 -> covid-19 in a complex manner.
 
Mij said:
Dr. Anthony Fauci was very excited yesterday regarding the antiviral drug Remdesivir 'blocking the virus'.
https://www.niaid.nih.gov/news-even...esivir-accelerates-recovery-advanced-covid-19

They may never be able to develop a vaccine, but drugs are looking promising to manage the illness.
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Remdesivir is ineffective at reducing viral load (once already infected) or reducing mortality in COVID patients.

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext

Do not believe the hype from the USA.
 
"The frequent use of corticosteroids in our patient group might have promoted viral replication, as observed in SARS and MERS, although these studies only reported prolongation of the detection of viral RNA, not infectious virus. Furthermore, we have no answer to whether longer treatment course and higher dose of remdesivir would be beneficial in patients with severe COVID-19".

Wouldn't this be an important factor as to why the studies differ?
 
Mij said:
"The frequent use of corticosteroids in our patient group might have promoted viral replication, as observed in SARS and MERS, although these studies only reported prolongation of the detection of viral RNA, not infectious virus. Furthermore, we have no answer to whether longer treatment course and higher dose of remdesivir would be beneficial in patients with severe COVID-19".

Wouldn't this be an important factor as to why the studies differ?
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There were no statistical differences in corticosteroid use between the patient and placebo groups (numerically, slightly higher in placebo group).

The US study may well have allowed patients to use corticosteroids too.
Note that the US study changed their primary outcome (from published protcol) to something far less stringent.
 
From that thread
Where do the Shenanigans come in? Well, remember how maybe this Chinese trial showed a shortened course in a subset of patients? Like tamiflu? But didn’t change mortality? Well a month ago the NIAID trial changed their endpoints to remove death and instead look at dz duration.
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Then, even more fishy, *the same day* as this Lancet trial is release, Gilead and NIAID claim a “positive trial” and they’ve “shortened the course of the disease significantly”. Notably, the mortality benefit did not reach significance
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By the end of the day, reports that FDA is going to emergently approve remdesivir for treatment of COVID. Gilead gets what they want. No one will want to be in a control arm in further trials and they will argue all future trials must be noninferiority.
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Absolute genius. You have to salute them. On the day a negative trial of their drug is reported, based on a press release they took over the news cycle, and with some midstream edits to their endpoints their now “positive” trial wins them FDA approval and a halted trial.
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AIM ImmunoTech inks deal to research vaping device as a vehicle for Ampligen to treat coronavirus
AIM believes Ampligen has potential as a prophylactic/early-onset therapeutic against the coronavirus (COVID-19). The drug showed 100% preclinical efficacy against the viral infection in a mouse trial, and it has been generally well tolerated when administered nasally to humans.

The agreement allows AIM to conduct research in China on the efficacy of the Smoore inhalation device as a delivery method for Ampligen.
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https://www.proactiveinvestors.com/...for-ampligen-to-treat-coronavirus-916966.html
 
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