Vaccines, Drugs and Other Treatments

[Lucy]

First, a couple of links to external sources that are updated regularly with stuff about how US doctors are treating covid today:

https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-management-in-hospitalized-adults

https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-outpatient-evaluation-and-management-in-adults

COVID-19 - EMCrit Project

(lots of other interesting pages on this site, many related to covid research)

[Lucy]

Some posts stolen from the old actuarial outpost:

posted by Campbell:
https://theconversation.com/we-found-and-tested-47-old-drugs-that-might-treat-the-coronavirus-results-show-promising-leads-and-a-whole-new-way-to-fight-covid-19-136789?fbclid=IwAR1rnC908I7WNCL-yPkiXNzI2DAkEXcY5624W9M0EMWRRJ1gRuP9GAICruU

Testing in cells is an important and exciting first step. elkor/E+ via Getty Images
We found and tested 47 old drugs that might treat the coronavirus: Results show promising leads and a whole new way to fight COVID-19

Summary

The more researchers know about how the coronavirus attaches, invades and hijacks human cells, the more effective the search for drugs to fight it. That was the idea my colleagues and I hoped to be true when we began building a map of the coronavirus two months ago. The map shows all of the coronavirus proteins and all of the proteins found in the human body that those viral proteins could interact with.

In theory, any intersection on the map between viral and human proteins is a place where drugs could fight the coronavirus. But instead of trying to develop new drugs to work on these points of interaction, we turned to the more than 2,000 unique drugs already approved by the FDA for human use. We believed that somewhere on this long list would be a few drugs or compounds that interact with the very same human proteins as the coronavirus.

We were right.

Our multidisciplinary team of researchers at the University of California, San Francisco, called the QCRG, identified 69 existing drugs and compounds with potential to treat COVID-19. A month ago, we began shipping boxes of these drugs off to Institut Pasteur in Paris and Mount Sinai in New York to see if they do in fact fight the coronavirus.

In the last four weeks, we have tested 47 of these drugs and compounds in the lab against live coronavirus. I’m happy to report we’ve identified some strong treatment leads and identified two separate mechanisms for how these drugs affect SARS-CoV-2 infection. Our findings were published on April 30 in the journal Nature.

Every place that a coronavirus protein interacts with a human protein is a potential druggable site. QBI Coronavirus Research Group, CC BY-ND
The testing process
The map we developed and the FDA drug catalog we screened it against showed that there were potential interactions between the virus, human cells and existing drugs or compounds. But we didn’t know whether the drugs we identified would make a person more resistant to the virus, more susceptible or do anything at all.

To find those answers we needed three things: the drugs, live virus and cells in which to test them. It would be optimal to test the drugs in infected human cells. However, scientists don’t yet know which human cells work best for studying the coronavirus in the laboratory. Instead we used African green monkey cells, which are frequently used in place of human cells to test antiviral drugs. They can be readily infected with the coronavirus and respond to drugs very closely to the way human cells do.

After infecting these monkey cells with live virus, our partners in Paris and New York added the drugs we identified to half and kept the other half as controls. They then measured the amount of virus in the samples and the number of cells that were alive. If the samples with drugs had a lower virus count and more cells alive compared to the control, that would suggest the drugs disrupt viral replication. The teams were also looking to see how toxic the drugs were to the cells.

With dozens of drugs each needing full testing, to get results in four weeks required round-the-clock effort. Quantitative Biosciences Institute, CC BY-ND
After sorting through the results of hundreds of experiments using 47 of the predicted drugs, it seems our interaction predictions were correct. Some of the drugs do in fact work to fight the coronavirus, while others make cells more susceptible to infection.

It is incredibly important to remember that these are preliminary findings and have not been tested in people. No one should go out and buy these drugs.

But the results are interesting for two reasons. Not only did we find individual drugs that look promising to fight the coronavirus or may make people more susceptible to it; we know, at a cellular level, why this is happening.

We identified two groups of drugs that affect the virus and they do it two different ways, one of which has never been described.

Disrupting translation
At a basic level, viruses spread by entering a cell, hijacking some of the cell’s machinery and using it to make more copies of the virus. These new viruses then go on to infect other cells. One step of this process involves the cell making new viral proteins out of viral RNA. This is called translation.

When going through the map, we noticed that several viral proteins interacted with human proteins involved in translation and a number of drugs interacted with these proteins. After testing them, we found two compounds that disrupt the translation of the virus.

The two compounds are called ternatin-4 and zotatifin. Both of these are currently used to treat multiple myeloma and seem to fight COVID-19 by binding to and inhibiting proteins in the cell that are needed for translation.

Plitidepsin is a similar molecule to ternatin-4 and is currently undergoing a clinical trial to treat COVID-19. The second drug, zotatifin, hits a different protein involved in translation. We are working with the CEO of the company that produces it to get it into clinical trials as soon as possible.

The coronavirus attacks human cells using dozens of devious tricks. narvikk/iStock Getty Images Plus via Getty Images
Sigma receptors
The second group of drugs we identified work in an entirely different way.

Cell receptors are found both inside of and on the surface of all cells. They act like specialized switches. When a specific molecule binds to a specific receptor, this tells a cell to do a specific task. Viruses often use receptors to infect cells.

Our original map identified two promising MV cell receptors for drug treatments, SigmaR1 and SigmaR2. Testing confirmed our suspicions.

We identified seven drugs or molecules that interact with these receptors. Two antipsychotics, haloperidol and melperone, which are used to treat schizophrenia, showed antiviral activity against SARS-CoV-2. Two potent antihistamines, clemastine and cloperastine, also displayed antiviral activity, as did the compound PB28 and the female hormone progesterone.

Remember, all these interactions have so far only been observed in monkey cells in petri dishes.

At this time we do not know exactly how the viral proteins manipulate the SigmaR1 and SigmaR2 receptors. We think the virus uses these receptors to help make copies of itself, so decreasing their activity likely inhibits replication and reduces infection.

Interestingly, a seventh compound – an ingredient commonly found in cough suppressants, called dextromethorphan – does the opposite: Its presence helps the virus. When our partners tested infected cells with this compound, the virus was able to replicate more easily, and more cells died.

Laboratory testing is excellent at generating leads but clinical trials must be done to know if these findings translate to the real world. Quantitative Biosciences Institute, CC BY-ND
This is potentially a very important finding, but, and I cannot stress this enough, more tests are needed to determine if cough syrup with this ingredient should be avoided by someone who has COVID-19.

All these findings, while exciting, need to undergo clinical trials before the FDA or anyone else should conclude whether to take or stop taking any of these drugs in response to COVID-19. Neither people nor policymakers nor media outlets should panic and jump to conclusions.

Another interesting thing to note is that hydroxychloroquine – the controversial drug that has shown mixed results in treating COVID-19 – also binds to the SigmaR1 and SigmaR2 receptors. But based on our experiments in both labs, we do not think hydroxychloroquine binds to them efficiently.

Researchers have long known that hydroxychloroquine easily binds to receptors in the heart and can cause damage. Because of these differences in binding tendencies, we don’t think hydroxychloroquine is a reliable treatment. Ongoing clinical trials should soon clarify these unknowns.

Treatment sooner rather than later
Our idea was that by better understanding how the coronavirus and human bodies interact, we could find treatments among the thousands of drugs and compounds that already exist.

Our idea worked. We not only found multiple drugs that might fight SARS-CoV-2, we learned how and why.

But that is not the only thing to be excited about. These same proteins that SARS-CoV-2 uses to infect and replicate in human cells and that are targeted by these drugs are also hijacked by related coronaviruses SARS-1 and MERS. So if any of these drugs do work, they will likely be effective against COVID-22, COVID-24 or any future iterations of COVID that may emerge.

Are these promising leads going to have any effect?

The next step is to test these drugs in human trials. We have already started this process and through these trials researchers will examine important factors such as dosage, toxicity and potential beneficial or harmful interactions within the context of COVID-19.

[Lucy]

Posted by me (in response to above):

That’s really interesting. And rather hopeful. Although the bit about dextromethorphan helping the virus replicate sounds bad.

It’s important to know how a drug works, because it matters for WHEN to give it in the course of the infection. I was talking to a friend (Call him James) who is researching covid, and he tells me there are 4 stages of immune response

1. immediate & non-specific, the first cells to be infected signal other cells to slow down their RNA replication. Because this stage isn’t mediated by immune cells, it’s called something weird like “acellular”, and because immunologists mostly study immune cells, it’s not much studied. But it’s critical to our immune response to viruses.

2. innate immune response, where immune cells go out to kill infected cells and generally attack “not self”. This is the part of the immune response where cytokines are generated, to call other immune cells to battle.

3. adaptive immune response, where the body generates antibodies specific to this virus. It usually takes a week or two for this to gear up. This is the immune reaction that typically clears the virus from your body, assuming the other stages kept you alive and well enough to mount an effective active immune response.

4. the creation of memory cells, where your body catalogs this virus as “something to deal with if it shows up again”, and creates long-live immune cells that can spit out antibodies quickly. Creating these is the goal of vaccines, I think.

So, the first two steps are critical. James tells me that because of the effect of stage 1, the second generation of cells that are infected often produce only 1/100th of the number of viral particles as the first generation of infected cells. This is one reason why disease is dose-dependent, despite the exponential growth of pathogens in your body.

Stage 1 is also the immune response that is mimicked by drugs like tamiflu and remdesivir, which is why they mostly work if you take them early-on. Tamiflu works best if you take it within 12 hours of being infected, and doesn’t work at all once you are really sick with the flu. The same is likely true of remdesivir, except that with covid there is probably a second window of effectiveness, because the virus has the odd property of jumping from the respiratory system to other types of cells, and that process may resemble an initial infection. HOWEVER, remdesivir interferes with cell reproduction in general, not just with the reproduction of viral RNA, and stage 3 of the immune response (the stage that can actually clear the virus) depends on ramping up reproduction of immune cells. So if you take drugs like these too late into the infection, they can prolong illness.

Other drugs, like steroids, ramp down inflammation and can protect against a “cytokine storm” or ARDS, where your body’s immune response goes into overdrive and can kill you. (James says that in China, the current covid protocol is to administer steroids on day 8 of the infection.) BUT, that same immune response is critical to stage 2, which is what prevents the virus from infecting all your cells while the rest of the immune system ramps up. (And every infected cell dies. You recover by clearing out the virus and the debris of the infected cells, and then growing new cells to replace the ones that died. People feel sick and weak for a while after the flu because it can kill 15% of the cells liming the lung, and it takes a couple of weeks to regenerate them.)

Anyway, that was a long post. But the point is that some drugs might be helpful prophylactically, some may be helpful at the onset of symptoms, and others may help those who are already critically ill. But those might be different drugs. So studies in cells that investigate the precise mechanism through which a drug works are important in developing treatment protocols.

[Lucy]

From campbell:

Critically ill patients given higher doses of chloroquine diphosphate were more likely to die than those given lower doses.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2765499

Summary

Importance There is no specific antiviral therapy recommended for coronavirus disease 2019 (COVID-19). In vitro studies indicate that the antiviral effect of chloroquine diphosphate (CQ) requires a high concentration of the drug.

Objective To evaluate the safety and efficacy of 2 CQ dosages in patients with severe COVID-19.

Design, Setting, and Participants This parallel, double-masked, randomized, phase IIb clinical trial with 81 adult patients who were hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was conducted from March 23 to April 5, 2020, at a tertiary care facility in Manaus, Brazilian Amazon.

Interventions Patients were allocated to receive high-dosage CQ (ie, 600 mg CQ twice daily for 10 days) or low-dosage CQ (ie, 450 mg twice daily on day 1 and once daily for 4 days).

Main Outcomes and Measures Primary outcome was reduction in lethality by at least 50% in the high-dosage group compared with the low-dosage group. Data presented here refer primarily to safety and lethality outcomes during treatment on day 13. Secondary end points included participant clinical status, laboratory examinations, and electrocardiogram results. Outcomes will be presented to day 28. Viral respiratory secretion RNA detection was performed on days 0 and 4.

Results Out of a predefined sample size of 440 patients, 81 were enrolled (41 [50.6%] to high-dosage group and 40 [49.4%] to low-dosage group). Enrolled patients had a mean (SD) age of 51.1 (13.9) years, and most (60 [75.3%]) were men. Older age (mean [SD] age, 54.7 [13.7] years vs 47.4 [13.3] years) and more heart disease (5 of 28 [17.9%] vs 0) were seen in the high-dose group. Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low-dosage and high-dosage groups, respectively. Lethality until day 13 was 39.0% in the high-dosage group (16 of 41) and 15.0% in the low-dosage group (6 of 40). The high-dosage group presented more instance of QTc interval greater than 500 milliseconds (7 of 37 [18.9%]) compared with the low-dosage group (4 of 36 [11.1%]). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%).

…

[Lucy]

Vitamin D deficiency may increase covid mortality: cross population review

https://www.medrxiv.org/content/10.1101/2020.04.08.20058578v3

The Possible Role of Vitamin D in Suppressing Cytokine Storm and Associated Mortality in COVID-19 Patients
Ali Daneshkhah, Vasundhara Agrawal, Adam Eshein, Hariharan Subramanian, Hemant Kumar Roy, Vadim Backman
doi: https://doi.org/10.1101/2020.04.08.20058578
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

Abstract
Abstract Background Large-scale data show that the mortality of COVID-19 varies dramatically across populations, although the cause of these disparities is not well understood. In this study we investigated whether severe COVID-19 is linked to Vitamin D (Vit D) deficiency. Method Daily admission, recovery and deceased rate data for patients with COVID-19 from countries with a large number of confirmed patients (Germany, South Korea (S. Korea), China (Hubei), Switzerland, Iran, UK, US, France, Spain, Italy) as of April 20, 2020 were used. The time-adjusted case mortality ratio (T-CMR) was estimated as the number of deceased patients on day N divided by the number of confirmed cases on day N-8. The adaptive average of T-CMR (A-CMR) was further calculated as a metric of COVID-19 associated mortality in different countries. Although data on Vit D level is not currently available for COVID-19 patients, we leveraged the previously established links between Vit D and C-Reactive Protein (CRP) and between CRP and severe COVID-19, respectively, to estimate the potential impact of Vit D on the reduction of severe COVID-19. Findings A link between Vit D status and COVID-19 A-CMR in the US, France, and the UK (countries with similar screening status) may exist. Combining COVID-19 patient data and prior work on Vit D and CRP levels, we show that the risk of severe COVID-19 cases among patients with severe Vit D deficiency is 17.3% while the equivalent figure for patients with normal Vit D levels is 14.6% (a reduction of 15.6%). Interpretation Given that CRP is a surrogate marker for severe COVID-19 and is associated with Vit D deficiency, our finding suggests that Vit D may reduce COVID-19 severity by suppressing cytokine storm in COVID-19 patients. Further research is needed to account for other factors through direct measurement of Vit D levels.

Note that this article still hasn’t been published. The authors made some changes and resubmitted it. I’m not sure what that means for it’s ultimate fate.

[Lucy]

Vitamin D deficiency may increase covid mortality: retrospective review of individual patients with varying severity of disease

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3571484

Vitamin D Supplementation Could Possibly Improve Clinical Outcomes of Patients Infected with Coronavirus-2019 (COVID-19)
9 Pages Posted: 9 Apr 2020 Last revised: 7 May 2020
Mark Alipio
Davao Doctors College; University of Southeastern Philippines

Date Written: April 9, 2020

Abstract
The rapid spread of COVID-19 in many areas of the world calls for preventive health measures. Although basic guidelines on infection control are suggested, treatment has remained the best choice to avert mortality. However, for the time being, there are no known vaccines for the disease. In this paper, a multinomial logistic regression was used to predict clinical outcomes of patients infected with COVID-19 based on 25-hydroxyvitamin D [25(OH)D] levels, the barometer for Vitamin D status. A retrospective multicentre study of 212 cases with laboratory-confirmed infection of SARS-CoV-2 was conducted. Data pertaining to clinical features and serum 25(OH)D levels were extracted from the medical records. For statistical analysis, Mann-Whitney U and χ² tests were used to compare differences in the clinical outcomes. Multinomial logistic regression was used to explore the association between serum 25(OH)D level and clinical outcomes of the cases. Frequency and percentage were used for categorical variables. Mean was used for continuous variables. A p-value below 0.01 was considered statistically significant. Of the 212 cases of COVID-19, majority had ordinary clinical outcome. Mean serum 25(OH)D level was 23.8 ng/ml. Serum 25(OH)D level was lowest in critical cases, but highest in mild cases. Serum 25(OH)D levels were statistically significant among clinical outcomes. Majority had insufficient Vitamin D status, most of them were not severe. Vitamin D status is significantly associated with clinical outcomes. A multinomial logistic regression analysis reported that for each standard deviation increase in serum 25(OH)D, the odds of having a mild clinical outcome rather than a severe outcome were approximately 7.94 times (OR=0.126, p<0.001) while interestingly, the odds of having a mild clinical outcome rather than a critical outcome were approximately 19.61 times (OR=0.051, p<0.001). The results suggest that an increase in serum 25(OH)D level in the body could either improve clinical outcomes or mitigate worst (severe to critical) outcomes, while a decrease in serum 25(OH)D level in the body could worsen clinical outcomes of COVID-2019 patients. In conclusion, this study provides substantial information to clinicians and health policy-makers. Vitamin D supplementation could possibly improve clinical outcomes of patients infected with COVID-19. Further research should conduct randomized controlled trials and large population studies to evaluate this recommendation.

[Lucy]

Vitamin D deficiency associated with more severe disease: another retrospective review of individual patients with varying severity of covid-19

https://www.medrxiv.org/content/10.1101/2020.04.24.20075838v1

Vitamin D Insufficiency is Prevalent in Severe COVID-19
View ORCID ProfileFrank H. Lau, Rinku Majumder, Radbeh Torabi, Fouad Saeg, Ryan Hoffman, Jeffrey D. Cirillo, Patrick Greiffenstein
doi: https://doi.org/10.1101/2020.04.24.20075838
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
AbstractInfo/HistoryMetrics Preview PDF
Abstract
Background: COVID-19 is a major pandemic that has killed more than 196,000 people. The COVID-19 disease course is strikingly divergent. Approximately 80-85% of patients experience mild or no symptoms, while the remainder develop severe disease. The mechanisms underlying these divergent outcomes are unclear. Emerging health disparities data regarding African American and homeless populations suggest that vitamin D insufficiency (VDI) may be an underlying driver of COVID-19 severity. To better define the VDI-COVID-19 link, we determined the prevalence of VDI among our COVID-19 intensive care unit (ICU) patients. Methods: In an Institutional Review Board approved study performed at a single, tertiary care academic medical center, the medical records of COVID-19 patients were retrospectively reviewed. Subjects were included for whom serum 25-hydroxycholecalcifoerol (25OHD) levels were determined. COVID-19-relevant data were compiled and analyzed. We determined the frequency of VDI among COVID-19 patients to evaluate the likelihood of a VDI-COVID-19 relationship. Results: Twenty COVID-19 patients with serum 25OHD levels were identified; 65.0% required ICU admission.The VDI prevalence in ICU patients was 84.6%, vs. 57.1% in floor patients. Strikingly, 100% of ICU patients less than 75 years old had VDI. Coagulopathy was present in 62.5% of ICU COVID-19 patients, and 92.3% were lymphocytopenic. Conclusions: VDI is highly prevalent in severe COVID-19 patients. VDI and severe COVID-19 share numerous associations including hypertension, obesity, male sex, advanced age, concentration in northern climates, coagulopathy, and immune dysfunction. Thus, we suggest that prospective, randomized controlled studies of VDI in COVID-19 patients are warranted.

[Lucy]

By the way, a few comments about the vitamin D link, which I’m not going to bother to source:

1. Not only does it help explain the disparity in outcomes between darker and lighter skinned individuals, it also helps explain the disparity of outcomes between obese and slim individuals. While poking around for these studies, I found a lot of articles pointing out that fat cells tend to take up vitamin D, and serum vitamin D levels in obese people are lower than those in slimmer people, and vitamin D deficiency is more common in obese people. As a fat person, I have dug out the vitamin D supplement my doctor recommended a couple of years ago, when I randomly tested low, and I’m taking it again. I’m also trying to spend some time in the sun. Some study in the UK found that 13 minutes of sunlight on 1/3 of the skin, 3 times a week, was adequate to increase vitamin D to healthy levels in most of the (presumably pale-skinned) people in the study.

2. The potential importance of the innate immune system (which is bolstered by vitamin D) and the risk of an overactive adaptive immune response (vitamin D helps reduce the risk of a cytokine storm) are sort of bad news for vaccines. Vaccines are all about the adaptive immune system, and there are cases where vaccines increase the risk of the adaptive immune system over-reacting to a virus. (That being said, there ARE some veterinary vaccines for animal coronaviruses. I am still hoping we’ll get a good vaccine.)

3. Apparently calves are sometimes treated with vitamin D for a bovine coronavirus.

But note that another possible reason obese people are hot harder is that obesity tends to lead to higher levels of inflammation throughout the body. I didn’t mean to imply vitamin D was the whole story, but it might be an important piece of the story.

[Lucy]

From Campbell (5/18)

https://ctmirror.org/2020/05/17/cautious-enthusiasm-for-plasma-treatment-in-covid-19-cases/

‘Cautious enthusiasm’ for plasma treatment in COVID-19 cases

Summary

Stamford Hospital is treating most of its critically ill coronavirus patients with blood plasma from people who have recovered, after stunning turnarounds in several patients who were gravely ill.

“We started with only the sickest patients on respirators. Then we offered it to all of the patients on respirators, then all the patients in the ICU, and now all the COVID patients in the hospital on 40 percent oxygen, not with a ventilator,” said Dr. Paul Sachs, director of pulmonary medicine. “So far, there has been cautious enthusiasm.”

Plasma transfusions are gaining traction at other hospitals throughout Connecticut and nationally as well, as doctors wait for a breakthrough treatment. Nuvance Health, which includes Danbury and Norwalk hospitals, reports more than 200 patients system-wide treated with plasma so far. The network opened its COVID-19 plasma donation centers recently and already counts about 1,750 donors in its database.

Trinity Health of New England, which includes Saint Mary’s Hospital in Waterbury and Saint Francis Hospital and Medical Center in Hartford, is running a plasma transfusion trial. Hartford HealthCare and Yale New Haven Health are transfusing patients who fit the protocol established in a national plasma transfusion clinical trial overseen by The Mayo Clinic, which began last month. As of Monday, Hartford HealthCare has transfused more than 215 patients across its network.

As the number of survivors grows, more plasma will become available, and the number of transfusions will increase, said Dr. Mahalia S. Desruisseaux, an infectious disease expert at Yale.

While it’s too early to cite data from trials, “there’s clearly a benefit” to the transfusions, she said. “Anecdotally, the earlier you administer it, the better you do. Are you giving it to someone who’s going to get better anyway? We don’t know that yet.”

In Stamford, Henry Woerz, 76, of New Canaan, continues to recover after he received the first plasma transfusion in Connecticut on April 10. Before the procedure, he had spent 21 days on a ventilator, with his condition going from bad to worse. The hospital had called his sons Craig, Jeff and Jason “basically, to come in to say goodbye,” Craig Woerz recalled.

The Woerz brothers learned about plasma transfusions from their father’s primary doctor, Remi Rosenberg, and they recruited potential donors online. Then the brothers and Rosenberg appealed to Stamford Hospital to try a transfusion. Craig Woerz said he “appreciated the hospital’s collaborative spirit. There was never a push out of the hospital, and we never gave up.”

Stamford Hospital is one of the few independent hospitals left in Connecticut. “Because we are an independent, medium-sized hospital, we are maybe more nimble,” Sachs said. He and his team wrote up a protocol for a transfusion trial and submitted it to the Food and Drug Administration (FDA). Woerz became the first recipient.

“We were overwhelmed with patients coming in and had absolutely no treatment. We were just throwing things off the wall to see if it stuck,” Sachs said. “The first rule is do no harm, and we hadn’t heard of any adverse effects with convalescent plasma. This appeared to be an experimental, compassionate, possibly plausible remedy with a good safety record.”

When a virus or infection strikes, the body’s immune system makes cells and proteins to fight it. In many patients who have recovered from COVID-19, their plasma remains rich with these antibodies for at least a month afterward. A transfusion can put the little antibody soldiers to work in another critically ill patient. For more than a century, doctors have used convalescent blood plasma to combat diseases, from the Spanish flu to measles to polio to Ebola. Following the COVID-19 outbreak in China, two small studies showed that convalescent plasma was used there to treat 15 patients who ultimately survived.

CARL JORDAN CASTRO PHOTO :: C-HIT.ORG

Dr. Paul Sachs and his team wrote up a protocol for a transfusion trial and submitted it to the FDA.

Woerz received two small baggies of antibodies over five hours. Two units of plasma are now the standard protocol at Stamford Hospital for all appropriate COVID-19 patients. (The Mayo Clinic trial recently changed its national protocol to one or two units, so Stamford has joined that trial as well.)

“He had such a dramatic change the day after he got the plasma, and within a week he was off the respirator with high levels of oxygen,” Sachs said. “The rate at which he survived and the time point at which he pivoted his progression are hard to ignore, but I would emphasize this is not a randomized trial, and it is difficult to impossible to make firm conclusions.”

Since the plasma transfusions began in Stamford, about 40% of patients have been extubated, 45% remain on ventilators and 15% have died.

From survivor To donor

Amy Harel, an orthodontist in Fairfield who survived COVID-19, said she regrets not bringing her father to a Connecticut hospital for treatment. On a trip to Disney World in March, a stomach bug kept her father, Ron Panzok, in the family’s suite at the hotel. Days after they returned, Panzok headed to the emergency room near his Long Island, N.Y., home, and learned he had COVID-19. Everything deteriorated from there. The entire family got COVID-19: both Harels, their 18-month-old daughter, and the aunt and uncle who drove everyone to the airport.

Panzok, 66, had been “a healthy, hardworking man who biked and had a physical job,” Harel said. Now he was sedated with paralytics, spending week after week on a ventilator, resulting in acute respiratory distress syndrome and complete kidney failure. “The hospital was so insane they called it the Wild West. All day every day, I spent researching treatments and trying to get someone to pay attention to my dad.”

No sooner did Harel connect with one doctor, she’d discover her father had been transferred to a different ICU. Finally, she tracked down the ICU chief. She pleaded with him to try a plasma transfusion. “Every time I asked, he said, ‘We’re waiting [for approval].’ It was a nightmare.”

Eventually, the hospital sidestepped administrative red tape and received emergency approval from the FDA for Panzok’s transfusion. But the wait took its toll. Though he is finally breathing on his own, her father needs dialysis and falls asleep after saying a sentence. “He’s alive, thank God. It’s a miracle,” his daughter said, “though now I’m worried about his quality of life.” Panzok will need six to nine months of rehabilitation.

Harel is convinced that recovered plasma saved her father, and she hopes to save others with her plasma. When she received a call from the Fairfield health department, which has been checking up on her regularly after her positive diagnosis, they encouraged her to donate at Norwalk Hospital’s new plasma center.

Harel spent two hours there recently, watching her blood cycle through a machine that separated her red and white blood cells, saline, and plasma, spinning out the yellowish plasma, and returning the rest of the blood to her. “Seeing the plasma going into the bag was shocking to me because I didn’t expect to see it. But I donated because it helped my dad, and I want to help others,” she said.

[Lucy]

5/18

You know, those two articles Campbell posted are great news, but they make me nervous.

I don’t know that we want to immunize every healthcare worker immediately… Vaccines don’t always work, they occasionally make matters worse, and these ones are going to go to market with very little testing. I suppose there will be limited supply, so not all the front-line workers will be vaccinated right away whatever the official goal is.

Still, a really strong benefit to convalescent serum is not only a good thing all by itself, it also speaks to the plausibility of a vaccine working. So that article is all good news. I hope the formal tests pan out and prove it really is effective.

[Lucy]

MayanActuary 5/18

I don’t know that we want to immunize every healthcare worker immediately… Vaccines don’t always work, they occasionally make matters worse, and these ones are going to go to market with very little testing. I suppose there will be limited supply, so not all the front-line workers will be vaccinated right away whatever the official goal is.

By the time they would be able to be rolled out to every healthcare worker we should have some decent testing.

Moderna’s (greenman’s article) completed Phase 1 on 45 participants. 3 had adverse reactions, all were in the highest dosage group (250mcg), and all recovered on their own. The two lower doses work well, so they are going to stop the higher dose trial.

Phase 2 has hundreds of people.

Phase 3 this summer (assuming Phase 2 goes well) usually has thousands of people.

If that goes well, they would up it again and get 10s of thousands of people for a trial. Each phase has to wait the mandated 42 days between trials to observe adverse effects.

Mass injection wouldn’t happen until probably early 2021.

So, while rushed, safety would be at a point that it wouldn’t just incapacitate every healthcare worker upon injection, and should significantly help them. I DO want to immunize everyone right away once a vaccine successfully passes through those multiple phases.

[Lucy]

5/21

Experimental vaccines and recovering from covid both provide (at least short term) immunity in rhesus macaques.

https://news.harvard.edu/gazette/story/2020/05/vaccines-found-that-may-protect-against-covid-19-in-animal-models/?utm_source=SilverpopMailing&utm_medium=email&utm_campaign=Daily%20Gazette%2020200521%20(1)

…
In the first study, the team found that six candidate DNA vaccines — each formulation using a different variant of the key viral protein — induced neutralizing antibody responses and protected against SARS-CoV-2 in rhesus macaques.
…
After exposing nine adult macaques to the SARS-CoV-2 virus, the researchers monitored viral levels as the animals recovered. All nine animals recovered and developed antibodies against the virus. More than a month after initial infection, the team re-exposed the rhesus macaques to the virus. Upon second exposure, the animals demonstrated near-complete protection against the virus. These data suggest that animals develop natural protective immunity against the virus and the disease that it causes.
…

Summary

BY
Jacqueline Mitchell
BIDMC Communications
DATE
May 20, 2020

With nearly 5 million confirmed cases globally and more than 300,000 deaths from COVID-19, much remains unknown about SARS-CoV-2, the virus that causes the disease. Two critical questions are whether vaccines will prevent infection with COVID-19, and whether individuals who have recovered from COVID-19 are protected against re-exposure to the virus.

Now, a pair of new studies led by researchers at Harvard-affiliated Beth Israel Deaconess Medical Center (BIDMC) suggests the answer to these questions is yes, at least in animal models. Results of these studies were published today in the journal Science.

“The global COVID-19 pandemic has made the development of a vaccine a top biomedical priority, but very little is currently known about protective immunity to the SARS-CoV-2 virus,” said senior author Dan H. Barouch, director of the Center for Virology and Vaccine Research at BIDMC. “In these two studies, we demonstrate in rhesus macaques that prototype vaccines protected against SARS-CoV-2 infection and that SARS-CoV-2 infection protected against re-exposure.”

In the first study, the team found that six candidate DNA vaccines — each formulation using a different variant of the key viral protein — induced neutralizing antibody responses and protected against SARS-CoV-2 in rhesus macaques.

Barouch and colleagues, who began working toward a COVID-19 vaccine in mid-January when Chinese scientists released the SARS-CoV-2 genome, developed a series of candidate DNA vaccines expressing variants of the spike protein, the part used by the virus to invade human cells and a key target for protective antibodies. The vaccines are designed to train the body’s immune system to recognize the virus swiftly upon exposure and respond quickly to disable it.

To assess the efficacy of the vaccines, the researchers immunized 25 adult rhesus macaques with the investigational vaccines. Ten animals received a sham version as a control group. Vaccinated animals developed neutralizing antibodies against the virus. Three weeks after a booster vaccination, all 35 animals were exposed to the virus. Follow-up testing revealed dramatically lower viral loads in vaccinated animals, compared with the control group. Eight of the 25 vaccinated animals demonstrated no detectable virus at any point following exposure to the virus, while the other animals showed low levels of virus. Moreover, animals that had higher antibody levels had lower levels of the virus, a finding that suggests neutralizing antibodies may be a reliable marker of protection and may prove useful as a benchmark in clinical testing of SARS-CoV-2 vaccines.

The vaccines are designed to train the body’s immune system to recognize the virus swiftly upon exposure and respond quickly to disable it.
In the second study, the team demonstrated that macaques that recovered from COVID-19 developed natural protective immunity against re-infection with the virus. The results shed much-needed light on the critical question of just how much, if any, immunity does infection with SARS-CoV-2 provide against subsequent encounters with the virus.

“Individuals who recover from many viral infections typically develop antibodies that provide protection against re-exposure, but not all viruses generate this natural protective immunity,” said Barouch, who is also professor of medicine at Harvard Medical School, a co-leader of the vaccine development group of the Massachusetts Consortium on Pathogen Readiness, and a member of the Ragon Institute of MGH, MIT, and Harvard.

After exposing nine adult macaques to the SARS-CoV-2 virus, the researchers monitored viral levels as the animals recovered. All nine animals recovered and developed antibodies against the virus. More than a month after initial infection, the team re-exposed the rhesus macaques to the virus. Upon second exposure, the animals demonstrated near-complete protection against the virus. These data suggest that animals develop natural protective immunity against the virus and the disease that it causes.

“Our findings increase optimism that the development of COVID-19 vaccines will be possible,” said Barouch. “Further research will be needed to address the important questions about the length of protection as well as the optimal vaccine platforms for SARS-CoV-2 vaccines for humans.”

Future studies will test the Ad26 based vaccines that Barouch is developing in partnership with Johnson & Johnson.

[Lucy]

Campbell 5/21

from 2005

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread
Martin J Vincent,1 Eric Bergeron,2 Suzanne Benjannet,2 Bobbie R Erickson,1 Pierre E Rollin,1 Thomas G Ksiazek,1 Nabil G Seidah,2 and Stuart T Nicholcorresponding author1
Author information Article notes Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
Go to:
Abstract
Background
Severe acute respiratory syndrome (SARS) is caused by a newly discovered coronavirus (SARS-CoV). No effective prophylactic or post-exposure therapy is currently available.

Results
We report, however, that chloroquine has strong antiviral effects on SARS-CoV infection of primate cells. These inhibitory effects are observed when the cells are treated with the drug either before or after exposure to the virus, suggesting both prophylactic and therapeutic advantage. In addition to the well-known functions of chloroquine such as elevations of endosomal pH, the drug appears to interfere with terminal glycosylation of the cellular receptor, angiotensin-converting enzyme 2. This may negatively influence the virus-receptor binding and abrogate the infection, with further ramifications by the elevation of vesicular pH, resulting in the inhibition of infection and spread of SARS CoV at clinically admissible concentrations.

Conclusion
Chloroquine is effective in preventing the spread of SARS CoV in cell culture. Favorable inhibition of virus spread was observed when the cells were either treated with chloroquine prior to or after SARS CoV infection. In addition, the indirect immunofluorescence assay described herein represents a simple and rapid method for screening SARS-CoV antiviral compounds.

[Lucy]

Campbell 5/26

https://www.wsj.com/articles/study-points-to-efficacy-of-convalescent-plasma-for-covid-19-11590177304

Study Points to Efficacy of Convalescent Plasma for Covid-19
Sick patients who got plasma transfusions from those who had recovered from the coronavirus infection had better survival rates compared with a control group

Summary

A study of hospitalized patients with Covid-19 infections provided a sign that blood-plasma transfusions from recovered patients improve survival rates, the largest research effort to date to shed light on the therapy’s efficacy.

The study, posted on the Medrxiv public server on Friday, compared 39 Covid-19 patients who received convalescent plasma transfusions with similar, matched patients who didn’t receive the therapy, all at Mount Sinai Hospital in New York during the same 16-day period.

Researchers at Icahn School of Medicine at Mount Sinai and the Johns Hopkins Bloomberg School of Public Health found the patients who received convalescent plasma had better outcomes compared with similar patients who didn’t get the transfusions. In the study, the plasma recipients were more likely to remain stable or show improvement in their requirements for supplemental oxygen. They also had improved survival when compared with the control patients.

While the findings haven’t undergone peer review or publication in a scientific journal, they provide more evidence that convalescent plasma could be a possible stopgap treatment until vaccines and more targeted therapies are developed.

Earlier this month, a national study involving thousands of Covid-19 patients who received the transfusions appeared to indicate the therapy was safe. Investigators in that study said they couldn’t determine whether plasma caused the improved outcomes because every patient in the study had received it.

The Mount Sinai researchers addressed that problem by creating their own control group, made up of Covid-19 patients who didn’t get the plasma but had similar characteristics and variables, including age, gender, length of hospital stay, oxygen requirement on the day of transfusion and whether they were administered drugs such as hydroxychloroquine and the antibiotic azithromycin.

The researchers were able to scour electronic health records and apply what they called an “aggressive matching algorithm” to find close patient matches. Even so, the investigators acknowledged that despite their best efforts, their conclusions aren’t as strong as those derived from a traditional clinical trial. The study, the largest to date to look at efficacy of convalescent plasma in Covid patients, is still relatively small.

According to the study, on the day of the transfusion, most of the patients who received plasma required supplemental oxygen and four required mechanical ventilation. By day 14 after transfusion, the condition of 18% of the patients who received the plasma had worsened compared with 24.3% in the matched control group.

As of May 1, the authors wrote, 12.8% of the plasma recipients had died compared with 24.4% of the control patients. “Overall, we observed improved survival for the plasma group,” they wrote.

[Lucy]

6/16

I don’t have time right now to look up the actual study, but a cheap steroid, dexamethasone, has been found to reduce the risk of death in patients who are on oxygen or ventilators.

https://www.bbc.com/news/health-53061281

Coronavirus: Dexamethasone proves first life-saving drug
By Michelle Roberts
Health editor, BBC News online
A cheap and widely available drug can help save the lives of patients seriously ill with coronavirus.
The low-dose steroid treatment dexamethasone is a major breakthrough in the fight against the deadly virus, UK experts say.

The drug is part of the world’s biggest trial testing existing treatments to see if they also work for coronavirus.

It cut the risk of death by a third for patients on ventilators. For those on oxygen, it cut deaths by a fifth.
…
The drug is already used to reduce inflammation in a range of other conditions, and it appears that it helps stop some of the damage that can happen when the body’s immune system goes into overdrive as it tries to fight off coronavirus.
…
In the trial, led by a team from Oxford University, around 2,000 hospital patients were given dexamethasone and were compared with more than 4,000 who did not receive the drug.

For patients on ventilators, it cut the risk of death from 40% to 28%. For patients needing oxygen, it cut the risk of death from 25% to 20%.
…

[Lucy]

6/16

That’s not super-exciting news, though, because corticosteroids have been widely used outside the UK to treat inflammation in covid patients for a while. For instance

https://emcrit.org/ibcc/covid19/#steroid_for_severe_hypoxemic_respiratory_failure

Currently, the best evidence with COVID-19 comes from Wu et al 3/13/20.
Retrospective, single-center study describing 201 patients with COVID-19 pneumonia.
Among patients with ARDS, the use of methylprednisolone correlated with reduced mortality.
Typically steroid is used in the sickest patients, so this will create a bias towards seeing worse outcomes in patients treated with steroid. A correlation in the opposite direction is surprising, suggesting that steroid could be causing benefit.
Thus, it may be sensible to use low-dose corticosteroid in patients with substantial hypoxemia and elevated inflammatory markers (e.g. C-reactive protein).
Regimens used in China were typically methylprednisolone 40-80 mg IV daily for a course of 3-6 days, which seems reasonable (Shang et al. 2/29). Equivalent doses of dexamethasone (7-15 mg daily, typically 10 mg daily) could have an advantage of stimulating less fluid retention, since dexamethasone has less mineralocorticoid activity. Notably, this dose of steroid is consistent with doses used in the DEXA-ARDS trial.

Notice the dates of those studies. (bolding added)

still, there are a lot of guidelines out there advising against using steroids, which apparently didn’t appear to help for SARS1.

This article is graphics-heavy, so I won’t post any of it, but it gives a good explanation of the timing issues around using steroids to treat covid.
https://emcrit.org/pulmcrit/steroid-covid/

[Lucy]

That’s what I scraped from the old AO. I guess it’s time to add new stuff about vaccine trials, etc.

[Lucy]

Oh, here’s something I saw yesterday – more promising news re vitamin D

The Journal of Steroid Biochemistry and Molecular Biology

Volume 203, October 2020, 105751

https://www.sciencedirect.com/science/article/pii/S0960076020302764

“Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study”

Basically, a prospective, randomized (but not blinded) study looked at 76 people hospitalized for covid-19. 50 of them were treated with a vitamin D metabolite that is more rapidly absorbed than vitamin D, and the others weren’t. They were all also treated with the then-best-available treatment. Of the 50 given vitamin D, 1 ended up in the ICU, and all 50 recovered. Of the 26 controls, 13 ended up in the ICO and 2 died.

They controlled for what they understood to be major risk factors at the time, but did not record BMI, which has since been found to be highly predictive of covid 19 outcomes.

[Lucy]

I have seen it – it was even posted on the ao, but in a much longer thread. Thanks for bringing it here.

Yes – if that proves to be true, there are apparently several widely available drugs that can help regulate bradykinins, and which might become useful treatments.