Encephalitis Linked to COVID-19 Reported

Clinicians from Henry Ford Health System in Detroit, Michigan, have reported the first presumptive case of acute necrotizing hemorrhagic encephalopathy associated with COVID-19.
“As the number of patients with COVID-19 increases worldwide, clinicians and radiologists should be watching for this presentation among patients presenting with COVID-19 and altered mental status,” the clinicians advise in a report published online March 31 in Radiology.
“This is significant for all providers to be aware of and looking out for in [COVID-19] patients who present with an altered level of consciousness. This complication is as devastating as severe lung disease,” Elissa Fory, MD, a neurologist with Henry Ford who was part of the team of medical experts that made the diagnosis, said in a statement.
“We need to be thinking of how we’re going to incorporate patients with severe neurological disease into our treatment paradigm,” Fory added.
Brent Griffith, MD, radiologist with Henry Ford and senior author of the case report, said the case shows “the important role that imaging can play in COVID-19 cases.”

Diagnosed via Neuroimaging

The 58-year-old woman presented with a 3-day history of fever, cough, and muscle aches ― symptoms consistent with COVID-19. She was transported by ambulance to the emergency department and showed signs of confusion, lethargy, and disorientation.
The woman tested negative for influenza, but a rapid COVID-19 test confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) infection. She was later diagnosed with acute hemorrhagic necrotizing encephalopathy.

“The team had suspected encephalitis at the outset, but then back-to-back CT and MRI scans made the diagnosis,” Fory said in the statement.
Noncontrast head CT revealed “symmetric hypoattenuation within the bilateral medial thalami with a normal CT angiogram and CT venogram,” the team reports in their article. Brain MRI showed “hemorrhagic rim enhancing lesions within the bilateral thalami, medial temporal lobes, and subinsular regions.”
The patient was started on intravenous immunoglobulin but not high-dose steroids, because of concern for respiratory compromise. As of April 1, the patient was hospitalized in serious condition. Henry Ford Hospital has not provided an update.
Acute necrotizing encephalopathy (ANE) is a rare complication of viral infections, but until now, it has not been known to have occurred as a result of COVID-19 infection. ANE has been associated with intracranial “cytokine storms,” and a recent report in the Lancet suggested that a subgroup of patients with severe COVID-19 might develop a cytokine storm syndrome.
Commenting for Medscape Medical News, Cyrus A. Raji, MD, PhD, assistant professor of radiology and neurology, Washington University in St. Louis, Missoui, said, “Since this is just one report of one patient, the findings are the most preliminary we can conceive, and more research is needed to determine the extent to which COVID-19 may affect the central nervous system.”
Fory, Griffith, and Raji have disclosed no relevant financial relationships.
Radiology. Published online March 31, 2020. Full text
https://www.medscape.com/viewarticle/928069

COVID-19: Maybe Just Say NO?

I’ve just submitted a hypothesis paper to The Lancet calling for an urgent multicenter prospective randomized controlled trial of arginine and citrulline supplementation for the purposes of pre- and post-exposure prophylaxis against the “novel coronavirus” (SARS-CoV-2). Whether or not that gets accepted, let alone, implemented, however, I feel compelled to put my thoughts forward here, possibly to a broader audience that might benefit. Right off the bat, however, let me give the disclaimer that this does not constitute medical advice — only medical hypothesis.
Here’s what we know so far:
1. Women do better than men with COVID-19. We saw that in the original SARS epidemic in 2003, where being male carried a 67% greater mortality, and we are seeing it again with data from many countries supporting similar gender-inequality. Women, of course, have a lot more estrogen, and estrogen results in increased nitric oxide (NO).
2. Laboratory research from that first SARS epidemic showed that NO not only inhibits the ability of coronavirus to attach to cells (by decreasing the adherence capability of its S or “spike” proteins to the ACE2 receptor) but also inhibits viral replication.
3. Stem cells are being actively researched right now with eight clinical trials underway at the time of this writing. Their activity is complex but seems to have a lot to do with using NO to suppress immune cell hyperreactivity.
4. Lastly, of course, there are also a handful of trials underway looking directly at the effect of nitric oxide in advanced respiratory disease from coronavirus.

So why not just give people NO? It’s a little complicated; first of all, it’s a gas (literally). Hence the inhaled trials in advanced pulmonary disease. Also for the record, it should be noted that NO is extremely complex in terms of its activities, with different and even contradictory effects in many situations depending on concentration, stage of disease, etc.
In other words, NO is potentially quite dangerous. It can have detrimental effects on the immune system or turn the immune system against a person (which is part of the issue, we think, in severe, advanced COVID-19). There is some very limited and again contradictory evidence that in some situations it may promote cancer.
Probably more pertinent from a population risk standpoint, however, is the fact that NO can really mess with blood pressure and put people’s hearts, brains and kidneys at risk if they have a lot of comorbid cardiovascular disease. That’s one reason they teach everybody in ACLS courses to ask about use of “the blue pill” before offering nitroglycerin in angina.

Speaking of sildenafil (and probably tadalafil); since they increase NO, why not try these to ward off coronavirus? First of all, there’s the whole social distancing thing (sorry). In all seriousness, it appears that those drugs may work primarily on one of the NO-synthesizing enzymes that doesn’t really have much to do with the immune system, and in fact may even suppress the important “inducible” NO synthase enzyme that seems to play a much bigger role in immune functions.
Which brings me to my main point and idea here; probably the best way to increase NO is to adopt a healthy lifestyle including regular and consistent exercise. But with time being of the essence now, supplementation with arginine and/or citrulline, two amino acids you can buy over-the-counter (or preferably online nowadays), might be the smartest way to increase NO.
Arginine is the only precursor to NO, meaning NO doesn’t get created in the body except via the transformation of arginine. Many studies over the years have shown that increasing arginine does increase NO, and also improves immune function, and I’m most familiar with that work in the context of surgery. We put a lot of people on arginine before their operation to reduce the risk of wound infections — what we call “immunonutrition.” However, arginine is poorly absorbed by the body, whereas citrulline is much more readily absorbed and serves as a precursor for arginine. In fact, some 60% or so of the NO created by the body is thought to come from citrulline.
All that to say, since I’m not a premenopausal female, I’ve started supplementing with arginine at 2 g per day and citrulline at 1.5 g per day. I’ve got my family and friends, and my staff at the office doing the same thing. I’m NOT saying everyone should do this — again, there are some risks depending on someone’s underlying health status, and those need to be taken into consideration, with consultation preferably from your physician. To reiterate — this does not constitute medical advice.
What I am doing is calling for urgent research into this simple, universally available, inexpensive means of potentially preventing this virus from replicating within hosts. If you happen to decide the potential benefit outweighs the potential risk for yourself, that’s on you. Just don’t buy up and hoard all the stock on Amazon, please.
Heath McAnally, MD, MSPH, is a board-certified anesthesiologist, pain physician, and addictionologist practicing in Alaska (the military sent him there and he decided to stay). If he wasn’t trying to guide people in improving their own lives, teaching medical students to do the same, or writing about it, he’d probably be outdoors right now slogging up a mountain with a good friend or two.
https://www.medpagetoday.com/infectiousdisease/covid19/85770

JPMorgan’s plan delay led to virus outbreak on trading floor

JPMorgan Chase (NYSE:JPM) had planned to have staff at its stock-trading operation split among three separate sites around New York City on March 9 in response to the COVID-19 outbreak.

But the technology wasn’t ready and management told many traders to report to its Manhattan headquarters as usual, the Wall Street Journal reports.

The firm traded a record number of shares in the bank’s history on that day. But one of the employees that showed up that day was sick and turned out to have COVID-19.

In three weeks, some 20 employees who worked on that floor tested positive for the virus and 65 more were quarantined.

A company spokesman said that more than 80% of its traders are working remotely, those who are in the office are more than six feet apart, and employees at risk of infection are sent home.

But salespeople and traders say they feel pressured to come into the office, and managers remind staff that their performance in recent weeks will help determine their compensation.

One manager, the firm’s global head of equities, told employees that the company’s business would suffer if too many employees worked from home. With rivals lagging, he saw the situation as an opportunity to gain market share.

https://seekingalpha.com/news/3558400-jpmorgans-plan-delay-led-to-virus-outbreak-on-trading-floor-wsj

The long path to an effective coronavirus vaccine

What is biopharma doing to develop vaccines against Covid-19, and what are the properties of each approach? Vantage takes a look.

While efforts to develop treatments for Covid-19 continue, it will probably not be possible to declare the pandemic truly over until an effective vaccine exists. Here numerous companies are also active, and a Vantage analysis reveals nearly 25 projects that should be of special interest.
Among these an mRNA vaccine has seized the early lead, courtesy of Moderna, though Johnson & Johnson’s promise to develop an AAV vector-based approach on a non-profit basis might have the most promise. However, despite understandable enthusiasm, the road to having a vaccine approved is long and treacherous.
The need to build sufficient manufacturing infrastructure is just one aspect that will slow the process, and that is before a vaccine with a sufficient efficacy is developed. It could also take a while to find a product with the right mix of safety and ability to generate antibodies that offer sufficient protection.
A recent article by the Coalition for Epidemic Preparedness Innovation (CEPI) in the NEJM pointed to the industry’s ability to respond quickly to the need for pandemic flu vaccines, but said those against Sars had not followed a similar path. Additionally, Covid-19 is an RNA virus, and the industry’s vaccine efforts against this type of pathogen, notably RSV, have underwhelmed.
Early attention
It might surprise that in the coronavirus pandemic Moderna’s mRNA-1273, rather than more traditional vaccine approaches, has seized early attention. One key advantage of RNA (and DNA) vaccines is that they use synthetic processes and do not require culture or fermentation, offering much faster manufacturing.
Moderna itself claims that mRNA vaccines are better at mimicking natural infection, and highlights the “agility” of its manufacturing system. Production for a phase II trial could begin in a few months, and ultimately could allow millions of doses to be made.
Pfizer, which through a deal with Biontech hopes to enter the clinic with another mRNA vaccine this month, told Vantage: “We are working at record pace. While the development process can generally take years, we are working with partners and government agencies to find opportunities to save time wherever we can.”
Unique antigens
Mechanistically, a prophylactic vaccine works by exposing the immune system to antigens unique to the virus in question, seeking to prime the immune system for the quick generation of large amounts of antibodies in the event of an actual infection.
An mRNA vaccine, for instance, comprises mRNA that codes for expression of such a protein antigen. Different vaccines have different properties in terms of whether they generate humoral (B cell and antibody) versus cellular (effector T cell) immunity, and at which sites this is elicited.
Beyond the modality that each vaccine approach uses, and whether adjuvanting is needed to potentiate the immune response, a key consideration is clearly the choice of antigen.
By far the most popular approach has been to target epitopes on Covid-19’s spike protein, a structure found on the surface of the virus. Ideally, antibodies raised against this could bind the virus immediately and stop the infection of host cells. Some vaccines target other so far undisclosed epitopes or proteins.

Selected vaccines in development for Covid-19
Company/org	Vaccine	Type	Target	Detail
Moderna/NIAID	mRNA-1273	mRNA vaccine	SARS-CoV-2 spike protein	First clinical subjects dosed
Cansino Biologics	Ad5-nCoV	AAV5 vaccine	SARS-CoV-2 spike protein	China study under way
Shenzhen Genoimmune	LV-SMENP-DC	Synthetic minigene vaccine	Multiple antigens	Clinical trial started Mar 2020
University of Oxford	COV001	Chimp AAV vaccine	SARS-CoV-2 spike protein	Clinical trial was to have started Mar 2020
Biontech/Pfizer	BNT162	mRNA vaccine	?	Clinical trial starting Apr 2020
Inovio	INO-4800	DNA vaccine	SARS-CoV-2 spike protein	Clinical trial starting Apr 2020
Johnson & Johnson	?	AAV26 vaccine	?	Clinical trial starting Sep 2020
Altimmune	AdCOVID	AAV vaccine	SARS-CoV-2 spike protein	Clinical trial starting Q3 2020
Emergent/Vaxart	?	Undisclosed non-replicating virus	?	Clinical trial starting H2 2020
Geovax	?	VLP vaccine	?	Clinicl trial starting by end 2020
Arcturus	LUNAR-COV19	mRNA vaccine	?	Partnership with Duke-NUS Medical School
Sanofi	?	DNA vaccine	Viral surface proteins	Collaboration with BARDA
Translate Bio/Sanofi	?	mRNA vaccine	?	Deal signed
Dynavax/Clover/GSK	COVID-19 S-Trimer	Trimerised fusion protein	SARS-CoV-2 spike protein	Deals signed
Greffex	?	AAV5 vaccine	?	Preparing for animal testing
Akers	?	?	Major structural proteins	Licensed candidate from Premas
Curevac	?	mRNA vaccine	?	Denies that US offered exclusive vaccine deal
AJ Vaccines	?	Protein subunit vaccine	SARS-CoV-2 spike protein	Started precelinical development
Heat Biologics	?	gp96-based vaccine	Multiple antigens/epitopes	Started precelinical development
Anges/Takara Bio	?	DNA vaccine	?	Collaboration with Osaka University
Epivax	?	Protein subunit vaccine	SARS-CoV-2 spike protein	Collaboration with Uni of Georgia
Generex/Epivax	?	Protein subunit vaccine	Multiple epitopes	To develop Ii-key peptide vaccines
Ibio	?	Protein subunit vaccine	?	Filed patent
Applied DNA/Takis	?	DNA vaccine	SARS-CoV-2 spike protein	Collaboration to identify candidates
Source: WHO list, EvaluatePharma & company statements.

The CEPI has outlined how carrying out multiple activities simultaneously rather than linearly could curtail development times in a pandemic, and J&J says an accelerated timeline could see its lead vaccine being ready for emergency use in 2021.
That would represent an extraordinarily fast turnaround, but even so a vaccine of some sort might be needed even sooner. Thus even a suboptimal vaccine with moderate efficacy that could merely reduce the severity of Covid-19 infection might be a viable way of protecting people as next winter approaches, some think.
“It is hard to imagine fully returning to a pre-Covid-19 life until we have an effective vaccine, most of the population has been infected, or we have therapies that can turn nearly 100% of severe cases into nothing more than the annual ‘flu’,” says Dan Chen, chief medical officer of IGM Biosciences and a coronavirus expert by virtue of his PhD thesis.
This will require global governments to follow through on funding promises. The NEJM paper’s authors caution that the Sars and Zika epidemics ended before vaccine development was complete, at which point federal funding dried up and developers were left nursing losses.
Biopharma obviously wants to play its role in the pandemic, but it will be acutely aware that all too often vaccine development represents an economic black hole.

Traditional and pandemic vaccine development paradigms. Source: CEPI & NEJM.

https://www.evaluate.com/vantage/articles/analysis/vantage-views/long-path-effective-coronavirus-vaccine

CDC recommends face masks for public: coronavirus briefing

The CDC is recommending the public use cloth face masks to help prevent the transmission of COVID-19, President Trump said at the White House coronavirus task force briefing.

They’re not recommending use of medical-grade or surgical masks.

The recommendation is voluntary and doesn’t substitute for the social distancing and hand-washing guidelines already recommended; Trump said he’s choosing not to wear a mask.

Blue Cross Blue Shield won’t require co-pays for coronavirus testing or treatment.

Treating uninsured people who COVID-19 will be covered under the CARES Act, Trump said.

Update at 5:42 PM: More than $3.5B of guaranteed loans for small businesses have been processed in the first day of the paycheck protection program under the CARES Act, he said.

5:45 PM: Separately, Bank of America received more than 58K customers applied for $6B of loans, CNBC reports.

5:53 PM: Dr. Deborah Birx, the White House coronavirus task force response coordinator, said the task force continues to watch Detroit and Chicago and has concerns about Colorado; Washington, DC; and Pennsylvania.

5:55 PM: Department of Health and Human Services Secretary Alex Azar said healthcare exchanges will have a special enrollment period to allow uninsured people who have recently lost their jobs to sign up for health insurance.

5:58 PM: CDC changed its recommendation on face masks for the general public because of new evidence that the virus is being transmitted by people with COVID-19 who aren’t exhibiting symptoms, said Surgeon General Jerome Adams.

6:02 PM: When asked if he agrees with Dr. Anthony Fauci’s opinion that all states should have stay-at-home orders, Trump said he’ll leave it up to the governors.

6:10 PM: Trump allowed two cruise liners to dock today. Some of the passengers will go back to Canada and the U.K. “We had to take care of the sick people,” he said.

6:14 PM: Trump said Russian and Saudi Arabian leaders told him they want to resolve their oil production dispute.

6:15 PM: He said he discussed tariffs with oil executives, who he met with today. They didn’t ask for a bailout, Trump said.

6:34 PM: “Am I thinking about imposing tariffs on Saudi Arabian oil right now? No, but it’s a tool,” he said. Ultimately, the marketplace will resolve the Russia, Saudi Arabia oil dispute, he said.

6:37 PM: Trump brings up the need to invest in America’s infrastructure, specifically speaking about “roads, highways, tunnels, airports, everything.”

6:41 PM: “The general election will happen on Nov. 3,” he said.

6:42 PM: Briefing ends.

This is a developing story; check back for updates.

The U.S. has 270,473 confirmed COVID-19 cases and 6,889 deaths, according to Johns Hopkins University.

https://seekingalpha.com/news/3558399-cdc-recommends-face-masks-for-public-coronavirus-briefing

XBiotech up 23% after hours on Covid-19 convalescent plasma program

XBiotech (NASDAQ:XBIT) will collaborate with non-profit BioBridge Global in an FDA program to collect and distribute convalescent plasma from people who have recovered from COVID-19 infection.

The company has developed a clinical test that BioBridge Global subsidiary QualTex Laboratories will use to identify natural antibodies to SARS-CoV-2 in donated plasma.

South Texas Blood & Tissue Center, another BioBridge subsidiary, will collect the plasma and will provide blood samples to XBIT for use in developing a True Human antibody therapy for the infection.

Shares up 23% after hours.

https://seekingalpha.com/news/3558392-xbiotech-up-23-after-hours-on-convalescent-plasma-program-for-covidminus-19

BioSig up 41% ahead of briefing on COVID-19 candidate

Thinly traded micro cap BioSig Technologies (BSGM +41.3%) is up on almost a 12x surge in volume in reaction to its upcoming “telebriefing” on Tuesday, April 7, to discuss recently acquired Vicromax, a broad-spectrum antiviral that, it says, has shown strong activity against COVID-19 in cell cultures.

Clinical trials assessing Vicromax alone and in combination other drugs are next up.

https://seekingalpha.com/news/3558342-biosig-up-41-ahead-of-briefing-on-covidminus-19-candidate