An update my boss wrote for friends and family. It's not official, just opinion.
April 11, 2020: 1,500,000 Cases Later
DISCLOSURE: Upon starting this update Saturday morning EST, the official case count reported globally was technically 3 people short of 1,500,000 positive cases from the first note March 21 of 287,329 positive cases (1,444,977). While this constitutes a forward looking statement, by the time this update is finished, the confirmed global count should be more than trued up. Furthermore, if you are seeking that decimal point level of precision, I would guide you to the epidemiologists for further analysis rather than this note which is intended for friends and family!
On a more somber note, there has been, and will continue to be, tragic suffering and mortality this weekend in the world for those that have succumbed to severe infections of COVID-19. We have passed 100,000 deaths officially so far (for perspective, flu related mortality, where we do have antivirals and vaccines for vulnerable people, would be from 12-60K). Depending on how we handle the next few weeks, we could end up being just 15-20 times worse than a flu season, or we could end up a lot worse. Sadly, some of those spending the weekend in the ICU trying to change the mortality statistics will become part of the statistics as a result of infection themselves. That said, there are some positive things we can reflect on this Easter weekend that may give some hope about how we will get through this, and some innovative approaches may help the world recover faster. Many people are rightfully worried about our economy,but it is not a bad weekend to put things in perspective (seeing your family 24 hours a day while remembering when to change from day pajamas to night pajamas). One thing that seems to be most troubling is that many people don’t see a path yet to HOW things gets better, or WHEN things gets better. While we are not declaring victory on this pandemic, this is perhaps a turning point as the Battle of the Bulge. No, we haven’t yet won the war, but we are starting to not lose.
Map Reading – The Big Picture
By way of analogy, at the 60,000 foot level, this pandemic looks like a global brushfire with strong easterly winds. It burned first through Asia and embers sparked strongly in Europe with the US flaring a few weeks later. The size of the red dots (total cases) in the Hopkins tracker is now maxed out so we can no longer tell whether a location has 10,000 cases or 100,000 cases. The brown dots below (active cases) give a better sense of where the fire is burning today compared to how much has burned so far. Recall that viruses need humans as fuel to replicate. So they are helpless without us.
Some people like to use the metric of ‘R0’ for spreading potential of a virus. At a population level, if the virus has an R0 of 2-3 it is like spreading wildfire in dry brush with a strong breeze. If R0 gets below 1, it is like a fire trying to spread across concrete with no wind to carry the embers. It just burns out when the fuel is spent. Staying at home gets the R0 below 1 and makes the virus burn out.
https://coronavirus.jhu.edu/map.html So if we want to figure out how long it takes for the fire to burn out with the fire breaks we have in place now, we can start looking at other countries where it has been burning earlier. While Spain as an example, has less cases overall than the US, it has twice the numbers on a per capita basis (3,462/1M people in Spain vs 1,576/1M people US) and it has been burning longer than the US. The curve below shows that the active cases (number of infected people) in Spain have started to level off. From March 13 through April 3rd, Spain was a burning wildfire with no signs of slowing down. The US on the other hand, really took off around March 22nd. Of course, active case records have measurement bias (different testing rules, testing kit availability etc) and some people like to debate the alternate hypothesis than in the fact things may really be improving. Mortality is a late measurement tool (and has bias), but is a bit more accurate.
So the encouraging thing is that Spain does appear to be flattening out now in number of active cases. And the number of new deaths per day are encouraging. So how long does it take for the fire to burn out? If we look at the decay rate in China, it was about 35 days after the peak of active cases when people started getting back to work slowly. We may not be able to count on this for the US, but it is a complete curve. If Spain starts on a downward slope of active cases by the end of next week however, they will likely have another 30 days, but it will give us more to work with. If everyone knew today that May 20th would be the exact day for the US we would all love to put it on our calendars and start planning. More likely places like New York will come out a little earlier and a few other states will come out a little later. And then we have to talk about how we treat people in the interim, and how we get people back online.
Blood, Tests and Medicine
As noted before, vaccines are definitely in the pipeline, yes they ARE moving forward, and yes I think they will come, but I would not show up at Walgreens asking for your COVID flu shot before the end of 2021. Injecting perfectly healthy people with mixtures of stuff we make in the lab has a higher bar when it comes to first doing no harm. Once a vaccine is proven safe and effective, it will get out there and it will be inexpensive and everyone will be able to get it.
Today clinicians are basically working off one test for active viruses (PCR), a few drugs (chloroquine cocktails, IL6 antibodies) and potentially blood bank derived ‘hyperimmune’ plasma from people that have recovered from infection. The latter is something that is likely to help in a number of ways, including testing for those that have been exposed. Many of my friends in other fields seem to think convalescent plasma means going to old folks homes and taking their blood, so I think the term hyperimmune plasma is probably easier to understand (perhaps).
On the antiviral front, last Friday the New England Journal of Medicine reported out a case study of patients that were given the experimental antiviral remdesivir under compassionate use. For people that develop medicine for a living, the data are frustrating and difficult to articulate. If we were to rely on historical controls, we could be very enthusiastic about the data below. Many patients with both severe disease (intubated) and moderate disease (mild support) improved lung function on this medicine in this small case study. But the cases had no testing for reductions in viral load, and it is well “possible” that the patients treated recovered better for reasons other than the medicine. What we can say is that the medicine tested at the doses used, did not appear to have any severe side effects at the dose tested. The manufacturer of this medicine has some large trials in the US that will be reading out in a few weeks however, and have sufficient numbers in a severe patient population and a mild patient population that I think the drug can be rolled out quickly if the data are clear. The company has several hundred thousand vials already produced so this is an imminent opportunity to help patients if the data support it. This is something that could be deployed to hospitals in 4-6 weeks. So this NEJM publication supports the ongoing trials which will read out soon.
On the hyperimmune plasma side, this is an interesting opportunity that also ties in with new testing methods for finding out who has been exposed to the virus already. There are a number of antibody therapies approved today derived from pooled plasma of healthy blood donors. I spent many (painful) years developing a polyclonal immunoglobulin product with a pharmaceutical company for people with primary immune deficiency. They are produced from healthy donor plasma that have antibodies to different viruses and pathogens people are normally immunized against (measles, hepatitis etc). You inject the antibodies into children and adults that cannot make their own antibodies, and voila, it protects them from infections. In the case of COVID-19, when someone has recovered from an infection, they will produce high levels of antibodies in their blood that help protect them against future infection. FDA has licensed the use of donated plasma from people immune to COVID19. There are no trials to prove it works for COVID19 yet, but it has worked in the past and its pretty quick to get to hospitals. This type of COVID19 blood drive could help people that cannot make antibodies fast enough on their own to fight off the infection. As we move from just being able to test for active infections by PCR to using a quick blood test for antibodies against COVID 19 this also serves a dual purpose. On the one hand we can help identify people that have recovered from COVID 19 infections that can donate blood to help treat patients with active infection at risk of getting very sick. On the other hand we can also identify people that are not likely to be infected again and could be back at work quickly if they were confirmed to be immune.
There has recently been more investigation into trying to understand how some people get a fever but never end up with severe respiratory distress, while others that can be very young and healthy still end up in the ICU. One theory is that the viral load you are infected with could have a big impact on whether your immune system wins or the virus wins. There are sadly some people working in hospitals that are young and healthy but succumb to the disease. The thought is that they may be getting infected with a high level of virus. This theory is really old and goes back to the 1700’s from small pox infections. In short, if someone is infected with a new virus, the immune system needs nearly 10 days before it can mount a response to a new disease. Getting infected with a high viral insult, say 100,000 viral particles in sneeze droplet versus 100 viral particles on a surface, is harder for the immune system to catch up. By the time the immune system builds up on day 10, the virus had a 1000 fold head start and the outcome is lethal. Elderly with a weaker immune system also may not be able to catch up with even a lower viral insult. So while we often think of infection as a binary outcome of “infected” or “not infected”, the race between the immune system and the virus is one that can vary (in addition to many other genetic, age and health dispositions people are looking at). All of these can make the difference between whether a healthy person ends up in the ICU or just has a bad fever and cough.
So in a matter of weeks, once our wildfires have largely run out of fuel from the fire breaks, we may have blood antibody testing ramping up to find out which people are immune and will not carry the virus to others (for example nearly 1/100 people in New York today are positive), and perhaps 1-2 therapies like remdesivir and immune plasma shown effective for those that end up in the hospital with severe cases. At that point I can certainly imagine a phased approach to getting back online in stages. With just a little bit of discipline, we can split companies into 2 groups that work separate shifts and can be merge 3-4 weeks later assuming no new infections in either group. And perhaps those who blood is seropositive for immunity can work double shifts. And with this largely behind us and a vaccine in 2021 we will look back to 2020 as the year we found a new level of appreciation for at least hand sanitizers and toilet paper!
Be Well
Greg
