COVID Transmissions for 12-31-2020

Happy New Year!

Dec 31, 2020

Good morning! I decided to do a 12-31 issue as a surprise gift to all of you.

It has been 410 days since the first documented human case of COVID-19. Much to the relief of many, today is the final day of 2020. This will be the last issue for this week.

A few headlines today, some reader comments, and a bit of a dive into my past as a writer.

As usual, bolded terms are linked to the running newsletter glossary.

Keep the newsletter growing by sharing it! I love talking about science and explaining important concepts in human health, but I rely on all of you to grow the audience for this:

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Now, let’s talk COVID.

Calculating patients’ “viral load”

A recent article in The New York Times, “You’re Infected With the Coronavirus. But How Infected?,” discusses an important issue in COVID-19 testing: https://www.nytimes.com/2020/12/29/health/coronavirus-viral-load.html

I normally really like Apoorva Mandavilli’s work, but this one I felt was too abstracted and didn’t give enough details to readers to really understand the science underlying what she is talking about. I’d like to supplement that by adding my own insight:

Essentially, the article is about clinical labs now being able to provide the healthcare practitioners who request COVID-19 testing with additional details on their patients’ results. In the past, RT-PCR testing of suspected COVID-19 patients was a simple yes or no answer, but the testing assay actually tells us a lot more than that. In the US at least, my understanding was that the FDA actually required the result to be yes or no, but the article calls that into question, so I’m not sure why it was only a “yes” or “no” answer before. However, what is definitive is that it is now allowed for testing companies to provide additional information to physicians about the amount of virus RNA that has been detected in a patient sample, and that is going to change things in COVID-19 care.

In the article, the additional information is described as “viral load,” but I don’t agree with terming it this way. Viral load usually refers to the number of infectious viral particles per milliliter in a patient sample. RT-PCR can give you a count of how many virus RNA genomes are present in the patient sample. Not all virus RNA genomes detected are actually part of virus particles. Some of them are junk from virus particles that the immune system has destroyed, or from infected cells that the virus has killed. So, we can’t call it a strict assessment of “viral load.” It does tend to correlate with viral load, but I think directly equating them oversimplifies the results in a way that could be misleading.

The reason this could be misleading is that many patients continue to test positive by RT-PCR for months after their infection is resolved. This does not mean that they have some “viral load.” What they have is a lot of leftover virus genome fragments that are being flushed out of their bodies now that the immune system has beaten the infection. PCR-positive does not mean virus-positive necessarily; it is simply a stand-in that makes testing more efficient. To actually detect infectious virus would take multiple days just to complete the testing procedure, and would require significant laboratory work. We wouldn’t be able to test even a fraction of patients if that were the standard. RT-PCR helps us to test more people faster, but I want everyone who reads this newsletter to understand its limitations.

Now, that said, it has some big advantages also. Earlier this week, I explained how RT-PCR can be used to measure the amount of RNA in a sample, a circumstance in which it is called “qRT-PCR,” which I’ll copy here for convenience:

qRT-PCR
For what it’s worth, the “q” in qRT-PCR stands for “quantitative.” qRT-PCR is a very accurate technique for the measurement of the amount of RNA present in a sample. It is the technique currently used in the “PCR” tests for COVID-19. It relies on simple mathematics of a chemical reaction that doubles the amount of signal at every step. The number of steps it takes to be able to detect a signal tells you how much RNA you started with. It’s elegant and it works.
I know that’s a little technical, so I’ll describe it by analogy. Eyes are not perfect tools. There are certain things that are too small for us to see. Imagine that I put a line of text on a screen in front of you, and it was far too small for you to read. Then, I ask you the question: what is the size of the font in this text? Obviously you would not be able to answer since you cannot even see the text properly. However, what if you knew that the smallest font you could read is 8 points in size? What if you could ask me to double the size of the font, at will? Imagine that you did, and I had to double the size of the font three times before you were able to read it. If it took three doublings (2 x 2 x 2 = 8) of the font size to get to 8 point font, that means the original font size was 1 point.
This is how qRT-PCR works to quantify RNA. There is a limit of detection, below which we cannot get a reliable signal from the reaction. We know how much nucleic acid is present when that limit of detection is passed. If we count how many doubling steps it takes to get to that limit of detection, we can divide by two the appropriate number of times and figure out how much was in the original sample.
PCR reliably doubles the amount of nucleic acids in a sample. It doesn’t multiply them by 1.4 or 1.7—it doubles them. As a result, this technique is very accurate.

In the setting of a COVID-19 test, qRT-PCR can be used to determine how many viral genomes were present in the original sample. This is given as a “Ct” value, which stands for “cycle threshold.” To elaborate on that, a Ct of 8 means that 8 cycles of doubling (2 raised to the 8th power) raised the amount of signal enough for the genome to be detectable. From this information we can reverse-engineer the amount of viral genome that was present in the original sample. The lower the Ct, the more viral RNA was in the original sample. 8, by the way, is very high. qRT-PCR reads are thought to become less reliable around 35 cycles, with numbers that exceed this representing detection of trace amounts of RNA or even erroneous reaction products.

However, below 35 we can begin to get interesting information about the clinical state of the patient. Specifically, lower Cts indicate a patient who is likely more contagious and more at risk for severe disease. Understanding the Ct of the patient when they present for care is an important datapoint for knowing what treatment approaches may work for them. A patient whose Ct is already in the 30s when they first test positive after being sick is probably not going to have the most serious case. A patient with a Ct around 10 may end up in serious trouble and a medical intervention might be warranted to keep their case from worsening.

I’m not going to speak to the specific thresholds that might be informative here because I am not an expert clinician and I haven’t seen a lot of research on this topic. However, I have seen enough to know that there are thresholds that are informative and that this change in the testing reports is going to help physicians give their patients care. It may also help physicians advise patients on when it’s safe to end their isolation, which would also be a huge win. There’s a lot to be happy about with this change, and I think this is unequivocally good news.

Intentional vaccine spoilage in Wisconsin

I saw a story tonight about 500 doses of the Moderna RNA vaccine being intentionally spoiled by an employee at a clinic in Wisconsin: https://www.fox6now.com/news/aurora-grafton-discarded-covid-19-vaccine-incident-was-intentional

This story is, in a word, horrible. The employee has been fired and there was a referral for criminal charges, which I think are well-warranted. Vaccine supplies are limited and the destruction of these doses means that 500 people will need to wait to be protected from COVID-19. During that time of waiting, some of those 500 people may die of COVID-19. This is especially likely since the most at-risk populations are right now the ones with access to vaccine.

I share this story because it highlights that some people are actively against progress and vaccines. These people are harmful and they hurt others. Their actions can be deadly. I don’t know if antivaccination activism was the reason for this intentional spoilage situation, but I do know how harmful it can be to people who end up catching preventable diseases, and I also can’t think of any other reason a person would intentionally spoil vaccine doses.

I’m incensed to hear about this, but I’m sharing it because I think everyone needs to recognize the threat posed by dangerous conspiracy theories and ignorance in a society besieged by a deadly virus. This pandemic is already an uphill battle. We can’t let this kind of situation become more widespread.

What am I doing to cope with the pandemic? This:

Reorganizing my writing

I’ve been off work for the week and I’m trying to get my past writing sorted out a bit better. Some of you will be aware of this, but as of 2015 I had written 12 published science fiction short stories, and had also written a number of viral articles. My transition to for-profit employment from graduate schools, combined with some other changes in the world, substantially slowed my productivity, however.

I’d like to get back into that more seriously going forward. As it turns out, I’ve written quite a lot in the last 5 years, but not all of it is completed nor in shape—nor even editable to shape—for publication. With my time off, I decided to spend part of today sorting through that work to triage it. That’s the source of one of the links in the “Talk Back” section today.

The real message here is that with the last days of 2020, I’m trying to reset something I’ve fallen behind on so that I can start the year feeling prepared to move forward again. Hopefully we can all start 2021 with renewed focus on things we love to do.

Yesterday, a reader named Jensen left me the following comment. I went back and forth a little bit on whether or not to share it. It’s depressing but I think many of us can really relate to it. I’m sharing to a degree because I don’t think this reader is alone in their feelings:

is there any hope left at all?
I am in such despair at this point. I miss everyone. I miss hugging and being able to play board games in person and getting coffee and having a job. My whole family works in the arts, and we are drowning. The vaccines aren't rolling out fast enough. No one in the US is willing to give the aid we need to shut down, and even if we had it no one has the guts to actually enforce the kind of complete shutdown we need to stop this. I feel we are looking at soon having a mutation that the vaccine won't work against and never being able to do anything ever again. Endless isolation until society collapses. I'm so tired.

I really get it. This year has been exhausting and desperate. It has been frightening and maddening. That may not change soon, but I do think it will change. Here is the reply that I gave:

I'm sorry that you feel this way. I definitely understand why you do. I'm glad you felt comfortable sharing it with me this way. I really do think things are going to get better.
I don't think we are in serious danger of an escape mutant defeating the current vaccines in development. While viruses do often mutate, we are fortunate to have an excellent mechanism for immunity in the form of the adaptive immune system. The adaptive immune system doesn't react to just one part of a viral sequence, but rather to many different parts of the virus protein that generates the immune response; these parts are called "epitopes." Antibodies and T-cell responses are generated to a variety of epitopes along the virus protein. If one epitope mutates, there is another epitope to react to that has not mutated.
Not every epitope can mutate enough to escape the immune system. Something that needs to be kept in mind is that virus proteins are not just used for recognition by the immune system; they have actual functions in the virus life cycle that must be fulfilled. If they mutate to an extreme degree, then these functions will be disrupted. Every amino acid in a protein has subtle effects on the total structure of that protein. There is not always a big "mutational space" that the virus can explore. Most mutations are not terribly helpful to the virus, and some even actively harmful to the successful completion of the virus life cycle.
Under these constraints, it's pretty hard for a virus to easily escape a good vaccine. Influenza virus is able to gradually escape vaccines for a variety of complicated reasons, not least of which is that it has a very high mutation rate. It also has a segmented genome, which means it can trade segments with other variants of influenza. Finally, it has won a kind of genetic lottery by evolving a mechanism by which specific sites on one of its surface proteins, the hemagluttinin protein, are much more likely to generate an immune response than other parts of the virus are. These sites also happen to be very mutable. The influenza virus can therefore change its immune signature with some amount of freedom, but this is still not a quick process. It typically takes a year or so for the virus to even begin to escape, and can take up to 5 years for cross-reactivity with antibodies to old lineages to be lost. So even for the virus that most commonly requires revaccination, this type of mutational escape really isn't easy.
Most viruses are not so capable of mutational escape. Measles virus, for example, doesn't seem to mutate at all to escape the vaccine that we have made against it. That vaccine is highly effective, and it has to be, because measles is extremely contagious.
The SARS-CoV-2 vaccines seem to produce a diverse response to the antigen that they present, which is great because that reduces the chance of mutational escape. Likewise, the virus does not have as frequent a mutation rate as influenza virus or even measles virus. I really doubt that the virus will be capable of easily escaping the vaccines that have been developed.
However, even if such a variant should arise, we are well-protected by the advent of new technologies in the form of mRNA vaccines. Because the principle of the vaccine is that it just provides an mRNA sequence, it can be readily modified to reflect any strains that might emerge. The factories can begin to churn out any new vaccine the day that a new sequence is discovered. Instead of having to come up with an entirely new vaccine, the makers will just need to edit some sequences within the existing manufacturing program. This is going to have a big impact on seasonal influenza virus vaccination as well, I imagine.
I can't really comment on the political situation. I wish that the government in the US were doing more to fight this. I suspect that soon it will be. This morning, Anthony Scaramucci tweeted that there are just "two Scaramuccis" left until Biden is inaugurated, and he has indicated that he plans to aggressively deal with the pandemic in ways that we haven't yet. I'm hopeful for that to come to pass. I think it's going to get better.

I really do think it will get better. But we need to stick together and support each other. That’s one of the reasons I decided to share this comment. All of you, you’re not alone. You’re not alone if you feel bad and you’re not alone if you’re hoping for better—or even if you’re not.

In addition, I had some comments from…myself. Specifically, when I went hunting through my old writing folder today I found a guest post that I had written for a friend’s blog during the 2009 swine-origin influenza virus pandemic, when I was just a 1st-year graduate student. The post was about the changes that I could predict in disease intelligence and surveillance over the next 50 years. I totally forgot about writing it. Finding it again, now, during another pandemic, was kind of surreal. I decided to react and respond to my predictions from 2009, with 11 years of education and perspective. If you’d like, you can read that post, “Disease intelligence in a Twitter world,” here, with my commentary:

https://johnskylar.medium.com/disease-intelligence-in-a-twitter-world-23d1559e4327

You might have some questions or comments! Send them in. As several folks have figured out, you can also email me if you have a comment that you don’t want to share with the whole group.

After reading responses about the frequency of the newsletter, I’ve decided that I won’t be making major modifications to the schedule. In January, I may be changing the schedule such that the Wednesday issue is sent to paid subscribers only, to recognize their support for this project. The other 4 issues a week will continue to go to everyone. Whether I make this change or not, I plan to continue to write this newsletter 5 days a week.

Join the conversation, and what you say will impact what I talk about in the next issue.

Also, let me know any other thoughts you might have about the newsletter. I’d like to make sure you’re getting what you want out of this.

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