Any new news on why this is severe/lethal to some, and not others?

The Quarantine Zone
1

So about a week and a half ago, we found out that my dad indeed does have COVID-19. He’s essentially bedridden and lives in a nursing home in the Houston area that has several cases.

He actually had to go to the hospital because he had a serious infection- while he was there, they tested him and it turned out that he had COVID-19 too. But that doesn’t seem to have really caused him any issues- the infection seems to have been the main thing making him acutely ill.

What’s perplexing is that in all regards, he would seem to be a severe risk - 75 years old, Parkinsons, hypertension, diabetic, infection, etc… And yet, he somehow just shrugged off this virus like it wasn’t all that big of a deal.

Meanwhile, I read about people in their thirties and younger catching this and ending up in the ICU and dying from it.

Anyone know why this might be? This is the really perplexing part for me- we seem to have such a wide span of reactions to it- anything from asymptomatic to very quickly lethal, and nobody’s figured out why yet.

2

A Chinese study might give us a clue.

3

I cannot wait to read the book about this in 20 years. It seems important to me that across the board, it’s been dramatically less lethal for small children and signficantly less lethal for women. Men may be more likely to do things like smoke, so that may be noise, but the children thing is really dramatic. If we understood why, that might carry some important clues about why this is so much more lethal for some than for others.

4

Early on there was some speculation about blood type, and certain types being more susceptible. I haven’t heard much about it since. I also recently saw an article about how the virus affects the blood and clotting factors were involved. Maybe people already prone to clotting issues are more at risk? It is fascinating reading the quickly evolving hypotheses and medication trials. Did you see the story about the common pet med (Ivermectin?) may help somewhat? I sure hope we can find a treatment avenue quickly.

5

It is likely that there are specific genetic factors that indicate a predisposition to infection of the viruses’ preferred cell tropism, e.g. a certain configuration of proteins in the cell membrane or elsewhere in the machinery of the cell that make some people more inclined to severe infection. It has also been suggested in light of clear data that people with darker skin (not just “black” but other ethnicities with darker skin) have a higher incidence of serious COVID-19 presentations that Vitamin D, which is naturally produced by lighter skin people in greater quantity, may be a significant factor in the progression of the disease. While I have seen nothing definitive on that topic taking Vitamin D supplements–which are a general immune system booster anyway–is certainly an easy lifestyle modification to make with essentially no downside as long as you don’t exceed the maximum recommended dosage.

Stranger

6

I have not seen any follow up but one possible contributing factor is that there is a difference based on blood type.

Blood Type May Affect COVID-19 Risk: Study

7

And what are the sample sizes for each group and corresponding statistical confidence intervals? In the Chinese mainland, approximately half of all people have a Group O blood type, while only about a quarter are Group A. In the United States and most European countries, the prevalence of those groups is roughly even.

If anything about blood type were a discriminating factor I would actually expect it to be the Rhesus (Rh) factor for a number of reasons.

Stranger

8

Possibly related issue. Apparently the Black Death of the 14th century created some genetic mutations that conferred immunity to HIV on modern descendants.

It seems to me that something like this could be at work.

9

A prominent innate source of variation in immune response is the Major Histocompatibility Complex, aka Human Leukocyte Antigen - google MHC haplotype or HLA haplotype.

MHC molecules sit on the surface of certain cells that process any proteins that they find and present them to the immune system for inspection. The MHC is the most genetically diverse region of the human genome, and it’s subject to active natural selection for diversity: it’s often an advantage to have different MHC alleles to the majority around you, where the difference in itself is a virtue.

Early in life, the adaptive immune system generates a huge random diversity of antibodies and receptors; then those that recognize “self” (molecules that are naturally present in the healthy human body) are deleted before the system goes active. If this were all that happened, it would be easy for pathogens to evade the adaptive immune system by evolving to superficially resemble the shape of molecules that are naturally present in the healthy body.

But the MHC system is much smarter than this. It uses what amounts to encryption, where the encryption key that scrambles the shape of a protein is the MHC allele.

Instead of just presenting proteins in their natural form to the receptors of the immune system, in Antigen-Presenting Cells any proteins that are found are systematically chopped up into samples that are bound to MHC molecules and presented for inspection on the outside of the cell. The shape that the immune system receptors “see” on the surface of these cells is not just the natural shape of the sampled protein, it is the shape when complexed with the MHC molecule. So the effective shape is a function of both the shape of the sampled protein and the shape of the MHC molecule. Since MHC molecules are highly diverse in the population, the same pathogen protein will be “encrypted” into a slightly different presented shape in the context of each different MHC allele. MHC polymorphism in the population creates a wide diversity of different encryption keys, making it vastly more difficult for a pathogen to evolve to always resemble “self” molecules. What is important is not how a protein looks in its raw state, but how it looks in its encrypted state when presented on the MHC molecule.

It’s an inevitable consequence of this system that when a new pathogen arises, it will by chance form a more distinctive and obviously “non-self” shape when complexed with some MHC alleles than with others. So the immune system receptors in people with some MHC haplotypes may more easily detect its presence and eliminate it.

We don’t yet know how important this is for COVID-19, but HLA haplotyping is routine (it’s the same thing as tissue typing for transplants), so I’m sure it will eventually be studied in detail. There are one or two preliminary publications looking at stats, but I’m not aware of anything based on actual testing of patients.

10

There are always going to be exceptions. Your 30 year old friend that died was an exception to the norm. Your Dad surviving even though he had numerous risk categories was an exception.

If you are older, and are predisposed with a vulnerable condition, there is a greater likelihood that you won’t survive it.

11

Sure, but there’s a difference between an outcome being uncertain because we don’t yet understand the significance of all factors, and something being truly random. This is surely the former case, and questions about factors other than just age and comorbidity are extremely important.

12

What makes you think this is “surely” not random?

13

Well, it seems worth looking into.

14

Because the factors that affect pathogen infectiousness and susceptibility are not random, just as incidence of cancer is not random but instead is based upon environmental exposure, genetic predisposition, et cetera. There may be different types of factors including things like nutrition and stress but the virus doesn’t just flip a coin to decide to attack; it exploits specific vulnerabilities to infect and reproduce.

Stranger

15

I’m not disputing that for a given individual, given our current state of knowledge, there may be a large effectively random component in the outcome. That’s even true for diseases that we understand comparatively well, because biology is so complicated.

But the distinction I’m drawing is that effective randomness due to lack of knowledge does not imply that the course of the disease in a particular individual is not ultimately deterministic. It doesn’t imply that we must throw up our hands in hopelessness at the possibility of understanding other significant factors that may be important in determining the likely outcome.

16

Article in The Atlantic online. Presumably COVID-related articles are available to non-subscribers. I don’t know if you have to register or anything. It’s a LONG article.

Why Some People Get Sicker Than Others
COVID-19 is proving to be a disease of the immune system. This could, in theory, be controlled.

17

This makes me wonder something…I’m enrolled in the bone marrow registry, and a handful of years back I got a letter from the registry begging me to renew my commitment to being a donor because I have an extremely rare HLA profile. They noted that I will probably never match anyone, but if I do, I may be someone’s only match so that’s why it’s important to stay a potential donor (I thought we couldn’t back out until we were 61, but I guess some people do); and apparently reading between the lines I’m screwed if I ever needed bone marrow.

Would having an really uncommon HLA profile be helpful here? I’m guessing not since I get other respiratory viruses, but I’ve also never had a stomach bug despite how prolific those are so I figure my immune system does have some quirks.

18

There are two effects here.

The straightforward one is that different HLA haplotypes will just by chance be better or worse when you are exposed to a new pathogen. This is just a function of the variation in the sequence and shape of the HLA molecules, not of their frequency in the population. In this static respect, before the pathogen has had time to evolve significantly, there’s no reason that a rare haplotype confers any advantage. Your particular sequence and shape of HLA molecules may be better or may be worse.

But then there’s a dynamic evolutionary process. Over time, a pathogen will tend to evolve to evade immune systems with relatively common HLA haplotypes, simply through encountering them more frequently. At that stage, after the pathogen has been subject to natural selection in human hosts and evolved significantly, a rare HLA haplotype is likely to be an advantage. A pathogen can’t evolve to evade something it has never encountered before.

At this early stage of SARS-CoV-2 in human hosts, I would doubt that the rarity of your HLA haplotype conveys any advantage against SARS-CoV-2 simply by virtue of its rarity. It will just be a matter of chance whether it’s better or worse. But the rarity of your HLA haplotype will confer a statistical advantage in later waves of infection after the virus has evolved significantly and adapted to the human population. You have a statistical advantage against all pathogens.

19

Your rare haplotype gives you a probabilistic advantage, other things being equal, against any pathogen that has been evolving in human hosts for a significant time. But it’s only a statistical advantage - there are many other factors that may predominate and make you more or less susceptible to any specific pathogen.

20

Here’s an article about a link between nitrogen dioxide levels and COVID-19fatalities. It maps pretty well to population density, but that would have more of an influence on infection rates and not fatalities. Air pollution damage may be a contribution factor in how deadly this thing is.