Please don’t contribute to what is already a veritable swamp of disinformation, Dr. Jetelina.
“Immunity debt” isn’t a thing, because we know that immune systems don’t get stronger with repeat exposure to viruses. Additionally, this idea doesn’t hold up under even the most piddling questions from a non-scientist like me, such as:
1) If this were true, why are states that never had masking/distancing/“school lockdowns” (like in the Southern states) still suffering major waves of illness? Shouldn’t they have been spared these so-called “catch-up” waves, since they have been letting viruses tear through populations this whole time? I live in Georgia, where masking was NEVER a thing— even in medical settings— and schools never had masking requirements and only closed for about 8 weeks in April-May 2020. And I know that many other states— Alabama, Mississippi, Florida, South Carolina, Texas, Arizona, Oklahoma, Kentucky all come to mind— were the same way. So, if one were to buy into the “immunity debt” idea, why are those states still seeing record illness levels?
2) Why are places like Sweden, which famously boasted about its refusal to lockdown, still recording high excess deaths?
3) Why are places like India— which occasionally tries to do the mask mandate thing but hasn’t been very consistent across its enormous population — still getting slammed with waves of COVID and other weird opportunistic infections?
4) We know that the astronauts lucky enough to go to space have to quarantine before a space trip (no hospitals up there) and those going to the ISS stay up there— in a disease-free environment— for months. We know that their bodies are subjected to extensive study and analysis upon their return— which is how we know about the effects of gravity on muscle and bone, for example— and not once in the last 50 years has anyone found an astronaut with “immunity debt” from lack of viral exposure. We also know that immune-naive babies are born every hour of every day of every year all over the world, and we don’t see crushing waves of illness as those little immune systems run up against pre-2020 viruses.
5) Why is this “immunity debt” phenomenon totally new in medical literature and never seen before 2021, and only to justify a “return to normal”? In fact, before 2021, public health officials’ position was that AVOIDING illness was the better way to go, instead of loudly courting repeat illness as they are now, in service to this “immunity debt” deity that they invented out of thin air.
Also, Dr. J, if your position is that the evidence is “thin” on COVID-induced immune dysregulation, then you’re not looking too hard. There are dozens of studies highlighting the effects on CD4, CD8, and T cells at this point.
Lymphopenia/lymphocytopenia, a lack of white blood cells to fight infection, is caused by several things— but even according to official statements from NIH and pharmaceutical company Merck, one of the main causes of that condition is a COVID infection.
Nov 30, 2023Liked by Katelyn Jetelina, Edward Nirenberg
Oh dear. Just two comments.
1) Dr. J makes reference to immunity debt in discussing the effect of water sanitation on polio transmission. This occurred in the early 20th century and we were all taught about this phenomenon in medical school. Yes, there was massive poliovirus immunity debt. It was why there were 40,000 cases of paralytic polio in the U.S. in the summer of 1949. The solution was not simply a vaccine, but an oral vaccine to eliminate enteric replication.
2) Words matter. The concept of a “stronger” or “weaker” immune system is a NON-medical concept. No such thing. Why? Because the immune system is incredibly multifaceted. One can have specific or generalized immune deficits... for example, IgG subclass deficiencies, heritable leukocyte deficiencies, or post-viral T cell suppression.
I have learned that if I read something written by a person whose life work is Epidemiology and it doesn’t sound right, most likely I’M the one who has insufficient knowledge. And medicine has been my life’s work.
"I have learned that if I read something written by a person whose life work is Epidemiology and it doesn’t sound right, most likely I’M the one who has insufficient knowledge." Ditto. Alas, as you have discovered, some folks want to leap straight on to the Tinfoil Hat Train. SARS-Cov-2 has produced a lot of immunology and virology graduates of YouTube University.
I think these are valid questions and it's disappointing to see them unanswered with a reference to tinfoil hats. I'd like to hear JK and EN's answers as I am not medically qualified and want to learn from scientists.
I think it's telling that Dr. Jetelina didn't answer anything I asked, but "liked" the post that essentially is "admonishing" me for asking reasonable questions.
Megan you asked some very good questions, since I haven't seen a direct reply, I thought I would jump in as several have some straightforward answers:
Regarding your point: "“Immunity debt” isn’t a thing, because we know that immune systems don’t get stronger with repeat exposure to viruses."
You are correct that the term "Immunity debt" was a new term introduced post pandemic, and has no use in literature prior to 2020 that I can find (and not even casually used either).
There has been a pretty swift "flip" in PH on Immunity debt as it's cousin "Immunity Gap" has seemingly been embraced. See this comparison of front page of Google for how the results of Immunity Debt during 2022 compare to results of Immunity Gap during 2023:
There is a striking difference how media and PH talked about Immunity Debt in 2022 ("It's problematic" -AHCJ, "no evidence"-McGill, "even if true it was worth it"-Slate, "no such thing"-Vox, "Don't blame immunity debt"-Bloomberg).
And how media and PH talk about Immunity Gap in 2023 ("It explains surge in China" -WHO; "Let's quantify it in immune naive RSV children"-Lancet; "Probably why"-CNN)
There was a sudden shift in talking about it and attitude, no doubt.
HOWEVER, while the terms Immunity Debt/Gap are new, the concept has been around ~33 years - it was called "The Hygiene Hypothesis", an umbrella term to many theories seeking to explain the increase in allergies and autoimmune disorders including MS, IBS, Crohns, Type1 Diabetes, etc - in proportion to both the elimination of many historic pathogens (polio, mumps, smallpox, etc) and increased sanitation and hygiene.
In pop culture the "Hygiene Hypothesis" was largely as taken as self evident as can be seen in the 2001 black comedy "Bubble Boy", and George Carlin's hilarious rant on our obsessing with hand sanitizer.
And aspects of the hypothesis did turn out to be true - for example the late 90's guidance for women to avoid eating tree nuts/peanuts while pregnant and lactating was found to have increased rates of nut allergy in children and largely overturned in the early 2010's.
Additionally, it's accepted fact that the Native Americans and Indigenous People in the Americas died in the millions due to, for better lack of a term, their own "Immunity Gap".
Bottom line (did YLE trademark that yet?), while Immunity Debt and Immunity Gap are new terms, they describe long established theories.
Specific replies to your numbered points:
1) This is a fantastic question, because the corollary question applies as well. If we ascribe our NPIs (social distancing, kids out of school, masks, etc) as the reason why flu/RSV went away during 2020, why did it also go away in places that didn't participate (South Dakota, Florida, Georgia, Sweden, Finland, Denmark, etc). I've suggested elsewhere we should explore the theory of "viral interference" - where a new pathogen is believed to "knock out" existing pathogens (we saw this in 2009 when H1N1 delayed RSV season https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657134/)
I'm not sure of your claim of "they are seeing record levels of illness"? What does RSV incidence look like if we compare the states you mentioned between 2000-2023?
2) See my previous comment - I'm not sure where you heard this, but this is incorrect. Sweden has low excess mortality since early 2021 and overall through the pandemic among the lowest total excess mortality in the world (back and forth with Norway for best outcome).
3) India. This claim took me a day to dive through, I'm not seeing what you mean. According to OWID, cases, deaths, vaccinations all are near zero since late 2022. There was a small wave in Spring 2023 (I can find news articles about this too), though it was a fraction of the 2022 wave. Test reporting ended to OWID mid 2022 though, so likely OWID isn't useful anymore. So, where are you finding this info? I scoured r/India on reddit, can't find much talk of Covid, did some targeted google searches and come up empty. Appears India moved on from Covid. Can you share sources showing otherwise?
4) I think the entire "immunity debt/gap/hygiene hypothesis" focuses on children. An Astronaut is an adult who has already encountered all these pathogens for decades and incredibly fit. To your point, not just astronauts, but seamen and others in the Navy, Antarctic explorers, post Columbian explorers (e.g., Lewis and Clark) remove themselves from society for months/years and don't appear to face a consequence when rejoining society. Key word is "don't appear". We have no idea if Astronauts/Sailors/scientists in the Biosphere happened to have a mild cold within weeks of their mission, because to my knowledge, we have never done prospective studies following them around in search if they got the sniffles.
As for "immune naive babies", unclear what you refer to. Do you mean "all babies", or specifically immunocompromised babies?
5) As noted above, "Immune debt" is very new term, but tangential concepts have been proposed and debated for just over 3 decades. (and for centuries we knew populations who didn't grow up with specific pathogens were at great risk as the Mayans found out when the Spaniards arrived).
I'm not convinced of how you framed: "before 2021, public health officials’ position was that AVOIDING illness was the better way to go, instead of loudly courting repeat illness as they are now"
I think that's a mischaracterization of both pre and post 2021 PH guidance.
Avoiding illness was never promoted above living life prior to 2021, nor was it considered feasible. Steps to avoid illness included "Wash hands, Eat right, get sleep, workout, take Zinc/Vitamin C, get your flu vaccine,avoid people who are already sick when possible". That was it. There was no one in PH arguing to cancel Thanksgiving, avoid going out in public, engage in community masking, work remotely, avoid sending children to in-person school, etc.
These were all brand-new concepts introduced in 2020.
I think a better description of what has happened is that PH has slowly returned to the pre-pandemic understanding that avoidance of common colds, flu, RSV is not sustainable, and can't be realistically achieved long term.
No one is recommending going out and get infected by the cold or the flu or covid. It's just acknowledged that these viruses will always be with us.
As for "COVID-induced immune dysregulation" - yes, there are lots of papers on it. There are also lots of papers on other things which aren't necessarily true (I assume you agree with me Ivermectin doesn't help fight Covid, yet I could show you lots of papers showing it is effective).
My question is: What makes Covid 19 so special compared to the other coronaviruses out there? Why would only this coronavirus cause "immune dysregulation"?
“2) Why are places like Sweden, which famously boasted about its refusal to lockdown, still recording high excess deaths?”
That’s incorrect. They returned to baseline mortality February 2021 and have been at close to baseline ever since. We only have 42 weeks of data for 2023, but so far Sweden on track to have another uneventful year (total deaths in those 42 weeks lower than 5 yr & 3 yr pre-pandemic averages)
Sweden has among the lowest excess deaths of all countries in the world for which we have credible data (back and forth with Norway, just recently passed New Zealand).
All of this is reproducible using the mortality.org datasets
Here’s raw deaths comparing Sweden to her neighbors + South Korea. (Nordic countries all have lowest excess mortality in the world - that’s why put in South Korea for a comparison).
Didn’t include 2023 because each country reports different number of weeks, but spot checking Nordic countries Sweden will have less excess deaths than her neighbors this year unless something changes last 10 weeks of 2023.
I think there is a combination of factors at play, including temporary immunity debt from quarantine/previous infection prevention measures… but I think the additional argument that immune system dysregulation is occurring much more broadly than we would like to admit, needs to be considered. Here is a somewhat alarming counterpoint, but worth a read and discussion:
Hi Ryan- Thanks for your comment! I just don’t see the biological plausibility given the current level of evidence. As you know, this is key for casual epidemiological statements. I look forward to reading through this list of evidence, thanks for sending. But right off the bat, I noticed a lot of this evidence listed is pre-vaccines and among very severe cases, which as we noted in my post, was concerning but a very different landscape than today
Thanks Katelyn - that was my impression, too, and does not mirror what I'm seeing in the office. But I do see a significant cumulative burden of what I can only assume are post-Covid problems after doing extensive work ups for fatigue, shortness of breath, seemingly more frequent URI's, etc. These cases are not the majority, and I appreciate your zoomed out view as an epidemiologist greatly! I won't panic, or try to stoke undue fear. A thorough read of all the referenced studies can be really scary, but always important to look at the macro realities, and overall Covid trends are so much better than pre-vaccine I agree.
This collection of references is cherry-picked and ignores more recent evidence. It also pushes multiple hypotheses that are not substantiated by epidemiological data e.g. superantigenic properties of SARS-CoV-2's spike protein (if this were true, why would we not routinely be seeing a toxic shock-like syndrome in vaccinees?).
Thanks for weighing in. It does try to present a thesis rather than a nuanced consideration of other studies and epidemiological data, hence the cherry picking. I do think there are truths and good science quoted therein, mostly pre-vaccine as Katelyn points out, but I think keeping this line of investigation and consideration open is important in a non-binary world where Covid is neither all good nor all catastrophic.
Thanks for you article today, it was very well done and level headed.
Thanks for your insights! Are there any recent studies on how COVID infections affect the immune system, specifically comparing vaccinated children to unvaccinated children?
It's hard to get a control group for this kind of study because of how common COVID-19 is. We do have data showing that the responses infants mount to SARS-CoV-2 infection tend to be more durable than that of older children because of some unique quirks of their immune system:
Can you please explain how the references are cherry-picked and ignores more recent evidence? At a glace, the Reading List appears to include 79 links to research from years 2020 through 2023.
Most of their studies claiming exhaustion rely entirely on surface markers present on T cells which are also generated upon activation. They do not actually assess the function of the T cells- in studies that do, the T cells are not shown to have exhausted behavior, but rather are highly active.
They have many references claiming to show a decline in various immune cell populations after COVID-19. These declines are almost uniformly transient in longitudinal data, the notable exceptions being in those who are hospitalized with regard to CD8 T cells and NKT cells (although even there one could argue that the overlap between the control group and COVID groups is considerable and again, may be driven by hospitalized patients).
A superantigen hypothesis has been advanced to explain MIS-C and other devastating manifestations of COVID-19, arguing that the spike protein contains an insert that induces massive proliferation of T cells bearing a particular TCR beta clonotype, in the manner that is seen with toxic shock syndrome. While it is an interesting idea and there is some evidence for it (although there is also evidence against it), if this idea were true, we would expect that any exposure to a spike protein would be inducing a toxic shock-like syndrome. This is clearly not happening.
They also misrepresent what the literature actually says (in large part because the author of that post seems to not understand what it says). A classic example is this study:
The WHN post author writes: "Important paper showing immune function was not restored even at 8 months." This paper says nothing about their immunological function- this was not assessed. It shows that those who have long COVID have evidence of persistent, ongoing inflammation 8 months later.
It goes on and on.
The WHN is fundamentally not a credible source of information on this subject, I am afraid.
I’m hoping it’s alarmist in the sense that most people recovering from Covid do pretty well macroscopically, we continue to see reductions in hospitalization and death rates, and the worst case scenarios of immune system senescence and dysregulation are not the norm. But the article is so well-referenced and logical that I’m changing my adjective to “alarming” from “alarmist.” Thank you. Stay safer than most are being out there. And hope that nasal vaccines add a key layer of additional mucosal protection in the future (?)
Thanks, I really appreciate your kind reply and for sharing more information, including the macroscopic (admittedly, I learned a new word, I've never encountered that before) view. I'll be honest that I'm maintaining a position of healthy skepticism on reported reductions in hospitalizations and death rates. This is because I want more information about the accounting/accumulation of that data. I'm concerned about the possibility of many gaps and oversights, especially since we dismantled surveillance systems and contact tracing programs (wastewater is great though, I just wish it was more robustly funded and we had additional tools). Wishing you health and safety too. And yes, I'm looking forward to nasal vaccines as well as other advances in the field of vaccines. While I hold onto that hope, I'm also calling for a return to universal masking with high-quality respirators in healthcare settings so that we can protect each other, especially our most vulnerable community members.
I love this, thanks for such a reasonable reply. I'm pretty sure macroscopic is a real word, and the meaning is self evident regardless, right?!
I continue to wear an N95 in the office for my own protection and for community beneficence. We see Covid, flu, RSV in the office now, and many people think they just have a cold/allergies until I test and often find otherwise. And many of my patients are in their 80's, 90's, and two are over 100... with another ready to hit triple digits in a month!
I think Dr. Jetelina's response to my comment is very reasonable above, check it out. Prudent precaution, shades of gray, and overall trends towards our situation improving I think are the overarching themes, but with notable exceptions to the rule as over 200 people a day in the US are still dying of Covid.
What about the data that shows that over 70% of household Covid spread started with a child? How does having ZERO protections on schools help the children stay healthy? What are the consequences of repeat infections and constant absenteeism? Many school boards won't allow student to stay home for the appropriate amount of time to not spread disease to everyone around them? Mask mandates and proper filtration/ventilation are illegal in Florida. We can't protect ourselves or the kids. I have always avoided school age children (and their parents) this time of year because school aged kids have always been viral incubators of plague and that's only gotten worse.
Isn't brain damage a big issues especially with Covid infection in children?
I'm not sure where you got the idea that we're calling for a lack of protective measures given that we explicitly write that COVID remains a significant problem that causes many issues and at multiple points emphasize the key role of vaccination. We have both strongly advocated for protecting children repeatedly throughout the pandemic and continue to do so.
We have seen that a vaccine-only strategy is not effective for containing COVID, and arguably it isn't doing a good job of even mitigating the impacts of COVID on a population level, given that vaccination does not prevent infection, transmission, or Long COVID. Add to that the fact that vaccination rates for children are absolutely abysmal and you have not acknowledged that reality and pivoted to promoting NPIs, and I fail to see where you have "advocated for protecting children".
Well, there's what health professionals are calling for, and there's what governments at various levels are doing. Sadly, there seems to be a large gap between the two in some parts of the country.
“In the first 2-3 years of the pandemic, RSV and flu, for example, were incredibly suppressed due to pandemic control measures.”
We didn’t have mandated control measures in place for that long, and implementation was not consistent throughout the U.S.. I’ve seen this statement elsewhere many times, and it just isn’t supported. Just think about it.
Immune dysfunction due to previous COVID infection(s) needs to be looked at more closely, especially in children, who will be dealing with the repercussions for decades.
So am I the crazy one since I still mask and avoid crowded I door spaces? We hear about vascular damage, heart attacks, strokes, etc. Is that from people looking to rile up people like me who are still overly cautious? It’s a sincere question because everyone else has moved on.
I must agree with the authors that are doubting immunity debt. There are a lot of articles that point to covid affecting much of the immune system. Cardiovascular-wise there is good evidence that there is an acute and a subacute phase that is immune modulated and can continue for many months for some people and place them at higher risk for myocardial infarction, aneurysm and stroke… even with mild- moderate symptoms. I suspect in children this can present more clinically with elevated levels of autoimmunity (MISC, diabetes, Crohn’s, celiac etc) and immune dysfunction seen with repeated illness and inability to fight off infection. By now some would have had 2-3 covid infections/ year without any mitigation efforts. In my practice we have found people who are positive for elevated inflammatory cytokines for many months and others who have elevated d-dimer and fibrinogen levels over 1 year post covid infection. I have had hospitalized patients who have had necrotizing pneumonia (supposedly rare)- thought to have occurred because the beta amyloid clots from covid which are typically thicker than normal cardiovascular clots block smaller areas of the arteries that did not allow antibiotics to get to the areas needed to alleviate infection. Additionally, there is the mounting amount of research in immunology that says covid causes so much dysfunction to so many cells for many months with the average recovery time being around 6-8 months or longer. I agree with the other authors that covid infection is multifactorial with an overall effect to decrease resilience to fight off infection. If children are being repeatedly infected, then I can imagine that they will essentially be in a chronic immunocompromised state. In the US only 51% of schools used covid ESSER funds to improve air quality. My kids are sitting in classrooms where CO2 levels are consistently greater than 1600 ppm. This is twice what is recommended by CDC to decrease respiratory viral infections. Because covid had such a low mortality rate for children many schools thought they could put the money elsewhere (new pool, new admin building etc.) Covid is the flu right?... and no one would notice. Sept 2024 is the last month to use COVID ESSER funds. Our school district was given 36.5 million. The school district refuses to tell us what HVACs they have changed and what air improvements they have done. Last year we were 40.3% chronically absent. We will see what this year brings. Our area has had no real mitigation efforts for the last 2.5 years. Something else is happening.
If 10 percent of the population (or more) have long covid, then I suspect that at minimum that group would be at risk for chronic immune dysfunction with repeated infection and no mitigation effort. I suspect clinically this number is more but those infected then recover, and with some mitigation, they don’t get reinfected again so frequently.
Here are a few research sites and articles related to immune dysfunction and covid… there is so much more not listed.
We analyzed 71 COVID-19 patients compared to recovered and healthy subjects using high dimensional cytometry. Integrated analysis of ∼200 immune and >30 clinical features revealed activation of T cell and B cell subsets, but only in some patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses could reach >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable to uninfected subjects. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. These analyses identified three “immunotypes” associated with poor clinical trajectories versus improving health. These immunotypes may have implications for therapeutics and vaccines.
A prospective cohort of patients with COVID-19 infection between 16 March 2020 and 30 November 2020 was identified from UK Biobank, and followed for up to 18 months, until 31 August 2021.
I have appreciated Dr J's newsletter and calm, reasoned approach throughout the pandemic, but this one is a real disappointment. The idea that there were extensive lockdowns and masking throughout the country or world is simply not accurate. The (many) states that actively prohibited anti-covid measures are still experiencing record illness. Same with countries who didn't lock down. Why is no one able to respond to this?
Having had RSV or the flu one season doesn't stop you from getting it the next, so in what way does NOT getting it one season make you MORE susceptible the next?
With anywhere from 15-70% of the population experiencing long covid, a syndrome which most studies and doctors seem to agree is related to inflammatory processes, do we now think systemic inflammation DOESN'T make one more susceptible to illness? Why would it NOT be related to how frequently people seem to be getting sick, and how much sicker they seem to be getting?
T cells and B cells are not the only elements of a functioning immune system, not by a long shot, and saying no one has reproduced one paper's suggestion that covid harms B cells isn't even a great argument that it doesn't harm them. How does this make the case for covid harming the immune system "weak"?
This post feels like a lot of wishful thinking. It feels like being asked to disregard what we're seeing in front of our faces: friends and family sick all the time, over and over, with lots of weird things and not just flu or RSV.
My scientific expertise is in other areas, but I will observe that I’ve read comments from a number of scientists who have worked on HIV for years to decades and who are thoroughly convinced on the question whether COVID infection does indeed cause a progressive dysregulation of the immune system.
This has been the first Fall season since the pandemic began that I have heard so many coughing young children out in public. They are everywhere I go. Very productive coughs. What I can't understand is why the parents are bringing these children out in public, stores and even restaurants.
I hate to add anecdotes but my daughter told me that last week in her 7th grade class, 11 out of 14 girls were either out sick or present in school displaying sick symptoms (coughing, vomiting (!)). She doesn’t keep track of the boys much. She is the only kid wearing a mask (Enro) indoors at great social cost but way less infections than classmates x 2 years. We give her the choice.
As always, thank you for keeping us informed. I have other COVID-related questions and wonder if you have any related evidence to share with us:
- are we making any progress on understanding long-covid?
- do we know anything about the long term effects of getting covid? I remember reading somewhere that there was a correlation between kids who had gotten COVID and kids who suddenly developed type-1 diabetes or other auto-immune diseases. Have we reached any sort of conclusions? Thank you!
We absolutely are making progress in learning about long COVID. One of the challenges is that what we call long COVID is probably not one, but many conditions, each with a distinct mechanism driving disease, which will therefore probably require distinct treatment. One recent study (https://www.cell.com/cell/pdf/S0092-8674(23)01034-6.pdf) suggests that long COVID involves major changes to the metabolism of serotonin driven by the persistent inflammation in the condition. This suggests that the condition could be helped by SSRIs for reasons not related to their psychiatric role.
The data regarding diabetes is complex. In some studies there is clearly a rise in diagnoses of type 1 diabetes concurrent with the emergence of COVID-19 (https://jamanetwork.com/journals/jama/fullarticle/2805461). Because if it is left unmanaged, type 1 diabetes causes significant, notable symptoms, it is not likely that there were any kind of change to surveillance of the condition that could give these results. At the same time, a large study in Denmark (https://diabetesjournals.org/care/article/46/6/1261/148729/Risk-of-Type-1-Diabetes-in-Children-Is-Not) did not find an increased risk, and Nordic countries are generally among the best for doing these kinds of analyses because of the level of detail that they can extract from medical records since they have everything linked together in their databases. We also have data suggesting that COVID-19 can cause an elevation in blood sugar through increasing sugar production in the liver, the major reservoir for sugar in the body (https://www.pnas.org/doi/10.1073/pnas.2217119120), which could account for some of the changes seen to blood sugar control after COVID-19, although this normalizes over time after recovering. As for autoimmune diseases as a whole, there does appear to be an indication of an increased risk, which is markedly reduced after vaccination (https://www.thelancet.com/action/showPdf?pii=S2589-5370%2823%2900331-0) but we need to be aware of the limitations in that these studies are retrospective.
So, to my knowledge, that T1D is caused by viral infection prior to COVID-19. Particularly by enterovirus in genetically susceptible children. Of course we have other viruses like EBV or mybe even co-infections?
It has a complex etiology. Viral infections (including by enteroviruses, rotavirus, even varicella) has long been suspected and thought to play a role in the risk but it isn’t a simple straight line causation
A related (naive?) question; has there been any data on "imunity debt" in the ever shrinking group of people that are continuing agressive precautions against Covid-19? Are people that have been vaccinated at every opportunity, are masking and have not been infected with, well, anything in 3 years putting themselves at risk from lack of exposure?
Vaccination counts toward exposure in terms of keeping the immune system trained against a specific pathogen. But yeah, I think this is a valid question. Epidemiologist and Immunologist Michael Mina touches on it in this interview: https://www.nytimes.com/2023/10/05/opinion/covid-pandemic-michael-mina.html?unlocked_article_code=1.CU0.Rk5L.ZovU8oNmh2Hj&smid=url-share. If I am paraphrasing him correctly, he's saying what made Covid-19 dangerous wasn't that Covid-19 is an especially and uniquely destructive virus, it's just that our immune systems had never seen it before so we were defenseless. Our immune systems are only as good as their ability to recognize a threat and mount a defense. Same reason someone born and raised in the United States might have a severe reaction to a pathogen in Africa that doesn't bother the locals. If exposure is inevitable, then maybe it's better to be exposed in bits and bobs enough to keep the immune system primed, than to practice such aggressive avoidance that any time you DO encounter a virus, especially one you don't get regularly vaccinated against, (because one will catch up to you eventually) it's a 'novel' one to your body.
I'm not sure our immune systems are doing that great when people are getting re-infected quite often compared to the flu and those re-infections can vary from asymptomatic to mild to worse than a flu. COVID seems unique in that any one person could get any one of many different symptoms at different severities.
Could our immune system be producing useless non-neutralizing antibodies because of over-vaccination with mRNA vaccines, or could the selection of the spike protein as the target have been a huge blunder?
One study, published in the journal Nature Medicine, found that over-vaccination with mRNA vaccines in mice led to the production of non-neutralizing antibodies that could actually enhance infection with the virus.
Another study, published in the journal Cell Reports, found that over-vaccination with mRNA vaccines in humans led to the production of a type of antibody called an Fcγ2R inhibitory antibody. These antibodies can interfere with the immune system's ability to clear infections.
2. The antibodies you allude to are those that signal through Fcγ2R which has both activating and inhibitory isoforms in the immune system. It is a mistake to say that inhibition automatically indicates impaired infection clearance. Engagement of activating Fc receptors promotes inflammation that leads to tissue damage. The key to a successful immune response is not just to clear the threat but to do so with as little tissue damage as possible. In those who received the ChAdOx-1 vaccine, protection against COVID-19, after matching for levels of neutralization, was found in those who mounted less inflammatory responses to it, whereas those who had more potent inflammation became sickened:
Have to admit you reminds me of a TWiV, episode. "Mice Lie, Monkey Exaggerate" . By any chance you have the links. I like to look at the data and methodology. Thanks
I think the evidence for "immunity debt" is weak at best. Influenza last year was at typical levels. Early in the season, but otherwise typical. Childhood vaccination is down which is certainly a problem. All of the respiratory diseases undergo cyclic variation, which may or may not have anything to do with COVID or precautions against COVID taken during the pandemic. COVID may have nothing to do with any of this. None of the hot linked literature in your post is convincing.
Hi Andrew- thanks for your comment. Flu was pretty typical last year, you’re right. But that’s a virus that isn’t as detrimental to kids like RSV. The lack of immunity among kids has a far different population-level impact than to adults that have immune memory.
Please do not conflate the debunked 'immunity debt' with what Dr J has previously called 'catch-up.' They are 2 entirely different notions. Instead of looking for examples of the term being used to mean catch-up, look at the examples of the term being used to mean 'let it rip,' and see the potential for harm in using the term at all.
Immunity debt makes no sense to me - I don't understand how the pool of susceptibles increases when infection by the viruses concerned do not induce lasting immunity. Otherwise we would not need yearly flu vaccines, for example. Could you clarify this for me?
Can part of the increase be attributed to relaxation of public health measures (decreased masking, decreased participation in vaccinations) which would allow increased spread, not just of CoVid, but also of RSV & flu?
Please don’t contribute to what is already a veritable swamp of disinformation, Dr. Jetelina.
“Immunity debt” isn’t a thing, because we know that immune systems don’t get stronger with repeat exposure to viruses. Additionally, this idea doesn’t hold up under even the most piddling questions from a non-scientist like me, such as:
1) If this were true, why are states that never had masking/distancing/“school lockdowns” (like in the Southern states) still suffering major waves of illness? Shouldn’t they have been spared these so-called “catch-up” waves, since they have been letting viruses tear through populations this whole time? I live in Georgia, where masking was NEVER a thing— even in medical settings— and schools never had masking requirements and only closed for about 8 weeks in April-May 2020. And I know that many other states— Alabama, Mississippi, Florida, South Carolina, Texas, Arizona, Oklahoma, Kentucky all come to mind— were the same way. So, if one were to buy into the “immunity debt” idea, why are those states still seeing record illness levels?
2) Why are places like Sweden, which famously boasted about its refusal to lockdown, still recording high excess deaths?
3) Why are places like India— which occasionally tries to do the mask mandate thing but hasn’t been very consistent across its enormous population — still getting slammed with waves of COVID and other weird opportunistic infections?
4) We know that the astronauts lucky enough to go to space have to quarantine before a space trip (no hospitals up there) and those going to the ISS stay up there— in a disease-free environment— for months. We know that their bodies are subjected to extensive study and analysis upon their return— which is how we know about the effects of gravity on muscle and bone, for example— and not once in the last 50 years has anyone found an astronaut with “immunity debt” from lack of viral exposure. We also know that immune-naive babies are born every hour of every day of every year all over the world, and we don’t see crushing waves of illness as those little immune systems run up against pre-2020 viruses.
5) Why is this “immunity debt” phenomenon totally new in medical literature and never seen before 2021, and only to justify a “return to normal”? In fact, before 2021, public health officials’ position was that AVOIDING illness was the better way to go, instead of loudly courting repeat illness as they are now, in service to this “immunity debt” deity that they invented out of thin air.
Also, Dr. J, if your position is that the evidence is “thin” on COVID-induced immune dysregulation, then you’re not looking too hard. There are dozens of studies highlighting the effects on CD4, CD8, and T cells at this point.
Lymphopenia/lymphocytopenia, a lack of white blood cells to fight infection, is caused by several things— but even according to official statements from NIH and pharmaceutical company Merck, one of the main causes of that condition is a COVID infection.
Oh dear. Just two comments.
1) Dr. J makes reference to immunity debt in discussing the effect of water sanitation on polio transmission. This occurred in the early 20th century and we were all taught about this phenomenon in medical school. Yes, there was massive poliovirus immunity debt. It was why there were 40,000 cases of paralytic polio in the U.S. in the summer of 1949. The solution was not simply a vaccine, but an oral vaccine to eliminate enteric replication.
2) Words matter. The concept of a “stronger” or “weaker” immune system is a NON-medical concept. No such thing. Why? Because the immune system is incredibly multifaceted. One can have specific or generalized immune deficits... for example, IgG subclass deficiencies, heritable leukocyte deficiencies, or post-viral T cell suppression.
I have learned that if I read something written by a person whose life work is Epidemiology and it doesn’t sound right, most likely I’M the one who has insufficient knowledge. And medicine has been my life’s work.
"I have learned that if I read something written by a person whose life work is Epidemiology and it doesn’t sound right, most likely I’M the one who has insufficient knowledge." Ditto. Alas, as you have discovered, some folks want to leap straight on to the Tinfoil Hat Train. SARS-Cov-2 has produced a lot of immunology and virology graduates of YouTube University.
I think these are valid questions and it's disappointing to see them unanswered with a reference to tinfoil hats. I'd like to hear JK and EN's answers as I am not medically qualified and want to learn from scientists.
I think it's telling that Dr. Jetelina didn't answer anything I asked, but "liked" the post that essentially is "admonishing" me for asking reasonable questions.
Megan you asked some very good questions, since I haven't seen a direct reply, I thought I would jump in as several have some straightforward answers:
Regarding your point: "“Immunity debt” isn’t a thing, because we know that immune systems don’t get stronger with repeat exposure to viruses."
You are correct that the term "Immunity debt" was a new term introduced post pandemic, and has no use in literature prior to 2020 that I can find (and not even casually used either).
There has been a pretty swift "flip" in PH on Immunity debt as it's cousin "Immunity Gap" has seemingly been embraced. See this comparison of front page of Google for how the results of Immunity Debt during 2022 compare to results of Immunity Gap during 2023:
https://imgur.com/a/MxMXjzY
There is a striking difference how media and PH talked about Immunity Debt in 2022 ("It's problematic" -AHCJ, "no evidence"-McGill, "even if true it was worth it"-Slate, "no such thing"-Vox, "Don't blame immunity debt"-Bloomberg).
And how media and PH talk about Immunity Gap in 2023 ("It explains surge in China" -WHO; "Let's quantify it in immune naive RSV children"-Lancet; "Probably why"-CNN)
There was a sudden shift in talking about it and attitude, no doubt.
HOWEVER, while the terms Immunity Debt/Gap are new, the concept has been around ~33 years - it was called "The Hygiene Hypothesis", an umbrella term to many theories seeking to explain the increase in allergies and autoimmune disorders including MS, IBS, Crohns, Type1 Diabetes, etc - in proportion to both the elimination of many historic pathogens (polio, mumps, smallpox, etc) and increased sanitation and hygiene.
In pop culture the "Hygiene Hypothesis" was largely as taken as self evident as can be seen in the 2001 black comedy "Bubble Boy", and George Carlin's hilarious rant on our obsessing with hand sanitizer.
https://www.youtube.com/watch?v=X29lF43mUlo
And aspects of the hypothesis did turn out to be true - for example the late 90's guidance for women to avoid eating tree nuts/peanuts while pregnant and lactating was found to have increased rates of nut allergy in children and largely overturned in the early 2010's.
Additionally, it's accepted fact that the Native Americans and Indigenous People in the Americas died in the millions due to, for better lack of a term, their own "Immunity Gap".
https://en.wikipedia.org/wiki/Native_American_disease_and_epidemics
Bottom line (did YLE trademark that yet?), while Immunity Debt and Immunity Gap are new terms, they describe long established theories.
Specific replies to your numbered points:
1) This is a fantastic question, because the corollary question applies as well. If we ascribe our NPIs (social distancing, kids out of school, masks, etc) as the reason why flu/RSV went away during 2020, why did it also go away in places that didn't participate (South Dakota, Florida, Georgia, Sweden, Finland, Denmark, etc). I've suggested elsewhere we should explore the theory of "viral interference" - where a new pathogen is believed to "knock out" existing pathogens (we saw this in 2009 when H1N1 delayed RSV season https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657134/)
I'm not sure of your claim of "they are seeing record levels of illness"? What does RSV incidence look like if we compare the states you mentioned between 2000-2023?
2) See my previous comment - I'm not sure where you heard this, but this is incorrect. Sweden has low excess mortality since early 2021 and overall through the pandemic among the lowest total excess mortality in the world (back and forth with Norway for best outcome).
3) India. This claim took me a day to dive through, I'm not seeing what you mean. According to OWID, cases, deaths, vaccinations all are near zero since late 2022. There was a small wave in Spring 2023 (I can find news articles about this too), though it was a fraction of the 2022 wave. Test reporting ended to OWID mid 2022 though, so likely OWID isn't useful anymore. So, where are you finding this info? I scoured r/India on reddit, can't find much talk of Covid, did some targeted google searches and come up empty. Appears India moved on from Covid. Can you share sources showing otherwise?
4) I think the entire "immunity debt/gap/hygiene hypothesis" focuses on children. An Astronaut is an adult who has already encountered all these pathogens for decades and incredibly fit. To your point, not just astronauts, but seamen and others in the Navy, Antarctic explorers, post Columbian explorers (e.g., Lewis and Clark) remove themselves from society for months/years and don't appear to face a consequence when rejoining society. Key word is "don't appear". We have no idea if Astronauts/Sailors/scientists in the Biosphere happened to have a mild cold within weeks of their mission, because to my knowledge, we have never done prospective studies following them around in search if they got the sniffles.
As for "immune naive babies", unclear what you refer to. Do you mean "all babies", or specifically immunocompromised babies?
5) As noted above, "Immune debt" is very new term, but tangential concepts have been proposed and debated for just over 3 decades. (and for centuries we knew populations who didn't grow up with specific pathogens were at great risk as the Mayans found out when the Spaniards arrived).
I'm not convinced of how you framed: "before 2021, public health officials’ position was that AVOIDING illness was the better way to go, instead of loudly courting repeat illness as they are now"
I think that's a mischaracterization of both pre and post 2021 PH guidance.
Avoiding illness was never promoted above living life prior to 2021, nor was it considered feasible. Steps to avoid illness included "Wash hands, Eat right, get sleep, workout, take Zinc/Vitamin C, get your flu vaccine,avoid people who are already sick when possible". That was it. There was no one in PH arguing to cancel Thanksgiving, avoid going out in public, engage in community masking, work remotely, avoid sending children to in-person school, etc.
These were all brand-new concepts introduced in 2020.
I think a better description of what has happened is that PH has slowly returned to the pre-pandemic understanding that avoidance of common colds, flu, RSV is not sustainable, and can't be realistically achieved long term.
No one is recommending going out and get infected by the cold or the flu or covid. It's just acknowledged that these viruses will always be with us.
As for "COVID-induced immune dysregulation" - yes, there are lots of papers on it. There are also lots of papers on other things which aren't necessarily true (I assume you agree with me Ivermectin doesn't help fight Covid, yet I could show you lots of papers showing it is effective).
My question is: What makes Covid 19 so special compared to the other coronaviruses out there? Why would only this coronavirus cause "immune dysregulation"?
“2) Why are places like Sweden, which famously boasted about its refusal to lockdown, still recording high excess deaths?”
That’s incorrect. They returned to baseline mortality February 2021 and have been at close to baseline ever since. We only have 42 weeks of data for 2023, but so far Sweden on track to have another uneventful year (total deaths in those 42 weeks lower than 5 yr & 3 yr pre-pandemic averages)
Sweden has among the lowest excess deaths of all countries in the world for which we have credible data (back and forth with Norway, just recently passed New Zealand).
All of this is reproducible using the mortality.org datasets
Here’s raw deaths comparing Sweden to her neighbors + South Korea. (Nordic countries all have lowest excess mortality in the world - that’s why put in South Korea for a comparison).
Didn’t include 2023 because each country reports different number of weeks, but spot checking Nordic countries Sweden will have less excess deaths than her neighbors this year unless something changes last 10 weeks of 2023.
https://imgur.com/a/fzB6wbI
I think there is a combination of factors at play, including temporary immunity debt from quarantine/previous infection prevention measures… but I think the additional argument that immune system dysregulation is occurring much more broadly than we would like to admit, needs to be considered. Here is a somewhat alarming counterpoint, but worth a read and discussion:
https://whn.global/scientific/covid19-immune-dysregulation/
Hi Ryan- Thanks for your comment! I just don’t see the biological plausibility given the current level of evidence. As you know, this is key for casual epidemiological statements. I look forward to reading through this list of evidence, thanks for sending. But right off the bat, I noticed a lot of this evidence listed is pre-vaccines and among very severe cases, which as we noted in my post, was concerning but a very different landscape than today
Thanks Katelyn - that was my impression, too, and does not mirror what I'm seeing in the office. But I do see a significant cumulative burden of what I can only assume are post-Covid problems after doing extensive work ups for fatigue, shortness of breath, seemingly more frequent URI's, etc. These cases are not the majority, and I appreciate your zoomed out view as an epidemiologist greatly! I won't panic, or try to stoke undue fear. A thorough read of all the referenced studies can be really scary, but always important to look at the macro realities, and overall Covid trends are so much better than pre-vaccine I agree.
This collection of references is cherry-picked and ignores more recent evidence. It also pushes multiple hypotheses that are not substantiated by epidemiological data e.g. superantigenic properties of SARS-CoV-2's spike protein (if this were true, why would we not routinely be seeing a toxic shock-like syndrome in vaccinees?).
Thanks for weighing in. It does try to present a thesis rather than a nuanced consideration of other studies and epidemiological data, hence the cherry picking. I do think there are truths and good science quoted therein, mostly pre-vaccine as Katelyn points out, but I think keeping this line of investigation and consideration open is important in a non-binary world where Covid is neither all good nor all catastrophic.
Thanks for you article today, it was very well done and level headed.
Thanks for your insights! Are there any recent studies on how COVID infections affect the immune system, specifically comparing vaccinated children to unvaccinated children?
It's hard to get a control group for this kind of study because of how common COVID-19 is. We do have data showing that the responses infants mount to SARS-CoV-2 infection tend to be more durable than that of older children because of some unique quirks of their immune system:
https://www.cell.com/cell/pdf/S0092-8674(23)00978-9.pdf
Can you please explain how the references are cherry-picked and ignores more recent evidence? At a glace, the Reading List appears to include 79 links to research from years 2020 through 2023.
As we discussed in the post:
Most of their studies claiming exhaustion rely entirely on surface markers present on T cells which are also generated upon activation. They do not actually assess the function of the T cells- in studies that do, the T cells are not shown to have exhausted behavior, but rather are highly active.
They have many references claiming to show a decline in various immune cell populations after COVID-19. These declines are almost uniformly transient in longitudinal data, the notable exceptions being in those who are hospitalized with regard to CD8 T cells and NKT cells (although even there one could argue that the overlap between the control group and COVID groups is considerable and again, may be driven by hospitalized patients).
A superantigen hypothesis has been advanced to explain MIS-C and other devastating manifestations of COVID-19, arguing that the spike protein contains an insert that induces massive proliferation of T cells bearing a particular TCR beta clonotype, in the manner that is seen with toxic shock syndrome. While it is an interesting idea and there is some evidence for it (although there is also evidence against it), if this idea were true, we would expect that any exposure to a spike protein would be inducing a toxic shock-like syndrome. This is clearly not happening.
They also misrepresent what the literature actually says (in large part because the author of that post seems to not understand what it says). A classic example is this study:
https://www.nature.com/articles/s41590-021-01113-x?s=09
The WHN post author writes: "Important paper showing immune function was not restored even at 8 months." This paper says nothing about their immunological function- this was not assessed. It shows that those who have long COVID have evidence of persistent, ongoing inflammation 8 months later.
It goes on and on.
The WHN is fundamentally not a credible source of information on this subject, I am afraid.
Thanks for posting the link. Could you please share what characterizes/marks this piece as alarmist in nature?
I’m hoping it’s alarmist in the sense that most people recovering from Covid do pretty well macroscopically, we continue to see reductions in hospitalization and death rates, and the worst case scenarios of immune system senescence and dysregulation are not the norm. But the article is so well-referenced and logical that I’m changing my adjective to “alarming” from “alarmist.” Thank you. Stay safer than most are being out there. And hope that nasal vaccines add a key layer of additional mucosal protection in the future (?)
Thanks, I really appreciate your kind reply and for sharing more information, including the macroscopic (admittedly, I learned a new word, I've never encountered that before) view. I'll be honest that I'm maintaining a position of healthy skepticism on reported reductions in hospitalizations and death rates. This is because I want more information about the accounting/accumulation of that data. I'm concerned about the possibility of many gaps and oversights, especially since we dismantled surveillance systems and contact tracing programs (wastewater is great though, I just wish it was more robustly funded and we had additional tools). Wishing you health and safety too. And yes, I'm looking forward to nasal vaccines as well as other advances in the field of vaccines. While I hold onto that hope, I'm also calling for a return to universal masking with high-quality respirators in healthcare settings so that we can protect each other, especially our most vulnerable community members.
I love this, thanks for such a reasonable reply. I'm pretty sure macroscopic is a real word, and the meaning is self evident regardless, right?!
I continue to wear an N95 in the office for my own protection and for community beneficence. We see Covid, flu, RSV in the office now, and many people think they just have a cold/allergies until I test and often find otherwise. And many of my patients are in their 80's, 90's, and two are over 100... with another ready to hit triple digits in a month!
Thanks for your advocacy on behalf of them.
The article you linked to is alarming, and seems to contradict Dr. Jetelina's post above. As a non-scientist, I don't know what to think!
I think Dr. Jetelina's response to my comment is very reasonable above, check it out. Prudent precaution, shades of gray, and overall trends towards our situation improving I think are the overarching themes, but with notable exceptions to the rule as over 200 people a day in the US are still dying of Covid.
Thank you. Your and Dr. Jetelina's comments are all very helpful.
What about the data that shows that over 70% of household Covid spread started with a child? How does having ZERO protections on schools help the children stay healthy? What are the consequences of repeat infections and constant absenteeism? Many school boards won't allow student to stay home for the appropriate amount of time to not spread disease to everyone around them? Mask mandates and proper filtration/ventilation are illegal in Florida. We can't protect ourselves or the kids. I have always avoided school age children (and their parents) this time of year because school aged kids have always been viral incubators of plague and that's only gotten worse.
Isn't brain damage a big issues especially with Covid infection in children?
All this messaging is so weak. What happened?
I'm not sure where you got the idea that we're calling for a lack of protective measures given that we explicitly write that COVID remains a significant problem that causes many issues and at multiple points emphasize the key role of vaccination. We have both strongly advocated for protecting children repeatedly throughout the pandemic and continue to do so.
We have seen that a vaccine-only strategy is not effective for containing COVID, and arguably it isn't doing a good job of even mitigating the impacts of COVID on a population level, given that vaccination does not prevent infection, transmission, or Long COVID. Add to that the fact that vaccination rates for children are absolutely abysmal and you have not acknowledged that reality and pivoted to promoting NPIs, and I fail to see where you have "advocated for protecting children".
Well, there's what health professionals are calling for, and there's what governments at various levels are doing. Sadly, there seems to be a large gap between the two in some parts of the country.
They aren't less susceptible.
“In the first 2-3 years of the pandemic, RSV and flu, for example, were incredibly suppressed due to pandemic control measures.”
We didn’t have mandated control measures in place for that long, and implementation was not consistent throughout the U.S.. I’ve seen this statement elsewhere many times, and it just isn’t supported. Just think about it.
Immune dysfunction due to previous COVID infection(s) needs to be looked at more closely, especially in children, who will be dealing with the repercussions for decades.
So am I the crazy one since I still mask and avoid crowded I door spaces? We hear about vascular damage, heart attacks, strokes, etc. Is that from people looking to rile up people like me who are still overly cautious? It’s a sincere question because everyone else has moved on.
No, it is still reasonable to continue precautions to avoid getting COVID-19.
I must agree with the authors that are doubting immunity debt. There are a lot of articles that point to covid affecting much of the immune system. Cardiovascular-wise there is good evidence that there is an acute and a subacute phase that is immune modulated and can continue for many months for some people and place them at higher risk for myocardial infarction, aneurysm and stroke… even with mild- moderate symptoms. I suspect in children this can present more clinically with elevated levels of autoimmunity (MISC, diabetes, Crohn’s, celiac etc) and immune dysfunction seen with repeated illness and inability to fight off infection. By now some would have had 2-3 covid infections/ year without any mitigation efforts. In my practice we have found people who are positive for elevated inflammatory cytokines for many months and others who have elevated d-dimer and fibrinogen levels over 1 year post covid infection. I have had hospitalized patients who have had necrotizing pneumonia (supposedly rare)- thought to have occurred because the beta amyloid clots from covid which are typically thicker than normal cardiovascular clots block smaller areas of the arteries that did not allow antibiotics to get to the areas needed to alleviate infection. Additionally, there is the mounting amount of research in immunology that says covid causes so much dysfunction to so many cells for many months with the average recovery time being around 6-8 months or longer. I agree with the other authors that covid infection is multifactorial with an overall effect to decrease resilience to fight off infection. If children are being repeatedly infected, then I can imagine that they will essentially be in a chronic immunocompromised state. In the US only 51% of schools used covid ESSER funds to improve air quality. My kids are sitting in classrooms where CO2 levels are consistently greater than 1600 ppm. This is twice what is recommended by CDC to decrease respiratory viral infections. Because covid had such a low mortality rate for children many schools thought they could put the money elsewhere (new pool, new admin building etc.) Covid is the flu right?... and no one would notice. Sept 2024 is the last month to use COVID ESSER funds. Our school district was given 36.5 million. The school district refuses to tell us what HVACs they have changed and what air improvements they have done. Last year we were 40.3% chronically absent. We will see what this year brings. Our area has had no real mitigation efforts for the last 2.5 years. Something else is happening.
If 10 percent of the population (or more) have long covid, then I suspect that at minimum that group would be at risk for chronic immune dysfunction with repeated infection and no mitigation effort. I suspect clinically this number is more but those infected then recover, and with some mitigation, they don’t get reinfected again so frequently.
Here are a few research sites and articles related to immune dysfunction and covid… there is so much more not listed.
https://libguides.mskcc.org/CovidImpacts/Immune
https://libguides.mskcc.org/CovidImpacts/SecondaryBacterial
https://www.frontiersin.org/articles/10.3389/fmed.2023.1011936/full A review of cytokine-based pathophysiology of Long COVID symptoms
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9967513/#:~:text=Currently%2C%20it%20is%20hypothesized%20that,Multiple%20tissue%20damage%20and% Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID
Post-acute sequelae of COVID-19 is characterized by diminished peripheral CD8+β7 integrin+ T cells and anti-SARS-CoV-2 IgA response
https://whn.global/covid-19-and-immune-dysregulation-a-summary-and-resource/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8898834/
Front Immunol. 2022; 13: 843342.
Published online 2022 Feb 21. doi: 10.3389/fimmu.2022.843342
Depletion and Dysfunction of Dendritic Cells: Understanding SARS-CoV-2 Infection
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-021-02228-6
Published: 14 January 2022 Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection
https://www.cdc.gov/fungal/covid-fungal.html
https://www.nytimes.com/2020/06/26/health/coronavirus-immune-system.html How the coronavirus short circuits the immune system
https://www.biorxiv.org/content/10.1101/2020.05.20.106401v1
We analyzed 71 COVID-19 patients compared to recovered and healthy subjects using high dimensional cytometry. Integrated analysis of ∼200 immune and >30 clinical features revealed activation of T cell and B cell subsets, but only in some patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses could reach >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable to uninfected subjects. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. These analyses identified three “immunotypes” associated with poor clinical trajectories versus improving health. These immunotypes may have implications for therapeutics and vaccines.
https://www.unboundmedicine.com/medline/citation/32405080/Decreased_T_cell_populations_contribute_to_the_increased_severity_of_COVID_19_
Decreased T cell populations contribute to the increased severity of COVID-19.
Clin Chim Acta. 2020 Sep; 508:110-114.
https://www.biorxiv.org/content/10.1101/2020.05.18.101717v1
Immunologic perturbations in severe COVID-19/SARS-CoV-2 infection
https://www.medrxiv.org/content/10.1101/2020.06.08.20125112v1
A consensus Covid-19 immune signature combines immuno-protection with discrete sepsis-like traits associated with poor prognosis
https://pubmed.ncbi.nlm.nih.gov/32425950/
Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19)
Bo Diao et al Front Immunol. 2020
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-021-02228-6#Sec1
Long-term perturbation of the peripheral immune system months after SARS-CoV-2 infection
Whole blood RNA sequencing reveals significant perturbations to gene expression in COVID-19 convalescents until at least 6 months post-infection
https://www.nature.com/articles/s41590-021-01113-x
Profound dysregulation of T cell homeostasis and function in patients with severe COVID-19
https://www.infectioncontroltoday.com/view/covid-19-study-suggests-long-term-damage-immune-system
https://www.nature.com/articles/s41423-021-00728-2
Dendritic cell deficiencies persist seven months after SARS-CoV-2 infection
https://www.frontiersin.org/articles/10.3389/fmed.2023.1011936/full A review of cytokine-based pathophysiology of Long COVID symptoms
https://cardiab.biomedcentral.com/articles/10.1186/s12933-021-01359-7
Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin
https://www.science.org/doi/abs/10.1126/scitranslmed.abq1533 Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts 9 Aug 2023
https://www.science.org/doi/10.1126/scitranslmed.abq1533
Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts
https://www.nih.gov/news-events/nih-research-matters/sars-cov-2-can-cause-lasting-damage-cells-energy-production August 22, 2023 SARS-CoV-2 can cause lasting damage to cells’ energy production
https://journals.physiology.org/doi/full/10.1152/ajpcell.00426.2020
Mitochondrial metabolic manipulation by SARS-CoV-2 in peripheral blood mononuclear cells of patients with COVID-19
https://www.embopress.org/doi/full/10.15252/emmm.202013001
Altered bioenergetics and mitochondrial dysfunction of monocytes in patients with COVID-19 pneumonia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10179190/
Int J Mol Sci. 2023 May; 24(9): 8034.
Published online 2023 Apr 28. doi: 10.3390/ijms24098034 Possible Pathogenesis and Prevention of Long COVID: SARS-CoV-2-Induced Mitochondrial Disorder
https://www.bmj.com/company/newsroom/study-finds-increased-risk-of-serious-blood-clots-up-to-six-months-after-covid-19/
https://pubmed.ncbi.nlm.nih.gov/36652991/
A prospective cohort of patients with COVID-19 infection between 16 March 2020 and 30 November 2020 was identified from UK Biobank, and followed for up to 18 months, until 31 August 2021.
https://academic.oup.com/cardiovascres/advance-article/doi/10.1093/cvr/cvac195/6987834 COVID-19 infection, including long-COVID, is associated with increased short- and long-term risks of CVD and mortality.
https://pubmed.ncbi.nlm.nih.gov/33510633/ Impact of COVID-19 on Mitochondrial-Based Immunity in Aging and Age-Related Diseases
https://www.sciencedirect.com/science/article/pii/S0092867423010346
Serotonin reduction in post-acute sequelae of viral infection
I have appreciated Dr J's newsletter and calm, reasoned approach throughout the pandemic, but this one is a real disappointment. The idea that there were extensive lockdowns and masking throughout the country or world is simply not accurate. The (many) states that actively prohibited anti-covid measures are still experiencing record illness. Same with countries who didn't lock down. Why is no one able to respond to this?
Having had RSV or the flu one season doesn't stop you from getting it the next, so in what way does NOT getting it one season make you MORE susceptible the next?
With anywhere from 15-70% of the population experiencing long covid, a syndrome which most studies and doctors seem to agree is related to inflammatory processes, do we now think systemic inflammation DOESN'T make one more susceptible to illness? Why would it NOT be related to how frequently people seem to be getting sick, and how much sicker they seem to be getting?
T cells and B cells are not the only elements of a functioning immune system, not by a long shot, and saying no one has reproduced one paper's suggestion that covid harms B cells isn't even a great argument that it doesn't harm them. How does this make the case for covid harming the immune system "weak"?
This post feels like a lot of wishful thinking. It feels like being asked to disregard what we're seeing in front of our faces: friends and family sick all the time, over and over, with lots of weird things and not just flu or RSV.
My scientific expertise is in other areas, but I will observe that I’ve read comments from a number of scientists who have worked on HIV for years to decades and who are thoroughly convinced on the question whether COVID infection does indeed cause a progressive dysregulation of the immune system.
This has been the first Fall season since the pandemic began that I have heard so many coughing young children out in public. They are everywhere I go. Very productive coughs. What I can't understand is why the parents are bringing these children out in public, stores and even restaurants.
Because sadly, many people are not willing to inconvenience themselves for the sake of others' health.
I hate to add anecdotes but my daughter told me that last week in her 7th grade class, 11 out of 14 girls were either out sick or present in school displaying sick symptoms (coughing, vomiting (!)). She doesn’t keep track of the boys much. She is the only kid wearing a mask (Enro) indoors at great social cost but way less infections than classmates x 2 years. We give her the choice.
https://www.statnews.com/2023/09/10/covid-cases-rise-new-normal-coronavirus/
Welcome to the new normal.
As always, thank you for keeping us informed. I have other COVID-related questions and wonder if you have any related evidence to share with us:
- are we making any progress on understanding long-covid?
- do we know anything about the long term effects of getting covid? I remember reading somewhere that there was a correlation between kids who had gotten COVID and kids who suddenly developed type-1 diabetes or other auto-immune diseases. Have we reached any sort of conclusions? Thank you!
We absolutely are making progress in learning about long COVID. One of the challenges is that what we call long COVID is probably not one, but many conditions, each with a distinct mechanism driving disease, which will therefore probably require distinct treatment. One recent study (https://www.cell.com/cell/pdf/S0092-8674(23)01034-6.pdf) suggests that long COVID involves major changes to the metabolism of serotonin driven by the persistent inflammation in the condition. This suggests that the condition could be helped by SSRIs for reasons not related to their psychiatric role.
The data regarding diabetes is complex. In some studies there is clearly a rise in diagnoses of type 1 diabetes concurrent with the emergence of COVID-19 (https://jamanetwork.com/journals/jama/fullarticle/2805461). Because if it is left unmanaged, type 1 diabetes causes significant, notable symptoms, it is not likely that there were any kind of change to surveillance of the condition that could give these results. At the same time, a large study in Denmark (https://diabetesjournals.org/care/article/46/6/1261/148729/Risk-of-Type-1-Diabetes-in-Children-Is-Not) did not find an increased risk, and Nordic countries are generally among the best for doing these kinds of analyses because of the level of detail that they can extract from medical records since they have everything linked together in their databases. We also have data suggesting that COVID-19 can cause an elevation in blood sugar through increasing sugar production in the liver, the major reservoir for sugar in the body (https://www.pnas.org/doi/10.1073/pnas.2217119120), which could account for some of the changes seen to blood sugar control after COVID-19, although this normalizes over time after recovering. As for autoimmune diseases as a whole, there does appear to be an indication of an increased risk, which is markedly reduced after vaccination (https://www.thelancet.com/action/showPdf?pii=S2589-5370%2823%2900331-0) but we need to be aware of the limitations in that these studies are retrospective.
Hello
So, to my knowledge, that T1D is caused by viral infection prior to COVID-19. Particularly by enterovirus in genetically susceptible children. Of course we have other viruses like EBV or mybe even co-infections?
It has a complex etiology. Viral infections (including by enteroviruses, rotavirus, even varicella) has long been suspected and thought to play a role in the risk but it isn’t a simple straight line causation
A related (naive?) question; has there been any data on "imunity debt" in the ever shrinking group of people that are continuing agressive precautions against Covid-19? Are people that have been vaccinated at every opportunity, are masking and have not been infected with, well, anything in 3 years putting themselves at risk from lack of exposure?
Vaccination counts toward exposure in terms of keeping the immune system trained against a specific pathogen. But yeah, I think this is a valid question. Epidemiologist and Immunologist Michael Mina touches on it in this interview: https://www.nytimes.com/2023/10/05/opinion/covid-pandemic-michael-mina.html?unlocked_article_code=1.CU0.Rk5L.ZovU8oNmh2Hj&smid=url-share. If I am paraphrasing him correctly, he's saying what made Covid-19 dangerous wasn't that Covid-19 is an especially and uniquely destructive virus, it's just that our immune systems had never seen it before so we were defenseless. Our immune systems are only as good as their ability to recognize a threat and mount a defense. Same reason someone born and raised in the United States might have a severe reaction to a pathogen in Africa that doesn't bother the locals. If exposure is inevitable, then maybe it's better to be exposed in bits and bobs enough to keep the immune system primed, than to practice such aggressive avoidance that any time you DO encounter a virus, especially one you don't get regularly vaccinated against, (because one will catch up to you eventually) it's a 'novel' one to your body.
I'm not sure our immune systems are doing that great when people are getting re-infected quite often compared to the flu and those re-infections can vary from asymptomatic to mild to worse than a flu. COVID seems unique in that any one person could get any one of many different symptoms at different severities.
Could our immune system be producing useless non-neutralizing antibodies because of over-vaccination with mRNA vaccines, or could the selection of the spike protein as the target have been a huge blunder?
One study, published in the journal Nature Medicine, found that over-vaccination with mRNA vaccines in mice led to the production of non-neutralizing antibodies that could actually enhance infection with the virus.
Another study, published in the journal Cell Reports, found that over-vaccination with mRNA vaccines in humans led to the production of a type of antibody called an Fcγ2R inhibitory antibody. These antibodies can interfere with the immune system's ability to clear infections.
1. Non-neutralizing ≠ useless. Antibodies have many functions beyond neutralization that can be protective in the context of infection:
https://www.pnas.org/doi/10.1073/pnas.2217590120
2. The antibodies you allude to are those that signal through Fcγ2R which has both activating and inhibitory isoforms in the immune system. It is a mistake to say that inhibition automatically indicates impaired infection clearance. Engagement of activating Fc receptors promotes inflammation that leads to tissue damage. The key to a successful immune response is not just to clear the threat but to do so with as little tissue damage as possible. In those who received the ChAdOx-1 vaccine, protection against COVID-19, after matching for levels of neutralization, was found in those who mounted less inflammatory responses to it, whereas those who had more potent inflammation became sickened:
https://www.nature.com/articles/s41590-023-01513-1
We also see that neutralizing antibody levels continue to rise with boosting to COVID-19.
I hope scientists are looking in to the questions you raise and not dismissing them out of hand as “misinformation/disinformation.”
Have to admit you reminds me of a TWiV, episode. "Mice Lie, Monkey Exaggerate" . By any chance you have the links. I like to look at the data and methodology. Thanks
I think the evidence for "immunity debt" is weak at best. Influenza last year was at typical levels. Early in the season, but otherwise typical. Childhood vaccination is down which is certainly a problem. All of the respiratory diseases undergo cyclic variation, which may or may not have anything to do with COVID or precautions against COVID taken during the pandemic. COVID may have nothing to do with any of this. None of the hot linked literature in your post is convincing.
Hi Andrew- thanks for your comment. Flu was pretty typical last year, you’re right. But that’s a virus that isn’t as detrimental to kids like RSV. The lack of immunity among kids has a far different population-level impact than to adults that have immune memory.
Please do not conflate the debunked 'immunity debt' with what Dr J has previously called 'catch-up.' They are 2 entirely different notions. Instead of looking for examples of the term being used to mean catch-up, look at the examples of the term being used to mean 'let it rip,' and see the potential for harm in using the term at all.
https://healthjournalism.org/blog/2022/12/why-using-the-term-immunity-debt-is-problematic-for-reporters/
I am also seeing the term, "immunity gap", being used. Same misguided term but where's the evidence? https://www.mcgill.ca/oss/article/covid-19-medical-critical-thinking/claims-immunity-debt-children-owe-us-evidence
Immunity debt makes no sense to me - I don't understand how the pool of susceptibles increases when infection by the viruses concerned do not induce lasting immunity. Otherwise we would not need yearly flu vaccines, for example. Could you clarify this for me?
Can part of the increase be attributed to relaxation of public health measures (decreased masking, decreased participation in vaccinations) which would allow increased spread, not just of CoVid, but also of RSV & flu?
This would promote an increased force of infection that can take advantage of the much larger than usual susceptibility pool, yes.
The question is why the rates of RSV and flu are so much higher than before the pandemic, when we also had no masking.