For some time, we have been hearing many in the U.S. say that everyone has been infected with SARS-CoV-2 and already had COVID-19. I am guessing that those folks fall into one of three camps:

1. Those who assume this is the case because everyone they know has already had COVID. We need to urge caution with these kinds of observations because much to my chagrin, COVID mitigation measures have become pervasive social and entrenched ideological issues. In other words, we have seen many examples in which the social networks people have are increasingly ideologically aligned. In fact, so much so that, sadly, I am told or have heard about many examples in which families have been torn apart over politics and views on COVID. Those who have embraced COVID mitigation measures are more likely to have social networks that embrace these practices (and therefore know people who have not been infected yet) and those who have been emotionally charged and who have battled against mitigation measures are more likely to have similarly aligned social networks. Thus, it is not surprising that everyone one knows in the latter group has been infected. In my case, I have many friends and family members, as well as many acquaintances who have asked for my advice throughout the pandemic who, to the best of their knowledge, have not yet been infected.
2. There is a coordinated effort among some who have promoted from early on in the pandemic that everyone (some do make exceptions for certain high-risk groups) should get infected or that society would benefit from all of them getting infected. Some earnestly, but erroneously, believed that this would promote so-called “herd immunity” (if you want to read more about herd immunity, Dr. Epperly and I devote nearly an entire chapter in our new book about this concept and why it was flawed in the case of COVID-19: https://www.press.jhu.edu/books/browse-all?keyword=Pate%20and%20COVID-19%20), but others did this for less well-intentioned reasons, including some who are part of antivax campaigns and others who were funded by various groups to spread disinformation. It is beyond the scope of this blog post to get into all the details of folks in this group, but if you want to read more, but just a little more, here is one of many articles that discusses one organized effort (there are others such as America’s Frontline Doctors) https://www.respectfulinsolence.com/2023/06/02/censorship-the-word-disinformation-artists-use-when-called-out/, and if you are very interested in this topic and want to explore it more deeply, then here is a book that I can recommend (I am currently about half-way through it): We Want Them Infected by Jonathon Howard, M.D. https://redhawkpublications.com/We-Want-Them-Infected-p547021769. 
3. The final group comprises those who sincerely believed this to be true and based their belief on published data, but misunderstood what the data was telling us. The CDC and others do “seroprevalence” studies, by which they determine what percentage of the group sampled have antibodies against a particular infection, in this case SARS-CoV-2, and if the group is large enough, then they project what the “seropositivity” rate (the proportion of the population that does have antibodies) is in the general population. The problem is in how you interpret that data and how well the tested group represents the diversity in the general population. So, the remainder of this blog post will be based on interpreting the seroprevalence data.

First, a high-level review of antibodies. There are 5 major categories of antibodies (we abbreviate them with the prefix “Ig” for immunoglobulin (which is the biochemical name for an antibody) and then follow that prefix with a letter that tells us which major class the antibody or immunoglobulin falls into): IgA, IgD, IgE, IgG and IgM. For this blog post, we are only going to talk about IgG. (If you are losing your mind that I am not telling you about the other classes, here is a brief synopsis just to maintain your sanity):

• IgA – these are largely antibodies that reside in mucosal surfaces – nasal lining, gut lining, etc.), but they also are found in our tears and saliva to guard other parts of our body in which bacteria and viruses may try to make entry, and are even found in breast milk potentially helping protect newborn infants (who don’t yet make their own antibodies). When you hear me or others discuss mucosal immunity (which provides for a more rapid response to a pathogen we have already been exposed to previously, and for which we hope to be able to develop with vaccines of the future that hopefully will prevent infection and won’t require that you have previously been infected) IgA is an important component (but certainly not the entire armamentarium) of that mucosal immune defense.
• IgD – we don’t yet fully understand the role of this class of antibodies, but they appear to enhance the ability of cells that produce antibodies to do so and they do help in preventing respiratory infections presumably by activating certain types of white blood cells that you likely have not heard of before, such as basophils and mast cells.
• IgE – these antibodies are often the culprits in allergic and anaphylactic reactions. These antibodies are not always problematic for us, in fact, they play an important role in defending your body from certain multicellular parasites, such as worms.
• IgM – for most bacterial and viral infections or when vaccinating against these types of infection, IgM is the body’s first antibody response, but it is short-lived, so while most often, we test people for IgG in their blood as a marker of whether they have previously been vaccinated against or infected with a particular bacteria or virus (IgG is produced days later than IgM and persists longer than IgM), if we are concerned that someone may have just recently been infected (less than 2 weeks), we will often test for IgM and IgG because the IgG may return negative even though they are very recently infected, but often the IgM test will return positive.

Okay, back to IgG. So, when you read a report about a seroprevalence study, it is important to read exactly what did they test for. Almost always, these studies are based on IgG tests. If so, just understand that if there is a high level of infection going on in the population sampled, jumping to a conclusion as to the percent of the group, or a projection as to the percent of the total population that has been infected can be underestimated and there are other ways in which the data may overestimate the population immune status. How?

First, how might it be underestimated? In the situation I referenced, where there is still a high level of infection going on, realize that people who have been infected within the past week to 2 weeks are likely to test negative for IgG, either because their bodies have not yet had time to produce IgG, or they have started producing IgG, but it is early and those levels may not be high enough to be detected by the particular testing methodology being used.

We can also underestimate the percent of a population that is protected against infection based on seroprevalence studies in a couple of ways. First, antibody levels are dynamic, that is to say they are changing all the time. For most infections that we would be testing for, the body’s response is to make a large number of antibodies, but then reduce that production as the infection comes under control. And, that is a good thing.

As I mentioned, what we commonly refer to as antibodies are biochemically immunoglobulins. You likely, at some point, have had a blood test that measures your blood protein (commonly reported on your lab report as “total protein.” I didn’t contemplate going into math during this blog post, but here we go. Generally speaking, total protein = albumin + globulins. In other words, albumin is a protein (many of you have heard of that, and the level of albumin may be reported on your lab test report, usually right after the report of total protein).

Globulins are also proteins and they comprise a number of different types of proteins, many of which you likely have never heard of, but the largest component of globulins are immunoglobulins! Now, some lab reports will list out total protein, albumin and globulins, but most only list total protein and albumin. In those cases, I just use advanced calculus and subtract the value for albumin from the value for total protein and you get the value for globulins!

One last medical pearl and then I need to get back on topic, as a general rule, your globulin level should be less than your albumin level. When the lab report just lists the total protein and albumin, as long as the albumin level is normal, I usually just look to make sure that the albumin level is at least half of the value of the total protein.

Why would the globulin level ever be higher than the albumin? Well, we could have a situation in which the albumin level is low (decreased production of albumin, such as severe malnutrition or liver disease or increased losses of albumin through the gut or the kidneys). But, if the albumin level is normal and the globulin level is higher than the albumin level, that is when I look for acute infection (because the body is producing a large amount of immunoglobulins) or conditions in which the body produces high levels of globulins (inflammatory conditions that are not infections) in which the globulins that are elevated are not immunoglobulins (although patients with rheumatoid arthritis who produce rheumatoid factor may produce elevated levels of immunoglobulins (IgM) and non-immunoglobulin globulins) and blood disorders in which the types of cells that make immunoglobulins have gone rogue and are making excessively high levels of immunoglobulins such as seen in multiple myeloma and Waldenstrom macroglobulinemia.

My point in all of this is that if your antibody levels went up in response to infection, but never went down, we would be in real trouble from a health standpoint. Antibodies are immunoglobulins and immunoglobulins are a type of globulin, and globulins are proteins. Proteins are relatively large biochemicals in our blood compared to other things carried in our blood such as glucose (sugar), potassium, etc. In the disorders I mentioned above where the cell type that makes antibodies (B-cells) has gone wild making excessive antibodies (e.g., multiple myeloma and Waldenstrom macroglobulinemia, and especially in the latter), these proteins can thicken the blood and cause all kinds of problems, especially related to clogging up small blood vessels. Thus, the normal functioning of our immune system is to reduce production of immunoglobulins over time following either vaccination or infection and rely on so-called memory cells that have seen the protein from the vaccine or prior infection (in the case of COVID, the spike protein of the SARS-CoV-2 virus) that have retained the blueprint for making antibodies that are specific to that protein and have all the machinery of the body ready to go to pump out more and newer antibodies faster than if never before exposed to that protein in case of a booster dose of vaccine or a future infection.

In some infections, especially those that are mild, the body of some people will not produce much antibody and it may reduce to below the levels of detection of an antibody test giving a negative result, when the person has in fact been previously infected and may be protected by virtue of their memory cells as well as other components of their immune system that are not tested in these seroprevalence studies.

Another way that the percent of population immune protection may be underestimated is if we select the wrong group or wrong test for the seroprevalence study. For example, if we conduct a seroprevalence study of influenza antibodies among college students for past circulating strains of influenza, the results would underestimate the immune protection of an older population who lived when those strains were circulating and were previously infected by them. Conversely, if we tested these same college students in the first months of the fall semester for currently circulating influenza strains, we could anticipate getting a very high percentage of students who are seropositive and that might overestimate the seroprevalence of the general population.

But, here is the most important part. We have to know which antibodies specifically were tested for in the seroprevalence study. In terms of COVID, if the test is for antibodies to the spike protein, then people will be positive whether infected, vaccinated or vaccinated and then infected. Thus, when the CDC or anyone else states that 96.4% of those sampled at a point in time tested positive for SARS-CoV-2 antibodies, that does not necessarily mean that 96.4% of the general population has been infected.

Let’s dive into a study that was just published so that I can explain to you how I analyze this type of data. This study came out yesterday: Estimates of SARS-CoV-2 Seroprevalence and Incidence of Primary SARS-CoV-2 Infections Among Blood Donors, by COVID-19 Vaccination Status — United States, April 2021–September 2022 (cdc.gov)

So, here is how I analyze this report. I first look at the title to get an idea of what the authors are likely to try to show in their report: “Estimates of SARS-CoV-2 Seroprevalence and Incidence of Primary SARS-CoV-2 Infections Among Blood Donors, by COVID-19 Vaccination Status — United States, April 2021–September 2022.”

What impressions do I draw? First, the study is apparently designed to provide only an estimate, not the actual, exact measure of seroprevalence and incidence of infection. Second, the study reportedly is going to look at both seroprevalence and at infection rates, therefore, I already assume that they will not be simply relying on IgG assays against the spike protein (because you are exposed to spike protein both from vaccination and from infection. Therefore, to separate these out, I expect to see the investigators test for an antibody that you would only make if infected, e.g., IgG against the nucleocapsid (so-called anti-N) or another protein of the virus that is not contained in the vaccine.)

I also see that their study is going to be based upon blood donors (this makes sense because it is easy to get blood for testing from blood donors!), so we have to be mindful of how those who donate blood might differ from the general population, if they do.

Additionally, we already see from the title that they are likely to put these donors into groups according to vaccination status.

Finally, of critical importance is the time period – April 2021 to September 2022. When I see that, I conclude that first, this covered a time period when we went through a number of waves of different variants – alpha, then delta and then omicron. Secondly, it tells me that whatever that estimate is, it may not be the same today.

Now, having stated all this, there are occasions where an editor comes up with the title of the paper, not the researchers, so never rely solely on the title to draw your conclusions. But, for me, reading the title starts my juices flowing as to what am I going to be looking for and thinking about as I read the paper.

The first thing I do is look at the sample size – in other words, how many people were tested (the more the better). It was 72,748 people, so that seems like a large number, but my next question is how much of the total pool of blood donors does this represent (generally, the larger the better). It was 51%, which ordinarily would concern me as too low, however, in this case, it is actually better than what I thought it might be. This is a longitudinal study, which means that they followed the participants throughout that period of time. Many blood donors, unfortunately, do not donate regularly or frequently enough to provide all the data points needed for this study. Further, there needed to be data available during each period of the study as to the infection status and vaccination status of each study participant. This is data that is not generally collected on blood donors, so it took a lot of extra effort to collect all this data in all 72,748 participants.

As we read further, we see that, in fact, they do utilize antibody to the nucleocapsid protein to identify those previously infected and utilize the conversion of antibody to the nucleocapsid protein from negative to positive in a three-month interval in order to calculate infection incidence rates.

So, what were the findings from this study?

1. During the second quarter of 2021 (April–June), an estimated 68.4% of persons aged ≥16 years had infection- or vaccination-induced SARS-CoV-2 antibodies, including 47.5% from vaccination alone, 12.0% from infection alone, and 8.9% from both.
2. By the third quarter of 2022 (July–September), 96.4% had SARS-CoV-2 antibodies from previous infection or vaccination, including 22.6% from infection alone and 26.1% from vaccination alone; 47.7% had hybrid immunity.
3. During all periods, higher prevalence of hybrid immunity was observed among Black and Hispanic populations than among White and Asian populations.
4. Among persons with no previous infection, the incidence of first infections during the study period (i.e., conversion from anti-N–negative to anti-N–positive) was higher among unvaccinated persons.
5. From April–June 2021 through January–March 2022, the incidence of first SARS-CoV-2 infections among unvaccinated persons was 67.0%, compared with 26.3% among vaccinated persons (p<0.05). From January– March 2022 through April–June 2022, the incidence among unvaccinated persons was 21.7% and was 13.3% among vaccinated persons. Between April–June 2022 and July–September 2022, the incidence among unvaccinated persons was 28.3%, compared with 22.9% among vaccinated persons (p><0.05). ><0.005) [for the non-statisticians, p values are a statistical indication of how likely the finding is truly a significant difference compared to random chance; in this case, a p value less than 0.005 suggests this difference is truly and significantly different]. From January– March 2022 through April–June 2022, the incidence among unvaccinated persons was 21.7% and was 13.3% among vaccinated persons. Between April–June 2022 and July–September 2022, the incidence among unvaccinated persons was 28.3%, compared with 22.9% among vaccinated persons (p<0.05).
6. Incidence of first SARS-CoV-2 infections was higher among younger than among older persons.

What can we take away from this study?

1. The starting time period for this study was April 2021. This was after the first year of the pandemic when vaccines were unavailable and those who wanted to avoid infection largely had to rely on so-called non-pharmaceutical interventions (NPIs) – distancing, avoiding large groups of people, wearing masks, etc. The vaccine roll-out began for non-healthcare workers in January, but was prioritized for high-risk groups initially.
2. By April of 2021, the wild-type virus (original strain, if you will) had largely disappeared and was replaced by progressively more transmissible variants over the course of 2021, 2022 and 2023. In April of 2021, the new variant predominating in the U.S. was alpha.
3. It is striking to note, that at least among blood donors, that even as of June 2021, nearly 70% (47.5/68.4 x 100 = 69.4) of those with antibodies were from vaccination, who had no history or evidence of prior infection.
4. By the end of the study period (September 2022), with the emergence of far more transmissible variants delta and omicron, 27% of those with antibodies (26.2/96.4 x 100 = 27) still had no history or evidence of infection. With the development of progressively greater degrees of immune evasion by new variants, nearly half of those with antibodies had so-called hybrid immunity as a result of vaccination and infection (47.7/96.4 x 100 = 49.5%).
5. The prevalence of hybrid immunity is lowest in adults aged ≥65 years, possibly due to higher vaccination coverage and earlier availability of COVID-19 vaccines for this age group, as well as to higher levels of adoption of behavioral practices (NPIs) to avoid infection.
6. The authors conclude that “In this study, unvaccinated persons had higher rates of infection (as evidenced by N antibody seroconversion) than did vaccinated persons, indicating that vaccination provides some protection against infection.) Of course, it is also likely that those who seek vaccination may be self-assessed to be at higher risk than the general population and therefore were also more likely to continue NPIs in addition to getting vaccinated.
7. Statements to the effect that everyone has been infected by the SARS-CoV-2 virus and had COVID by now are likely exaggerated, but certainly were as of September of 2022. In fact, if the blood donor population is generalizable to the US population, this would suggest that as of September of 2022, almost 87 million Americans may not yet have been infected. Of course, with the continued loosening of COVID countermeasures and the increasing transmissibility of more recent variants, these numbers may have significantly changed by now. Further, this estimate assumes that infection rates in children are the same as adult blood donors, and there is reason to believe that in fact, it may be higher in children.

Nevertheless, it appears that there is a far greater number of yet uninfected Americans than has been commonly believed to be the case. This is good from the standpoint of the population risk for and burden of Long COVID (obviously, you cannot develop Long COVID if you have not been infected). On the other hand, with waning immunity from vaccines and lack of boosters that reflect the currently circulating variants, these previously uninfected persons may be at significantly increased risk if infected.

Since early in the pandemic, I have urged the public not to focus only on deaths from COVID. I cautioned then that getting infected:

• Can result in you infecting someone else who may experience severe disease, even if you are not concerned for yourself and suffer only mild disease;
• Will at minimum disrupt your life by missing work or school and, for many, cause symptoms that can range from a nuisance to extremely annoying (e.g., loss of taste, loss of smell, or persistent ringing in the ears);
• Does cause some people to experience severe disease and be hospitalized, even if they do survive; and finally,
• We know from other viruses, even ones that in some cases cause rather mild illness, that decades later we discover some people develop long-term health effects resulting from those infections, e.g., chickenpox virus (varicella zoster virus) –> shingles; Epstein Barr Virus (one of the viruses that cases infectious mononucleosis) –> multiple sclerosis and a number of unusual malignancies (cancers or lymphoma); human papilloma virus –> cervical cancer (as well as cancers of the vulva, vagina, penis, anus, and oropharynx). Certainly not all viruses cause serious long-term health issues and even those that do don’t cause them in everyone. However, since we don’t really understand this virus and haven’t had long enough time to study it to know the long-term health effects, it is prudent to take reasonable steps to protect yourself and your families from infection.

Based upon what little we did know at the beginning of the pandemic, for someone my age, the risk of severe disease was the greatest concern because I was more likely to die of natural causes before I might develop any of these potential long-term health conditions, if there are any from this virus. On the other hand, long-term health conditions would be a much greater concern for children for whom schools and parents largely threw caution to the wind and some even suggested that it was beneficial for children to get infected in order to develop so-called herd immunity. (Dr. Epperly and I devote nearly an entire chapter on this flawed concept in our newly released book: Preparing for the Next Global Outbreak https://www.press.jhu.edu/books/browse-all?keyword=Pate%20and%20COVID-19%20.

By the fall of 2020, there was emerging and growing evidence for what we now call Long COVID or post-acute sequelae of COVID-19 (PASC). I wrote an update on my blog about this condition yesterday.

However, in 2021, we started seeing signals that there may very well be other serious sequelae from COVID that were flying under the radar. I began to caution the public that there may be other serious long-term effects from COVID-19 other than just Long COVID, but given that we did not have good evidence, I did not go into specifics wanting to avoid being accused of fear-mongering, as so many of us already were.

In today’s blog piece, I am just going to comment on two serious concerns resulting from COVID. There are others, and I have addressed at least five such conditions in previous blog posts (the increase in type I and type II diabetes following COVID, the development of multisystem inflammatory syndrome in children (MIS-C), the later recognized multisystem inflammatory syndrome in adults (MIS-A), postural orthostatic tachycardia syndrome (POTS), and myalgic encephalitis/chronic fatigue syndrome (ME/CFS)).

When a patient tests positive for SARS-CoV-2 infection, develops severe disease, is hospitalized, admitted to the ICU and placed on a ventilator to help keep the patient’s oxygen levels up and the patient has the classic lung changes that we see with COVID, especially in the first two years of the pandemic, it is not difficult to determine that the patient’s death in the hospital when all of our therapies have failed was due to COVID-19. However, we have long realized that there were patients who died within a period of months or even a year following their hospitalization and apparent recovery or simply following a mild or moderate infection that may not have even required medical attention, and certainly not hospitalization, unexpectedly and without another obvious explanation for their death.

One way that we can quantify these deaths that did not occur within 30 days of infection that we often saw with severe disease, but still potentially due to the delayed effects of COVID-19, is to examine so-called “excess deaths.”

Deaths occur every day in the U.S. and across the globe. In large populations, it is fairly easy to project the anticipated number of deaths for an upcoming year by looking at the actual deaths from recent prior years and adjusting for changes in the age distribution of the population. When we see higher numbers of deaths than those projected, we call those “excess deaths.” We also typically divide these deaths into age groups so that we can determine in which age groups those excess deaths are occurring. We also regularly conduct epidemiologic studies to determine the causes of deaths (e.g., automobile accidents, heart disease, cancer, etc.). That gives us a list of the top causes of deaths in the population and even allows for different lists of top causes of deaths for different age groups.

Looking at this data, it was striking to see that there were many warning signs of long-term consequences from COVID. By February of 2022, we saw data indicating that there appeared to be an increased risk of developing a number of cardiovascular disorders following COVID-19, perhaps affecting as many as 4% of all those infected, even with mild disease. Of special concern to me was the mounting evidence that these risks might further increase with each additional reinfection.

By fall of 2022, most of us who study COVID were well convinced that the risk for all kinds of cardiovascular signs, symptoms, diseases and consequences was significantly increased in the year following COVID, including young adults who frequently dismissed the risks of getting infected. In one such study, Excess risk for acute myocardial infarction mortality during the COVID‐19 pandemic – Yeo – 2023 – Journal of Medical Virology – Wiley Online Library, investigators examined excess deaths over a decade (4/1/2012 – 3/31/2022) due to acute myocardial infarctions (AMI) (heart attacks) by age groups. This would give researchers a baseline of heart attack deaths based on trends over a seven-year period prior to the pandemic, as well as a three-year trend during the pandemic.

Before the pandemic, AMI-associated mortality rates decreased across all subgroups, likely due to improved education of the public regarding the importance of blood pressure control, the declines in smoking, and the focus by hospitals of getting people into the cardiac catheterization lab within 30 minutes for interventions that can prevent or at least minimize damage to the heart.

Concerningly, these trends in declining deaths from heart attacks reversed during the pandemic, alarmingly, with the greatest increase seen in younger adults (ages 25 – 44), among both men and women. Excess deaths from heart attacks were most pronounced among those aged 25 – 44 (29.9% relative increase), with relative mortality rate increases ranging from 23 – 34% for the younger age groups to 13% – 18% for older age groups.

And, while many have promoted the narrative that Omicron causes mild COVID, these increases in mortality rates associated with heart attacks persisted throughout the study period, even into the Omicron waves of early 2022.

While it is not proven how SARS-CoV-2 infection precipitates heart attacks over the year following COVID, there are some plausible explanations that I mentioned yesterday in my Long COVID blog post. Namely, SARS-CoV-2 infection causes high degrees of inflammation and can cause micro-clots in some persons. It is believed that the coronary arteries, which carry blood to the heart muscle itself, can become inflamed by the virus and the immune response to the virus (the latter may be more intense in younger adults compared to older adults, potentially explaining why young adults have the highest relative increase in heart attacks following COVID) resulting in narrowing of the arteries and resultant decrease in blood flow to the muscle, which may allow for blockages to the artery from the body’s normal clotting mechanism or by the abnormal micro-clots that we see in some people following COVID-19.

Also in 2022, I had growing concerns about the potential for neurological impairment and diseases following COVID-19. I recall the early studies dating back to March of 2022 revealing that the brain structure could actually be altered following infection as seen on imaging studies, including even a reduction in brain volume, which was very concerning to me. Further, we were seeing more and more patients with neurological signs and symptoms, not just loss of taste or smell and the commonly referred to “brain fog,” but even patients with signs that resembled Parkinson’s disease and rarely patients with a presentation resembling encephalitis (inflammation of the brain with confusion, altered states of consciousness, etc.) that required hospital care.

In yesterday’s blog post, I explained that one theory as to what may be leading to the development of Long COVID is the persistence of virus (or parts of the virus) that may result in ongoing inflammation and overstimulation of the immune system. Recent studies have raised concern that one place where virus or viral components may be persisting is spaces in and around the skull and lining of the brain.

Concerningly, a recent study suggests that ongoing inflammation in the brain may occur even in patients who seemingly had a mild illness with COVID.

We are now seeing that COVID can accelerate the progression of dementia in those with early dementia and can precipitate dementia in those presumably at risk for dementia, but without signs or symptoms of dementia prior to their infection.

A recent study (The functional and structural changes in the hippocampus of COVID-19 patients | SpringerLink) reveals that COVID-19 can stunt the growth of new neurons (nerve cells) in the brain, the process by which the brain repairs itself. This can result in the development of neurodegenerative disorders, including dementia and specifically, Alzheimer’s Disease. The study shows that a part of the brain called the hippocampus, a complex structure that is located deep in the brain and has an important role in memory and learning, is particularly susceptible to injury from the SARS-CoV-2 virus.

There is a very important kind of cell in the brain called microglia, which we previously thought was predominantly a structural support cell, but have learned has an important role in supporting the health of brain cells and the immune response to infections. These microglia are particularly activated during SARS-CoV-2 infection and a cytokine storm-like event (hyperinflammation due to the exuberant release of inflammatory chemicals) can occur inside the brain. With the microglia no longer able to support the repair of neurons, neurodegeneration can occur and the brain, the hippocampus in particular, has diminished ability to repair itself.

I don’t write this blog post to scare anyone. It appears that most people will not develop any of these long-term complications. Rather, I write this to counter the narrative that COVID is over, the pandemic is over, COVID is just a cold or like the “flu, or that COVID is only a threat to the elderly. I merely encourage you to continue to employ precautions when feasible and avoid complacency. I don’t worry for myself. I worry for all the children that we continue to fail to protect, even though schools could implement changes that would not be political or controversial and could keep more kids in school during COVID, as well as our annual cold and flu seasons. Maybe kids will be fine a decade or two from now, even when we allow them to be repeatedly infected and unvaccinated. On the other hand, we are unlikely to know whether they will be fine for many years, and at that point, it likely is too late for those affected.

Unfortunately, no one has a way to identify at this time who will develop long-term problems and who will not. We also should not conclude that we have seen every possible long-term problem manifest by now.

You may think that the title is a bit weird, but it is intentional. I am going to give a brief overview of the current understanding of Long COVID. However, I have practiced medicine long enough to understand that our knowledge about who gets certain diseases, why those individuals get the disease, what mechanisms are causing the disease manifestations and treatments for diseases evolve over decades. There are many reasons for this, but the explosion in our knowledge and understanding of immunology and genetics are two of the main ones. In fact, today, we are beginning to use a combination of genetic editing and, in some cases, the use of certain immune cells to treat cancers, and potentially even cure sickle cell disease, something that was once unimaginable by doctors practicing medicine when I started.

Let’s start with what is the definition of Long COVID. Now, you would think this is a simple question to answer – it isn’t. There is not agreement among different countries, researchers or treating physicians as to what criteria must be met for this diagnosis. We can’t even agree on the name – Long COVID, post-COVID conditions, chronic COVID, and post-acute sequelae of SARS-CoV-2 infection (PASC) – to name just a few.

So, here is the definition that the U.S. Department of Health and Human Services came up with:

“Long COVID is broadly defined as signs, symptoms, and conditions that continue or develop after initial COVID-19 or SARS-CoV-2 infection. The signs, symptoms, and conditions are present four weeks or more after the initial phase of infection; may be multisystemic; and may present with a relapsing– remitting pattern and progression or worsening over time, with the possibility of severe and life-threatening events even months or years after infection. Long COVID is not one condition. It represents many potentially overlapping entities, likely with different biological causes and different sets of risk factors and outcomes.” https://www.covid.gov/longcovid/definitions.

Now, as a physician who specializes in the diagnosis of diseases in adults, let me tell you these criteria are not that helpful, especially because the milder symptoms that we see in some patients following COVID can also be reported randomly among the general population. Note that there is no diagnostic test for this condition or host of conditions, unlike blood cell counts for the diagnosis of anemia, blood sugars for the diagnosis of diabetes, etc.

So, the authors of a study published in the Journal of the American Medical Association (Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection | Neurology | JAMA | JAMA Network) asked the question that all doctors dealing with this condition ask: What symptoms are differentially present in SARS-CoV-2–infected individuals 6 months or more after infection compared with uninfected individuals, and what symptom-based criteria can be used to identify post-acute sequelae of SARS-CoV-2 infection (PASC) cases?

The investigators analyzed data from 9764 participants in the RECOVER adult cohort, a prospective longitudinal cohort study, and 37 symptoms across multiple pathophysiological domains were identified as present more often in SARS-CoV-2–infected participants at 6 months or more after infection compared with uninfected participants (the occurrence of the symptom had to be 50% higher in the infected group vs. the uninfected group). 

The authors were able to use various methodologies, including statistical modelling, to come up with a list of the most differentiating symptoms and a weighting score for each.

This is in part based upon the actual frequency with which certain symptoms are seen in PASC patients (see Figure B below):

Based upon the symptoms the patient presents with and the scores assigned by the weighting methodology above, we can then see in Figure A above that a score of 12 seems to be the threshold for high confidence in the diagnosis of PASC or Long COVID.

While all of this is nice, and certainly is helpful, I have no doubt that our understanding of this disease (or cluster of related diseases) will change and evolve over time. I also believe that we will develop better diagnostic testing for these conditions. We should all keep in mind that given that there appear to be different subgroups of patients with PASC involving a differing predominance of signs and symptoms (e.g., those that predominantly have postural orthostatic tachycardia syndrome (POTS) or those with a myalgic encephalomyelitis/chronic fatigue syndrome-like presentation) and different underlying potential underlying pathogenetic abnormalities (more on this below), it may very well be that SARS-CoV-2 can produce different pathological sequelae in different people that in turn leads to different manifestations and presenting syndromes. Once we understand these better and can differentiate them into different specific syndromes, the data presented above that reflects the combination of all these syndromes may look very different when we can sort patients by specific syndrome. For example, in the study above, the investigators noted that patients seemed to fall into one of four clusters of symptoms: Cluster 1 was characterized by loss of or change in smell or taste; cluster 2 by post-exertional malaise and fatigue; cluster 3 by brain fog, post-exertional malaise, and fatigue; and cluster 4 by fatigue, post-exertional malaise, dizziness, brain fog, gastrointestinal symptoms, and palpitations.

We also need to be careful to evaluate each patient separately to understand their pre-existing and underlying health conditions as well as their severity of illness with COVID. For example, for those patients who developed severe COVID and required critical care services, we need to be able to distinguish Long COVID or PASC from a well-described post-intensive care syndrome which has occurred in patients long before COVID came on the scene and for which there are many overlapping signs and symptoms.

We still don’t fully understand the difference in risk for Long COVID based upon the variant you get infected with. Earlier studies have suggested that Long COVID was more frequent and more severe when people were infected with variants prior to Omicron (before December 2021). Nevertheless, it is staggering to note that even during Omicron, studies have repeatedly suggested that 10% of those infected will develop Long COVID. There have been inconsistent reports of increased risk for Long COVID if people have more than one infection. However, almost every study shows that being vaccinated significantly reduces, but does not eliminate, your risk of developing Long COVID with breakthrough infections.

Although to some, the percentage of infections resulting in Long COVID may seem small, when applied across large populations, the numbers are staggering. For example, recent estimates are that 65 million people across the globe have Long COVID. I don’t think that the U.S. has begun to appreciate what this will mean to businesses as they will at some point likely experience decreased employee productivity and increases in employee health care and disability costs that may lead to price increases and further loss of competitiveness in the international markets.

An article on May 5 of this year published by Fortune (American worker productivity declines 5 straight quarters | Fortune) revealed that employee productivity is declining at the fastest rate in 75 years, at a time when industrialization, Lean operating methods and automation should be increasing productivity significantly and had, until recently. Of course, economists will have to tease out the effects of disruptions to businesses in 2020, whether remote work has increased or decreased productivity, the so-called new state of “quiet quitting,” and other possible confounding factors, but multiple reports have acknowledged that Long COVID is impacting the workforce, for example, https://www.mckinsey.com/industries/healthcare/our-insights/one-billion-days-lost-how-covid-19-is-hurting-the-us-workforce, https://www.cnbc.com/2023/01/30/long-covid-has-underappreciated-role-in-labor-gap-study.html, and https://www.fastcompany.com/90777619/long-covid-is-still-draining-many-workers-heres-how-it-affects-productivity, with one study revealing that 22% of those with Long COVID were unable to work and another 45% had to reduce their hours of work https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00491-6/fulltext.

We are still evaluating the underlying pathogenesis of Long COVID following infection with SARS-CoV-2. There is mounting evidence for persistence of either viral proteins or viral RNA in various tissues, months after infection. This could indicate that in some of those with Long COVID, the immune system has been weakened in such a way that the body’s natural protection cannot effectively kill and clear the virus, or that the virus is finding areas of the body in which the cells of the immune system cannot effectively enter and destroy the virus. Persistence of virus can lead to a chronic inflammatory state that may be a factor in the symptoms experienced by those with Long COVID. To explore this hypothesis further, a study is now underway to treat patients with Long COVID with a 15-day course of Paxlovid (this is three times the normal duration of treatment with this antiviral drug that is used to prevent severe outcomes in patients at high risk who are currently infected with SARS-CoV-2) in order to see whether the antiviral can help the body rid itself of the virus and then subsequently relieve the signs and symptoms of Long COVID suffered by these patients.

We have also detected the reactivation of latent viruses such as Epstein-Barr virus and certain herpes viruses with COVID that may play a role in whether someone is at higher risk of developing Long COVID.

Another possibility is that changes can occur due to the inflammation from an acute SARS-CoV-2 infection, both at the site of infection, and in distal organs such as the brain. Even a mild SARS-CoV-2 respiratory infection can result in long term changes in the brain.

It also appears that many people with Long COVID have micro-clots (small blood clots that are not normal blood clots, but intertwined with abnormal proteins), and it is suggested that these clots may be interrupting the blood flow in small blood vessels, perhaps decreasing oxygenation of some tissues and organs that might in turn cause some of the signs and symptoms we see in some Long COVID patients.

There is also evidence that SARS-CoV-2 may interfere with an important cellular structure, called mitochondria, that are important for the generation of energy needed for proper cellular function.

A surprising number of people with Long COVID have autoantibodies (antibodies produced by the body against its own cells or cellular components. Autoantibodies, too, can produce a state of hyper-inflammation, which as I noted above may be a contributor to Long COVID signs and symptoms.

It may be that we still haven’t identified the exact causative factor in the development of Long COVID, or it could be that some combination of the factors above contributes to it.

The good news is that there is much research going on in this area, and we are sure to learn more over the next few years. For now, for minimizing your chances of developing Long COVID and some other serious health issues that I will discuss in future blog posts, I give everyone the following advice:

If you have not yet been infected, stay current on the vaccines and try to continue to avoid infection as long as you can.

If you have been infected, stay current on the vaccines and try to avoid a reinfection for as long as you can.

I remain concerned that there is much we still do not know about the long-term health implications of infection with SARS-CoV-2.

A Guide to Planning from the Schoolhouse to the White House

This day has been a long time coming. Our book is officially released today!

You can access our book from local bookstores, Walmart (beginning 4/24) and many other distributors, including:

1. Through Johns Hopkins University Press https://www.press.jhu.edu/books/title/12896/preparing-next-global-outbreak.
2. Through Amazon https://www.amazon.com/s?k=preparing+for+the+next+global+outbreak&i=stripbooks&crid=1QOIUSEF2AJ7L&sprefix=Preparing+for+the+next+%2Cstripbooks%2C169&ref=nb_sb_ss_fb_1_23

In print, Kindle version or audiobook.

• As an audiobook https://www.audible.com/pd/Preparing-for-the-Next-Global-Outbreak-Audiobook/B0C1TGGDN2.

How did this book come to be?

In May of 2020, while I was learning everything I could about this novel virus and the disease it causes; providing 4 – 5 press and media interviews/day; fielding calls from friends, family and business owners seeking advice as to how to mitigate their personal or business risks; answering questions and providing education on Twitter (@drpatesblog); talking to local health care leaders; learning what I could from and asking questions of virologists, epidemiologists, immunologists, and infectious disease physicians; and serving on the Governor’s Coronavirus Work Group, my wife suggested that I write a book about all this. I remember my response: “I don’t have any time to write a book.” All of the above activities consumed every day as well as the majority of the day.

In late summer, some private schools asked for my help as they prepared for their fall opening. In October, a large public school district asked for my help the week before teachers threatened to call in for a sick day and parents had begun picketing because almost everyone was unhappy with the school district’s handling of the pandemic.

In late November, I received a call from a dear friend and colleague – Dr. Ted Epperly. Dr. Epperly is President and CEO of a network of federally qualified health centers that care for disadvantaged Idahoans and he runs the Family Medicine residency training program in Idaho. He had served on the Central District Health board – the largest public health district in Idaho – for 15 years, until the Ada County Commissioners decided to replace him with a physician who was promoting disinformation about COVID-19 and particularly anti-vax misinformation.

I remember the call well: “David, we should write a book together.” Well, now two people who were important to me were saying the same thing. I remember thinking at the time that the US and the world had gotten so much of this wrong, and I did feel that it was important to document the mistakes, the successes and the lessons learned given that a future pandemic is certain, and we cannot afford to repeat the same mistakes. I also remember thinking that there certainly have been books written about past pandemics, but not a book that had the kind of behind-the-scenes details of what happened and the lessons learned from those pandemics. Seeing the need for a book that would actually help prepare us for the next pandemic based upon the lessons from this one, I answered Dr. Epperly, “yes,” before we hung up.

What is this book?

The book contains 117 recommendations for those whose responsibilities include pandemic and public health emergency planning and for those from the World Health Organization to the CDC, to the White House, to state and local elected leaders to school leaders and their school board members. While this book should be of interest to all public health and health care leaders, many people throughout this pandemic realized that they did not often get good, reliable advice and may be very interested in the book as they realize that during the next pandemic (which I will be greatly surprised if we do not experience within a decade), they need to be in a position to discern multiple sources of conflicting information to decide the best course for themselves and their families.

This is not really a book about the COVID pandemic, rather it is a book about preparing for the next global outbreak based on the lessons learned from the COVID pandemic.

What does the book cover?

Chapter 1: The SARS-CoV-2 virus and the COVID-19 pandemic

In this chapter, we recount how the COVID-19 pandemic unfolded abroad, in the US and in Idaho. We explain a lot of the concepts about how a novel virus is transmitted, infects people and is spread across countries and continents. We introduce many essential concepts of epidemiology, virology and immunology. We also discuss the concepts of herd immunity and post-viral syndromes. We also provide our first 12 recommendations in this chapter.

Chapter 2: Pandemic Surveillance and Early Response in the Future

The COVID-19 pandemic gave us many opportunities to see how delayed our recognition of an outbreak of a novel virus can be, especially if that outbreak occurs in a closed society or highly authoritarian one, and how inadequate our current responses are to contain the outbreak. Our travel bans did little to contain the entrance of the virus into the US, in fact, the first identified case entered the US days prior to the implementation of the travel ban. We also saw how ineffective our symptomatic screenings of passengers arriving from another country were. In this chapter, Dr. Epperly and I provide 6 recommendations to improve both our surveillance and response to future outbreaks.

Chapter 3: The Intersection of COVID-19 and Society

We saw the profound impact social media played in this pandemic. Further, we saw how politics dominated the pandemic response, including at the highest levels of the federal government to the most local of politics – school boards. We provide 17 recommendations in this chapter.

Chapter 4:  The Haves and Have-Nots

We have known that there are intrinsic racial and ethnic disparities embedded in the US health care system long before this pandemic. However, these became amplified during the pandemic. While much has been written on this general topic, we provide 4 recommendations with respect to the handling of the next pandemic.

Chapter 5:  The Growing Fire

In this chapter, we discuss the public health reactions and interventions and the public push-back to those measures. We make 7 recommendations for the future.

Chapter 6:  Man versus Virus

In this chapter, we explore examples of differing public health responses on the part of countries, states and even counties and the resulting outcomes achieved. We make 2 recommendations in this chapter.

Chapter 7: Needed Changes to the Federal Response

In this chapter, we make 9 recommendations for changes to the federal preparedness and response to future pandemics. One huge issue that is not receiving near enough attention is the vulnerabilities of our national stockpiles and supply chains.

Chapter 8:  The Future Role of the States

The COVID-19 pandemic demonstrated that, absent changes to our federal approach to future pandemics, states will carry the heaviest burden. States must make changes to their public health emergency plans accordingly, and we would recommend a reevaluation of the state’s public health structure and infrastructure, including considerations of state stockpiles.

Chapter 9:  Preparing Future Doctors, Nurses, and Public Health Workers for the Next Pandemic

This current pandemic exposed national and regional shortages of health care professionals, and also demonstrated the pressures that could be placed on our health care capacity due to health care workers being infected or exposed to the virus. In our careers, neither Dr. Epperly or I have ever seen the amount of hostility and disrespect shown to health care and public health workers. As a consequence, we are seeing the early retirements, resignations or change in type of work in all of these groups of professionals that is further threatening pre-existing shortages. We make 10 recommendations in this chapter that are of urgent and great importance given that we don’t know how much time we have until the next pandemic.

Chapter 10:  Preparing Public Health Departments for the Next Pandemic

Since the many advancements in the 1900s involving sanitation, water quality and food handling, the investments in public health have dwindled. The new threats of global travel, ecological pressures resulting from man’s continued encroachment on wildlife habitats and the increasing proportion of new, emerging infections that are the result of zoonotic transmission (animal -> human) have been underappreciated and under-funded by legislative bodies. We make 12 recommendations in this chapter relating to improving and strengthening our public health infrastructure and functioning in preparation for the next pandemic.

Chapter 11:  The Rejection of Science

During the pandemic. We experienced an overwhelming push of misinformation, disinformation and conspiracy theories, often promoted by well-organized, well-funded groups, as well as foreign adversaries, in a very coordinated manner that undermined our public health efforts to a very significant degree. We provide 6 recommendations to better confront these efforts in the next pandemic.

Chapter 12:  Dangerous and Erroneous Approaches

In this chapter, we review two failed approaches to bringing this pandemic under prompt control – the sequestering of elderly and high-risk individuals and the promotion of infection in the others in order to achieve “herd immunity,” and the considerations involved in these two approaches for future pandemics. We make 3 recommendations.

Chapter 13:  Vaccines and Variants

We first review considerations for the development of new vaccines in response to a future novel virus, as well as some recommendations on implementation of vaccination programs. We then discuss the risk for development of variants with failure to control the wide-spread transmission of a novel virus, especially RNA viruses. We provide 5 recommendations.

Chapter 14:  Preparing Schools for the Next Pandemic

This is my wife’s favorite chapter, and I suppose mine as well. It is a critically important chapter because schools play a critical role in the transmission of epidemic and pandemic viruses. It is our favorite chapter because we provide new and original recommendations that I developed while advising schools that are effective and can be of tremendous benefit to school leaders and board members who are generally ill-equipped to manage a pandemic response with poor guidance from federal public health authorities. We provide 6 recommendations in this chapter.

Chapter 15:  Leadership Lessons from the Pandemic

There are many leadership lessons resulting from how various leaders at all levels of government and the US health care system handled the pandemic. Some leaders excelled during this time, many failed, and most were in between. We discuss these leadership lessons and attributes and provide our final 10 recommendations.

Chapter 16:  Recommendation Checklists

In this chapter, we pull out all of our 117 recommendations and conveniently group them by type of organization that will be involved in the preparedness for the next pandemic and management of it. This is intended to assist all these types of organizations as they hopefully will now update their pandemic plans.

People who follow my blog or follow me on Twitter will not be surprised that I disagree with the decisions made by some hospitals to end mask requirements in healthcare facilities. In fact, I previously wrote a blog piece as to why.

However, I also realize that health care leaders are dealing with very challenging situations and enormous pressures to end their requirements, especially when others in their service area end theirs. So, while I may not have agreed with the decisions, I certainly would have provided them with advice that might have helped them better formulate their new policies and communicate their decisions to the community. Perhaps lessons from some hospitals or health systems that have already announced their decisions might help those considering such a move.

Timing

When I ran a health system and had to make decisions that I knew were likely to upset some people (in other words, almost every decision I made), I always tried to understand why my decision might upset those people and how it might negatively impact them, so that I could consider whether I could come up with a solution that would mitigate that harm resulting from the decision. In this case, I suspect that many people would celebrate the end to masks, as they have already abandoned masks long ago, if they ever adopted them in the first place. So, who would potentially be negatively impacted by the decision and why?

Well, I can tell you from the people that I talk to who some of these people are – those who are at high risk and have therefore been doing all that they can to protect themselves and those who are not at high risk but are concerned about getting infected or getting infected again and potentially transmitting the infection to someone they love who is at high risk.

So, the first thing I would have advised is acknowledge these folks and their concerns. One concern many have is that their last booster was in September or October and they know that their protection is likely waning by now. It is widely anticipated that the FDA Commissioner and CDC Director may authorize another booster for these high-risk patients in roughly 1 week. Let me repeat that – one week.

It was a missed opportunity to not state something like: “Out of concern for the health and well-being of our most vulnerable patients, this new policy will not go into effect for two weeks (for example) to allow those who wish to be boosted an opportunity to do so before this new policy goes into effect. In fact, we will be offering vaccinations [at these locations and at these times with priority for those at high risk or scheduled hospital visits or procedures].”

I can tell you that I talk to immunocompromised patients all the time who seek out my advice. They have felt that society has abandoned them for the past three years, which is largely true, but they always felt that at least their health care providers would protect them. Nothing in the messaging I have seen from several organizations acknowledged these patients nor expressed concern for them. The statement above could have helped at least show a little sensitivity towards them.

Rationale

Be as transparent as you can be and if you can’t or won’t share the rationale, then tell the audience that; don’t provide an alternative rationale that is not true or accurate.

In every public statement I have seen, the rationale begins with a less than convincing argument or even misinformation, usually something to the effect of low community transmission rates, or a decline in community transmission rates or a “review of the latest COVID-19 data.” In each case, I have then looked up the community transmission levels in the locale of those hospitals and health systems, and to my surprise (to clarify, I am not surprised by the community transmission levels I saw, but by the fact that those organizations would characterize those transmission levels as low or as any justification that masks are no longer needed) the levels are not at all consistent with what the hospital or health system is offering as its rationale.

Now these are pretty sophisticated health care organizations. Its not like they don’t know how to interpret the data correctly. It generally would lead me to conclude that they either have other data or other reasons, but for some reason don’t want to be transparent about it. I think that is a mistake. First, if you use a rationale that is demonstrably false, you gaslight those who know better and you are losing credibility and trust. It is hard to regain either once lost.

This is particularly regrettable at a time when there are so many who are promoting misinformation and disinformation and convincing the public that they are knowledgeable experts. When those in the public who want to know the facts so that they can make their own health decisions don’t know who to trust, they have always been able to turn to their doctor and/or local hospital. If they can no longer trust their doctor and their hospital to give them the facts and truth, then I fear where they will turn to for their advice. Worse, those hospitals and health systems lose the high ground to call out other misinformation and disinformation being spread in their communities.

There have been many times when my leaders have not been able to agree to a recommendation on a challenging issue.  In those cases, I had to make the decision knowing that I would please some and disappoint others who I worked with everyday and greatly respected and cared for. Those are difficult decisions to make. But, in each case, I would acknowledge the different points of view, thank them for their input and then carefully explain my decision including my reasoning. Obviously, I would never know whether I reached the right decision for days, months or years, but in every case, those who were disappointed with my decision always knew that I carefully considered all the input and could at least understand my reasoning, even though they still might have reached a different conclusion were they the CEO.

Given what we have been through this past three years, I can understand that leaders may be reluctant to deliver what some will consider to be bad news. I would advise these leaders that reasonable people understand that difficult decisions have to be made, and they can accept those decisions better if leaders will treat them like reasonable people and tell them the reasons behind the decision and don’t insult them by misrepresenting the reasons or sugar-coating them. And, as for the unreasonable people, there is nothing you can tell them that will make them change their minds, so just focus on the reasonable people (who despite what you might conclude from social media, is still the majority of people).

Don’t throw in extraneous and irrelevant reasons in an attempt to buttress an already weak rationale.

Each of the public announcements or pronouncements I saw made reference to declines in other respiratory viruses, with one organization going so far as to pronounce an end to the flu season! As to the latter, again, why state something that is verifiably false? Although influenza transmission has declined significantly, this influenza season is not officially over and there are still more than one thousand people hospitalized in the US with influenza, so avoid stating things that will merely undercut your credibility. Either tell us your real reasoning, or tell us that you cannot share your reasoning with us, but don’t make stuff up.

Now, why do I say that you shouldn’t throw in the fact that other respiratory virus transmission has gone down to buttress your rationale for ending your mask requirement? Because now you have just told the public that respiratory virus transmission in the community is a material factor in deciding whether to require masks or whether to end masking. There is a new variant in the US that is causing serious problems in some other countries. If that variant does the same thing in the US in, say July (when the influenza season really will be over) and there are many patients being admitted to the hospital with COVID-19, staff are getting sick, the spread of COVID to hospitalized patients has increased and you now want to explain to the public why masks are being required, when asked why you are reinstating masks since there are very low levels of circulation of other respiratory viruses, do you now have to twist yourself in knots explaining why that really doesn’t matter after all? And, in November or December, when there is a large circulation of respiratory viruses, but no significant new surge from SARS-CoV-2, what is your reasoning then for not implementing a mask requirement, when a reporter or the public questions why low circulation of respiratory viruses is a reason for ending mask requirements, but high levels doesn’t seem to be a basis for implementing mask requirements?

Empathy

There seems to be a widespread deficiency of empathy. The public statements I have read have been short in length and lacking in any acknowledgement or consideration for those who will now be in fear for their safety in one of the few places they rely to keep them safe.

My advice would have been to acknowledge this fear and impact, especially when I see language in some statements such as “this has been a very thoroughly considered decision.” Maybe it was, but if you don’t address “the elephant in the room,” those who are in fear are not going to believe that it was thoroughly or carefully considered.

When you are taking something away (as some of those who are at high risk will perceive this), then tell them what you are doing to mitigate that loss or help make up for it as an acknowledgement that you know that this decision may be placing them at additional risk. For example, can you provide any reassurance that xx% of our patient care staff are fully vaccinated and up-to-date? Or can you state that only those who are can go maskless, but other staff who are not will continue to be required to mask (as is commonly done in handling influenza vaccinations)? Or can you state that all staff are screened for temperature and symptoms daily? Or is there still testing of all new admissions to the hospital? Is there any periodic testing of staff? Can you at least explain to the public what changes you have made in ventilation, filtration and/or air treatment? What about special accommodations for those who are at high risk? For example, can you provide a clinic or urgent care facility where you will keep masking in place that they can access for care? Can you offer high risk patients a separate waiting area that has high rates of air exchanges and HEPA filtering and where everyone in that room is required to wear masks? I think most of the immunocompromised and high-risk patients I talk to would see this as a sign that at least the health care facility cares about their health conditions and is trying to find a compromise to balance the competing interests of those who can’t wait to be rid of masks and those who feel that their lives may very well depend upon them.

In other words, the message solely conveying we are going mask optional is very different than we are ending the mask requirement, but at the same time, we understand that without masks, high risk patients will now be at higher risk in the hospital than in their homes, so we are making these additional accommodations for them. Empathy goes along way, even when you feel unable to fully address someone’s concerns.

For the love of God, please have someone who is not intimately involved in the decision read your statements and policy before you publish them.

I have been in this situation countless numbers of times. I have been working on some document very hard and very long, I have read it twenty times, and I think it makes perfect sense to me. The problem is that you have blinders on. Especially, when it is a big change, a change that you know is risky or a change that you know is going to upset some people. Then, I get my assistant to read it, my editor to read it, a board member to review it, or if it is not confidential or sensitive, I may have my wife read it. It is amazing how many times I thought I was saying one thing and the person took it the other way or they catch a glaring omission. Sometimes, they find that I wrote something stupid.

So, could that have helped these hospitals and health systems? Absolutely. What are some examples?

Amazingly, but probably because those who drafted these documents just assumed this to be the case, while all of these public documents mention that there will be some circumstances where masking will still be required (e.g., in a bone marrow transplant unit or in a long-term care facility), not one of them states that patients with probable or confirmed COVID-19 and their visitors and their caregivers will be required to mask! Of course, there are situations in which the patient cannot be masked, but this is an obvious concern to those who are at high risk who may have to receive care in a health care facility. Why not just come out and reassure these folks?

Here’s another example. One policy that I saw stated: “Symptomatic visitors are discouraged from visiting.” WHAT!?!?! So, someone is burning up with fever and having frequent coughing fits and you’re going to tell them, “We would discourage you from visiting, but ultimately, it’s your choice”?

One final point, since I think I have made my point. In one document I read explaining some of the areas of the hospital where masking will still be required, it stated something to the fact of “masks will still be required in our operating rooms,” at which point I sprayed the coffee in my mouth all over my laptop. Good heavens, while I was just beginning to try to come to grips with the idea that you aren’t going to require masks in a hospital, now you imply to me that you considered whether to continue wearing masks in the operating room!?!! I didn’t even realize that was a possibility until you pointed that out.

Be internally consistent

This is one of the most frequent problems I see when I review hospital policies. This was a flagrant problem with visitor policies early in the pandemic. As an example, many hospital policies would allow for a visitor with a laboring mother, but not with a patient who had undergone surgery and is still woozy from the anesthesia and pain medications.

What I now see is announcements that generally state something to the effect that “patient safety is our highest priority.” In one case, a health system offered the statement that: “Masks have been, and continue to be, an effective tool for preventing the spread of infections by respiratory route.” But, “we are ending our mask requirement!” What!?!? How does that make any sense when you just said nothing is more important than keeping your patients safe and masks are effective at doing so?

Anticipate questions from patients, families and the public.

• If a patient contracts COVID while in the hospital, will you tell the patient and their family?
• If a patient was exposed while in the hospital, e.g., a nurse caring for the patient yesterday is out sick today and tests positive for SARS-CoV-2, will you notify the patient and family?
• If a patient was exposed, will you do serial testing of the patient?
• Are you still quarantining infected staff members and isolating close contacts? Will staff returning to work after 5 days of isolation for COVID-19 still be required to mask for at least an additional 5 days or does mask optional apply to them as well?

• How will you know if your decision was wrong?

While there certainly may be real-life circumstances for making this decision, few experts in the field would be able to say that the decision is consistent with the science or evidence at present. So, what steps are you taking to monitor the impact of this decision and to identify quickly if the decision results in patient harm? Will you be tracking nosocomial COVID-19 before and after the decision and making that data available to the public? Will you report the outcomes of nosocomial SARS-CoV-2 infections? Will you be monitoring infections among especially vulnerable patients in the hospital and in the immediate period post-discharge, such as neonatal ICU patients, newborns, young children, pregnant women, etc.? Will you be monitoring infection rates among staff? What change in metrics would cause you to revert back to mask requirements?

Many people, like me, were experiencing shock and awe with these announcements. Being honest; being as transparent as you can be about the real rationale for the decisions, including sharing data where applicable; not trying to distract us with irrelevant and extraneous reasons for the decision; demonstrating empathy for those who will be negatively impacted by the decision, particularly if you can also offer some alternative measures that you can adopt to mitigate the potential harms resulting from the decision you are making; not overlooking the obvious; avoiding stating stupid things; and being internally consistent will make a huge difference in delivering a message that is going to be controversial and upsetting to some. An additional nice touch, especially when you can’t be sure that things might not get worse with your decision, is to simply acknowledge that, explain how you will monitor the situation to identify quickly if things are getting worse, and what you do in that event.

Let’s first clear up a technicality: it is not actually the origins of COVID-19 that is at the center of the debate. We know that COVID-19 is a disease that is caused by a virus named SARS-CoV-2 (an acronym for severe acute respiratory syndrome – coronavirus followed by the number 2 because the first severe acute respiratory syndrome caused by a coronavirus was identified in 2003. Now that we have identified another new SARS coronavirus, you will often see reference to the virus that caused an epidemic back in 2003 as SARS-CoV or SARS-CoV-1 to distinguish it from the newly recognized (or novel virus) SARS-CoV-2 that has caused the pandemic that was declared such on March 11, 2020.

The actual controversy is as to the origins of the SARS-CoV-2 virus itself.

If this were a presentation to physicians, public health experts or scientists, I would present the issues in a much more technical manner. But, this is intended for the public and assumes that the audience knows very little about virology, disease outbreak investigations, evolutionary biology, genetics, epidemiology, etc. Therefore, I am going to keep this at a high level. Of course, the trade-off is that I will necessarily oversimplify some matters and present some information that may have technical exceptions or other considerations – a level of complexity that we are not going to dive into, and frankly is not necessary for you to have a good general understanding of the issues. Despite the complexities, it is possible for the public to be informed, and I will do my best to do so.

Why is there so much uncertainty and controversy surrounding the question of the origin of SARS-CoV-2?

1. Politicization. As in most things these days, even this question, which can only be answered through scientific and forensic investigation and data, has become politicized. When an issue gets politicized, as this has, then we see many people align with their political tribes rather than following where the evidence takes them. In fact, many people who have dug in on one or the other hypothesis, cling to and defend that hypothesis with extremely limited understanding of what really is a complex matter. Unfortunately, when people of either side dig in and focus all of their energy on defending their party line, they are no longer objectively evaluating the evidence as we would have a jury do, but rather they become the equivalent of the prosecutor or defense attorney arguing their respective positions and trying to explain the evidence in a way that remains supportive of their side of the case in order to persuade the jury to their point of view.
2. The desire to attribute blame. Although there are likely many potential motives for why some people argue so fervently for a certain position and against the other, when something as sudden and unexpected and bad as this pandemic has been occurs, it is human nature to want to have someone to blame for it. A lab leak provides a more limited and identifiable number of organizations and people to direct blame at, whereas a zoonotic spillover event (infection transmitted from animals to humans) makes it far less clear who to blame and is far less satisfying.
3. The desire to avoid admitting vulnerability. Of course, the converse, assigning blame to a zoonotic spillover event can be uncomfortable in that it underscores our vulnerability to future such events that can turn our lives upside down with little notice, and begs the difficult question as to what our country plans to do to protect us from and respond to future such events.[1]
4. Loss of trust and credibility. Distrust has been amplified during the pandemic. Some prominent purveyors of disinformation as to other aspects of the pandemic – e.g., COVID is a hoax; COVID is no worse than the flu; ivermectin prevents and cures COVID-19; vaccines were causing cancers and hundreds of thousands of deaths, etc. – were early to insist that SARS-CoV-2 was the result of a lab-leak. I don’t rule out that possibility, however, when the loudest voices in support of lab-leak have already lost their credibility and have been known to lie about other related matters, unfortunately, it resulted in undermining the lab-leak hypothesis out of the gate, or worse, caused others to dig in against that possibility merely so as not to be associated with that group of people.
5. Conflicting government intelligence assessments. It also has been difficult to sort this all out because we have learned that our intelligence agencies are divided on which scenario they think is most likely, with some agencies favoring a zoonotic spillover event, others favoring a lab leak, and still others indicating that they don’t have enough evidence to offer any assessment, though almost all have indicated that their assessments are of “low confidence.” Only the FBI’s assessment (favoring a lab leak) was of “moderate confidence.” According to the Office of the Director of National Intelligence website:   https://www.dni.gov/nctc/jcat/jcat_ctguide/intel_guide.html site, the confidence levels are described as follows:

HIGH CONFIDENCE generally indicates that the judgments are based on high-quality information or that the nature of the issue makes it possible to develop a solid judgment.

MODERATE CONFIDENCE generally means that the information could be interpreted in various ways, that the intelligence community has alternative views, or that the information is credible and plausible but not corroborated sufficiently to justify a higher level of confidence.

LOW CONFIDENCE generally means that the information is scant, questionable, or very fragmented, so it is difficult to make solid analytic inferences; it could also mean that the intelligence community has significant concerns about or problems with the sources.

We see people jump on whichever intelligence assessment is consistent with their preconceived views as evidence that their position is correct, when one can see from these confidence levels that low confidence is essentially no confidence and that even moderate confidence is far from certain.

• The bases for government intelligence assessments remain classified. For those, who like me, remain open to all possibilities, it is also difficult to come to a firm opinion on the origins because while much of the scientific evidence is published and publicly available, the intelligence assessments remain classified, so we don’t know what evidence any of those agencies might have that might impact our assessment. Before I would be willing to make a definitive opinion, I would want to know that I have seen all the relevant data and evidence.
• Lack of transparency and access for investigations on the part of China. The best and most helpful evidence for either a lab-leak or a zoonotic spillover event(s) (in other words transmission of infection from an animal to a human) is evidence that can only be gained in the region where the earliest cases were found – in this case, in Wuhan, China. While the World Health Organization (WHO) did conduct an initial investigation in Wuhan, the investigators were not given access to all areas and all the data that they requested. Obviously, these limitations limit the amount of data that disease outbreak investigators can gain that may provide us with answers. However, two points are worth making. First, even if investigators were granted unbridled access, it is possible that we might not be able to determine the animal source if it was a zoonotic spillover event. Second, many have pointed to China’s lack of transparency as evidence in support of a lab leak and China’s efforts to keep it from being discovered. And, while I am in no position to rule that possibility out, we should remember that China is not transparent about most things. In other words, if China was transparent about everything else, but secretive only about this outbreak, I think it would be much stronger evidence that the Chinese government felt it had something to hide in this regard. Further, I believe that China not only would want to conceal a lab leak if they believed that is what happened, but I think there is plenty of information to suggest that China was trying to conceal any evidence that the virus originated in China, including if the virus was spread in a wet market.

We should keep in mind that every modern-day president of the United States has also stated that he would not allow foreign government inspectors into U.S. research laboratories to conduct investigations of our laboratory operations. In addition, after the WHO conducted its first visit as part of its investigation, but before it returned for its second visit, President Trump stated that China should pay reparations of $10 trillion for its role in the pandemic. https://thehill.com/policy/international/china/557025-trump-demands-china-pay-reparations-for-role-in-coronavirus/. Of course, when a government starts making threats to another country and suggesting highly damaging penalties, it should not be surprising that any cooperation may come to an abrupt end.

My point here for this discussion is to acknowledge that China has not been transparent and has not been fully cooperative, but that in of itself is not strong evidence of a lab leak to the exclusion of all other possibilities. As an example, a finding that SARS-CoV-2 originated from the wet markets would still bring embarrassment and undesirable consequences to the Chinese President and government. Having been the source for two outbreaks with epidemic and now pandemic consequences would create tremendous pressure on China to halt its wet markets, a significant source of employment and economic activity, as well as a custom and tradition for many Chinese people, including some who consider some of the more exotic animals as a delicacy. It would not only embarrass the Chinese government, but feed into more anti-Chinese hate rhetoric and targeting, but also more calls for China to make huge reparations at a time when the Chinese economy is already facing strains. Further, there is mounting evidence that some animals were being sold at the markets illegally, which would further embarrass and bring criticism to the Chinese government for not diligently enforcing its laws.

As to the origins of SARS-CoV-2, we can consider 4 possible scenarios:

1. A zoonotic spillover event. SARS-CoV-2 evolved in nature and was transmitted by bats to animals that were subsequently transported to the wet markets for sale, that in turn transmitted the virus to humans.
2. Lab leak. SARS-CoV-2 had been obtained from samples taken in natural settings and the virus was transported to the Wuhan Institute of Virology for research purposes when through a lapse in safety procedures, the virus infected a lab worker who then transmitted the virus to others kicking off the pandemic.
3. Engineered virus. This is really a variation of number 2, which supposes that instead of the virus appearing in nature and then studied in the lab, the virus does not appear in nature, but instead was purposefully manipulated or engineered in the lab to create a virus with enhanced infectivity and/or virulence.
4. Bioweapon. SARS-CoV-2 was developed for purposes of biowarfare.

I think that the first two scenarios are the only serious considerations. Let’s explore why.

The Intelligence Community issued a statement on the origins of COVID-19 in 2020 and has reaffirmed in 2023 that its assessment in this regard has remained unchanged:

The Intelligence Community also concurs with the wide scientific consensus that the COVID-19 virus was not manmade or genetically modified.

Intelligence Community Statement on Origins of COVID-19 (dni.gov).

Thus, while the intelligence community remains divided as to the question of whether SARS-CoV-2 precipitated a pandemic through a zoonotic spillover event or a lab leak, the intelligence agencies are in complete agreement that scenarios 3 and 4 above are not considerations. To explain how we would know that the virus was not engineered or manipulated, this is where I am going to have to oversimplify because things get very complicated and involve genetics and biochemistry, which I love, but I am going to assume you do not. It is important to start with the fact that science has not progressed to the point where the Chinese or anyone else could design and create a virus from scratch. The technology and knowledge do exist to be able to modify viruses, but in these cases, we have to start with an already existing virus. Further, while we can force certain changes to the virus through laboratory techniques or through infecting animals in the laboratory, the modified virus is not unrelated to the prior versions and the changes to the virus leave identifiable signs that can be tracked from the original form of the virus to the modified version.

Further, our sequencing technologies have significantly advanced to where we can readily pick up new mutations and even recombinations (where genetic material from two different viruses are swapped in creating a new virus). Further, often we can detect genetic material from an animal host in a viral specimen that can tell us what species of animal was infected with the virus. Finally, we sometimes see biochemical changes to samples that we can tell could not have occurred in cell cultures in a laboratory, but only by interaction with a host’s immune system (meaning that the virus had to infect and interact with some host rather than just existing in a test tube, so to speak).

The possibility that SARS-CoV-2 was developed by the Chinese as a bioweapon defies logic. First, Bioweapons 101 emphasizes that you do not release a bioweapon developed against foreign adversaries in your own country in a highly populated city and in Bioweapons 102 you learn that you should vaccinate your population and leaders before you release the bioweapon, not a year or two later. Second, Chinese scientists have done leading research on coronaviruses and would know that case fatality rates for coronaviruses range from < 1% to about 35%. An important life lesson for me (thanks, Dad!) was that when I decided that I was going to fight back against a bully, I needed to deliver an effective punch that would render the bully so much pain or bleeding from his nose that the fight would be over before my opponent could strike back. It makes no sense to release a bioweapon on another country that would only kill 1 – 2% of the population of that country, especially if that would consist mostly of elderly citizens and not the part of the population of the age of military service. With a novel virus like SARS-CoV-2, Chinese scientists likely would not be able to predict its mortality rate in advance of deploying the weapon and infecting people, but could not reasonably predict that its mortality rate would be higher than 40% at the very highest. There are many other choices of far more lethal viruses. If the Chinese intended to release a bioweapon on say the United States, they would act very differently:

1. Release the bioweapon in the U.S. not in China and then rely on people to transport the virus by being infected and travelling internationally.
2. Pick a far more lethal virus because if you release a bioweapon that is easily identifiable and traceable that doesn’t deal a crippling blow to the US, you have just entered into war with the U.S. and will pay a severe price for whatever gains you think you have achieved with the bioweapon.
3. Vaccinate your population before you release the bioweapon, not one – two years later.

So, let’s assume that you buy my arguments and agree that the two most likely considerations for where the virus came from are either a natural zoonotic event where an infected animal at the wet markets infected humans, who then spread the virus to other humans or a lab leak in which a laboratory worker was inadvertently infected and subsequently spread the infection to others precipitating a pandemic.

If the World Health Organization (WHO) or other disease outbreak scientists were to go about determining which was the actual cause, and were granted the authority to examine any records and collect any evidence, they would consider the following, among other things:

Lab Leak

1. What research was being conducted in the laboratory?
2. What viruses are kept in the laboratory? Are any of those viruses SARS-CoV-2 or closely related viruses?
3. What animals are in the laboratory?
4. What biosafety measures were in place? What safety training was provided for workers? Were there any safety lapses? Were there any safety audits or inspections?
5. Did any laboratory workers develop any unexplained illnesses? If so, did any receive any medical evaluation, testing or treatment?
6. Did any family members or contacts of laboratory workers develop unexplained illnesses? If so, did they receive any medical evaluation, testing or treatment?

Zoonotic transmission

1. What animals were sold in the market? In particular, were there animals on site known to be hosts for coronaviruses, such as palm civets, pangolins, prairie dogs or raccoon dogs?
2. Had any animals brought to the market been noted to be sick or died before sale?
3. Where were the animals brought from? Were they captured from the wild or grown on farms?
4. Were any swabs collected from any of those animals or from cages, walls, tables, chairs, butchering equipment, floors, drains, sinks, or other sources within the market that would allow examination for viral genetic material?
5. Have any samples of carcasses, tissues or blood from any of the animals been retained and frozen?

In investigating a potential lab leak, of critical importance is whether the lab was working with the virus that has appeared in the general population and what kind of research was being conducted. It is important to note that some laboratory investigations would pose extremely low, if any, risk because research techniques used for some research purposes would result in inactivated virus, incapable of infecting animals or humans. Many research projects would not require propagation of the virus. If not propagated, then the viral counts are generally low (decreasing the risk of infection even in the event of an accidental exposure) and less handling of the virus is generally involved (reducing the opportunities for accidental exposure). Even if there were efforts to culture and amplify the SARS-CoV-2 virus, the most widely used process for cell culture of viruses routinely results in the loss of the specific structure found in SARS-CoV-2 from human specimens that has been at the core of the argument of many insisting that its presence is evidence that the virus was engineered (the furin cleavage site). We do know that the Wuhan Institute of Virology (WIV) did a lot of research on coronaviruses. In fact, the head of that lab often attended and presented at international virology conferences and many scientific papers were published from that lab. So, even without full transparency, we know a lot about the viruses being studied at WIV and the techniques being used. The closest known virus being studied and for which studies have been published would still be too distant to have been the precursor virus to SARS-CoV-2.

Like many research laboratories, WIV was known to carry out experiments with viruses on mice (mice are selected in part because other research animals are considerably more expensive and often cost-prohibitive). And laboratory experts indicate that the process of repeatedly administering infectious virus to mice would likely be the highest risk laboratory activity to result in accidental infection of a laboratory worker if there was any breach in the safety protocols.  However, the wild type virus (the original virus responsible for the outbreak and earliest cases) was incapable of infecting mice. It was not until much later in the pandemic that the virus evolved to favor a specific mutation (N501Y) that allowed the virus to infect mice and other rodents, as we now know can happen in rats such as those recently sampled in NYC. If researchers aimed to make the virus more transmissible through repeated mutations in animal models (a number of persons promoting the lab leak scenario suggest that the biggest support for this hypothesis is how well adapted this virus was for human transmission from the onset of the pandemic as opposed to a natural transmission that would gain increased transmissibility over time (as in fact was what we observed), then the virus would likely have evolved to acquire this mutation in the same manner that it did naturally over the course of the pandemic, yet, this mutation was not seen in sequences of the virus from the beginning of the pandemic. Even if so-called gain of function research was being conducted, when wild type virus was used on mice by other researchers during the pandemic for which genetic changes are made to enable the mouse to be infected, the virus did not become more pathogenic or transmissible, adding evidence that even if covert research was taking place, it is unlikely researchers would have continued gain of function research on this virus after these disappointing results and this would have been even more reason not to consider this virus as an effective potential bioweapon.

In laboratories such as WIV, it is customary to collect and store blood samples from lab workers so that in the event of a question about accidental infection, we can go back to those prior samples and perform tests such as antibody testing to determine the time period in which the worker was last seronegative (without antibody evidence of prior infection) and then seroconverted (now shows evidence of antibodies signaling infection unless the worker was vaccinated against that particular pathogen). We are told that such samples were collected and that there was no evidence that any workers seroconverted prior to the onset of the pandemic. However, to the best of my knowledge, WHO investigators were not provided with those specimens for independent testing.

There were conflicting reports as to whether any lab workers had become ill. Although there were some reports indicating that one or more lab workers did become ill (as many as three), this was also during the time China was experiencing its cold and flu season and I am not aware of any medical records or testing results that have been made public that created suspicion that any of the lab workers had anything other than an infection with a circulating respiratory virus, though without testing we would be unable to make that determination.

As for investigating a potential zoonotic transmission, there were many reports and pictures providing evidence that the markets typically did have many animals known to be hosts for coronaviruses. Also, it is widely known that these animals are kept in cages in close proximity to each other, often stacked one upon another without solid bottoms to the cages such that urine, feces and secretions would likely contaminate other animal cages and animals.

It has been reported that animals were frequently transported from southern parts of China to the various wet markets. There are extensive bat caves and bat populations in the southern regions of China. Bats have long been known to be hosts to numerous coronaviruses and bat caves have often been sampled to detect new or novel strains of coronaviruses and other viruses since 2003. So, here again, there is a need to clarify some of the language being used. For those who state that the origins of SARS-CoV-2 are the Huanan wet market in Wuhan, that does not seem the most likely scenario to me, and I don’t think that is exactly what they mean. Rather, Wuhan, and the wet markets there do seem likely to be the site of the spillover, but many of these animals were transported from other areas of China to Wuhan, infected already, I would suspect, and of course, the reason they are referred to as intermediary hosts is that they are in a chain of transmission that begins with bats, and those bats are more likely to be located in the southern regions of China. Further confusing this whole issue is that, as we describe in our book, the first outbreak can be the first cases of infection, however, it is not necessarily so. An outbreak that leads to a large number of cases, some of whom get very sick alerts us to a disease outbreak and a potential novel virus. However, there could have been isolated cases that preceded the first known outbreak that because they were isolated, did not arouse attention or concern and went undetected, perhaps attributed to a cold or the flu. In fact, one report studying the earliest sequences available suggests that in fact, the sequences obtained from the market may be further down (i.e., evolved later in time) the phylogenic tree (in essence the family tree for a virus) than some sequences obtained outside of Wuhan, such as Guangdong Province, the same province from which both HCoV-HKU1 and SARS-CoV-1 are thought to have originated, or at least where they were first identified.

The strongest evidence for zoonotic transmission would be if animals at the market had been tested for the virus and had turned up positive. However, officials moved in quickly when news of the disease outbreak first appeared and removed the animals. It is unknown whether the Chinese government conducted any testing of these animals. The next strongest evidence would be if we knew where the animals came from and we could identify the virus in the same kind of animals in those areas. Other evidence would be if animals and people living nearby where these animals for the wet markets were obtained tested positive for antibodies for SARS-CoV-2 before the pandemic had first manifested in that area.

Some prominent virologists, geneticists and evolutionary biologists presented findings at the WHO’s Scientific Advisory Group for the Origins of Novel Pathogens in March from the analysis of genetic sequences of the virus obtained from swabs at the wet market that were just publicly released by scientists at the Chinese CDC.

As noted above, when a virus’ genetic material is recovered after it has caused infection, genetic material from the host animal may sometimes be combined with the virus genetic material. Some of the sequences just made available show genetic material consistent with raccoon dogs, animals known to be hosts for coronaviruses, and in large enough amounts that experts think contamination is unlikely an explanation. While this discovery is of limited significance because it was not collected until 1/12/20, and does not prove that a raccoon dog was infected with SARS-CoV-2 or that an infected raccoon dog was the intermediary host and source of the spillover events, together with the fact that many swabs from carts, animal-processing equipment, sewage wells and water drains at the market revealed genetic material of the virus, is certainly evidence that raccoon dogs were there at the market and raises the possibility that raccoon dogs may have played a role in the transmission of infection. Of course, animals of all kinds were kept in very close proximity. it is certainly possible that another species infected the raccoon dogs, or the raccoon dogs infected another species that in turn spilled over to humans, if raccoon dogs were infected at all. We simply can’t say for sure.

Wildlife and bat surveillance for novel organisms, and in this case, in search of a SARS-CoV-2 host or an animal species that harbors a progenitor virus candidate is challenging due to the vast number of hosts of coronaviruses, the vast geography over which these animals can be found, and the fact that the SARS-CoV-2 accumulates mutations rapidly with forward transmission and especially with cross-species transmission, as well as the fact that high rates of recombination (the swapping of segments of genetic material between viruses) occur in nature.

Today, in murder cases, for example, we like to have a body, the murder weapon, a convincing motive, fingerprints and DNA that put the suspect at the murder scene along with eye witnesses and cell phone data that establish the time of the crime and overcome any alibis the accused may have. Of course, none of these are required for a conviction, and in fact, many cases are brought and convictions obtained based on circumstantial evidence.

This is likely where we find ourselves with respect to the origins of SARS-CoV-2. Given the time that has passed, and the lack of cooperation and access from China, we likely will never know the origin with 100% certainty. To continue my legal analogies, we don’t require juries to make decisions with 100% certainty in their review of the evidence. For civil matters, juries are to decide cases based on whether the plaintiff has proved their case by a preponderance of the evidence – in other words, is their version of the case more likely than not. In criminal matters, juries are to decide cases on the basis of whether the prosecution has proved their case beyond a reasonable doubt – in other words, the prosecution has presented the case such that the juror has no reasonable doubt as to the defendant’s guilt and none of the defendant’s witness testimony, defenses or explanations are enough to create a reasonable amount of doubt as to the defendant’s guilt relating to the offense that is being charged.

I like to say that I am “origins agnostic,” meaning that I have no vested interest in either scenario and neither finding would alter my work or approach to this pandemic. That doesn’t mean that the origins answer doesn’t make any difference. It does with regards to our nation’s international relationship with China and what steps our country and other countries might take to ensure China’s cooperation in making sure it takes steps to prevent a similar event in the future.

But, as far as I am concerned, the fact that both scenarios are considered to be realistic possibilities, means that we need countries to come together to discuss ways to mitigate both risks. Experts in virology and laboratory operations need to come together to identify the vulnerabilities in our current system that could lead to a lab leak, and determine new standards that can mitigate these risks, along with some politically acceptable manner in which compliance with safety measures can be assured. At the same time, we must come to grips with the growing number of zoonotic infections and measures to reduce opportunities for spillover events, research directed at rapid detection of novel viruses, improved infection control measures for wet markets and animal exports/imports, improved speed and effectiveness of disease outbreak investigations, research directed at new antivirals and other therapeutics, research into more effective and rapidly deployable vaccines, more focus on the elimination or at least control of outbreaks with viruses already identified as having high pandemic potential, and more research into the biology, transmission, virulence and pathogenesis of disease of novel viruses with high mortality rates and high pandemic potential.

So, what would be my verdict if I was a juror? I simply could not reach the level of “beyond a reasonable doubt,” when I know that our government’s intelligence community is coming to different conclusions as to which scenario is more likely and they are as of yet keeping their evidence classified, even though their confidence levels suggest that evidence is not high quality or reliable. Of concern, I don’t even know that these intelligence agencies have shared their evidence and data with each other. Nevertheless, I would want the opportunity to review all the evidence for myself before coming to a verdict beyond a reasonable doubt.

However, I could reach a verdict based on the preponderance of the evidence, with that evidence being all of the evidence that is in the public realm as of the time of this writing. I would find in favor of a zoonotic spillover event. Here is why:

1. Lab leaks have certainly occurred, but the overwhelming majority of these occurred prior to the adoption of the current biosafety lab standards. No lab leak has ever resulted in sustained transmission, let alone an epidemic or pandemic.
2. While China has not allowed independent verification, the only evidence we have from the WIV is evidence that the lab was not conducting research on SARS-CoV-2 or a virus sufficiently closely related that could have served as the progenitor of SARS-CoV-2 and that serologic testing of laboratory workers’ blood samples prior to the onset of the pandemic failed to demonstrate any SARS-CoV-2 infections. This is not conclusive, but for purposes of my jury analogy, the prosecution has not provided any evidence to contradict these representations.
3. I give little weight to the argument that the WIV is in Wuhan, the outbreak was in Wuhan, therefore, the WIV must have been the source of the virus. First, our CDC has laboratories in Atlanta, Georgia. If we had a disease outbreak in Atlanta, my first thought would not be that it must be a lab leak from the CDC, but rather that Atlanta is an international air hub and a traveler from outside of Atlanta may have brought the disease there (e.g. this is what happened when a man with Ebola showed up to a Dallas hospital). Wuhan is a very large city (population > 11 million) with a large international airport. It would be very easy for an infection to be brought into the city and for a novel virus outbreak to be distributed throughout the globe so long as the virus does not make people very sick at the same time that they become infectious. Further, as suspicious as the location of the WIV is for an outbreak in Wuhan, I find it even more suspicious that Wuhan is the location for wet markets (at least four that we know of), sites that we have been able to establish as the origins for other zoonotic outbreaks, including SARS-CoV-1. In fact, epidemiological case contact tracing shows more connection of cases of COVID-19 to the markets than to the lab. Two of the three earliest known cases of COVID-19 have been linked to the Huanan market (where the swabs I referenced above were collected). Of all the cases identified in December of 2019 in China, 55% of the cases had a connection to a wet market (28% to the Huanan market) in Wuhan, however, I would also point out that there are contradictory reports that suggest that most cases in the first week of the outbreak did not have contacts with the markets. Note, given that SARS-CoV-2 is highly transmissible to close contacts and family members, you would not expect every case to have a direct connection (work or visit) to the markets if that was the site of the outbreak. My conclusion on this point is that WIV is no more suspicious as the site of origin than the Huanan market is as both are located in the city of the first known outbreak, but the epidemiologic contact tracing studies, while inconclusive, are certainly stronger in favor of the market than the lab.
4. Zoonotic transmissions account for approximately 75% of outbreaks with novel viruses (e.g., pandemic influenza viruses, monkeypox virus, Ebola virus, human immunodeficiency virus, hantavirus, SARS-CoV-1, MERS-CoV, Lassa virus, Nipah virus, rabies virus, and Marburg virus).
5. SARS-Co-V (2003) resulted from a zoonotic spillover event from palm civets in wet markets in China.
6. MERS-CoV (2012), another novel coronavirus that caused a large outbreak was a zoonotic transmission to humans from camels.
7. HCoV-HKU1, a coronavirus that is endemic and is largely thought of as a common cold virus, was first described in a large Chinese city (Shenzhen, Guangdong) in the winter of 2004, the result of a zoonotic transmission for which we still have ben unable to identify the intermediary host. (This is important because one of the arguments for lab leak is the assertion that a particular structure of the SARS-CoV-2 (the so-called furin cleavage site within the spike protein) is not naturally occurring and thus favors an engineered virus. However, the HCoV-HKU1 has this same structure.)
8. The recent sequencing data that I mentioned above is certainly not proof beyond a reasonable doubt, but I would place it in the category of a preponderance of the evidence when considered in light of all of the above, including the possibility that raccoon dogs may very well have been the intermediary host (i.e., bats [natural host] -> raccoon dogs [intermediary host] -> humans) or alternatively may have spread the infection to the animal that served as the intermediary host or may have been infected by that intermediary host.
9. There were two lineages of SARS-CoV-2 circulating at the same time in China during the outbreak. Lineage B, which is the lineage that became dominant globally in 2020 and ever since was linked to the Huanan market. Lineage A, which no longer circulates, was tied to other wet markets in Wuhan. Two lineages don’t make much sense for a lab leak, but provide additional support for zoonotic spillover events, notably more than one. The animals supplied to the wet markets were often transported together from the southern part of China and then distributed to the various wet markets. It is very plausible that an infected animal could have transmitted the virus to other animals, including other species of animals, given the close contact in which animals were caged and transported. With repeated transmissions and with infections in different animal species, one would expect some mutations to occur giving rise to the two separate lineages.
10. In my mind, there is scientific evidence in support of a zoonotic transmission, even though it is not enough to prove it beyond a reasonable doubt. On the other hand, unless our intelligence agencies have evidence that remains concealed from the public, there is no evidence for a lab leak. This doesn’t rule out a lab leak, it just means that in my mind, the evidence available to date weighs far greater on the side of a zoonotic transmission.

I want to again point out that there is no publicly known “smoking gun” here. We don’t have the swab of an animal at the wet market at the beginning or just prior to the outbreak with the recovery of infectious SARS-CoV-2 that is an identical sequence to the virus infecting the earliest known cases in humans. On the other hand, neither do we have evidence that WIV or any other laboratory in China had SARS-CoV-2 specimens in the laboratory or any other coronavirus close enough to be the progenitor of SARS-CoV-2 with seroconversion (a + antibody test to SARS-CoV-2) in a laboratory worker prior to the outbreak, nor evidence that a lab worker from a lab working with SARS-CoV-2 was ill prior to the outbreak and SARS-CoV-2 was recovered from that lab worker.

As I said, I do not have enough evidence to reach a verdict beyond a reasonable doubt. If I were to find out that the FBI has sworn statements from a lab worker who is a credible witness and provided authenticated copies of laboratory records evidencing that the lab was secretly working on SARS-CoV-2 and hiding it from the public and/or had blood specimens from lab animals or a lab worker with evidence of SARS-CoV-2 infection prior to the outbreak and that the FBI had signals intelligence that indicated that this research was indeed occurring prior to November of 2019, that might completely change my verdict. Of course, I would want to understand why the FBI only attributed moderate level of confidence to that evidence.

Unless some scientist or government has definitive evidence that they are currently keeping a secret, but later makes public or that evidence is somehow leaked (pardon the pun), my guess is that we will never know the origins of this virus beyond a reasonable doubt.

My purpose in writing this blog piece is not to convince you of one hypothesis over the other, because I am not convinced. I am persuaded towards the view of this being a zoonotic transmission and I have shared my current thinking, but I don’t conduct research with viruses and I am definitely not an evolutionary biologist, and I could certainly be wrong. Rather, my point in writing this was to merely help the lay public (non-scientists) understand the issues, the complexity and nuances to this debate, and provide you with enough information that you can think for yourself and come to your own conclusion without taking a position merely because your friends, family or social network has a particular point of view. In that same vein, please feel free to read the published articles for yourself. I have included a list of articles (I have included a couple of articles from the lay press for those who don’t enjoy reading scientific studies as much as I do!) that include both articles supporting a zoonotic spillover event and some supporting the lab leak hypothesis.

Realizing that we don’t know for sure and may never know with 100% certainty, my hope is that we take both possibilities seriously and embark on planning on how to reduce the risk of either origin for a future pandemic. Unfortunately, I suspect that the chances that even our own government, let alone the countries of the world, will undertake serious efforts to mitigate these risks is even less the chances we will ultimately know with certainty the origins of SARS-CoV-2.

 References and Further Reading:

1.      The Origin and Prevention of Pandemics – PMC (nih.gov)

2.      Ten years after SARS: where was the virus from? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3747529/.

3.      Bat cave solves mystery of deadly SARS virus — and suggests new outbreak could occur https://www.nature.com/articles/d41586-017-07766-9.

4.      Exposure to diverse sarbecoviruses indicates frequent zoonotic spillover in human communities interacting with wildlife – PMC (nih.gov)

5.      Identification of coronaviruses in farmed wild animals reveals their evolutionary origins in Guangdong, southern China | Virus Evolution | Oxford Academic (oup.com)

• Animal sales from Wuhan wet markets immediately prior to the COVID-19 pandemic | Scientific Reports (nature.com)

• SAGO statement on newly released SARS-CoV-2 metagenomics data from China CDC on GISAID (who.int)

• https://www.nytimes.com/2023/03/17/health/covid-origins-who.html?smid=nytcore-ios-share&referringSource=articleShare

• The Strongest Evidence Yet That an Animal Started the Pandemic – The Atlantic

1. Bat coronaviruses related to SARS-CoV-2 and infectious for human cells | Nature

1. Closest known relatives of virus behind COVID-19 found in Laos (nature.com)

1. A comprehensive survey of bat sarbecoviruses across China for the origin tracing of SARS-CoV and SARS-CoV-2 | Research Square

1. Surveillance of SARS-CoV-2 in the environment and animal samples of the Huanan Seafood Market | Research Square

1. Exploring the Natural Origins of SARS-CoV-2 in the Light of Recombination – PMC (nih.gov)

1. A Novel Potentially Recombinant Rodent Coronavirus with a Polybasic Cleavage Site in the Spike Protein | Journal of Virology (asm.org)

1. Did the coronavirus jump from animals to people twice? (nature.com)

1. The molecular epidemiology of multiple zoonotic origins of SARS-CoV-2 | Science

1. SARS-CoV-2 emergence very likely resulted from at least two zoonotic events | Zenodo

1. Breaches of safety regulations are probable cause of recent SARS outbreak, WHO says – PMC (nih.gov)

• Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia | NEJM

• The Huanan Seafood Wholesale Market in Wuhan was the early epicenter of the COVID-19 pandemic | Science

• A critical analysis of the evidence for the SARS-CoV-2 origin hypotheses | mSphere (asm.org)

• The origins of SARS-CoV-2: A critical review – ScienceDirect

• Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China – ScienceDirect

• Recovery of Deleted Deep Sequencing Data Sheds More Light on the Early Wuhan SARS-CoV-2 Epidemic | Molecular Biology and Evolution | Oxford Academic (oup.com)

• Ban on gain-of-function studies ends – The Lancet Infectious Diseases

• Genomic determinants of Furin cleavage in diverse European SARS-related bat coronaviruses | bioRxiv

• Unearthed genetic sequences from China market may point to animal origin of COVID-19 | Science | AAAS

• Pandemic origins and a One Health approach to preparedness and prevention: Solutions based on SARS-CoV-2 and other RNA viruses | PNAS

• A strategy to assess spillover risk of bat SARS-related coronaviruses in Southeast Asia | Nature Communications

• Virome characterization of game animals in China reveals a spectrum of emerging pathogens – PMC (nih.gov)

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[1] This was the question that prompted Dr. Ted Epperly and I to write our new book, Preparing for the Next Global Outbreak: A Guide to Planning from the Schoolhouse to the White House. The book is available for preorder Browse All | Hopkins Press (jhu.edu) and is available on April 18.

I was shocked to read a news release from the Oregon Department of Human Services and Oregon Health Authority issued on March 3, 2023. Oregon will lift mask requirement for health care settings April 3 (govdelivery.com).

The title of the memo is “Oregon will lift mask requirement for health care settings April 3.”

There are many problems with this decision. I would put my objections to it in two categories. The first category concerns matters upon which reasonable persons can disagree, but if you are going to take a position, at least make logical and internally consistent arguments to support your position and decision. The other category involves the fact that this decision is coming from a government agency charged with protecting the health of Oregonians, and yet there is no discussion as to how this decision serves the people of Oregon.

Let’s start with what the Oregon Health Authority’s purpose is:

Oregon Health Authority (OHA) – on its website (https://www.oregon.gov/oha/pages/portal-about-oha.aspx), the vision of OHA is “a healthy Oregon.” The mission is “Ensuring all people and communities can achieve optimum physical, mental and social well-being through partnerships, prevention and access to quality, affordable health care.”

Now, let’s examine the memo to see if the action being taken is consistent with the agency’s vision and mission and determine whether the termination of the rule is supported by the resolution of the concerns that prompted the rule.

The memo states that the mask requirement will end for workers, patients and visitors beginning April 3 in all health care settings, rescinding Oregon Administrative Rule (OAR) 333-019-1011.

The memo states: “Dean Sidelinger, M.D., M.S.Ed., health officer and state epidemiologist at OHA, said the lifting of Oregon’s health care mask requirement stems from data in recent weeks showing overall decreases in circulation of the three respiratory pathogens that triggered a surge in visits to hospital emergency departments and intensive care units last fall.”

So, let’s just look at the first argument – “data in recent weeks showing overall decreases in circulation of the three respiratory pathogens (SARS-CoV-2, RSV and influenza) that triggered a surge in visits to hospital emergency departments and intensive care units last fall.” But this action rescinds the administrative rule cited above. So, let’s review the language of that rule Oregon Secretary of State Administrative Rules. Here are the key provisions of that rule for purposes of this issue:

• “This virus (SARS-CoV-2) can be spread by infected persons without symptoms as well as those with symptoms.”
• The rule also mentions that successive variants have developed an increase in transmissibility in the face of waning vaccine effectiveness.
• “Consistent masking by health care providers in health care settings, as well as masking by visitors and patients provides protection to health care providers and to the people they care for. Masks act as source control if the provider has COVID-19 and provide a protective effect if a patient has COVID-19.”

Hopefully, you now see the first two logical flaws and inconsistencies in the argument for rescinding the rule – (1) the circulation of RSV and influenza were not among the reasons for the implementation of the rule, so the decrease in their circulation is irrelevant; and (2) a surge in visits to hospital emergency departments and intensive care units was not a reason for the implementation of the rule, so the fact that this most recent surge in visits has subsided is also irrelevant.

If we look a bit closer at the argument provided by OHA, the only part of this first argument for terminating the rule that is applicable to the reasons provided for implementing the rule is the fact that “data in recent weeks showing overall decreases in circulation (of SARS-CoV-2).” Let’s see how strong that argument is.

Here is the most recent epi curve for Oregon from the CDC:

Again, the argument for terminating the rule is: “data in recent weeks showing overall decreases in circulation (of SARS-CoV-2).” This is actually at least the seventh time since the beginning of the pandemic that this same statement could be made. On each of the prior six occasions, that decrease was followed by a subsequent increase in cases, often by a significant surge in cases. So, why terminate it now and what makes OHA think that there won’t be another surge? Also, not addressed is the fact that we know testing has significantly decreased. Many people are no longer testing when they get sick and many others are testing at home. The results of at-home tests do not show up in the publicly reported numbers of cases. The lack of complete reporting of cases has increased the importance of wastewater testing. The CDC’s wastewater surveillance reporting indicates that 3 testing sites in Oregon are reporting levels of SARS-CoV-2 detection in the range of 60 – 79% of the highest levels reported during the pandemic – hardly an indication that SARS-CoV-2 transmission is under control.

Let’s look at the next argument in the memo: “As of today, COVID-19 test positivity is at 10% and is expected to continue dropping.” First of all, the fact that testing positivity is at 10% is not reassuring. For those who follow this kind of data, you will recall that the goal is for testing positivity to be less than 5%. Thus, the current testing positivity rate cannot be a strong argument for terminating the rule. Rather, OHA’s argument must rely on their assertion that the testing positivity rate “is expected to continue dropping.” It is odd then, that if that is the strongest point of OHA’s argument relating to testing positivity, it offers no explanation as to why it is expected to continue dropping, and especially why OHA has confidence that the testing positivity will continue dropping or be at a low level in a month, when the rule is to be terminated. With the occasion of the first recombinant becoming the predominant circulating variant in the US that also appears to be more transmissible and more immune evasive than prior variants and with a significant rise in the detection of new recombinants emerging, what possible evidence would suggest that we can expect significantly lower transmission rates in the future? I would be delighted if that were the case, but I wouldn’t be placing any bets on that.

The next argument made is that the month-long notice of the termination of the rule allows health care providers adequate time for ”adjusting policies, training and procedures that ensure continued patient safety.” I am curious as to what changes OHA thinks health care providers can take that will ensure patient safety with the ending of the mask requirement and studies that clearly demonstrate SARS-CoV-2 can be a hospital-acquired infection.

The next argument is that this advance notice also “gives members of the public, particularly populations at increased risk of severe disease—communities of color, tribal communities, rural communities, lower-income communities, those with underlying medical conditions, seniors, and parents of vulnerable infants – a chance to plan health care visits and protective measures.” This argument gave me the most visceral reaction. I have so many questions for OHA. What more exactly does it think that those members of the public that are at increased risk of severe disease (keep in mind that a large percentage of people who require outpatient hospital services and hospitalization will fit in this category) should do or can do if their caregivers are no longer masked? The memo goes on to offer a single recommendation: those who are at high risk or who live with persons who are at high risk should continue to mask. Wow. How is it that we are supposed to mask those “vulnerable infants?” If Dr. Sidelinger was going through aggressive chemotherapy, would he really feel safe being cared for in a hospital by an unmasked caregiver team? In a damning admission that this public health agency knows better, it admits that “Masks remain an effective way to reduce transmission of respiratory viruses.” What this statement leaves out is that the evidence is clear that transmission is further reduced when everyone sharing the same air is wearing high quality masks.

The last sentence of the memo is a correct statement: “In order to protect themselves and their families and communities, people are strongly encouraged to stay up to date with vaccinations and boosters.” But, it is an incomplete one. Current vaccines do a great job of protecting people from serious disease, hospitalization and death, if people are fully vaccinated, and have received the bivalent vaccine. In Oregon, only 72.44% of residents have completed the initial vaccination series. According to the CDC data, only 21.3% of Oregonians have received the updated bivalent booster. This large percentage of the population is less protected than they could be. While doing a fairly good job of protecting against severe disease, with the development of progressively more immune evasive variants, vaccines have been less effective at preventing transmission of infection. Further, while vaccines do reduce the chance for development of Long COVID, even vaccinated persons who get infected remain at risk.

I certainly am not suggesting that masking in health care settings will be necessary forever, simply that I think it is ill-advised at present, given the following facts:

• Transmission levels remain high. Despite OHA’s rosy projections, I think few experts feel comfortable in making any long-term projections as to how SARS-CoV-2 will continue to evolve and what threats it may pose.
• Variants have been evolving to achieve higher levels of transmissibility and higher levels of immune evasiveness. A general principle of epidemiology is that higher transmissibility requires more mitigation measures, not less if the objective is to lower infection rates.
• Vaccine effectiveness has declined.
• Insufficient numbers of citizens have been fully vaccinated and boosted, and large portions of the population are experiencing waning immunity either from vaccination or infection.
• Studies of long-term consequences of SARS-CoV-2 infection are revealing more concerns, not fewer.
• With a very limited exception, we no longer have effective monoclonal antibody treatment options due to the fact that current variants have developed progressively more degrees of immune evasion.
• We previously could offer immunocompromised patients and patients with immunodeficiencies Evusheld as protection against infection. However, as with the monoclonal antibodies, current variants have also developed immune evasion to this therapy.

Of course, the good news is that while the rule will terminate, hospitals and other facilities and caregivers who care for high-risk patients are not required to end their mask requirements. This rule change will make it more difficult for those providers to continue requiring masking, but I encourage them to do so for now for the following reasons:

• Evidence-based care: The provision of health care services should be evidence-based in those cases where evidence exists. Masking in health care settings remains evidence-based at present.
• Trust: There has, in general, been a decline in levels of trust for health care providers during the pandemic for many reasons, including the promotion of disinformation and conspiracy theories by legislators, and unfortunately, by some physicians and even members of health boards. We must act in ways that assure the public that we have their best interests at heart and they do not have to fear that they are safer in their homes than in our hospitals.
• Ethics: A long-held principle for physicians, but one generally applicable to health care is primum non nocere (first, do no harm). When patients come to us for help, we are obligated to act in their best interests (not ours), and certainly, it is expected that we will do our best to keep them safe while in our care.
• Workforce issues: During the pandemic, there have been points at which capacity has been strained. But, throughout this time, there have been pressures on adequate staffing given employees quarantining due to exposure or isolating due to infection. We continue to experience health care professional shortages. While acute infections add to these short-term staffing challenges, we are only now learning about the health risks associated with repeated infections and with Long COVID. At a time when hospital finances are strained for most hospitals, it hardly seems prudent to increase the needs for travelers, decrease the capacity to treat patients, increase employee health care costs, and lose more employee productivity due to Long COVID.

One of the most heartbreaking revelations of the pandemic has been the general apathy towards protecting those who are immunocompromised. I have talked to many elderly persons, parents taking chemotherapy for cancer or immunosuppressive medications for autoimmune diseases or solid organ transplants, persons with immunodeficiencies and others who have felt that they have had to put their lives on hold and make extraordinary restrictions to their normal activities because the general populus has determined the need to protect their individual liberties takes priority. However, it is even more appalling when I see public health agencies or officials and health care providers failing to protect the immunocompromised.

I have talked to many of these immunocompromised individuals. They consider whether they are going to take the risks to go to the grocery store, get their hair done, or even go to the doctor’s office, and if so, how they will time their visit to minimize contacts with others. No doubt they have already put off many non-urgent health services. This change in masking could cause them to further avoid contacts with the health care system, and I fear, to the detriment of their long-term health.

Hospitals considering ending mask requirements would need to ask themselves how they would explain to a parent that their newborn contracted COVID-19 while in the hospital and is now ill. Keep in mind that these infants are not eligible for vaccination or most of the treatments authorized or approved by the FDA. They would be unable to answer what the long-term health consequences to that infant may be. Hospitals would also have to explain how a mother, father, grandmother or grandfather came into the hospital for a hip replacement or other service and died due to contracting COVID-19 in the hospital.

While health care providers have enjoyed some liability protections during the pandemic, many of those protections have now ended and the remaining will end with the ending of the Public Health Emergency. I have no doubt that we will begin to see lawsuits for negligence when patients contract COVID-19 in the hospital and develop complications or die.

To conclude, I suggest reporters consider a few questions for Dr. Sidelinger:

1. How will this decision to terminate the rule requiring masks in health care settings make patients safer and protect their health? (It won’t)
2. How will ending the requirement to wear masks in health care settings reduce the risks of asymptomatic transmission of SARS-CoV-2 from patients and visitors to staff, from other staff to staff and from staff to patients? (It won’t)
3. The rule that is being terminated stated: “Consistent masking by health care providers in health care settings, as well as masking by visitors and patients provides protection to health care providers and to the people they care for. Masks act as source control if the provider has COVID-19 and provide a protective effect if a patient has COVID-19.” Is this information no longer true? (It is still true)
4. Is it important to reduce infections with SARS-CoV-2 even if those infections do not cause severe illness or death? (Yes – there remains risk of long-term complications including Long COVID).
5. Are there health care workers who are in the high risk category whose health risks would be increased by the end of masking by patients, staff and visitors? (Yes)
6. Does infection of immunocompromised persons create a public health risk due to the potential for chronic infection, co-infections, mutations of the SARS-CoV-2 virus and recombinant events that can then enter the general population? (Yes).
7. The OHA memo acknowledges that “members of the public, particularly populations at increased risk of severe disease—communities of color, tribal communities, rural communities, lower-income communities, those with underlying medical conditions, seniors, and parents of vulnerable infants” will need the next month to plan their health care visits and protective measures.
   • a. It has long been realized, and the pandemic has amplified, that health care disparities exist in the US health care delivery system. Aren’t many of those groups mentioned in the memo as being at increased risk of severe disease and potentially harmed by this decision members of groups most impacted by these health care disparities? (Yes – specifically “communities of color, tribal communities, rural communities and lower-income communities.”) How will this decision not contribute to or worsen these health care disparities?
   • b. What planning and additional protective measures other than those these groups are currently doing do you recommend they undertake in order to mitigate the increased risk they will be at from ending the masking requirements in health care settings? The memo specifically points out the planning and protective measures parents should take for vulnerable infants. What additionally can be done to protect a vulnerable infant in the hospital if the staff and visitors are not wearing masks?

There are many steps that can be taken to get to the point where we can eliminate the need for high quality mask use in all health care settings. There is significant research in progress on new vaccines that might confer better mucosal immunity and less transmission of infection. We have learned a lot about improvements we can make to ventilation, air filtration and even air disinfecting measures.

I want to make sure that readers understand that I do not think masks in health care settings are a panacea. They are not. I still see health care workers wearing inadequate respiratory protection like surgical or procedure masks. I still see visitors and some staff wearing masks improperly. However, we must realize that:

• A vaccine only strategy is inadequate, especially in the light of uncontrolled transmission and the development of progressively transmissible and immune evasive variants.
• Perfect need not be the enemy of good, as the saying goes. In other words, even though masks are imperfect, reduction in the amount of virus transmitted can help avoid the development of severe disease.
• We have placed too much emphasis on mortality rates to the exclusion of focus on preventing other complications following acute infection – e.g., MIS-C; MIS-A; cardiovascular, neurological and other complications of infection; and Long COVID (PASC). The avoidance of these complications is also worth our attention and efforts at infection control.

With the 1/30/23 announcement that the Biden administration plans to end the COVID-19 public health emergency declaration in May, what does this mean for the public, for state governments and health care providers? Answer: Much more than you probably realize.

Background

The Trump administration issued the COVID-19 national emergency and the public health emergency (PHE) declarations in 2020. The PHE was declared on 1/31/20 by the Secretary of Health and Human Services. The national emergency was declared by President Trump on March 13, 2020.

The PHE declaration expires on its own after 90 days, unless renewed, and it has been repeatedly renewed (a total of 12 times[1]) by both administrations since its initial implementation on 1/31/20. The COVID-19 national emergency declaration is currently set to expire on March 1, 2023 and the PHE declaration is set to expire on April 11, 2023 (its last renewal having occurred on 1/11/23).

The administration has indicated its plans to extend both declarations until May 11, 2023, and then terminate both on that date. https://www.whitehouse.gov/wp-content/uploads/2023 /01/SAP-H.R.-382-H.J.-Res.-7.pdf. It appears that this decision was made in response to proposed legislation that would terminate both declarations immediately if passed. Although passage would be uncertain in the current Congress, I suspect that the Biden White House weighed that against the certain chaos abrupt termination would pose for states, health care providers and the public, especially those who depend on Medicaid for their insurance coverage. In fact, the Biden administration has previously assured states and health care providers that it would provide at least 60 days of advance notice before terminating the PHE. Of course, one can also speculate that the administration may have been looking for an excuse to terminate the PHE, and perhaps understandably so given Congress’ repeated refusals to appropriate more funding for the PHE.

Implications and Impacts

It is quite daunting to consider all of the interim measures put in place during the pandemic that may now be terminated with the termination of the PHE declaration. It is all the more daunting because some measures have been given an extension following the termination of the PHE declaration and some measures have been made permanent through agency rule-making or by statute.

1. FDA ability to grant Emergency Use Authorization (EUA) for vaccines, medications and medical devices.

It is of great concern to me that the contemplated ending of the PHE coincides with a time that:

• Evusheld has just had its EUA suspended;
• All previously authorized monoclonal antibody treatments have had their EUAs revoked or suspended[2];
• I anticipate that Molnupiravir will soon lose its EUA given studies showing little or no protection against severe disease and that treatment can promote the development of mutations;
• We need vaccines that provide better mucosal immunity and protection against infection and more therapeutic options, especially for the immunocompromised. Many new vaccines and therapeutics are currently in clinical trials;
• A surprisingly low percentage of the population has received a bivalent booster, especially in those who are over age 65;
• Our current vaccines have low effectiveness at preventing infection, transmission and PASC, with rapid waning of neutralizing antibody titers;
• A surprisingly low percentage of candidates for Paxlovid antiviral treatment are receiving the medication;
• We have a record number of new circulating variants with enhanced transmissibility and immune escape;
• We are learning much more about the potential detrimental long-term health consequences following even mild cases of COVID-19.

On February 4, 2020, the Secretary of Health & Human Services determined pursuant to section 564 of the Federal Food, Drug, and Cosmetic (FD&C) Act that circumstances exist justifying the authorization of emergency use of in vitro diagnostics for detection and/or diagnosis of SARS-CoV-2 pursuant to section 564 of the FD&C Act, subject to the terms of any authorization issued under that section. Federal Register :: Determination of Public Health Emergency.

On the basis of the Secretary’s determination that a public health emergency existed as of February 4, 2020, he also declared on March 27, 2020 that circumstances exist justifying the authorization of emergency use of drugs and biological products during the COVID-19 pandemic, pursuant to section 564 of the FD&C Act, subject to the terms of any authorization issued under that section. Federal Register :: Emergency Use Authorization Declaration

This concern about the ability of the FDA to continue to provide for EUAs was even greater in the past when the termination of the PHE could also result in the termination of the FDA’s authority to grant Emergency Use Authorizations to vaccines, biological products and medical devices. However, in 2013, the passage of The Pandemic and All Hazards Preparedness Reauthorization Act amended section 564 of the Federal Food, Drug and Cosmetic (FD&C) Act, 21 U.S.C. 360bbb-3, to provide more flexibility to the Health and Human Services Secretary to authorize the U.S. Food and Drug Administration (FDA) to issue Emergency Use Authorizations, not only during a declared public health emergency involving chemical, biological, radiological, and nuclear agents, but when there is an emerging threat and potential for the development of a public health emergency. The Secretary is no longer required to make a formal determination of a public health emergency under section 319 of the Public Health Service Act, 42 U.S.C. 247d before declaring that circumstances justify issuing an EUA. 

Fortunately, this appears to give the Secretary the latitude to provide the FDA with continued authority to grant Emergency Use Authorizations, but unfortunately this depends upon the view of whether there are emerging threats or the threat of a potential public health emergency of a political appointee subject to political pressures.

• Commercialization of vaccines, tests and therapies.

Under the PHE, most Americans have benefitted from the ability to obtain free COVID-19 testing and free vaccines and therapeutics without incurring out-of-pocket costs. With the termination of the PHE, vaccines, tests and therapeutics will move into the commercial market resulting in coverage determined by insurance plans, including deductibles and co-pays (other than vaccines, which should continue to be made available with no out-of-pocket costs pursuant to the Patient Protection and Affordable Care Act (ACA) of 2010 for those with ACA-covered health insurance[3]. But, note that the ACA does not prevent insurers from imposing cost-sharing for tests and treatments). Of course, those who are uninsured will often be faced with paying full price for their vaccines (There may be limited opportunities to receive free vaccines through the Section 317 Immunization Program, but few are aware of it or how to access it and it does not appear that Congress intends to fund this program as it is not a “mandatory” program (in other words, Congress has discretion as to whether to fund it and if so, how much to fund it). Some uninsured can also access vaccines through safety net providers on a sliding scale fee schedule based upon income). It has been widely reported that Pfizer is projecting prices for its COVID-19 vaccines in the range of $110 – 130 per dose (the government currently pays approximately $30 per vaccine dose for both Pfizer and Moderna). Not that the pharmaceutical industry would ever engage in price fixing, but Moderna has also subsequently indicated that it will consider a price of $110 – 130 per vaccine dose.

Medicare beneficiaries will continue to have access to COVID-19 vaccines, including boosters, with no cost-sharing so long as they have Medicare Part B coverage. Providers will continue to use the government’s inventory of COVID-19 vaccines until they are depleted. Then, Medicare will determine a payment rate for the vaccines as well as continue to pay an administration fee.

The American Rescue Plan Act and the Inflation Reduction Act require Medicaid and CHIP programs to continue to provide all ACIP-recommended vaccines, including the COVID-19 vaccines and boosters with no cost sharing from beneficiaries even once the PHE ends and the federal supply of vaccines has been exhausted. Under the provisions of these laws, states will receive 100% FMAP payments for the costs associated with administering the COVID-19 vaccines and boosters through the last day of the first quarter that begins one year after the PHE is terminated. After that point in time, state costs are reimbursed at the regular FMAP rate for that particular state and at the enhanced FMAP rate for CHIP.

The Vaccines for Children Program (VFC) will continue to provide access to COVID-19 vaccines for Medicaid-eligible children once the federal supply is exhausted (by purchasing the vaccine and then distributing it to VFC-registered providers. The Medicaid program will pay providers administration fees. For other Medicaid and CHIP enrollees, states will pay providers for the vaccine and its administration.

On 8/18/22. CMS indicated that it will continue to pay approximately $40 per dose for administering COVID-19 vaccines in outpatient settings for Medicare beneficiaries through the calendar year in which the PHE ends (2023). As of 1/1/24, CMS will set the payment rate for administering COVID-19 vaccines to align with the payment rate for administering other vaccines under Part B. (There is also an additional payment amount of approximately $35.50 per dose for administering COVID-19 vaccines in the homes of certain Medicare beneficiaries. These payments will end at the end of the calendar year in which the PHE ends, i.e., 2023.)

Paxlovid, which has been shown to be nearly 90% effective in reducing the risk of severe COVID, (hospitalization and death), will also no longer be free once the PHE is terminated. The government reportedly pays $530 for a course of Paxlovid. Without a good alternative, and without bulk buying and committed orders from the government, one can only imagine what the retail price for Paxlovid will be (Pfizer has not yet announced their projected price). However, given the projected quadrupling of the vaccine price (when there is an alternative available), one can imagine that the price will likely exceed $2,000, and thus be unaffordable to the uninsured.

After the termination of the PHE, CMS will pay for monoclonal antibody treatments for COVID-19, if there are any, in the same manner in which they pay for biological products under Section 1847A of the Social Security Act. (CMS did note that this could change when the final rule is issued for the Calendar Year 2023 Physician Fee Schedule and OPPS/ASC proposed rule.)

The government did not purchase a supply of remdesivir. Since the FDA updated the approval of VEKLURY (remdesivir) for use in the outpatient setting, CMS will continue to provide payment for this drug and its administration under Medicare Part B even after the termination of the PHE. In most cases, this will subject Medicare beneficiaries to the annual Part B deductible and a 20% co-insurance fee.

Medicare beneficiaries will likely have cost-sharing requirements for most COVID-19 treatments once the PHE ends. I am researching, but not yet clear, as to whether commercial health plans must offer and cover drugs and services that are only available under an Emergency Use Authorization. The Consolidated Appropriations Act of 2023 does require Medicare Part D plans to cover certain COVID-19 therapies (antivirals) that only have EUA, but these remain subject to cost-sharing.

The American Rescue Plan Act requires Medicaid and CHIP programs to cover all drugs and biological products for the treatment or prevention of COVID-19 with no cost sharing for enrollees through the last day of the first quarter that begins one year after the termination of the PHE. However, once that coverage period ends, Medicaid and CHIP must continue to cover FDA-approved COVID treatments, but these can then be subject to cost-sharing and utilization review. The law would not require coverage of treatments that are still under EUA, but states may choose to do so (so, for Idaho, that is likely a “no.”)

It remains to be seen whether the shift of costs from the government to commercial health plans and employer-sponsored health plans will result in premium increases, but it would not be surprising, especially when you add in the costs of providing care to those with PASC or Long COVID.

This commercialization of vaccines, tests and therapeutics will widen already well-documented health care disparities that occurred prior to, and were amplified during, the pandemic. I fear that we have not yet learned the lesson that controlling the community spread of a contagious disease requires ensuring availability of vaccinations, testing, and treatments to those in the community who are uninsured and underinsured.

In addition, given that there will not be large advance guaranteed purchase agreements with the government, one can be justified in worrying that if the near future will continue to be characterized by waves of COVID-19 and under-prescribing/underuse of Paxlovid, we could then see shortages of Paxlovid were we to experience a new large wave with a new variant that was causing more severe disease suddenly and significantly increasing demand, similar to what we have recently seen with children’s cold medicines and certain antibiotics, especially if that wave was world-wide or occurring simultaneously in many countries.

As far as at-home COVID tests, Medicare beneficiaries will bear the full cost once the PHE is terminated. During the PHE, Medicare implemented a demonstration program to allow Medicare beneficiaries to receive up to eight at-home COVID-19 tests per calendar month at no cost. However, this program expires with the termination of the PHE.

Provider COVID testing will be covered under Medicare Part B, but beneficiaries will still be responsible for the associated out-of-pocket costs. Medicare Advantage plans (Part C) may allow at-home COVID tests to be covered under any over-the-counter benefit they offer and they may choose through their plan design whether to require cost-sharing or not for provider COVID testing.

Medicaid and CHIP must cover COVID-19 at-home tests and provider testing for enrollees at no cost through the last day of the first quarter that begins one year after the PHE is terminated. After that point in time, states may decide whether to cover at-home tests and whether cost-sharing will be required, but there is no requirement to do so. Nevertheless, states must continue to cover provider-ordered COVID testing in a medical facility.

For commercial and employer sponsored health plans that are subject to the ACA, COVID-19 testing would fall under essential health benefits and therefore must be covered following the termination of the PHE. However, any essential health benefits that do not receive an A or B rating from the US Preventive Services Task Force (which COVID-19 testing has not) can be subject to cost-sharing by the health plan. Insurers can also require the testing be pursuant to a provider order, they can limit the number of tests per plan year, they can restrict testing to in-network facilities, and they can impose cost-sharing.

• Telehealth coverage/access

Throughout the COVID-19 public health emergency (PHE), CMS has used a combination of emergency authority waivers, regulations, enforcement discretion, and sub-regulatory guidance to ensure access to care and give health care providers the flexibilities needed to respond to COVID-19 and help keep people safer. Many of these waivers and broad flexibilities will terminate at the eventual end of the PHE.

The Coronavirus Aid, Relief, and Economic Security Act (CARES Act) of 2020 broadened CMS’ section 1135 (Social Security Act) waiver authority. Telehealth access and coverage was extended during the pandemic initially under CMS 1135 waivers that were retroactive to March 1, 2020 and in effect until the expiration of the PHE declaration. CMS then waived the restrictions on who can provide distant site telehealth services so as to allow any provider who is eligible to bill the Medicare program to provide these services (e.g., this would allow physical therapists, occupational therapists and speech language therapists to provide distant site telehealth services). That waiver was specified to end 151 days following the termination of the PHE declaration.

Under this same authority, CMS waived the requirement for certain services for the use of interactive telecommunications systems to furnish telehealth services to the extent video was otherwise required. CMS established “audio-only” E&M codes for those services covered by this waiver. This waiver was also declared to expire 151 days following the termination of the PHE declaration.  

Subsequently, some of these measures were codified under the Consolidated Appropriations Act of 2021. Some of these benefits were further extended or enhanced under the Consolidated Appropriations Acts of 2022 and 2023. For example, the Consolidated Appropriations Act of 2023 extended many of the telehealth flexibility waivers that were passed under Consolidated Appropriations Act of 2022, including geographic and originating site restrictions so that Medicare patients can continue to use telehealth services from their home and allowing audio-only telehealth services through December 31, 2024. In addition, the removal of restrictions on which providers can provide distant site telehealth services is extended through December 31, 2024 so that physical therapists, occupational therapists and speech language therapists can continue sessions via telehealth through that date.

In addition, the Consolidated Appropriations Act of 2023 further extended the date for which telehealth can be used to conduct recertification of eligibility for hospice services through December 31, 2024. That same statute extends the Acute Hospital Care at Home Program through the end of calendar year 2024.

Telehealth services for Rural Health Clinics (RHCs) and Federally Qualified Health Centers (FQHCs) are also extended until December 31, 2024 under the Consolidated Appropriations Act of 2023.

Under the Consolidated Appropriations Act of 2021, Medicare patients were able to receive telehealth services for behavioral health care in their homes in any part of the country, including most behavioral health services, such as counseling, psychotherapy, and psychiatric evaluations. The patient must have had at least one in-person visit with the provider in the six months before the telehealth visit in order to be eligible. This provision was extended through the end of calendar year 2024 by the Consolidated Appropriations Act of 2023.

• Medicaid enrollment

Passed by Congress in March 2020, the Families First Coronavirus Response Act was intended, in part, to shore up state finances by temporarily increasing the federal share of Medicaid funding for states. To protect health coverage during the pandemic, states were prohibited from disenrolling individuals from Medicaid for the duration of the federal PHE as a condition of accessing the enhanced funding. This “continuous coverage” requirement extends from March 18, 2020, through the end of the month in which the PHE ends. FFCRA § 6008.

Under the Families First Coronavirus Response Act, state Medicaid programs were eligible to receive an additional 6.2 percent federal funding match provided they met specific Maintenance of Effort requirements, including providing continuous eligibility to those enrolled as of March 18, 2020 or at any time thereafter during the PHE. When the PHE ends, states will need to redetermine the eligibility of over 80 million Medicaid enrollees, including an estimated 37.3 million children.

In a typical annual redetermination process, some number of enrollees lose Medicaid coverage due to changes in circumstances that impact eligibility (e.g., new employment or income increases). More commonly, Medicaid eligible people lose coverage (referred to as “churn”) as a result of administrative barriers like a lack of online options for renewing coverage, complicated paperwork and documentation processes, and personal circumstances that prevent individuals from responding to a renewal request on time (these challenges are particularly acute for individuals with significant health needs). Evidence suggests that churn – and not external factors like an improving economy driving income ineligibility for Medicaid – have been the primary sources of Medicaid enrollment decreases in recent years. https://familiesusa.org/wp-content/uploads/2019/09/Return_of_Churn_Analysis.pdf[5] https://familiesusa.org/wp-content/uploads/2019/09/Return_of_Churn_Analysis.pdf The FFCRA continuous coverage requirement effectively eliminates churn in Medicaid for the duration of the PHE.

The Centers for Medicare & Medicaid Services (CMS) released guidance that describes timelines and obligations for states to restart eligibility and enrollment activities following the end of the PHE. This guidance attempts to help mitigate coverage disruptions by giving states 12 months to complete the “PHE unwinding” process and requiring robust consumer communication, among other strategies. https://www.medicaid.gov/federal-policy-guidance/downloads/sho-21-002.pdf

The Urban Institute and Robert Wood Johnson Foundation estimated prior to the Biden administration announcement that if the PHE were to expire in April 2023, 18.0 million people will lose Medicaid coverage in the following 14 months. Of those, about 3.2 million children are estimated to transition from Medicaid to separate Children’s Health Insurance Programs, about 3.8 million people will become uninsured, about 9.5 million people will either newly enroll in employer-sponsored insurance after losing Medicaid or transition to employer-sponsored insurance as their only source of coverage after being enrolled in both employer-sponsored insurance and Medicaid sometime during the PHE, and more than 1 million people will enroll in the nongroup market, most of whom will be eligible for premium tax credits in the Marketplace. The Impact of the COVID-19 Public Health Emergency Expiration on All Types of Health Coverage (urban.org)

• Border control

The end of the PHE will also mean the end of the Title 42 border policy, which allowed border officials to expel foreign nationals and ignore asylum claims for the sake of public health protections. Title 42 restrictions were ordered to be terminated at the end of December, however, the U.S. Supreme Court overturned that decision and Title 42 remains in effect by subsequent order of the U.S. District Court. Five things to know about the end of Title 42 | The Hill.

• Nursing Home COVID-19 reporting

On May 8, 2020, pursuant to an interim final rule with comment posted by CMS, nursing homes were required to report resident and staff infections and deaths related to COVID-19. The rule was set to expire with the termination of the PHE, however, in the 2023 Home Health rule, CMS revised the infection control requirements that Long-term Care (LTC) Facilities must meet to participate in the Medicare and Medicaid programs so that these facilities continue the COVID-19 reporting requirements until December 2024.

• Loss of limited immunity for the administration of COVID-19 counter-measures by licensed health care professionals and hospitals

The Public Readiness and Emergency Preparedness Act (PREP), subsequently amended as the Public Health Service Act, which added Section 319F-3 that contains the limited immunity provisions, affords some limited liability to various to certain individuals and entities (Covered Persons) against any claim of loss caused by, arising out of, relating to, or resulting from the manufacture, distribution, administration, or use of medical countermeasures (Covered Countermeasures), except for claims involving “willful misconduct.” These legal protections expire 12 months following the termination of the PHE pursuant to the Secretary’s declaration.

• Reduction in payments to health care providers

Unless Congress intervenes, a 4% reduction in Medicare payments is scheduled for this year under the PAYGO (pay-as-you-go) budget rules that was supposed to take place in 2022, but was delayed.

Congress waived automatic 2% Medicare payment reductions under sequestration between May 1, 2020 and March 31, 2022. It is not clear whether Congress will further delay these cuts or accelerate given the current budget negotiations between Republicans and the White House attempting to significantly reduce spending and the national debt.

Congress increased payments to hospitals for inpatient COVID-19 admissions by 20% to account for the increase intensity of care, increased supply costs and the loss of revenue due to deferring elective procedures. These payments will end with the termination of the PHE.

• Reduction in SNAP (Supplemental Nutrition Assistance Program)

The largest effects for SNAP would arise from ending the pause on participation limitations for students and for able-bodied adults without dependents and from lengthening certification periods.

1. Ending of CMS emergency waiver authorities as well as other various regulatory authorities used to create flexibility for providers

It is expected that the following waivers or other flexibilities will end when the PHE is terminated:

1. Hospitals without walls (temporary expansion sites) – this allowed hospitals to provide hospital services in other hospitals and at sites that otherwise would not have been considered part of a healthcare facility, including the ability to set up temporary expansion sites that could accommodate increased capacity needs. CMS subsequently allowed additional flexibility for a hospital to utilize a hotel or other community facility. This flexibility end with the termination of the PHE.
2. CMS did allow for ASCs or free-standing emergency departments to temporarily enroll as a hospital during the PHE. The ability to enroll as a hospital was suspended on December 1, 2021 and those facilities that did enroll prior to 12/1/21 will have to meet the certification standards for hospitals or return to their ASC or free standing emergency room status when the PHE is terminated. Independent, freestanding emergency departments also will no longer be able to participate in Medicare as the temporary Medicare certification granted during the PHE will end.
3. Waiver of some EMTALA requirements. Under the PHE, CMS waived EMTALA requirements to allow hospitals to screen patients for emergency medical conditions at locations off the hospital’s campus in order to assist with controlling the spread of COVID. This waiver will terminate with the ending of the PHE.
4. CMS also waived certain paperwork requirements for hospitals that were considered to be impacted by a widespread outbreak of COVID-19 as determined by CDC guidelines, including relief from the timelines to provide copies of medical records and requirements to have written polices and procedures regarding visitation for patients in COVID-19 isolation. This waiver ends with the PHE termination.
5. CMS waived certain restrictions on placement of alcohol-based hand sanitizers to allow for increased availability for infection control measures. This waiver will terminate with the ending of the PHE.
6. CMS waived the requirement for quarterly fire drills at certain health care facilities, allowing a documented orientation and training program instead. This waiver will end with the PHE termination, but has already been terminated in June of 2022 for inpatient hospices and skilled nursing facilities.
7. CMS issued a waiver to allow hospitals to offer long-term care services (swing beds) without meeting all of the usual criteria for patients who no longer require acute care, but for whom the hospital and family have not been able to find a skilled nursing facility bed available. This waiver ends with the termination of the PHE.
8. CMS waived the limitations on number of beds and length of stay for patients at critical access hospitals. This waiver will end with the ending of the PHE.
9. CMS issued a waiver relating to the rural location for critical access hospitals to allow them flexibility in creating surge site locations that may not be in a qualifying rural area or at the distance required relative to other hospitals. This waiver will also end with the termination of the PHE. CMS issued a similar waiver for sole community hospitals and that waiver also expires at the end of the PHE.
10.  In order to  mitigate potential financial disincentives for hospitals to provide new COVID-19 treatments and to minimize any potential payment disruption following the end of the PHE, effective for discharges occurring on or after November 2, 2020 and through the end of the fiscal year in which the PHE ends, the Medicare program will make an enhanced payment for eligible inpatient cases that involve treatment with these new therapies (this would be a payment in addition to the DRG payment to avoid the costs for these treatments having to come out of the hospital’s bundled payment). There is a similar enhanced payments for new treatments available to hospital outpatient departments in addition to the APC fees. These enhance payments will also end with the termination of the PHE.
11. CMS issued a special price transparency requirement mandating that providers of a diagnostic test for COVID-19 were to make public the cash price for such tests on their websites. This special rule will terminate with the end of the PHE.
12. During the PHE, CMS paid hospital outpatient departments a symptom assessment and specimen collection fee of approximately $23 under new code C9803 (when not billed with a separately payable hospital outpatient service) to encourage hospitals to set up COVID-19 testing sites. After the ending of the PHE, this fee will no longer be paid separately. The payment for COVID-19 testing specimen collection will be packaged into the payment rate for COVID testing.
13. CMS issued limited waivers of the Stark Law relating to financial relationships with physicians for services solely related to COVID-19, including some that might otherwise violate the personal services and non-monetary compensation restrictions, as well as allowing for some additional benefits to the medical staff such as meals, laundry and child-care services. These waivers expire with the termination of the PHE.
14. CMS waived the requirement for verbal orders to be signed within 48 hours, but this waiver will end with the termination of the PHE.
15. CMS also waived some reporting requirements (e.g., deaths of patients who were in soft restraints at the time of their death) and some of the discharge planning requirements relating to the provision of data on quality measures and certain other information (e.g., a comprehensive list of facilities) about prospective facilities to which the patient may be transferred. These waivers also expire with the ending of the PHE.
16. CMS also waived some of the requirements relating to medical records, in particular the timeline for completion of the medical records by physicians and the requirement to provide patients with information about advance directive policies. These waivers end with the termination of the PHE.
17. CMS also waived the requirements for ongoing utilization review in hospitals. This too expires at the end of the PHE.
18. CMS waived some of the requirements relating to the Quality Assessment and Performance Improvement Plan, though it did not waive the obligation to maintain an effective, ongoing, hospital-wide, data-driven quality assessment and performance improvement program. This waiver similarly expires with the ending of the PHE.
19. CMS waived some of the requirements as to nursing services, particularly relating to the requirement for a current nursing plan of care for each patient in order to increase nursing time available for direct patient care. This waiver expires with the ending of the PHE.
20. CMS also waived the requirement for hospitals to maintain a current therapeutic diet manual at surge capacity sites. This waiver will terminate with the ending of the PHE.
21. CMS also indicated that it would not enforce the requirement for signature and proof of delivery for Part B drugs and DME when a signature cannot be obtained because of COVID disruptions. This will expire with the PHE ending.
22. During the PHE, CMS has allowed licensed physicians and other practitioners to bill Medicare for services provided outside of their state of enrollment. Once the PHE ends, the requirements for providing services out of state will defer to state laws.
23. CMS waived the hospital sterile compounding requirements to allow used face masks to be removed and retained in the compounding area to be re-donned and reused during the same work shift in the compounding area only in order to conserve scarce PPE supplies. This waiver ends with the termination of the PHE.
24. CMS also waived the time limits imposed under the Medical Staff requirements for those physicians whose privileges would otherwise expire before the medical staff and governing board can reconvene due to the impacts of COVID-19. This waiver also ends with the PHE.
25. CMS waived the requirements for physician supervision of CRNAs during the PHE. This will end with the PHE termination.

it is possible CMS could extend some of these waivers or use other authorities in some cases to continue programmatic changes. Further, CMS is evaluating which of the waivers were most effective and useful in order to prepare them for immediate roll-out with a future PHE.

Additional References

U.S. Department of Health and Human Services Public Health Emergency Declarations site: https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx

Medicaid.gov. Unwinding and Returning to Regular Operations after COVID-19.

Centers for Medicare & Medicaid Services (CMS). October 2022. COVID-19 Public Health Emergency Unwinding Frequently Asked Questions for State Medicaid and CHIP Agencies.

Centers for Medicare & Medicaid Services (CMS). October 2022. Ex Parte Renewal: Strategies to Maximize Automation, Increase Renewal Rates, and Support Unwinding Efforts.

Centers for Medicare & Medicaid Services (CMS). September 2022. Resources to Support System and Logic Testing for Unwinding.

Centers for Medicare & Medicaid Services (CMS). June 2022. Top 10 Fundamental Actions to Prepare for Unwinding and Resources to Support State Efforts.

Centers for Medicare & Medicaid Services (CMS). June 2022. Renew Your Medicaid or CHIP Coverage.

Centers for Medicare & Medicaid Services (CMS). May 2022. Eligibility & Enrollment Processing for Medicaid, CHIP, and BHP During COVID-19 Public Health Emergency Unwinding Key Requirements for Compliance.

Centers for Medicare & Medicaid Services (CMS). March 2022. State Health Official Letter # 22-001. RE: Promoting Continuity of Coverage and Distributing Eligibility and Enrollment Workload on Medicaid, CHIP, and Basic Health Program Upon Conclusion of the COVID-19 Public Health Emergency.

Centers for Medicare & Medicaid Services (CMS). March 2022. Medicaid and CHIP Continuous Enrollment Unwinding: A Communications Toolkit. 

• English toolkit
  • Spanish toolkit

Centers for Medicare & Medicaid Services (CMS). March 2022. Medicaid and Children’s Health Insurance Program Eligibility and Enrollment Data Specifications for Reporting During Unwinding.

Centers for Medicare & Medicaid Services (CMS). Medicaid and CHIP Continuous Enrollment Unwinding Speaking Request Form

Center on Budget and Policy Priorities. May 2022. Time to Get it Right: State Actions Now Can Preserve Medicaid Coverage When Public Health Emergency Ends.

Center on Budget and Policy Priorities. March 2022. Unwinding the Medicaid Continuous Coverage Requirement. Frequently Asked Questions.

National Academy for State Health Policy. September 2022. Unwinding Medicaid’s Continuous Coverage Requirement: State Communication Strategies.

National Academy for State Health Policy. March 2022. How States Are Getting Ready to Unwind Medicaid’s Continuous Coverage Requirement.

National Academy for State Health Policy. December 2021. States Plan for the End of the Medicaid Continuous Coverage Requirement.

Kaiser Family Foundation. Implications for Ending the COVID-19 Public Health Emergency.

Kaiser Family Foundation. August 2022. A 50-State Review of Access to State Medicaid Program Information for People with Limited English Proficiency and/or Disabilities Ahead of the PHE Unwinding.

Kaiser Family Foundation. March 2022. Unwinding of the PHE: Maintaining Medicaid for People with Limited English Proficiency.

Kaiser Family Foundation and Georgetown Center for Children and Families. March 2022. Medicaid and CHIP Eligibility and Enrollment Policies as of January 2022: Findings from a 50-State Survey. 

Georgetown Center for Children and Families. September 2022. 50-State Unwinding Tracker.

Georgetown Center for Children and Families. September 2022. Tips and Best Practices for Unwinding the Medicaid Continuous Coverage Protection.Funding for Health Care Providers During the Pandemic: An Update | KFF

Interim Final Rules and waivers: https://www.cms.gov/about-cms/emergency-preparedness-response-operations/current-emergencies/coronavirus-waivers.

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[1] Renewals on April 21, 2020; July 23, 2020; October 2, 2020; January 7, 2021; April 15, 2021; July 19, 2021; October 15, 2021; January 14, 2022; April 12, 2022; July 15, 2022; October 13, 2022; and January 11, 2023.

[2] One monoclonal antibody (Actemra/Tocilizumab) retains its EUA only for a certain subgroup of patients (those hospitalized for COVID-19, who are receiving systemic corticosteroids and requiring supplemental oxygen, mechanical ventilation or ECMO).

[3] Examples of health plans that are not subject to the ACA include grandfathered plans; healthcare sharing ministry plans; and short-term, limited duration plans.

Should we permit it and if not, what should we do about it?

The case of Ryan Cole

It is hard to imagine that we all have not said something to others at some point in our life that was misinformation. At times, we have all been misinformed.

Perhaps, if you are as old as me, you learned something in school that is no longer true, but you had not kept up in that area and didn’t realize that forty years later, something that we had been taught was found no longer to be the case. When I was doing my studies, I took a course in a field of science that was still in its infancy. I was listening to a podcast on the subject with experts in 2022 and realized that something I had been taught and learned as a concept has a new understanding that is quite different than what I was taught. Had I recently told others what I thought to be true, I would be innocently spreading misinformation – the unintentional spreading of information that I thought was true, but wasn’t. Fortunately, this particular concept has not been the subject of conversation or frankly, even of much interest, so I hadn’t spread it. It was something that was true in 1980, but no longer true in 2022.

Sometimes, my wife and I will get into a debate about what band or group first performed a song from our past or who is married to a certain celebrity. At times I dig in because I am certain I am correct. One would think after 42 years of marriage, I would know better than to challenge her breadth of knowledge on these subjects, but I hold out hope that one day, I might win an argument. Most of the time, I am misinformed or simply have an incorrect memory.

For the rest of this blog piece, I am not going to be discussing misinformation. It happens. It is by my definition unintentional, and in my experience, when people are confronted with the facts or correct information, they abandon their previously held thought and don’t continue to spread misinformation, unless they are a politician or running for office.

On the other hand, disinformation is an intentional spreading of incorrect information. Misinformation is generally spread with an intention to benefit the person it is being shared with. For example, during the pandemic, a person contacted me to check on a recommendation that a family member gave her for preventing COVID-19 (colloidal silver). I was glad she did ask me because that remedy being recommended will invariably harm a person if they take a high enough dose or a lower dose for a long-enough time. Obviously, this person who made the recommendation was completely unaware and thought she was being helpful to her family member and certainly was not trying to harm her relative. On the other hand, disinformation is never provided for the benefit of others, but rather the purveyors’ own self-interests. From time-to-time, we have all been provided with disinformation – perhaps because someone is trying to convince us to take actions to support their efforts that we would not absent being motivated by the untruths, perhaps someone is trying to convince us to buy their product through deceiving us, or perhaps someone is trying to protect their relationship or reputation with us by blaming someone else for a mishap.

Over the course of my life, my career and this pandemic, I have had many experiences in which people have tried to deceive me or I have had the opportunity to watch them try to deceive others. Just as there are clues that you should be hesitant to fall for an email or phone call scam, I have noticed many clues to identifying when someone is trying to peddle disinformation. These clues are important because few in the public will have the expertise to know if the information being presented is true, but you can identify clues from just listening to someone that should sound the alarm in your mind that this person may be trying to deceive you. We will be discussing the case of Dr. Ryan Cole, and he exemplifies almost all of these. I will contrast these points with what characterizes the experts that I trust.

1. They never admit that they have been mistaken in the past, or could be wrong now. In the case of this pandemic unfolding with a novel virus over three years now, any legitimate commentator or expert who has been offering perspective throughout the course of this event, will admit that they have been wrong about some things (I certainly have been), that they have learned new things from this virus (I have), and that they have been surprised that certain things they predicted did not come to pass (I have been surprised on more than one occasion). I know many brilliant epidemiologists, virologists, pulmonologists, infectious disease experts, pediatricians, etc. and everyone of us comment on errors we made or surprises that we did not see coming. In contrast, you can listen to those purposely attempting to deceive the public, and they will never admit a mistake or that anything they have said in 3 years has now been proven wrong with information we have gained from clinical trials.

• They make absolute, emphatic and dogmatic statements. There are few things in this world that are black and white in all people under all situations. That is especially true in medicine. My medical advice for a child is often different than for an adult with the same condition, especially if that adult is elderly. Sometimes patients have underlying conditions or are taking certain medications that cause us to modify our approach to a disease or condition than how we would treat that same disease or condition in someone without any other medical problems who is taking no medications. Experts also understand that our treatments change over time as we learn more about diseases or new medications and treatments are developed. Therefore, when you listen to respected experts, you will often hear them use qualifiers, such as, “in adults…,” “based upon what we know today,” “based upon the results of this study,” “we think that…,” “we don’t know the answer to that, but I would suggest,” or “I can tell you that in general …, but you should check with your doctor.” On the other hand, when you listen to purveyors of disinformation, they make absolute, blanket statements that are directed at everyone under all situations, without acknowledging that there is any need for you to talk to your doctor to assess your particular situation. One example from Dr. Cole is his statement that “Children survive [COVID-19] at a hundred percent.” Again, very few things are 100 percent in life. And, even if children rarely become severely ill with COVID-19, everyone should be alerted to a statement such as this one that surely there are some children who are immunocompromised, receiving cancer treatment, or have underlying health conditions that place them at risk. No medication is 100 percent effective [another statement from Dr. Cole is that “A hundred percent of world (ivermectin) trials have shown benefit.”], no treatment is 100 percent safe and few infections that can cause death in adults spare 100 percent of children. Of course, his statements were demonstrably false.

• They resort to emotionally-charged language and hyperbole. For example, Dr. Cole’s references to “the clot shot” and “needle rape” are so inflammatory and offensive that the language is meant to stir an emotional reaction from the listener rather than to engage in any real scientific debate about the vaccines. I don’t know any legitimate experts that would use derogatory knick-names for medical treatments or language like this. Many of us have treated victims of rape and sexual abuse. We would never compare one of the most psychologically damaging acts of violence against another human to a vaccination intended to safeguard their health.

Most recently, I have also noted a troubling set of recurring language and phrases reminiscent of Nazi Germany and white supremacy commonly being used by those purveying the disinformation or defending them. Phrases like “Nuremburg Code” and “crimes against humanity” seem to be favorites in referencing the vaccination programs and those who administer the vaccines.

• They often make claims from anecdotes to “prove” their assertions. Purveyors of disinformation often refer to anecdotal experiences to try to prove their point, such as “I treated xx patients with ivermectin and they all improved within 24-48 hours.” There are so many problems with this. First of all, how was the diagnosis of COVID-19 established? Do we know for sure that they had COVID-19? Second, were these all young, healthy 20- and 30-something-year-olds who would have been expected to have mild illnesses and get better regardless of treatment? Third, did the physician really follow-up the patients? The complaint from the Washington Medical Commission (WMC) alleges that Dr. Cole was not providing adequate follow-up on his patients. If that is true, how would he know whether they did well? In fact, the WMC also refers to sworn affidavits from physicians who did treat patients of Dr. Cole’s who deteriorated and ended up hospitalized, evidencing that Dr. Cole either did not follow-up on these patients or was not being truthful. Further, hospitalization and death often doesn’t occur with COVID-19 until the second week or later of illness. If a physician only follows patients for a day or two, he may be completely unaware that the patients decompensated, were hospitalized and/or died. This is especially true since Dr. Cole is a pathologist and would likely not have admitting hospital privileges and permission to treat hospitalized patients.

• They often will not back up their assertions with studies from reputable scientific journals or even provide a reference to data they are using to support their claims, and on the few occasions that references are provided, it is not uncommon for them to misrepresent the findings. Audrey Dutton of the Idaho Capital Sun has done some great reporting on this and I highly encourage readers to take a look at her article exposing Dr. Cole’s disinformation https://idahocapitalsun.com/2022/08/10/dr-ryan-coles-journey-from-boise-to-nashville-to-france-his-new-focus-monkeypox/.

• They almost never disclose their financial conflicts of interest. Early on in my blogging about COVID, I went into great detail about any potential conflicts of interest that could influence my points of view. From a psychological view, no one engages in a systemic campaign of disinformation without some personal benefit or potential benefit. Perhaps they merely seek publicity, fame and attention; perhaps they seek political favor or office; but I suspect most often, especially if one is willing to put their livelihood at risk, there must be significant financial reward. At the conferences they speak at and on the cable networks they are interviewed, I have never seen a disclosure of these conflicts of interest nor in the interviews, have I heard them asked about them.

We are not helpless victims when it comes to disinformation. First, we need to learn to recognize highly suspect sources and information with some of the clues I have outlined above. Further, we need to educate ourselves on how to assess credibility and reliability of sources and information.

First, as to credibility, take a look at what kind of doctor is providing this information. If the topic is complications of pregnancy and a dermatologist is offering advice on the subject, it doesn’t mean that it is necessarily wrong, but it should be cause for us to check it out to see if that advice is consistent with the advice of obstetricians and their professional associations, such as the American College of Obstetricians and Gynecologists. In this case, Dr. Cole, a pathologist might not be the kind of physician one would expect to be an expert in treating infectious illnesses. Again, that doesn’t mean that he can’t be knowledgeable, but one should probably check his advice against that of physicians who are experts or experienced in treating infectious illnesses. When you do, you find that Dr. Cole’s information is at odds with experts in the field as well as their professional organizations.

Second, you can search for fact checks on the internet. There are many available with experts disputing the information Dr. Cole has been spreading in his interviews and on videos.

Another easy thing to do is just to google local news sources and Dr. Cole. For example, you will come up with a number of articles (great reporting from Audrey Dutton) that provide all kinds of warning signs:

https://idahocapitalsun.com/2021/10/11/it-should-be-stopped-idaho-medical-group-files-complaint-against-dr-ryan-cole/.

• The Idaho Medical Association filed a complaint with the Idaho Board of Medicine against Dr. Ryan Cole
• According to the complaint, ““As a licensee under your jurisdiction, Dr. Cole has made numerous public statements in 2020 and 2021, concerning COVID-19 that are at significant odds with commonly understood medical treatment of COVID-19 and fail to meet the community standard of care.”
• “We believe many of those statements to be profoundly wrong, unsupported by medical research and collected knowledge, and dangerous if followed by patients or members of the public. Many of those statements have advocated that people not be treated appropriately and undoubtedly have led to and will continue to lead to poor health outcomes.”

And, this: https://idahocapitalsun.com/2021/12/16/idaho-doctors-pathology-board-accuse-dr-ryan-cole-of-endangering-public-health/. (by Audrey Dutton)

• Idaho physicians allege, in complaints to a Washington medical board, that patients came into their hospitals sick with COVID-19 after taking advice or treatment from Dr. Ryan Cole.
• The American Board of Pathology (ABP) also submitted a complaint against Dr. Cole and stated: ““He has advised patients to take hydroxychloroquine and ivermectin without scientific data to support their use in the treatment of patients with COVID-19.”
• The ABP’s complaint went on to state: “We also received an allegation that Dr. Cole may have provided prescriptions to patients in the absence of a physician-patient relationship and without sufficient medical record keeping.”
• The article also referenced sworn affidavits submitted by physicians in the Treasure Valley, including one from a physician that stated that her patients reported taking ivermectin “upon the advice or prescription of Dr. Ryan Cole” and were “quite surprised to learn that ivermectin did not prevent or cure their COVID infection.”
• Another physician’s affidavit indicated that he had seen some of Dr. Cole’s patients who were taking ivermectin for prevention or treatment of COVID-19, and yet “had developed severe COVID-19 and many require hospital admission, with some requiring critical care services.”

And, yet another article, https://www.spokesman.com/stories/2022/may/08/taking-covid-19-funds-pathologist-dr-ryan-cole-was/ with more great reporting by Audrey Dutton:

• VA officials “were flabbergasted” by Cole’s public statements, VAMC spokesperson Josh Callihan said in an interview earlier this year. The hospital removed Cole as a consultant last year.
• St. Luke’s Health Partners also removed Cole from its network as a result of its peer review.
• Dr. Cole touted his Mayo Clinic training, however, in a statement, Mayo Clinic distanced itself from Cole stating: ““Mayo Clinic is aware of claims made by Dr. Ryan Cole regarding vaccines. Dr. Cole was trained at Mayo Clinic but is not a Mayo Clinic employee. His views do not represent Mayo Clinic.” 
• Dr. Cole was a member of the College of American Pathologists (CAP). They issued a statement indicating: “The CAP fosters robust exchanges of varying professional opinions in the practice of medicine and individual pathologists are free to express their own personal views. However, the CAP does not condone Fellows of the organization disseminating COVID-19 information that is not firmly grounded in science.”

In hindsight, there were plenty of warning signs.

Let’s dig into the WMC statement of charges.

The WMC alleges that Dr. Cole violated four provisions of law that fall under the umbrella of “unprofessional conduct.”

1. The commission of any act involving moral turpitude or dishonesty relating to the practice of medicine.
2. Incompetence, negligence, or malpractice that presents an unreasonable risk of harm or actual harm to a patient.
3. Misrepresentation or fraud in any aspect of the conduct of the profession.
4. Interference with an investigation or disciplinary proceeding by willful misrepresentation of the facts before the disciplining authority or its authorized representative.

We can also look to the facts that the WMC has made public as a result of its investigations.

1. Dr. Cole made numerous false and misleading statements during public presentations regarding COVID-19, the COVID-19 vaccines, the use of ivermectin to treat COVID-19, and the effectiveness of masks.
2. Dr. Cole generated mistrust in the medical profession and in public health, and had a wide-spread negative impact on the health and well-being of our communities.
3. The WMC provides information about the negligent care of four patients by Dr. Cole, including:
   1. Prescribing medications that are not indicated for treatment of COVID-19;
   1. Failing to document adequate justification for the treatment in the medical record;
   1. Failure to take a history or perform a physical examination;
   1. Failing to obtain appropriate informed consent;
   1. Not providing an adequate opportunity for follow-up care;
   1. Treating patients beyond his competency level;
   1. Failure to advise patients about standard treatment guidelines and preventative measures.

No doubt that there will be supporters of Dr. Cole or physicians like him who will take any number of positions in support of him:

1. It should be his First Amendment right to say whatever he wants.
2. He’s a doctor and he should be able to prescribe whatever he wants.
3. He was just giving patients what they wanted.

I will address each of these, in turn, but before I do, I always find an exercise helpful to make sure that we are having an objective discussion and not allowing emotions to get in the way. There is no doubt the country is politically divided and the politicalization of COVID-19 has made objective, rational discussions about policy difficult, if not impossible. Most of us experience this kind of divide within our own families.

You may not even realize that your thoughts and beliefs regarding how COVID-19 should be handled are more emotionally-driven than fact-driven. Here is the exercise. For this discussion, make some changes to the fact scenarios and see if that changes your view. If so, your responses to the COVID-19 fact situations are likely being influenced by emotions or a philosophical point of view. I’ll help you do this below.

Let’s start with the First Amendment issue. While the First Amendment of the U.S. Constitution does guarantee citizens the right of free speech, there are long-held exceptions to this right. Constitutional Law professors commonly use the example that one does not have the right to go into a crowded movie theatre and shout “Fire!” just because that person wants the freedom to do so. The U.S. Supreme Court long ago upheld restrictions on publishing pornography on the internet despite claims that this would infringe upon First Amendment rights. We also have federal restrictions on marketing such that a pharmaceutical company cannot make the kinds of assertions about the effectiveness of its medications similar to the ones Dr. Cole made. The common theme here is that restrictions of the First Amendment are proper and legal where they serve to protect the health and welfare of the public.

Let’s distinguish Dr. Cole’s situation from some others that I would never support pursuing. First, if Dr. Cole wished to raise concerns about the effectiveness of treatments, the safety of vaccines or related issues with his colleagues or at medical conferences and engage in scientific debate, that would be fine. That is not what Dr. Cole did. Recall that Dr. Cole repeatedly spoke about seeing something on the order of a 20-fold increase in cancers that he impliedly or explicitly connected to the COVID-19 vaccines at his public speaking engagements, but to my knowledge, never allowed independent review of these cases (we already know of one case made public in which Dr. Cole diagnosed a patient with cancer that led to extensive surgery to remove the associated organs and tissues only for the hospital and outside consulting pathologists to find no evidence of cancer) nor to my knowledge did he ever notify the FDA, the CAP, or any other regulators or medical associations or even submit his findings for publication and peer review  (despite the fact that I can find no other similar such reports from any laboratory in the world).

It would also be fine if Dr. Cole wanted to give his thoughts or opinions with a disclaimer that he is not offering them as a physician or as medical advice, and that his positions are not supported by the medical community at large. The problem is that Dr. Cole engaged in a several years-long campaign of disinformation touting his medical and scientific expertise to influence the public to adopt his advice and positions.

It would also be fine for Dr. Cole to argue policy, e.g., the benefit or harms of mandates. These can be legitimate points of debate. The problem was that Dr. Cole presented false information as facts. This was not a debate about policies or uncertainties concerning the virus or the disease – this was an intentional, well-coordinated disinformation campaign.

Let’s look closer at some of the specific allegations.

1. Dr. Cole made numerous false and misleading statements during public presentations regarding COVID-19, the COVID-19 vaccines, the use of ivermectin to treat COVID-19, and the effectiveness of masks.

I could probably write 30 pages just on this topic, so let’s just take one part of it, the part that I suspect many are not concerned about, but should be: The use of ivermectin to treat COVID-19. Many, Dr. Cole included I suspect, will say, “Big deal. What is the harm in that? It is a long-used medication that has already been approved for treating other conditions and is reasonably safe.”

Is it ever appropriate for a physician to prescribe a medicine for a use other than what it is approved for? Certainly, there are occasions where this is appropriate. Those situations include when a patient has failed the usual and customary treatment, when a patient has an underlying condition for which the usual and customary treatment would not be appropriate, or when the patient is on medications that cannot be stopped that would interact negatively with the usual and customary treatment. Even so, the physician should discuss the situation with the patient, explain the risks and obtain the patient’s consent prior to proceeding. From what I can read of the WMC charges, none of these factors appear to be at play.

Ivermectin is relatively safe, however, it has a long list of possible side effects and adverse events – some common, others not; some minor; some just annoying (e.g., generalized itching); but others can be serious. Now, we all make risk/reward decisions every time we prescribe or take a medication. There is no medication that is completely safe for everyone and without any side effects or adverse events. Doctors make these risk/reward decisions with their patients all the time. Often, patients find their symptoms or disease so distressing that they find the potential risks well worth taking. Sometimes, people have a relatively minor problem and decide that they are not willing to assume the risk of significant side effects to treat something that is not that distressing to the patient.

But, all of the many well-designed, randomized trials have failed to detect any benefit for ivermectin in treating COVID. So, if you were in the exam room with me, I diagnosed your condition, and told you that I can prescribe a medication that won’t help you, what amount of risk of adverse effects would you be willing to accept? Would you be willing to accept any chance of a adverse event that would land you in the hospital or take your life? What about visual disturbances? What about one of the most serious skin disorders that there is? Would you take the risks even if I told you the risks were rare? Most people would say no. Why? Because the risk (a small or rare risk of a serious problem) will outweigh the  benefit (in this case, zero) of treatment in the minds of most rational people.

Some will respond, okay, but Dr. Cole said he treated people and they all got better. First, those statements are contradicted by physicians making sworn statements that they treated patients of Dr. Cole who ended up being hospitalized, in critical care or even dying from their COVID, despite Dr. Cole’s assertion that they all got better. I’m not saying that Dr. Cole is necessarily lying, he simply appears to not have followed at least some of these patients and may not know that they got worse. Most people don’t think of calling a pathologist when they can’t breathe and need an ambulance, and ER doctors are not likely going to call a pathologist to admit a patient to the hospital or the ICU.

To point out how flawed relying on anecdotes is, let’s assume that I had a group of 12 friends. We all got fully vaccinated and we all wore masks whenever we were out in public. We have no children living in the home and we all were retired or working from home. We would get together every day outside, distanced, taking our masks off only to have a daily cup of coffee. None of us got COVID. I then tweet, go on cable networks and make viral videos saying that I have the key to preventing getting COVID-19 – drink one cup of coffee each day. I then make up a reason to explain why coffee works – the heat and steam of the coffee clears out your sinuses and rids you of any virus in your nasal passages and the coffee has antiviral properties as it turns out that someone in some lab somewhere in the world put coffee in a culture with the SARS-CoV-2 virus and it was unable to grow. How strong of a scientific argument for coffee do you think I made? I hope you are not impressed. The sample size is small (13 if you count me). There was no comparison group to see if people who did get COVID drank coffee. There was also no accounting for confounding factors, such as the fact that my friends and I were at lower risk (no kids in the house and working from home) and we employed other public health measures known to protect us from getting infected. You should not rely on my anecdote and neither should we be persuaded by Dr. Cole’s.

But, even if I still haven’t persuaded you, there are two more problems with Dr. Cole prescribing ivermectin or me prescribing a cup of Joe every day. One problem is the lack of documentation in the medical records mentioned in the charges made by WMC. As I said above, there can be reasons for a physician to prescribe a medication that is not usually used for a certain condition, but in every state of the country, physicians are required to document their reasoning. First, in prescribing something out of the ordinary, the physician needs to document why in order to protect him or herself from a latter claim of negligence if the patient does suffer harm, and second, if there were reasons not to treat the patient with the standard medications for a disorder, you want those documented so that if the patient worsens and comes in for care, the doctor, or someone covering for that doctor, can be reminded of why the patient should not be prescribed the standard medications.

The key thing that should bother everyone reading this is that based upon what we can glean from the WMC complaint, it was not a matter that the patients had contraindications to vaccines or contraindications to treatments that we know work for COVID, but rather that Dr. Cole never offered these to the patients or explained why he didn’t. Had he done so, the patients refused, but asked for ivermectin and he then explained that we really don’t have good quality evidence to support their use, but they indicated that they still were willing to accept the risks with little chance of benefit, Dr. Cole might have avoided these charges.

Still, I may not have convinced you, so let’s put my little exercise into practice. Now, let’s take the situation of your child or your spouse or your parent. They unfortunately have a very serious cancer that is serious, but if left untreated will kill them. You seek the advice of a doctor for treatment. The doctor does not tell you about the treatments that are proven to work, but rather suggests an unproven treatment, or one that is not considered the standard of care. You take the doctor’s advice. Your child, spouse or parent deteriorates and requires hospitalization, intensive care or dies. (Remember, while Dr. Cole states that all of his patients did well on his treatment, other doctors have provided sworn testimony that they did treat some of Dr. Cole’s patients and they required hospitalization, intensive care or died). If you trusted the doctor, but he did not tell you about proven treatments for your family member, but instead pushed a drug that the majority of physicians and medical organizations stated should not be used, how would you feel? If you feel the same way that you did about ivermectin that it is perfectly fine for a physician not to offer you the standard and proven treatments, then we will just agree to disagree. However, if you think this situation is wrong, but it is fine for ivermectin, then you should consider that you are making an emotional or biased decision, not a logical one. Remember, that in the case of ivermectin, even the company that manufactures and distributes it, that would stand to financially benefit from wide-spread use of its medication for COVID, publicly warned against its use and indicated that the pharmaceutical company’s scientists saw no evidence of benefit of ivermectin in treating COVID-19.

I am going to finish up with three of the specific allegations under #3 above:

1. Failure to take a history or perform a physical examination;
2. Failing to obtain appropriate informed consent;
3. Not providing an adequate opportunity for follow-up care;

Why is failing to take a history or perform a physical examination a big deal? As doctors, we need to understand the particulars of a patient we are treating. With COVID, I need to understand the patient’s risk factors – age, health conditions that may increase risk and whether the patient may be immunocompromised in any way. You get this information from taking the patient’s history so that you can assess which treatment the patient needs and whether they can be safely treated at home or need to come to the hospital. Further, in taking a history, you will review the patient’s medications. This can be very important in considering potential drug interactions that may result from whatever I may prescribe to the patient (especially the case when prescribing Paxlovid). The physical examination allows me to assess how sick the patient is and whether there may be other medical problems going on (remember, there is no rule that you can only get one infection or condition at a time). Again, the findings from examining the patient are likely to influence which treatment I offer to a patient and whether that can be outpatient or needs to be inpatient treatment. I know of no state in which prescribing medication for a patient with whom you do not already have an existing doctor-patient relationship, a patient for which you have no medical history and have never performed a physical examination on would be considered acceptable medical practice.

The point about not obtaining informed consent, to me, is one of the gravest aspects of Dr. Cole’s conduct, if ultimately proven. It is one of the fundamentals of our profession that patients, so long as they are competent to do so, should decide which treatments we offer that they wish to undergo, if any. To equip a patient to decide on a course of treatment, we must explain what is wrong with them, what treatments are recommended, what the potential risks are of treatment, and if they are not inclined to be treated, what the risks of non-treatment are. Informed consent captures the notion that a patient cannot really provide consent unless they are informed.

If, as appears to be alleged in this case, Dr. Cole did not explain what the recommended treatments were, only offered non-recommended treatments, did not document a good reason why, and did not explain the risks of taking non-recommended treatment and forgoing recommended treatments, this is not informed consent; it is manipulation and coercion of the worst kind.

Finally, the WMC makes a charge for not providing adequate follow-up of patients. We can certainly have a debate about whether pathologists who do not have a hospital practice or hospital privileges, do not have an office or clinic in which to see patients on an ongoing basis, and do not typically treat infectious diseases should be offering their services to treat patients with a serious infection like COVID-19 that can last weeks and cause health consequences in the ensuing months or years. However, even if you come out on the side that yes, this makes great sense, then those physicians must meet the same basic standards of care as physicians who normally treat these patients. Another foundation of our profession is that we do not abandon patients. If you are going to engage in the practice of treating such patients, you must either make yourself available for follow-up needs of the patient, have a system in place for other physicians to provide that ongoing care when you are off or traveling to other states or countries to spread disinformation, or you must arrange for a hand-off to another physician or notice and a sufficient time for the patient to be able to identify and schedule a visit with another physician. What if a patient that Dr. Cole treated is experiencing an adverse effect from the ivermectin? What if the patient is unable to get the prescription filled as many pharmacies have refused to fill these prescriptions? What if the patient is worsening and the ivermectin does not seem to be working? We simply cannot leave patients without options for continuing care than to go to already overloaded and over-burdened emergency rooms.

Obviously, Dr. Cole will have his opportunity to respond to the charges and present his defense. However, if the charges are substantiated, we all should be able to agree that this conduct is unprofessional and is not what we would want for our friends and families. We should never embrace those who would try to manipulate the public for their own personal gains, especially those who have taken a solemn oath to help people and protect their health and who have been granted a privilege to practice medicine when so many are turned away each year from this amazing opportunity.

We should support telling the public the truth, providing them with the facts, and then allowing them to assess their own personal risks, those of their families and what they consider their obligation to society is, to then determine which health recommendations they will adopt. Our job as physicians is to provide our patients and the public with information upon which they may be informed to make their own health care decisions. Having the privilege to practice medicine is a tremendous honor, and with privilege comes responsibility. If the allegations against Dr. Cole are true, then he has violated every core tenant of our profession. That is terrible enough. The only thing worse would be if our state boards of medicine, our professional associations and our specialty certification organizations allow that conduct to continue and the public to be harmed without consequences to the physician.

I have been writing a blog series about the post-acute sequelae of COVID-19. My plans were to cover the many systems and organs of the body and what we have learned as to the Long-term health consequences some people may suffer following infection and why. I started with the nervous system.

However, while I have been working on this, a fabulous review of Long COVID was published[1] and it does much of what I intended to provide for you. Therefore, I am going to use this blog piece to wrap up my blog series by highlighting some of the information for you that is contained within this report.

• Long COVID (sometimes referred to as ‘post-acute sequelae of COVID-19’ or PASC) is a multisystemic condition comprising often severe symptoms that follow a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but can occur following even mild COVID-19.
• At least 65 million individuals around the world have Long COVID, based on a conservative estimated incidence of 10% of infected people and more than 651 million documented COVID-19 cases worldwide; the number is likely much higher due to many undocumented cases.
• The incidence is estimated at 10–30% of non-hospitalized cases, 50–70% of hospitalized cases and 10–12% of vaccinated cases. Thus, vaccination is important in reducing the chances of developing Long COVID and avoiding severe COVID-19 (which increases the chances for Long COVID), but even those who are vaccinated who develop breakthrough infections can develop Long COVID.
• Long COVID is associated with all ages and acute disease severities (mild, moderate, and severe) with the highest percentage of diagnoses between the ages of 36 and 50 years, and most Long COVID cases are in non-hospitalized patients with a mild acute illness.
• Hundreds of laboratory and clinical findings have been documented, with many patients experiencing dozens of symptoms across multiple organ systems. Long COVID encompasses multiple adverse outcomes, with common new-onset conditions including cardiovascular, thrombotic and cerebrovascular disease, type 2 diabetes, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia, especially postural orthostatic tachycardia syndrome (POTS).
• Symptoms can last for years, and cases of new-onset ME/CFS and dysautonomia are expected to be lifelong.
• There are currently no proven, effective treatments, though this is an area of active research.
• There are likely multiple, potentially overlapping, causes of Long COVID. Several hypotheses for its pathogenesis have been suggested, including persisting reservoirs of SARS-CoV-2 in tissues; immune dysregulation with or without reactivation of underlying pathogens, including herpesviruses such as Epstein–Barr virus (EBV) and human herpesvirus 6 (HHV-6) among others; impacts of SARS-CoV-2 on the microbiota, including the virome; autoimmunity and priming of the immune system from molecular mimicry; microvascular blood clotting with endothelial dysfunction; and dysfunctional signaling in the brainstem and/or vagus nerve.
• Risk factors potentially include female sex, type 2 diabetes, EBV reactivation, the presence of specific autoantibodies, connective tissue disorders, attention deficit hyperactivity disorder, chronic urticaria and allergic rhinitis, although a third of people with Long COVID have no identified pre-existing conditions.
• Higher prevalence has been reported among persons with Hispanic or Latino heritage.

• Socio-economic risk factors include lower income and an inability to adequately rest in the early weeks after developing COVID-19. This may be an important finding. I often hear from those with COVID, especially young, active adults, that after being sick for so long, they are anxious to resume their normal activities and exercise. However, we are increasingly seeing evidence that suggests overdoing it and not getting enough rest in the weeks following infection may pose increased risk for developing Long COVID.
• Long COVID impacts children of all ages. One study found that fatigue, headache, dizziness, shortness of breath, chest pain, abnormal smells, abnormal sense of taste, reduced appetite, concentration difficulties, memory issues, mental exhaustion, physical exhaustion and sleep issues were between 2 and 36 times more likely in individuals with Long COVID aged 15–19 years compared with controls of the same age. This has been another surprising feature in many patients I have spoken with following their infection. Many describe that their sleep cycle is disrupted (e.g., perhaps their normal bedtime was 10 p.m., but now they can’t fall asleep until 2 a.m.) or that they have days on end that they can’t sleep at all, followed by days in which all they do is sleep.
• Similarly to adults with Long COVID, children with long COVID experience fatigue, post-exertional exhaustion or feeling unwell, cognitive dysfunction, memory loss, headaches, orthostatic intolerance, sleep difficulty and shortness of breath.
• Although rare, children who had COVID-19 have increased risks of liver injury, acute pulmonary embolism, myocarditis and cardiomyopathy, venous thromboembolic events, acute and unspecified kidneyl failure, and type 1 diabetes.
• Infants born to women who had COVID-19 during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first year after delivery.
• Children experiencing Long COVID have hypometabolism in the brain similar to the patterns found in adults with Long COVID.
• Long-term pulmonary dysfunction is found in children with Long COVID and those who have recovered from COVID-19.
• Difficulties in studying Long COVID in children include that many children were never tested or have a documented + test, and children are much less likely to seroconvert (develop detectable antibodies in the blood) and, if they develop antibodies, are more likely to have a waning response months after infection compared with adults.
• Studies looking at immune dysregulation in individuals with Long COVID who had mild acute COVID-19 have found T cell alterations, including exhausted T cells, reduced CD4⁺ and CD8⁺ effector memory cell numbers and elevated PD1 expression on central memory cells, persisting for at least 13 months. Studies have also reported highly activated innate immune cells, a lack of naive T and B cells and elevated expression of type I and type III interferons (interferon-β (IFNβ) and IFNλ1), persisting for at least 8 months. A comprehensive study comparing patients with Long COVID with uninfected individuals and infected individuals without Long COVID found increases in the numbers of non-classical monocytes, activated B cells, double-negative B cells, and IL-4- and IL-6-secreting CD4⁺ T cells and decreases in the numbers of conventional dendritic cells and exhausted T cells and low cortisol levels in individuals with Long COVID at a median of 14 months after infection.
• The expansion of cytotoxic T cells has been found to be associated with the gastrointestinal presentation of Long COVID. Additional studies have found elevated levels of cytokines, particularly IL-1β, IL-6, TNF and IP10, and a recent preprint has reported persistent elevation of the level of CCL11, which is associated with cognitive dysfunction.
• The role of autoantibodies in Long COVID remains unclear. Multiple studies have found elevated levels of autoantibodies in Long COVID, including autoantibodies to the ACE-2 receptor, β₂-adrenoceptor, muscarinic M2 receptor, angiotensin II AT₁ receptor and the angiotensin 1–7 MAS receptor. High levels of other autoantibodies have been found in some patients with COVID-19 more generally, including autoantibodies that target the tissue (such as connective tissue, extracellular matrix components, vascular endothelium, coagulation factors and platelets), organ systems (including the lung, central nervous system, skin and gastrointestinal tract), immunomodulatory proteins (cytokines, chemokines, complement components and cell-surface proteins). A major comprehensive study, however, did not find autoantibodies to be a major component of Long COVID. High levels of autoantibodies in Long COVID have been found to be inversely correlated with protective COVID-19 antibodies, suggesting that patients with high autoantibody levels may be more likely to have breakthrough infections.
• Reactivated viruses, including EBV and HHV-6, have been found in patients with Long COVID (and have been identified in ME/CFS), and lead to mitochondrial fragmentation and severely affect energy metabolism. EBV reactivation has been associated with fatigue and neurocognitive dysfunction in patients with Long COVID.
• Several studies have shown low or no SARS-CoV-2 antibody production and other insufficient immune responses in the acute stage of COVID-19 to be predictive of Long COVID at 6–7 months, in both hospitalized patients and non-hospitalized patients.
• One study has reported low or absent CD4⁺ T cell and CD8⁺ T cell responses in patients with severe Long COVID, and a separate study found lower levels of CD8⁺ T cells expressing CD107a and a decline in nucleocapsid-specific interferon-γ-producing CD8⁺ T cells in patients with Long COVID compared with infected controls without Long COVID.
• SARS-CoV-2 viral rebound in the gut, possibly resulting from viral persistence, has been associated with lower levels and slower production of receptor-binding domain IgA and IgG antibodies.
• One hypothesis for why women are more likely to develop Long COVID than men is the fact that women are less likely to seroconvert, more likely to sero-revert (initially test + for antibodies in the blood, but later test -) and have lower antibody levels overall, including more antibody waning after vaccination.
• Viral persistence is also thought to be a possible driver of Long COVID symptoms; viral proteins and/or RNA has been found in the reproductive system, cardiovascular system, brain, muscles, eyes, lymph nodes, appendix, breast tissue, hepatic tissue, lung tissue, plasma, stool and urine.
• In one study, circulating SARS-CoV-2 spike antigen was found in 60% of a cohort of 37 patients with Long COVID up to 12 months after diagnosis compared with 0% of 26 SARS-CoV-2-infected individuals without PASC, likely implying a reservoir of active virus or components of the virus. Indeed, multiple reports following gastrointestinal biopsies have indicated the presence of virus, suggestive of a persistent reservoir in some patients.
• The damage that has been demonstrated across diverse tissues has predominantly been attributed to immune-mediated response and inflammation, rather than direct infection of cells by the virus. Circulatory system disruption includes endothelial dysfunction and subsequent downstream effects, and increased risks of deep vein thrombosis, pulmonary embolism and bleeding events.
• Micro-clots detected in both acute COVID-19 and Long COVID contribute to thrombosis.
• Long-term changes to the size and stiffness of blood cells have also been found in Long COVID, with the potential to affect oxygen delivery.
• A long-lasting reduction in vascular density, specifically affecting small capillaries, was found in patients with Long COVID compared with controls, 18 months after infection.
• A study finding elevated levels of vascular transformation blood biomarkers in Long COVID also found that the angiogenesis markers ANG1 and P-selectin both had high sensitivity and specificity for predicting Long COVID status.
• A large study found significantly increased risk of a variety of cardiovascular diseases, including heart failure, dysrhythmias and stroke, independent of the severity of initial COVID-19 presentation 1 year after SARS-CoV-2 infection.
•  Cardiac MRI studies revealed cardiac impairment in 78% of 100 individuals who had a prior COVID-19 episode (investigated an average of 71 days after infection) and in 58% of participants with Long COVID (studied 12 months after infection).
• One prospective study of low-risk individuals, looking at the heart, lungs, liver, kidneys, pancreas and spleen, noted that 70% of 201 patients had damage to at least one organ and 29% had multi-organ damage.
• In a 1-year follow-up study with 536 participants, the study authors found that 59% had single-organ damage and 27% multi-organ damage.

• Neurological and cognitive symptoms are a major feature of Long COVID, including sensorimotor symptoms, memory loss, cognitive impairment, paresthesia, dizziness and balance issues, sensitivity to light and noise, loss of (or phantom) smell or taste, and autonomic dysfunction, often impacting activities of daily living.
• Audio-vestibular manifestations of Long COVID include tinnitus, hearing loss and vertigo.
• Cognitive impairments in Long COVID can be debilitating, at the same magnitude as intoxication at the UK drink driving limit or 10 years of cognitive ageing, and may increase over time, with one study finding occurrence in 16% of patients at 2 months after infection and 26% of patients at 12 months after infection.
• Possible mechanisms for neuro-pathologies in Long COVID include neuroinflammation, damage to blood vessels by coagulopathy and endothelial dysfunction, and injury to neurons. Studies have found Alzheimer disease-like signaling in patients with Long COVID, peptides that self-assemble into amyloid clumps which are toxic to neurons, widespread neuroinflammation, brain and brainstem hypometabolism correlated with specific symptoms and abnormal cerebrospinal fluid findings in non-hospitalized individuals with Long COVID along with an association between younger age and a delayed onset of neurological symptoms.
• Multilineage cellular dysregulation and myelin loss were reported in a recent preprint in patients with Long COVID who had mild infections, with microglial reactivity similar to that seen in chemotherapy, known as ‘chemo-brain’.
• A study of brain imaging and cognitive testing revealed a reduction in grey matter thickness in the orbitofrontal cortex and para-hippocampal gyrus (markers of tissue damage in areas connected to the primary olfactory cortex), an overall reduction in brain size and greater cognitive decline in patients after COVID-19 without Long COVID compared with controls, even in non-hospitalized patients. 
• In the eyes, corneal small nerve fiber loss and increased dendritic cell density have been found in Long COVID, as well as abnormal pupillary light responses and impaired retinal microcirculation. Retinal hemorrhages, cotton wool spots and retinal vein occlusion have all been noted in patients with Long COVID.
• Low blood cortisol levels in patients with Long COVID as compared with control individuals have been detected more than 1 year into symptom duration. Low cortisol production by the adrenal gland should be compensated by an increase in adrenocorticotropic hormone (ACTH) production by the pituitary gland, but this was not the case, supporting hypothalamus–pituitary–adrenal axis dysfunction.
• Approximately half of patients with Long COVID meet criteria for ME/CFS. Up to 75% of people with ME/CFS cannot work full-time and 25% have severe ME/CFS, which often means they are bed-bound, have extreme sensitivity to sensory input and are dependent on others for care.
• A study of orthostatic stress in individuals with Long COVID and individuals with ME/CFS found similar hemodynamic, symptomatic and cognitive abnormalities in both groups compared with healthy individuals.
• Consistent abnormal findings in ME/CFS include diminished natural killer cell function, T cell exhaustion and other T cell abnormalities, mitochondrial dysfunction, and vascular and endothelial abnormalities, including deformed red blood cells and reduced blood volume.
• Patients with Long COVID have mitochondrial dysfunction including loss of mitochondrial membrane potential and possible dysfunctional mitochondrial metabolism, altered fatty acid metabolism and dysfunctional mitochondrion-dependent lipid catabolism consistent with mitochondrial dysfunction in exercise intolerance, redox imbalance, and exercise intolerance and impaired oxygen extraction.
• Dysautonomia, particularly POTS (postural orthostatic tachycardia syndrome), is commonly comorbid with ME/CFS.

• POTS is associated with G protein-coupled adrenergic receptor and muscarinic acetylcholine receptor autoantibodies, platelet storage pool deficiency, small fiber neuropathy and other neuro-pathologies. Both POTS and small fiber neuropathy are commonly found in Long COVID, with one study finding POTS in 67% of a cohort with Long COVID.
• Mast cell activation syndrome is also commonly comorbid with ME/CFS. The number and severity of mast cell activation syndrome symptoms substantially increased in patients with Long COVID compared with pre-COVID and control individuals, with histamine receptor antagonists resulting in improvements in the majority of patients.
• Shortness of breath and cough are the most common respiratory symptoms, and persisted for at least 7 months in 40% and 20% of patients with Long COVID, respectively.
• Several imaging studies that included non-hospitalized individuals with Long COVID demonstrated pulmonary abnormalities including in air trapping and lung perfusion.
• An immunological and proteomic study of patients 3–6 months after infection indicated apoptosis and epithelial damage in the airway but not in blood samples.
• Long COVID gastrointestinal symptoms include nausea, abdominal pain, loss of appetite, heartburn and constipation. The gut microbiota composition is significantly altered in patients with COVID-19, and gut microbiota dysbiosis is also a key component of ME/CFS.
• Gut dysbiosis lasting at least 14 months is reported in patients with PASC, and low levels of butyrate-producing bacteria are strongly correlated with Long COVID at 6 months.
• One study indicated viral persistence in the feces of 12.7% of participants 4 months after diagnosis of COVID-19 and in 3.8% of participants at 7 months after diagnosis.
• Most patients with Long COVID symptoms and inflammatory bowel disease 7 months after infection had antigen persistence in the gut mucosa.
• Several neurocognitive symptoms worsen over time and tend to persist longer, whereas gastrointestinal and respiratory symptoms are more likely to resolve.
• Pain in joints, bones, ears, neck and back are more common at 1 year than at 2 months, as is paresthesia (abnormal sensations), hair loss, blurry vision and swelling of the legs, hands and feet.
• Parosmia has an average onset of 3 months after the initial infection; unlike other neurocognitive symptoms, it often decreases over time.
• Few people with Long COVID demonstrate full recovery, with one study finding that 85% of patients who had symptoms 2 months after the initial infection reported symptoms 1 year after symptom onset. Future prognosis is uncertain, although diagnoses of ME/CFS and dysautonomia are generally lifelong.

As I wrap up this series on the post-acute sequelae of COVID-19, I am now going to shift to covering specific new insights on COVID-19 in more frequent posts, as well as returning to covering a broad range of public health, health policy, health law and health reform issues.

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[1] https://www.nature.com/articles/s41579-022-00846-2