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My First Blog Post

What is this blog, who should read it and what will you get?

Be yourself; Everyone else is already taken.

— Oscar Wilde.

This is the first post on my new blog. I’m just getting this new blog going, so stay tuned for more. Subscribe below to get notified when I post new updates.

What is this blog about?

I cover important current national and state-level issues in health care – particularly health care policy and health care law. Because of the nature of the topics I cover, they are at the intersection of health care and politics.

Why is this blog important?

Unfortunately, sources of information about these important issues are often biased, come with a particular political point of view or are written or sponsored by industry interests. Of course, I have biases of my own, but I also have the ability to present an issue objectively and discuss the pros and cons of all sides of the issue so that readers can make an educated opinion on the issue for themselves. I believe that if you give readers balanced and complete information, they will be able to engage in the discussion productively and come to well-informed opinions and solutions.

Of course, there are few issues in health care that I do not have an opinion about, and there are many who, because of my background and experience, want to know how I come out on a particular issue. I will share those opinions with you on the blog, but I will be clear and explicit with you when I am expressing my own view. You can then take it for what its worth.

Who is this blog for?

Really, any one with an interest in topical health care policy and legal issues. However, there are some who may have a particular interest in this blog:

  1. Health care CEOs. Health care leaders are very busy and barraged with information. They simply cannot read everything, and much of what they get is not completely objective. This is a site where CEOs can get up-to-date, important information on topics of importance to health care leaders that they can trust. As a recently retired health system CEO, I know what information CEOs need, and there are few other sources of information written by a CEO for CEOs. This is also a source of information that CEOs can use to provide important updates to their teams and their boards.
  2. Board members of hospitals, health systems, insurance companies and other health care organizations. Health care is complicated. It is particularly challenging for board members who come from other industries to understand the complexities of health care. This blog can serve to keep board members informed about important issues that their companies are likely dealing with, as well as to keep them informed as friends, family, neighbors and colleagues ask them about these topical issues since they are likely aware that they serve on a health care board.
  3. Students and other health care leaders. Students of health care will appreciate how complex issues are presented in an easy to understand blog. Current and future health care leaders need a good source of current information, but also a source that may challenge their thinking or help them think about current health care challenges in a fresh and new way.
  4. Journalists. Health care reporters and journalists can at times be challenged to get the information and background that will really help them understand a complex issue that they must digest in very little time in order to hit deadlines and to ask interviewees the “right” questions. This blog will help them do just that.
  5. Legislators. Legislators have a tough job. They have to make law about complex issues in areas of industry that they may not be expert in. To make matters worse, they are often inundated by parties and lobbyists that are interested in what is best for their business, not necessarily what is best for that state or our country. This is an unbiased source of information to help legislators understand these complex issues and the pros and cons of various positions.

Who am I and why should you trust what I have to write?

I am a physician, board certified in Internal Medicine. I practiced for ten years. I am also a health care attorney. I have taught a course titled Regulation of Health Care Professionals for about 13 years, first at the University of Houston Law Center and most recently at the University of Idaho College of Law. I have also written a text book by the same title.

I was the CEO of a large teaching hospital in the Texas Medical Center for almost four years and most recently, I was the President and CEO of a health system for a little over ten years. That health system was recognized for being a national leader in quality and for its transformation of its business model from fee for service to value (full risk arrangements).

While a health system CEO, I had a blog for about 8 years – Dr. Pate’s Prescription for Change.

How often will I post new information?

I am going to try to write something weekly. I am not going to commit to a specific day. There may be times that I miss a week. There will be others will I will post something more frequently, especially when there is breaking news. So, be sure that you are subscribed to the blog so that you receive notice when I have a new blog post. You can also follow me on twitter. I will tweet my new blog posts. My current twitter handle is @drpatestlukes, but I will be creating a new twitter handle soon given my impending retirement from St. Luke’s Health System. I will let you know as soon as that new twitter account is set up.

Medical Disinformation

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 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:

  • 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.

Long COVID

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.


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

Neurological Sequelae of COVID-19

Part III

In Part I of this series focused on the neurological long-term consequences of COVID-19, I reviewed what we know so far about anosmia (loss of smell) and parosmia (abnormal sense of smell). In Part II, I reviewed what we know about cognitive defects following COVID-19, or what many refer to as “brain fog.”

In this Part III, we will wrap up our review of neurological consequences of COVID-19, however, there remains much more that we could cover. This blog post will look at an autopsy study that provides evidence of viral persistence, one of the explanations thought to contribute to the development of Long COVID.

A very recent study sheds additional light on the issue of viral persistence in the brain and other tissues and organs based upon autopsy studies.

“SARS-CoV-2 Infection and Persistence in the Human Body and Brain at Autopsy” was published on December 14, 2022.[1] The investigators conducted complete autopsies on 44 patients who died with COVID-19, with extensive sampling of the central nervous system in 11 of these patients. The study included both patients who died with acute infection, as well as others with PASC (Post-Acute Sequelae of SARS-CoV-2 or Long COVID) lasting as long as 7 months. They found that evidence of viral persistence was widely distributed, especially in those who died with severe COVID-19. The evidence for viral persistence in both lung tissue and non-respiratory tissues (heart, lymph nodes, GI tract, adrenal glands and eyes was very strong in that they could culture replicating virus from these tissues. Persistent viral RNA was found in multiple anatomic sites throughout the brain as late as 230 days following onset of illness in one case.

SARS-CoV-2 RNA was detected in 84 distinct anatomic sites and body fluids (including plasma, pleural fluid and vitreous fluid). However, RNA levels were highest in respiratory tissues. More than half of the late cases had persistent RNA in the heart muscle, lymph nodes from the head and neck, the sciatic nerve, the eyes, and from all areas of the central nervous system sampled other than the dura mater.

The investigators observed very little evidence of inflammation or direct viral-induced cell damage outside of the respiratory tract. This is concerning relative to a person’s long-term health because it is possible that the persistent virus causes chronic antigenic stimulation of the immune system, which in turn may cause T-cell exhaustion and immune dysfunction (see later blog posts on immune system sequelae of COVID-19), but also because we don’t know whether the SARS-CoV-2 virus can be reactivated and cause disease if the patient is later treated with immunosuppressive medications or develops an immune-compromising condition.

The persistence of SARS-CoV-2 virus in the body is one of the theories as to why some people may develop Long COVID. Persistence of virus can mean persistence of antigenic stimulation of the immune system. In addition, a concern that must always be considered when people do not kill and eliminate viruses efficiently from their body, is whether they become latent and can be reactivated years later if the person becomes elderly, develops cancer, or requires immunosuppressive medications. In fact, with SARS-CoV-2 infections, we have seen cases in which latent viruses become reactivated, particularly Epstein Barr Virus (EBV) and Human Herpes Virus-6. The former has been associated with persons who develop myalgic encephalitis/chronic fatigue syndrome (ME/CFS) following COVID-19.


[1] https://doi.org/10.1038/s41586-022-05542-y.

Important Holiday Travel/Gathering COVID-19 Update and Health Advice

Practical tips and information

We all are excited about the upcoming holidays and seeing friends and family, but are in the midst of high levels of RSV and influenza transmission and the beginning of a new COVID-19 surge. There is important new information you should keep in mind, and additional planning to be done in the event you are traveling.

Planning

  1. Assess yours, your family’s and your guests’ risks. Important questions are:
    1. Where will you be gathering? This will be important when assessing ventilation. (See below) For most people, the answer is likely to be someone’s home.
    1. How many will be attending? The higher the number, the higher the risks.
    1. Will there be small children? If those children have been in school or day care or a nursery, then there are increased chances that they may have been exposed to a number of the circulating respiratory viruses, (as well as group A strep – more on this below) and early on in the illness, the child may not look sick or be able to report symptoms, but still be contagious. Thus, it may be helpful to check with the school or daycare to determine whether many children have been out sick lately and if so, with what.
    1. Will there be people in attendance who are ages 65 and older and/or people who are immunocompromised either by virtue of having an underlying immunodeficiency or by a disease that weakens their immune system or from treatments for a condition that weaken the immune system? These folks are at the highest risk for severe COVID-19, hospitalization and death. Further, unlike most adults, they will be at increased risk for severe disease from RSV.
    1. What risks of exposure have guests been incurring in the 3 – 5 days prior to the planned gathering? Obviously, the risks of someone bringing an infection to the gathering are greater in someone who has been traveling and attending meetings or conferences without wearing a high-quality mask than in someone who has been working from home and wore a high-quality mask for their travels to the gathering. I often hear people tell me that they feel safer because some of the intended guests had COVID-19 a month ago or two months ago. I understand their reasoning based on some data with variants that were circulating last year suggesting that those who were infected were likely protected from reinfection for a period of perhaps up to several months. However, I would caution that we do not have that kind of data for the variants circulating this year, that the current fast-increasing variants tend to be much more transmissible and immune evasive than prior variants, that people who were infected 1 – 2 months ago likely were infected with BA.4 or BA.5, and we do not have good data as to how protective, if at all, prior infection with BA.4 or BA.5 would be against these current new variants. BA.4 is largely gone and BA.5 continues to decline as it is overtaken by these new variants. The little data that we have could allow arguments both for and against some cross-immunity to new variants, but certainly we cannot feel confident in concluding that those previously infected individuals are protected from infection with more recent variants. In addition, I remind people that these persons may be of higher risk than others because (1) it is very likely that they continue to be involved in activities today that provided the opportunity 1 – 2 months ago for them to become infected and (2) in fact, they may be less cautious now than 1 – 2 months ago being under the impression that they have immunity from that prior infection.
  2. Be sure to have an adequate supply of at-home COVID tests. Don’t forget that every household has the opportunity to order 4 free at-home rapid antigen tests (2 boxes each containing 2 tests) right now if you have not already ordered them this month. I have already requested and received mine. You can order these free tests at www.special.usps.com. I am not sure you will receive yours in time for your holiday gathering, but it is worth a try, and even if not, these can be used to replenish your supply. If you already have a supply of tests, check the expiration dates to make sure that the tests are current. However, the FDA has recently extended the expiration dates for a number of home tests based on more testing since the agency issued their authorization for the tests. So, before tossing any of your current tests in the trash, check the FDA’s website at https://www.fda.gov/medical-devices/coronavirus-covid-19-and-medical-devices/home-otc-covid-19-diagnostic-tests#list to see if your test’s expiration date has been extended. If you are out of tests and don’t receive your free tests in the mail in time, you can find tests at most pharmacies and many grocery stores. A certain number of tests per month is covered under many insurance plans, so if you go to the pharmacy itself to make the purchase, they can determine your insurance coverage for the tests https://www.cms.gov/how-to-get-your-at-home-OTC-COVID-19-test-for-free.

There is also an exciting new option. There have been some at-home PCR test options previously, but earlier versions allowed you to obtain the specimen at home, but you still had to send it off to a laboratory for testing and results. More recent versions have allowed the testing at home, but have required the additional purchase of parts for the testing, and still, these tests could take an hour to perform. Now, the FDA has extended authorization to an “all-in-one” single use testing device and supplies that allows PCR testing at home in 30 minutes without the need to closely examine for a faint line, such as happens with the rapid antigen tests. When testing is complete, a light appears next to “positive” or “negative” letting you know what the result is. The device can then be placed in a baggie and tossed in the trash for disposal. I ordered some of these tests and was able to purchase them for under $30 each. If you are interested, you can find out more at www.lucirahealth.com. See below for more information about testing.

If you do become ill and you are an adult over 50, you have underlying medical conditions that make you high risk, and especially for those who are elderly (>75), it is very important to get tested. First, if you do have COVID-19, you will have significantly improved chances of avoiding developing severe disease requiring hospitalization or potentially causing your death if you get started on Paxlovid, an antiviral medication, within 5 days of developing symptoms. Even if you don’t have COVID-19, your doctor can check to see if you have influenza. If so, starting an antiviral within 48 hours will lessen the severity of illness and shorten the duration of your illness. Finally, your doctor can also check to make sure you or your child don’t have a group A strep infection that would require antibiotics.

  • Be sure you have a supply of over-the-counter fever-reducing medicines, cold-symptom relieving medicines, and high-quality masks. Be aware that there are shortages in many parts of the country of children’s over-the-counter medicines with many pharmacies and grocery stores reporting that their shelves are completely empty, so if you have children, make sure you spend the time now looking for where you can obtain your supply, rather having to search once your child is sick and perhaps many of the nearby pharmacies are closed or have reduced holiday hours.
  • Make a plan. Check with your doctor and your children’s doctors’ offices about (1) what their holiday hours will be; (2) how you can get access to testing and antivirals if you get sick when the office is closed (beware if they advise going to the ER because currently, most if not all ERs are already very busy, many are reporting significant delays (many hours and in some parts of the country I have heard of delays of up to a couple of days for evaluation if people are not suffering a life-threatening emergency. In many places, hospitals are experiencing capacity constraints resulting in people who are admitted to the hospital having to remain in the ER for their care for days due to a lack of beds elsewhere in the hospital}; and (3) what over-the-counter medications and doses they recommend for your children based upon their age if they do get sick over the holidays. There are “test to treat” locations in some parts of the country where you can go to be tested and if positive, have your antiviral medication be filled right there. You can check to see if there is such a site near you by going to Test to Treat​ | HHS/ASPR.
  • If you will be staying with someone else over the holidays, make a plan as to where you will go if you or your child becomes sick or tests positive so that you minimize the exposure to those you are staying with. Check out nearby hotels or rental homes that may have vacancies.
  • Know where to go for medical attention. Given that it is likely that your doctor’s office will be closed on Christmas and New Year’s Eve and on Christmas and New Year’s Day, identify one or more urgent care centers near where you live or are visiting. Check their website to verify days and hours of operation and check to see if they post waiting times on their website. If yours or your child’s illness does not seem to be severe, urgent care centers will likely be your best bet in that wait times are generally shorter and co-pays through your insurance are likely to be less.
  • Have a plan in the event of an emergency: In some parts of the country, the high volumes of illness, the increase in injuries that we see this time of year, and the reduced staffing due to illness and holiday scheduling has led to the overwhelming of ERs and to delays in EMS response times. Therefore, know where the nearest hospital is, and if you have small children, where the nearest pediatric hospital is. If you have more than one hospital nearby your home or where you will be visiting for the holidays and you are planning ahead, you can check with your doctor to see which hospital he or she recommends. There is no single source to identify the highest quality hospitals in your area, so I use a couple of websites. The first is the LeapFrog Hospital Safety Grades https://www.hospitalsafetygrade.org/search?findBy=state&zip_code=&city=&state_prov=ID&hospital=, which I use to get a sense of the hospital’s commitment and efforts towards ensuring patient safety. You can search hospitals by state to allow you to compare. I strongly prefer hospitals with an “A” grade for patient safety. I then look at quality scores and awards, and I like HealthGrades website for this: https://www.healthgrades.com/find-a-hospital. When you go to this webpage, type in hospitals and your city and state. The hospitals in your area should pop up in descending order of overall quality. When you click on the hospital, you will see recent quality awards, if any. Then, given that you most likely would need a hospital for a respiratory illness, you can click under the areas of pulmonary (lung diseases) and critical care (how well the hospital, its doctors, nurses and therapists perform in caring for patients in the intensive care unit) to see how that hospital’s quality outcomes are. Another indicator of the best hospitals that I use is Magnet status – a very difficult to achieve status to achieve for excellence in nursing that has been correlated with quality of care. You can go to https://www.nursingworld.org/organizational-programs/magnet/find-a-magnet-organization/ and scroll down to select the state you live in or are visiting, and the list of Magnet designated hospitals and the years in which they have been redesignated, if applicable, will appear. Of course, if you are not planning your choice of hospital in advance and you have an emergency, just go quickly to your nearest hospital.
  • Be prepared for the rare, but increasingly common situation in which not only hospitals, but EMS services are backed up. Given the pressure on the EMS system in some parts of the country, have a plan for how you would get a family member to the hospital if the illness or injury is not life-threatening or requiring advanced first aid or medical interventions prior to arrival at the hospital (i.e., an ambulance or medical helicopter is not necessary).
  • Plan for an extended wait time in the ER. Given the back-up in hospitals and the extraordinary time that you may have to spend in the ER with your child or family member, who will care for your other children in your home on short notice? Who will care for your pets if you are tied up in the ER for more than a day or if you are the sole care-taker of your pets and you have to be admitted to the hospital? Also, if you have vital medications that you have to take on a schedule that is shorter than the amount of time it may take for you to be seen and evaluated by a doctor, take those with you because a hospital cannot provide you with medications until after you are seen and evaluated by a physician and have physician orders for the medications. It is always good to have a list of medications with the dosage and frequency of the medicines noted. And, if you are in a foreign country, consider having a list of both the medical illnesses and the medications (use generic names of the medications along with doses and frequency) translated into the language used in that country if it is not English.
  • If you are traveling to another country, be sure to do your research. Consider whether that country is having a surge of cases and whether its health care system may be getting overwhelmed. For example, Hong Kong, South Korea, New Zealand, Japan, France and China are all having new surges right now. Those countries will not only pose inherently more risks of exposing you to illness, but may also create problems for you in terms of access to care. And, in some countries, you must consider whether they might institute a lock-down if the government determines cases are out of control that might impair your ability to return to the US as scheduled. You likely will want to make sure that you take extra medications with you in case you do become ill and can’t travel, are put in mandatory isolation or quarantine, or unable to return on schedule due to a lockdown or testing positive. A warning – also be sure to check that country’s restrictions as to what medicines you can bring into the country. I was quite surprised when my research showed that a European country had a law prohibiting the possession of a common anti-diarrheal medicine that is over-the-counter in the US and an Asian country that made it illegal to possess a common antihistamine that is over-the-counter in the US except in a lower dose that, to my knowledge, is not even available in that low dosage form in the US. You can get helpful information from the US embassy in the country that you are traveling to.
  • In addition, if traveling to another country, check to make sure what insurance coverage you will have in the event of illness. Many insurance companies will cover emergency care at a hospital, but they may not cover outpatient care, medications, oxygen or other services that might be needed. If that is the case, consider purchasing travel insurance. I am not aware of any US health insurance plans that would cover a medical evacuation if you are in a location where it is determined that the level of care you require can’t be met or if the hospital is overwhelmed and you can’t get all the care that you need. You can purchase insurance that will cover medical evacuation, but you need to ask questions such as (1) will the policy cover flying you home to the US or just to the nearest city or country that can provide the care (many provide only for the latter and even for a plan that will bring you back to the US, I had to search for one that wouldn’t just take me to the nearest medical center in the nearest state, but would bring me back home to a medical center here); (2) will the medical flight also carry your luggage back with you (I commonly see restrictions on the number of bags they will allow you to bring); and (3) will the medical evacuation flight allow your spouse or children fly back with you (many do not).
  • Also, if traveling to another country, you especially need to do your research as to how you would access care if sick and you needed testing and treatment, but also where you would go and how you would get there if hospital care was necessary.

Measures you can take to reduce your exposures at a family gathering

  1. Limit exposures in the several days leading up to the gathering and wear a high-quality mask whenever out in public for those 3 – 5 days prior to the gathering and on any public transportation taken to the gathering:  Family gatherings usually involve eating and drinking indoors, especially during the cold winter months, and this will increase risks of exposure due to the impracticability of wearing masks while eating or drinking. Nevertheless, wearing high-quality masks properly during any public transportation to the site of the gathering will considerably reduce exposure risks leading up to the family gathering. Contrary to many people’s impressions that travel by airplane is low risk, airports are crowded during the holidays, people are in close contact going through security and sitting at the gate or in airport restaurants and restrooms, and people from many distinct geographic regions are intermingled very possibly with variants that are common to that state or country of residence, but to which you have not yet been exposed. Further, while air circulation and filtration may be good when the flight is at cruising altitude, ventilation is usually poor when people are boarding or deplaning. There have been many well-documented outbreaks that have been connected to flights.

We also know from self-reporting and observations that many people will continue with their travel plans even if they realize they are sick. Many people are dismissive of the risks to others by transmission of whatever illness they have and many simply don’t want to cancel flights, hotel arrangements and other plans that they have been looking forward to.

In addition, limit your exposure in the week prior to your family gathering. Avoid large gatherings, work from home if you are able, wear a high-quality mask when you are out with others with whom you do not live (e.g., work or the grocery store).

  • Do not show up to the family gathering if you feel ill, or even if you have new symptoms that are not particularly bothersome, but you did not have in the preceding days, such as allergy-type symptoms or unexplained fatigue, and especially not if you feel feverish or have a fever. Encourage and get agreement from others attending the gathering that they will not show up if they feel ill or have unexplained symptoms.
  • Get the bivalent booster and encourage everyone else who will be in attendance to do so. If you don’t know where you can get the vaccine, open a text message and type in “438829” for the contact and then type in your zip code as the message. You will receive a text back that lists a couple of sites that are close by that have the vaccine. It will provide you with the name of the pharmacy or clinic, the address, and the phone number. It will also provide you with the email address http://www.vaccines.gov where you can find additional sites near you. If you need additional assistance, you can call 1-800-232-0233. While the booster is less effective in preventing infection and severe disease now that we have so many highly transmissible and immune evasive variants circulating around the world, studies have shown an advantage of the bivalent booster over the prior boosters you may have received, there is mounting evidence that if you have not received a booster within the past 6 months you have lost a significant part of its protection, and you still are less likely to be infected if everyone is boosted and based upon our latest studies, people of all ages have a 50% reduction in the potential for severe disease (i.e., illness that would cause you to need care at a hospital) with the bivalent booster, and that is especially important when our hospitals are already under significant capacity constraints. That reduction in severe disease for those over age 65 is actually 75%. Therefore, don’t put all your reliance on the vaccine to prevent you from getting infected (take the other measures I reference above and below), but this reduction in severe illness still makes the vaccine very worthwhile. While we would hope everyone has already received their bivalent booster, if you or someone else over the age of 5 hasn’t yet received it, please get it ASAP and recommend the others who have not yet received it to do so ASAP for whatever protection it will provide you in anticipation of your gathering.
  • Get your Flu shot. It is not too late, but get it now if you haven’t already. This year’s match looks quite good. Again, there may not be enough time by the time of your planned gathering to get the full effect of the vaccine if you haven’t already received it, but get it ASAP because influenza is at quite high levels in most countries in the northern hemisphere. Remember, if you are over age 65, be sure that you get the high-dose version of the vaccine.
  • If you are over age 65 and have not received your “pneumonia” shot, get that as soon as possible. This shot is to protect against one of the most common forms of bacterial pneumonia – one that can be quite serious in the elderly and individuals with certain underlying conditions (e.g., some cancers or if you don’t have your spleen or it is not functioning). The risk for bacterial infections increases after certain viral infections, and bacterial pneumonias have long been recognized as a serious complication of influenza. In fact, we are seeing evidence of a possible increase in invasive group A strep in children recently in the US that has been reported earlier this year in a number of other countries in Europe. Therefore, if your child develops fever and particularly, if it is accompanied by a rash, be sure that your child is evaluated for the many possible causes, including group A strep infection as antibiotic treatment is important to avoid some serious complications.
  • Most gatherings during these upcoming holidays will be indoors due to the weather. However, if you are fortunate to be spending your holiday gathering in a part of the country or world that has nice weather, please consider having your gathering outdoors. If indoors, try to optimize the air handling to minimize transmission of viruses to the extent you can. Opening a door or window can be very helpful, but may be impractical due to the weather conditions. You can explore adding a HEPA filter or MERV-13 filter to your furnace to filter the air. You also can use air purifiers and filters if you have them, or alternatively, you can make Corsi-Rosenthal boxes fairly easily and inexpensively https://engineering.ucdavis.edu/news/science-action-how-build-corsi-rosenthal-box. I would put one in each room where people will be congregating or sleeping. A way that you can assess whether you have achieved adequate ventilation is to use a CO2 monitor. You can purchase these for less than $100. I turn mine on during my flight, in my hotel room, or in the room where the gathering will take place. CO2 accumulates as there are more people in the space for longer periods of time in the absence of adequate ventilation. If you turned your CO2 monitor on outdoors, you would generally get a reading of about 440 – 450. For indoors, there are differences of opinions, but I shoot for CO2 levels less than 800. Certainly, I would not remain in a room unmasked if the CO2 levels exceeded 1,000.
  • Pre-event testing. Ideally, have every guest do a rapid antigen test upon arrival to town and the day of the gathering. If positive, they should not attend the gathering. Although most at-home COVID-19 tests indicate that they are for use in children over the age of 2, largely because they have not been tested in younger children, I can’t think of a reason that the tests wouldn’t work in all children, so check with your child’s primary care provider to see if they have any concerns about testing your child. If not, it may be particularly important to test these children with an at-home COVID-19 test before friends and family members come over since children under 2 are likely to have difficulties verbalizing symptoms to you. In addition, parents need to consider the risks that others will create for your children. After the age group of those over 65, children 0 – 6 months are the most commonly hospitalized group for COVID-19. Also, children under the age of 2, and especially those 0 – 6 months and even older children who have significant underlying health conditions such as asthma or neurodevelopmental disorders, are at the highest risks for severe RSV, which might result in hospitalization.

Unfortunately, the sensitivity of these at-home tests has declined with the emergence of these new variants. It is not that the variants are not detected by the tests, but rather, it may take testing two or three times over intervals of 48 hours each for the test to show up positive. So, a single pre-event test will give some assurance, but two negative tests over 48 hours will be much better assurance and three negative tests each spaced 48 hours apart will be the best possible assurance, though this is not likely to be feasible for all your guests. An alternative approach for those who have not had COVID-19 within the past 90 days is to do the at-home PCR test I mentioned above. This test needs only be done once and has a very high sensitivity rate of 98% (at least per the reports of the company to the FDA). PCR tests often are positive a day to two days before the rapid test becomes positive, so for those guests arriving in town the day of or day before the gathering, this approach may be the best.

I hope this is helpful. I wish you all happy and safe holidays!

Neurological Signs, Symptoms and Diseases following COVID-19

Part II – Cognitive Impairment (Brain Fog)

(See end for a summary of key take-aways)

In my last blog piece, we began an in-depth review of some of the neurological signs, symptoms and diseases that can follow COVID-19. That piece focused on one of the most common symptoms I get asked about – loss of smell (anosmia) or distorted sense of smell (parosmia). In this piece we will review what we know about cognitive impairment following COVID-19, often described by those affected as “brain fog.” As I did in my prior piece, I will review the studies first for the benefit of those who want a deep understanding of the problem, but I will conclude with “Key Take-Aways” for those who just want a summary of the studies in plain English.

It is estimated that 30 percent of persons who develop COVID-19 and require hospitalization will have neurologic symptoms, signs or disease resulting from their infection. However, it is also clear that even those with so-called “mild” COVID-19 can suffer from neurological sequelae following their infection.

Before digging specifically into cognitive impairment, let’s look at what we think we know about the impacts to the brain in general by SARS-CoV-2 infection.

A study published in August of this year[1], examined the molecular, cellular and morphological basis for infection of the brain in patients with COVID-19. This study examined a cohort of 26 individuals who died of COVID-19 in the first 5 months of the pandemic (thus, likely infected with the wild-type or original virus) and underwent autopsy. The investigators examined brain tissue under the microscope and looked for signs of cellular damage.  Among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. On average, SARS-CoV-2 spike protein could be detected in 37% of the brain cells, with about 66% of these cells being astrocytes. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Astrocytes are cells that are important to the support and function of neurons that carry electrical messages up and down the spinal cord and through our brains. Astrocytes are the major source of energy storage for the brain and play a critical role in the repair and regeneration of nerve tissue due to infection and/or inflammation.

SARS-CoV-2–infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites that are important to the functioning of neurons, as well as in the production of neurotransmitters. Human astrocyte infection also results in the secretion of substances from the astrocytes that reduce viability of neurons and leads to their death. Thus, this study supports that SARS-CoV-2 can reach the brain in at least some patients with COVID-19, infect astrocytes, and consequently, lead to neuronal death or dysfunction that perhaps explains or at least contributes to the neurological signs, symptoms and diseases that we see in some patients following COVID-19.

The investigators also performed high-resolution, high-magnet strength Magnetic Resonance Imaging (MRI) on 81 subjects diagnosed with mild COVID-19 infection (62 self-reported anosmia or dysgeusia [abnormal taste]) who did not require oxygen support during their infection within weeks to months following a laboratory-confirmed SARS-CoV-2 infection. These subjects were compared to 81 healthy, age- and sex-matched controls. The subjects with “mild” COVID-19 reported higher levels of anxiety and depression symptoms, fatigue, and excessive daytime sleepiness.

Compared to the healthy controls, the group with mild COVID-19 had areas of reduced cortical thickness (the cortex is the outer layer of the brain, the so-called gray matter, which is also the most neuron-rich part of the brain) exclusively in the left hemisphere, including the left gyrus rectus (this is located on the inferior surface of the frontal lobe and thought to be involved in higher cognitive functioning and personality), superior temporal gyrus (a site involved in processing sounds and comprehending language), inferior temporal sulcus (thought to be involved in processing complex visual patterns), and posterior transverse collateral sulcus (thought to be involved in visual processing, especially complex visual patterns).

A subgroup of 61 participants of the COVID-19 group also underwent neuropsychological evaluation, which assessed episodic verbal memory (logical memory subtest, immediate and delayed recall, Wechsler Memory Scale), sustained attention, and alternating attention and cognitive flexibility. The tests were performed a median of 59 days (range between 21 and 120 days) after diagnosis. The investigators observed fatigue in ∼70% of individuals and daytime sleepiness in 36%. Despite the high level of education of the participant subgroup (median of 16 years of education), the comparisons with Brazilian normative data (z scores were adjusted for age, sex, and education) showed that nearly 28% of participants presented impairments in immediate episodic verbal memory (immediate recall, including mild, moderate, and severe impairments), and ∼34 and 56% underperformed on sustained attention and alternating attention and cognitive flexibility, respectively.

The study findings demonstrated that cortical thickness atrophy (thinning) was associated with neuropsychiatric symptoms and cognitive impairment in COVID-19 patients with mild or no respiratory symptoms. Patients with cognitive dysfunction were often noted to have atrophy (shrinkage) in the orbitofrontal cortex (the outer layer of the brain just behind the eyes and over the nasal passages often referred to as prefrontal cortex) and these individuals were far more likely to experience anxiety.

Another study published in September of this year[2], examined the outcomes of those with COVID-19 who survived the at least a month from the date of their infection. The investigators reviewed the medical records of 154,068 patients with SARS-CoV-2 infection, including those with “mild” COVID-19, and 5,638,795 uninfected contemporary controls that were in the Veteran’s Administration medical record system. To further validate the estimates, the investigators built a pre-pandemic, historical control cohort of 5,859,621 patients. Those persons with COVID-19 had an increased risk of a wide range of post-acute neurological disorders after 1 year compared with an uninfected control population, including cerebrovascular disorders, cognition and memory disorders (memory problems and Alzheimer’s disease), peripheral nervous system disorders, extrapyramidal and movement disorders, musculoskeletal disorders, and sensory disorders. Overall, the investigators determined that patients with COVID-19 had a 42% increased risk of developing a neurological sequela in the year after infection, translating to 7% of infected people. Some of the neurological sequelae are chronic conditions that will require lifelong care and might impact patients’ lives and livelihood. The risks were higher in those who required hospitalization for their COVID-19, and even higher in those who required intensive care during their hospitalization.

Specific neurological sequelae included:

1.41 – 1.61 times increased risk of ischemic stroke resulting in 2.75 – 4.09 ischemic strokes per 1,000 persons infected at 12 months.

1.63 – 2.95 times increased risk of hemorrhagic stroke resulting in burden 0.11 – 0.35 brain bleeds per 1,000 infected persons at 12 months.

1.5 – 1.75 times increased risk for transient ischemic attacks (TIAs) resulting in 1.64 – 2.46 such events per 1,000 infected persons at 12 months.

1.29 – 5.62 times increased risk for cerebral venous thrombosis resulting in 0.01 – 0.14 cases per 1,000 infected persons at 12 months.

1.28 – 1.40 times increased risk of developing peripheral neuropathy (numbness, tingling and/or burning sensations sometimes accompanied by weakness in the extremities) resulting in 4.67 – 6.65 cases per 1,000 infected persons at 12 months.

1.25 – 1.39 increased risk of experiencing paresthesia (abnormal sensations usually in the arms and legs such as tingling or burning) resulting in 2.27 – 3.55 cases per 1,000 infected persons at 12 months.

1.21 – 1.40 increased risk of developing dysautonomia (a disorder of the autonomic nervous system which can result in a myriad of distressing symptoms including faintness or dizziness with changes in posture, rapid heart rate and palpitations, and frequent urination) resulting in 1.12 – 2.12 55 cases per 1,000 infected persons at 12 months.

1.24 – 1.77 times increased risk for developing Bell’s palsy (a partial paralysis of one side of the face) resulting in 0.16 – 0.51 cases per 1,000 infected persons at 12 months.

1.14 – 1.28 times increased risk for experiencing migraine headache disorder resulting in 1.36 – 2.76 new cases per 1,000 infected persons at 12 months.

1.25 – 1.45 times increased risk for developing non-migraine headache disorders resulting in 1.06 – 1.89 cases per 1,000 infected persons at 12 months.

1.61 – 2.01 increased risk for developing epilepsy and seizures resulting in 1.47 – 2.63 cases per 1,000 infected persons at 12 months.

1.32 – 1.50 times increased risk of experiencing abnormal involuntary movements resulting in 2.24 – 3.49 cases per 1,000 infected persons at 12 months.

1.25 – 1.51 times increased risk for developing a tremor resulting in 0.73 – 1.51 cases per 1,000 infected persons at 12 months.

1.28 – 1.75 times increased risk of developing Parkinson-like disease resulting in 0.50 – 1.34 cases per 1,000 infected persons at 12 months.

1.29 – 1.9 times increased risk of developing dystonia (abnormal and often repetitive movements) resulting in 0.21 – 0.63 cases per 1,000 infected persons at 12 months.

 1.13 – 1.79 tines increased risk for myoclonus (sudden, brief involuntary twitching or jerking movements) resulting in 0.04 – 0.26 cases per 1,000 infected persons at 12 months.

1.39 – 1.48 times increase in major depressive disorders resulting in 15.43 – 19.18 cases per 1,000 infected persons at 12 months.

1.34 – 1.44 times increase in stress and adjustment disorders resulting in 12.66 – 16.07 cases per 1,000 infected persons at 12 months.

1.33 – 1.42 times increase in anxiety disorders resulting in 10.93 – 13.99 cases per 1,000 infected persons at 12 months.

 1.33 – 1.71 times increase in psychotic disorders resulting in 0.66 – 1.43 cases per 1,000 infected persons at 12 months.

1.31 – 1.38 times increase in arthralgias (joint pain) resulting in 25.01 – 30.35 cases per 1,000 infected persons at 12 months.

1.77 – 1.9 times increase in myalgia (muscle pains) resulting in 14.75 – 17.23 cases per 1,000 infected persons at 12 months.

2.3 – 3.32 times increase in myopathy (muscle disease, weakness) resulting in 0.52 – 0.93 cases per 1,000 infected persons at 12 months.

1.18 – 1.25 times increase in hearing abnormalities or tinnitus (ringing in the ears) resulting in 10.05 – 13.75 cases per 1,000 infected persons at 12 months.

1.24 – 1.36 times increase in vision abnormalities resulting in 4.55 – 6.68 cases per 1,000 infected persons at 12 months.

3.45 – 4.75 times increase in anosmia (loss of smell) resulting in 0.86 – 1.32 cases per 1,000 infected persons at 12 months.

1.54 – 3.32 times increase in loss of taste resulting in 0.05 – 0.21 cases per 1,000 infected persons at 12 months.

1.38 – 1.5 times increase in dizziness resulting in 5.72 – 7.61 cases per 1,000 infected persons at 12 months.

1.31 – 2.12 times increase in somnolence resulting in 0.26 – 0.94 cases per 1,000 infected persons at 12 months.

1.40 – 3.35 times increase in Guillain–Barré syndrome resulting in 0.04 – 0.22 cases per 1,000 infected persons at 12 months.

1.16 – 2.84 times increase in encephalitis or encephalopathy resulting in 0.01 – 0.16 cases per 1,000 infected persons at 12 months.

1.11 – 2 times increase in transverse myelitis resulting in 0.00 – 0.11 cases per 1,000 infected persons at 12 months.

Focusing now on the subject of this blog piece – cognitive impairment following COVID-19, this study showed:

1.68 – 1.85 times increase in memory problems resulting in 9 – 11.2 cases per 1,000 infected persons at 12 months.

1.79 – 2.31 times increase in Alzheimer’s disease resulting in 1.27 – 2.10 cases per 1,000 infected persons at 12 months.

Another study published in October of this year[3] describes the neurobiology of the neurological sequelae of Long COVID.

Prominent among the lasting neurological sequelae following COVID-19 is a syndrome of persistent cognitive impairment known as “brain fog,” characterized by impaired attention, concentration, memory, speed of information processing, and executive function. Neuroinflammation alone can cause dysregulation of glial and neuronal cells and, ultimately, neural circuit dysfunction that negatively impacts cognitive and neuropsychiatric functions.

Infection due to SARS-CoV-2 may affect the central nervous system in (at least) six main ways:

  1. The immune response to SARS-CoV-2 in the respiratory system may cause neuroinflammation—increasing cytokines, chemokines, and immune cell trafficking in the brain, inducing reactive states of resident microglia and other immune cells in the brain and brain borders.
  2. SARS-CoV-2 rarely may directly infect the nervous system.
  3. SARS-CoV-2 may evoke an autoimmune response against the nervous system.
  4. Reactivation of latent herpesviruses, like the Epstein-Barr virus, may trigger neuropathology.
  5. Cerebrovascular and thrombotic disease may disrupt blood flow, disrupt the blood-brain-barrier function, and contribute to further neuroinflammation and/or ischemia of neural cells.
  6. Pulmonary and multi-organ dysfunction occurring in severe COVID-19 can cause hypoxemia (low oxygen levels in the blood), hypotension (low blood pressure), and metabolic disturbances that can negatively affect neural cells. 

Again, it is important to keep in mind that multiple mechanisms may be at play in the same patient and that different mechanisms may be triggered in different people. For example, neuroinflammation triggered by the immune response to the respiratory system infection and consequent dysregulation of neural homeostasis and plasticity is likely a more common mechanistic principle that occurs even after mild disease in the acute phase, while direct brain infection is likely an uncommon mechanism associated with severe COVID-19.

Cognitive function depends upon precision of activity in neural circuits, which in turn depends upon finely regulated interactions of neurons with glial cells, most notably astrocytes. In healthy, stable states of health, astrocytes control the formation and function of synapses (connections between neurons in these neural circuits). Another type of glial cell, oligodendrocytes, are important to fine tune these neural circuits by modulating the speed and amplitude of the electrical transmissions within and between axons (the portion of the neuron that transmits the electrical impulses (signals). Oligodendrocytes also provide important metabolic support to the axons to keep them healthy and high performing.

Microglia (including both astrocytes and oligodendrocytes) act as the main immune defense in the central nervous system. Similar to roles played by macrophages outside of the brain, these cells scavenge for the development of plaques, infectious agents and damaged neurons and synapses. They are exquisitely responsive to immunological signals and rapidly assume reactive phenotypes. However, in the reactive form, they do not retain the functions and ability to preserve the stable environment and plasticity of neurons. Microglial reactivity leads to secretion of cytokines and enhanced phagocytosis (ingestion of cells – in this case infected and damaged cells) that is intended to limit the spread of pathogens. When not properly regulated, these reactive microglia can profoundly disrupt neural circuit regulation, function, and plasticity in ways that can contribute to cognitive impairment and neuropsychiatric diseases.

Reactive astrocytes can further contribute to pathology, with certain states of reactive astrocytes inducing cell death of oligodendrocytes and of susceptible neurons. The neurotoxic sub-state of reactive astrocytes does not adequately support synaptic connections, which can further add to circuit dysfunction. This complex cellular dysregulation is thought to contribute significantly to cognitive impairment.

Alarmingly, a neuro-psychometric study examining patients with mild, moderate, or severe COVID-19 in a New York City hospital system followed from spring of 2020 through spring of 2021, found impairment in attention (10%), processing speed (18%), memory encoding (24%), and executive function (16%) evident at 7 months after infection.

A 2-year retrospective cohort study following 1,487,712 individuals with COVID-19 and a similar number of matched controls with a different respiratory infection found continued risk of cognitive impairment at 2 years from diagnosis.[4] 

The UK Biobank study compared magnetic resonance imaging (MRI) data before and after SARS-CoV-2 infection in 401 individuals and 385 matched controls. MRI data obtained an average of 141 days following COVID-19 diagnosis revealed widespread structural abnormalities, including a small but significant global decrease in brain volume, changes throughout the olfactory system, and structural abnormalities in the limbic system, cerebellum, and major white matter tracts (fimbria and superior fronto-occipital fasciculus).[5]

Another mechanism by which COVID-19 may injure the nervous system is through the production of autoantibodies and autoimmunity. In a study of six individuals hospitalized for COVID-19 with acute neurological symptoms, including encephalopathy, headache, and seizures, analyses of immune cells in blood and cerebral spinal fluid (CSF) revealed activated T cells and clonal expansion of unique T cell clones in the CSF not found in blood, suggesting a compartmentalized T cell response to an antigen in the central nervous system.[6] This is not a complete surprise as we have known for more than a year that hospitalized patients with moderate and severe COVID-19 produce a diverse set of serum autoantibodies against vascular cells, coagulation factors and platelets, connective tissue, extracellular matrix components and various organ systems, including the central nervous system.[7] In fact, cases of autoimmune encephalitis have been reported in patients with severe COVID-19 with the identification of anti-neuronal autoantibodies in patient CSF and sera in individuals with prominent neurological symptoms.

Another potential contributor to the pathophysiology of Long COVID and its neurological sequelae is reactivation of latent viruses. There are a number of viruses that humans are commonly exposed to that cause infection during which time the viruses are contained, but not eliminated (e.g., herpes viruses, Epstein-Barr Virus (EBV), cytomegalovirus (CMV), varicella-zoster virus (VZV), and human papilloma virus (HPV)). These latent viruses do not cause any direct clinical disease in their latent state, but they may contribute to the development of other diseases indirectly, for example cancers from EBV and HPV and multiple sclerosis from EBV. However, states of immune compromise or other acute viral infections can trigger the reactivation of these latent viruses, resulting in the production of infectious viral particles that can cause significant inflammation and symptoms, e.g., reactivation of varicella-zoster infection can result in painful shingles.

A study that followed 309 COVID-19 patients from the initial diagnosis to convalescence (2–3 months later) found that EBV viremia (Epstein Barr Virus in the blood) at the time of COVID-19 diagnosis was one of the four predictive factors for long COVID development.[8] Based on prior studies contributing to our understanding of EBV, this virus may contribute to neuroinflammation in long COVID patients due to viral pathogenesis (viral proteins and viral transcription factors) and/or host immune response to EBV infection (including the production of cytokines and autoantibodies).

Another latent virus that has been reported to be reactivated in some persons with COVID-19 is a collection of viruses known as herpes viruses, specifically herpes simplex viruses 1 and 2. Even before COVID-19, we would see cases of herpes simplex reactivation that results in herpes encephalitis, a life-threatening infection of the brain. Herpes virus reactivation could be a result of the steroids that we use to treat COVID-19 patients with severe disease, or it could be due to the immunopathology that can result from SARS-CoV-2 infection relating to T-cells (more on that in a later blog post). In this case, we have reports of herpes encephalitis occurring within several weeks of COVID-19 diagnosis suggesting that the steroids may be the most likely cause.

Another potential pathophysiological basis for long-term cognitive dysfunction following COVID-19 is ischemic stroke. Compared to other respiratory viruses, ischemic stroke is a greater risk from infection with SARS-CoV-2 than those other viruses. Ischemic strokes can confer lasting neurological sequelae and impair cognitive functions in a vascular-territory-dependent manner. Short of an ischemic stroke, small vessel thromboses and vascular dysfunction, including blood-brain-barrier disruption, can also influence neurological function in subtle but debilitating ways. This increased risk of thrombosis has been shown in studies demonstrating fibrin micro-clots and activated platelets in the blood of patients with long COVID.[9] Ischemic strokes and brain hemorrhages have been seen on autopsy of patients who died with severe COVID-19. However, other vascular injuries to the brain have been seen on autopsies of those who died with COVID-19, including microvascular (small blood vessels) injury and endothelial cell (the cells that line the blood vessels) activation with perivascular leakage (leakage surrounding the blood vessel) of the large plasma protein fibrinogen, indicative of blood-brain-barrier dysfunction, found throughout the brain and most prominent in the hindbrain (cerebellum [critical to functions such as balance and arm, leg and eye movements] and brainstem [critical to breathing, many of the cranial nerves and the transmission of signals from the brain to the body and vice versa]).

Key Take-aways

  1. Neurological sequelae are not uncommon following COVID-19 with estimates of impacting ~ 30% of those hospitalized with COVID-19 and perhaps ~ 7% of those with “mild” COVID-19.
  2. COVID-19 is able to cause damage to the brain in a number of different ways. As we discussed in the prior blog piece relating to anosmia, it appears that direct viral invasion of nerve cells is possible, but not the dominant mode of damaging the brain.
  3. SARS-CoV-2 can directly infect certain cells that are important to healthy, properly functioning nerve cells, namely astrocytes and oligodendrocytes. When these supporting cells are infected, they in turn both directly and indirectly can harm neurons.
  4. Various mechanisms may be involved in damaging the brain besides direct viral invasion, including the immune reaction to SARS-CoV-2 infection, reactivation of latent viruses, the formation of autoantibodies and damage to blood vessels large (ischemic stroke) and small (microvascular injury and endotheliitis).
  5. The changes caused by any of these pathophysiologic mechanisms, by themselves or in combination, may be sufficiently severe to cause neurocognitive and neuropsychiatric disorders. In fact, imaging studies have shown striking reductions in brain volumes following SARS-CoV-2 infection, with further studies showing that the loss of brain matter may disproportionately affect the cerebral cortex, the part of the brain that is most rich in number of neurons.
  6. There are many unanswered questions. While it appears that some people with cognitive impairments will improve with time, it is unknown whether these impairments can be permanent, and if so, what proportion of patients this may affect. Concerning for the possibility of life-long impairment in at least some people is the increased risk for development of Alzheimer’s dementia following COVID-19.
  7. It also is not clear whether all variants of SARS-CoV-2 have equal neuropathologic potential, or whether they may vary in their proclivity to cause neurological damage or the severity of that injury.
  8. It appears that the risk for neurological sequelae following COVID-19 increases with reinfections, and there is emerging data that indicate that the risk of cognitive impairment may be decreased in breakthrough infections of fully vaccinated individuals, although this decrease appears to be relatively small (somewhere around a 15% risk reduction). 
  9. My greatest concern is for the neurological harm that may be suffered by children, especially with repeated infections. There is simply little data to draw conclusions from, though there is reason for concern given that we know children can develop Long COVID. Further, the brains of children and young adults up to age 25 is still developing and presumably more vulnerable than older adults. While stress, anxiety, depression and educational loss has been ascribed to remote learning, little consideration has been given to the potential that COVID-19 may itself be responsible or contributing to these problems.

[1] Morphological, cellular, and molecular basis of brain infection in COVID-19 patients | PNAS.

[2] Long-term neurologic outcomes of COVID-19 | Nature Medicine.

[3] The neurobiology of long COVID: Neuron (cell.com).

[4] Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients – The Lancet Psychiatry.

[5] SARS-CoV-2 is associated with changes in brain structure in UK Biobank | Nature.

[6] Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms: Cell Reports Medicine.

[7] Diverse functional autoantibodies in patients with COVID-19 | Nature.

[8] Multiple early factors anticipate post-acute COVID-19 sequelae: Cell.

[9] Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/Post-Acute Sequelae of COVID-19 (PASC) | Cardiovascular Diabetology | Full Text (biomedcentral.com).

Neurological Signs, Symptoms and Diseases following COVID-19

Part I – Anosmia (loss of smell) and Parosmia (distorted smell)

(see end for a summary of key take-aways)

To all the followers of my blog, I am sorry that it has been so long since I last posted. I am going to pick up again in the series of blog posts on the long-term health consequences of COVID-19, and this current blog piece begins a look at neurological health effects resulting from COVID-19.

Part of my hiatus was due to time deadlines that had to be met for the book Dr. Epperly and I have written and will soon be released in April by Johns Hopkins University Press. For those of you interested in learning more about our book, or potentially wanting to pre-order a copy, you can read more at https://www.press.jhu.edu/books/title/12896/preparing-next-global-outbreak. Our book is entitled, “Preparing for the Next Global Outbreak” and it will be released on April 18, 2023. If you scroll down the page, you will find a description and a chapter outline, and if you scroll all the way down, you will find reviews and endorsements of the book by faculty members of the Harvard and Yale schools of public health, by a world-renown epidemiologist who served on the White House Transition Team related to the national COVID-19 response, a vaccinologist who led the team that developed a COVID-19 vaccine for use in middle and lower income countries, a critical care physician who also serves as a national medical correspondent for a number of networks, and a microbiology faculty member from our own College of Western Idaho.

Back to the long-term health consequences of COVID-19. We are learning a lot. For the rest of this blog series, we will focus on different parts or functions of the body. This blog post will begin to look at what we are learning about the neurological health consequences of COVID-19. Before we begin, it is important to make sure we understand the limitations of what I will present.

  1. The science is still evolving. We know a lot more today than at any prior point in the pandemic, but we will no doubt learn much more over time. Keep in mind, we often don’t develop a comprehensive understanding of viruses like SARS-CoV-2 for years, if not decades.
  2. While we are discussing “long-term” health consequences, keep in mind that many of the studies conducted are based on months or at most two years of follow-up. Therefore, it is difficult to know at this point whether someone who develops neurological symptoms will eventually improve or whether the symptoms are likely to persist or even progress over time.
  3. It is important to remember that studies of predominantly adults may not necessarily apply to children, that studies involving men may not necessarily apply to women, that animal studies may not completely represent what happens in humans, that the findings from autopsy studies may not represent the pathology that exists in persons who survive COVID-19, and that studies based upon small numbers of patients may not hold up when studies of large numbers of people are done in the future.
  4. Keep at the top of your mind that there are many factors that may determine whether someone develops any of the health consequences we are going to highlight over the remainder of this blog series, such as their age and gender, their medical history, their prior infection history, their vaccination history, the timing of whether infected or vaccinated first, which variant they were infected with, the viral load associated with their infection, what therapies they received, the severity of their illness, their genetic make-up, and the status of their immune system before and after the infection.
  5. We also must consider the possibility that different underlying pathophysiological processes may be at work in different people who appear to have the same long-term health condition. For example, perhaps persistence of the virus may be causative of a condition in one person, whereas the same condition in another patient is due to autoantibodies generated by the infection. Further, we must also consider that multiple pathophysiological processes can be occurring in one or even all patients with the post-COVID condition, e.g., perhaps there is both virus persistence as well as antibodies.

I will provide a lot of information, and I will also provide footnotes with links to the studies from which I base the review in case you want to look at any of these studies in more detail. Also, refer back to my earlier blog posts in this series if you need to review the virology, immunology or pathophysiology that is the basis for much of our discussion. Further, remember to review the blog post on interpreting clinical studies. In addition, at the end of each blog piece, I will summarize the learnings for you.

Anosmia – Loss of Smell

One of the most common questions I get from people concerning neurological sequelae from COVID-19 relates to anosmia – the loss of the sense of smell. Why do some people lose their sense of smell, what does it signify and will it resolve?

It has been reported that somewhere between 30 – 70% of patients following COVID-19 experience loss of smell, a decrease in their sense of smell or a distorted sense of smell, though the frequency has varied over the pandemic and perhaps the rate is different with different variants of concern. To those with their sense of smell intact, this might seem nothing more than an annoyance, but in fact, it is often quite distressing to patients and in severe cases can lead to life-threatening weight loss due to the accompanying loss of sense of taste and enjoyment of food. In most people, their sense of smell returns within a month, but in others it may persist.

There have been various hypotheses as to how SARS-CoV-2 induces loss of smell. These include indirect effects of the viral infection causing inflammation, swelling and potentially loss of olfactory epithelial cells (these are the cells lining the olfactory tissues); inflammation and loss of axonal neurons (these are the nerves involved in transmitting signals from the nose to the brain); inflammation and disruption of the microvasculature (small blood vessels) (specifically endothelial cell dysfunction, endothelial cell injury, endotheliitis [inflammation of the cells lining small blood vessels], and resultant disrupted microcirculation) that supplies the olfactory nerves and tissues given our knowledge that SARS-CoV-2 attacks cells that line these blood vessels; or direct viral invasion and resulting damage to the olfactory tissues, nerves or even portions of the brain associated with processing smells. Given the ability of the body to repair many of these tissues over time and the potential for some nerves to regenerate over time, it is expected that many patients will recover their sense of smell, but it is less clear whether the loss could be permanent in others.

A study published in JAMA Neurology on April 11, 2022 sheds some light on some of these questions.[1] In this cohort study, the investigators examined 23 deceased patients with COVID-19 and 14 matched controls between April 7, 2020 and September 11, 2021 (this time period would mostly have involved the original virus, Alpha and Delta). The olfactory bulb and tract (the olfactory sensory nerves that run from the nasal passages up to bulb in the front part of the brain at the base of the skull just above the nasal passages and then connect to portions of the temporal lobe (where we become consciously aware of smells), the hippocampus (where we form memories of smells), the amygdala (that triggers emotional responses to smells), the hypothalamus (in the center of the brain where multiple senses are routed and connected to our autonomic nervous system) and the reticular formation (where certain smells can elicit visceral responses, e.g., some smells triggering nausea or vomiting) in the back of the brain) was dissected, collected and evaluated by histologic exam (examination of stained tissues under the microscope); electron microscopy (a microscope so powerful that you can see the components of individual cells, including viruses; droplet digital polymerase chain reaction (this allows for the detection of nucleic acids that make up the SARS-CoV-2); immunofluorescence and immunohistochemistry (these methods allow one to look for specific proteins or other targets by using antibodies against those targets, and in the case of immunofluorescence, the binding of antibodies to a component of the virus causes the antibodies to light up vividly under the microscope). The investigators noted severe nerve damage, as well as disease of the small blood vessels involving the brain’s olfactory tissues in the deceased patients with COVID-19 compared to the controls, and these findings were more severe in the patients who died with COVID-19 who had complained of loss or disturbance of smell prior to death. In some cases, the degree of nerve damage was so severe that it would be expected, had the person survived, that the loss of smell or disturbance of smell would likely be permanent.

One hypothesis as to why anosmia may occur is direct invasion of the olfactory tissues by the virus. However, in this study, SARS-CoV-2 was detected in olfactory tissue only in 3 patients using droplet digital PCR or immunofluorescence, suggesting that olfactory pathology in most persons is not mediated by direct infection or injury to the nerve by the virus.

Endothelial cell (cells that line blood vessel walls) injury and dysfunction is common and well-documented in patients with COVID-19.

This study suggests that SARS-CoV-2 infection can damage the nerves that make up the olfactory bulb and tracts and damage the small blood vessels that are critical to the health and perfusion of these nerves without direct viral invasion.

Another study[2], also published in April of 2022, attempted to answer the question about what causes anosmia and the time course of recovery. Unlike the prior study in which the olfactory tissues can be examined post-mortem, obviously, this cannot be done in surviving humans. Therefore, the investigators used Syrian golden hamsters as an animal model, given that it is known that in many respects COVID-19 has similar manifestations in these hamsters as in humans.

The hamsters were inoculated with SARS-CoV-2 through their nasal passages at 6-weeks of age and samples were collected at several time points. Using immunofluorescence (antibodies against the virus that light up under the microscope when attached to the virus material), the investigators detected a significant number of SARS-CoV-2-positive regions throughout the olfactory epithelium (the cells that line the nasal passages) at 2 days post-infection (dpi), but not at 8 dpi (signifying that the hamsters were able to clear the virus from their nasal passages similar to humans and roughly on the same timeline). Interestingly, SARS-CoV-2-infected cells were observed not only superficially but also deep within portions of the nasal passages. The SARS-CoV-2 antigen was not observed in mature olfactory sensory neurons (OSNs) (these are the nerves that detect smells and transmit the signal from the nasal passages up towards the brain but in cells around the OSNs, mostly supporting cells (SCs). There are two types of SCs, but the ones of most concern for our purposes are the sustentacular cells that serve to provide metabolic and structural support to the olfactory epithelium and nerves. SCs are known to express the ACE-2 receptors that allow SARS-CoV-2 to bind to the cell membrane and enter (infect) the cells.

The numbers of SCs significantly decreased in the two of the four areas of the nasal passages and could not be determined in the one area due to the complete loss of the olfactory epithelium at 5 dpi, although the damage was recovered almost completely in all regions by 21 dpi. Interestingly, no SARS-CoV-2 antigen was detected within slices of the whole brain, including the olfactory bulb (OB) (this is the beginning of the main olfactory nerves – one on each side – that connects to the brain. It sits at the base of the brain, inside the skull, just above the nasal passages, with tiny branches (olfactory sensory nerves) that extend into the nasal cavity) and hippocampus.

The data from this study suggest that SARS-CoV-2 did not infect the brain parenchyma or that the level of infection was below detection limit, although some previous research has detected SARS-CoV-2 RNA and viral antigen in the brain.

Moreover, the researchers found that the olfactory epithelium thickness transiently decreased at 5 dpi but recovered fully by 21 dpi, as was the case for the SC numbers. Nevertheless, the density of mature olfactory sensory nerves did not completely recover up to 42 dpi, suggesting that the maturation of olfactory sensory nerves may be delayed and/or incomplete.

Such uneven damages to the olfactory epithelium may induce the unusual pattern of odor-induced activity in the olfactory bulb and contribute to development of parosmia (abnormal/distorted smells) during the recovery process.

These trends were also observed in the olfactory bulb, in which olfactory sensory nerves connect to clusters of nerves (called glomeruli) that all detect similar kinds of smells.

In the olfactory bulb, the density of the olfactory sensory nerve axon terminal of each glomerulus was significantly decreased within regions that contained cells with a certain enzyme. Interestingly, the size of the glomeruli themselves decreased not only in those regions, but also regions with cells that did not have that enzyme, suggesting that the multiple mechanisms may be in play that impacts olfactory bulb damage. These data indicate that SARS-CoV-2 infection impacts odor information processing within the whole olfactory bulb, but especially prominent in regions with cells containing this particular enzyme.

The researchers also examined the impact of SARS-CoV-2 on higher brain areas, including the piriform cortex (PC) and the hippocampus. Their findings indicate that SARS-CoV-2 infection in the nostril triggered the activation of microglia and astrocytes (these are structural cells in the brain that promote connections between nerve cells in neural circuits and that assist in the remodeling and repair of these circuits) even in the hippocampus, and that the impacts are significantly different in each layer of these structures. Thus, an interesting question could be posed as to whether the activated microglia and astrocytes could induce any changes in the neuronal circuits?

There are many reports that reveal glial cells induce synaptic modulation, synaptic loss, synaptic plasticity, and change of synaptic density. These changes may be associated with dementia. Therefore, the researchers did further examination of tissue from the hippocampus. Their findings may be associated with the prolonged activation of microglial cells, most notably significant at 42 dpi. These results suggest that intranasal inoculation of SARS-CoV-2 induces glial cell activation and changes dendritic spine density within the higher brain regions, including the hippocampus. These may underlie long-lasting sequelae of SARS-CoV-2 infection including depression, memory impairments, and brain fog, although more evidences to show synaptic dysfunction is needed.

Finally, let’s look at one more study[3]. This study was published as a pre-print on August 31, 2022. This study attempts to address the question as to whether different variants are more or less likely to cause the neuropathology that results in anosmia, again by using Syrian golden hamsters. To do so, they infected hamsters with different forms of SARS-CoV-2 – the original SARS-CoV-2, its ORF7-deleted mutant (ORF is open reading frame – a segment of genetic material that is part of the virus, but not its spike protein), and three variants: Gamma, Delta and Omicron/BA.1.

The investigators identified that SARS-CoV-2 Wuhan and the variants Gamma, Delta and Omicron/BA.1 are all capable of invading the brain of Syrian hamsters and of eliciting a tissue-specific inflammatory response. They were also able to demonstrate that SARS-CoV2 infects the olfactory bulbs, but the clinical profile, including the olfactory performance, is highly dependent on the variant. Fascinatingly, 62.5% of SARS-CoV-2 Wuhan-infected animals (compared to only 25% of the hamsters infected with the recombinant Wuhan strain with the ORF7 deletion) presented loss of olfaction; only 12.5% of Gamma-infected animals lost olfaction completely with 62.5% presenting an impaired olfactory performance (i.e., longer time to find the hidden cereals). In contrast, none of the Delta or Omicron/BA.1-infected animals presented signs of olfactory impairment.  

Remarkably, even if the olfactory performance differed according to the variant, positive viral titers were detected in the olfactory bulbs of animals from all infected groups, with Gamma-infected animals presenting the highest titer at 4 days post infection. These findings were corroborated by the detection of genomic viral RNA in the olfactory bulbs of animals from all infected groups as well.

When the animals were sacrificed and the brain was examined for presence of virus, the olfactory bulbs were the major infected structure in the brain.

Further, deletion of the ORF7ab sequence in the ancestral virus reduces the incidence of olfaction loss without affecting the clinical picture nor the neuro-invasiveness.

The authors conclude that the olfactory pathway is the main entry route by SARS-CoV-2 into the brain and corroborates the neurotropic potential of SARS-CoV-2 variants. Neuro-invasion and anosmia are therefore independent phenomena resulting from SARS-CoV-2 infection.

Key Take-aways:

  1. Anosmia (loss of the sense of smell) is a frequent symptom with SARS-CoV-2 infection, and it can be a long-term consequence of COVID-19. While it appears that the majority of persons infected will regain their sense of smell within a month, some people do suffer from persistent anosmia, and it is possible, though not certain, that this could be permanent in a minority of persons.
  2. It appears from human population studies and animal models that the frequency with which anosmia occurs may vary with different variants, and may be highly dependent upon the presence or absence of particular genetic sequences known as ORF7a and ORF7b.
  3. Autopsies of persons who have died with COVID-19 demonstrate that infection can cause significant damage to olfactory epithelial cells (cells that line the nasal passages); can cause indirect damage to the olfactory sensory nerves (i.e., damage from inflammation associated with infection rather than from direct viral infection of the nerves themselves); can cause direct viral invasion and at least a temporary reduction of the sustentacular cells, which are supporting cells for the olfactory epithelium and olfactory sensory nerves; and disruption to the small blood vessels in proximity to these olfactory nerve cells. At this time, it would appear that damage to the olfactory epithelial cells and mucosal lining of the nasal cavity may be the most important of these in determining whether a patient will experience anosmia.
  4. While SARS-CoV-2 appears able to directly infect olfactory sensory nerves and the olfactory bulb, this does not appear to be the main way in which anosmia results from COVID-19. In most cases, the damage appears to be indirect and perhaps due to the immune response mounted against SARS-CoV-2.
  5. The damage to olfactory epithelial cells (those that line our nasal passages) and animal studies that show variable damage to glomeruli within the olfactory bulb may help explain why some people develop parosmia (distorted sense of smell).
  6. There have been reports that persons who develop anosmia with COVID-19 may be more likely to have other neurological signs, symptoms and sequelae than those who don’t. It has been postulated that the anosmia is indicative that the virus has gained entry to the brain tissues through ascension up the sustentacular cells and other olfactory tissues. Though this appears possible in some individuals, this does not appear to be the dominant pathophysiologic explanation for other long-term neurological manifestations of COVID-19, because both human autopsy and animal studies suggest that only a minority of subjects have laboratory evidence of direct viral invasion in neural tissues.
  7. On the other hand, animal studies suggest that SARS-CoV-2 infection in the nasal cavity triggers immune, and possibly other, mechanisms of reaction in the brain that may be deleterious, particularly activation of microglial cells and astrocytes and damage to some dendritic cells. It is postulated, but remains unproven, that these changes may contribute to long-lasting sequelae of SARS-CoV-2 infection, including depression, memory impairments, and brain fog, possibly due to disruption of neuronal circuits in the brain, and that this may even play a role in the apparent increased risk for dementia following COVID-19 (more on this in a subsequent blog post).
  8. There remains much to be learned about the neuro-invasiveness of SARS-CoV-2. While there is mounting evidence to support the capability of SARS-CoV-2 to be neuro-invasive in humans, animal studies suggest that the degree of neuro-invasiveness may be highly variant-dependent. However, these same animal studies suggest that neuro-invasiveness and impairment of smell do not result from the same process.
  9. Although it remains uncertain, circumstantial evidence is mounting that reducing the viral dose (amount of infecting virus one is exposed to) may lesson the likelihood of developing anosmia, and by extension, perhaps lesson the likelihood of other neurological sequelae of COVID-19. The ways to reduce viral dose are effective masking and enhancements to ventilation and filtration of air indoors.

As I conclude part I, keep in mind

  1. I may have missed some other studies out there that may be relevant to this discussion. Although I read clinical studies many hours each day, I know that I can’t possibly identify or read every study out there. If I have missed an important article, please bring this to my attention.
  2. I have done my best to summarize what I think we know to date. I am not an ENT specialist or neurologist. I may not have gotten every detail correct. I do feel that I have captured the big picture, but I welcome being corrected if I screwed up a detail. Further, no doubt we will learn much more over the coming months and years. That new information may further elucidate what is happening, or it may show that something I stated above is no longer correct. I will bring these new studies to your attention the best that I can, and certainly will point out clearly if anything I wrote above is no longer correct.

Part II of this series of neurological signs, symptoms and disorders associated with COVID-19 will be forthcoming next week. When we complete the review of neurological problems, I will move on to cardiovascular signs, symptoms and disorders associated with COVID-19. Until then, be safe!


[1] https://jamanetwork.com/journals/jamaneurology/fullarticle/2790735.

[2] https://www.nature.com/articles/s41598-022-09731-7#:~:text=The%20impact%20of%20SARS%2DCoV,dendritic%20spines%20within%20the%20hippocampus.

[3] https://www.biorxiv.org/content/10.1101/2022.08.31.505985v1.

The Pathogenesis of Long COVID

We are well into my blog series on the health consequences of COVID-19 to survivors, including long COVID or PASC. In prior parts of this series, we have discussed what long COVID or PASC is, the fact that not all health consequences from infection with SARS-CoV-2 fit within this category, the potential magnitude of the problem long COVID or PASC, and in my last blog piece we dived into the pathogenesis and pathophysiology behind COVID-19 as preparation for this and my next blog piece that will delve into what we know about the possible pathogenesis of long COVID and the other health consequences that we see in some people who have recovered from COVID-19, many of whom had “mild” infections.

Before we do, I already have an update. A pre-print article (not yet peer-reviewed or published in a scientific journal) was released just two days ago from the day I am writing this. https://doi.org/10.1101/2022.05.26.22275532. This article is titled: A global systematic analysis of the occurrence, severity and recovery pattern of long COVID in 2020 and 2021. So, as we jump in, let’s put our science hats on and remember the information I presented to you earlier in this blog series about interpreting clinical studies. The first point to note is that this article examines cases of long COVID across the world. This should already raise two concerns for us. First, there is not yet a clear, consistent, or globally agreed upon case definition for long COVID or a diagnostic test or criterion (in other words, this remains a diagnosis of exclusion):

World Health Organization (WHO) clinical case definition: (It refers to long COVID as post-COVID-19 condition). Post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, and cognitive dysfunction but also others and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time.

US Centers for Disease Control and Prevention (CDC): Post-COVID conditions are a wide range of new, returning or ongoing health problems people can experience four or more weeks after first being infected with the virus that causes COVID-19. Even people who did not have COVID-19 symptoms in the days or weeks after they were infected can have post-COVID conditions. These conditions can present as different types and combinations of health problems for different lengths of time.

UK National Institute for Health and Care Excellence: (1) Ongoing symptomatic COVID-19 for people who still have symptoms between 4 and 12 weeks after the start of acute symptoms; and (2) post-COVID-19 syndrome for people who still have symptoms for more than 12 weeks after the start of acute symptoms.

Allow me to point out some of the fine points of differences:

  1. WHO: requires a history of probable or confirmed COVID-19.

CDC: acknowledges that long COVID can occur in people who had asymptomatic COVID-19 or may have had mild symptoms, but were not diagnosed as having COVID-19.

UK: Implies that the person must have had symptomatic COVID-19 with references to “ongoing symptomatic” and “still have symptoms.”

  • WHO: long COVID symptoms occurring 3 months from onset of infection and lasting at least 2 months.

CDC: long COVID symptoms four or more months after infection, but without specifying duration.

UK: long COVID symptoms are those persisting from initial infection for more than 4 weeks or the development of new symptoms characteristic of post-COVID-19 syndrome lasting more than 3 months following infection.

Thus, looking at the authors’ criteria for what they consider to be long COVID will be critical and depending which case definition is used, it may artificially limit the number of people who are included as cases- in other words, there is a risk that this will undercount cases. Second, we must remember that health systems vary greatly from country-to-country, with some having nationalized health care systems that have robust health records of their entire population (e.g., U.K., Israel) and others that have almost no health care infrastructure and are unlikely to have complete information on their populations. Thus, we run the risk of undercounting cases in developing countries, simply because they don’t have the public health infrastructure to test and identify cases, but in those countries, we also may face the risk of disproportionately high cases if they are able to be identified due to the fact that they were likely unvaccinated, resulting in more wide-spread infections, which will mean more of the population was at risk for long COVID. Finally, the time frame of 2020 and 2021 means that this will not include large numbers of infections from the various omicron surges and thus, if there are a large number of resulting cases of long COVID from omicron infection, those will not be included in this study.

This study is a cohort study (see my earlier blog post on understanding clinical trials) conducted in ten countries based upon the occurrence of three major symptom clusters of long COVID among representative COVID cases, but they use a meta-analysis methodology, which means that the authors are gathering their data in large part from published studies, and while this is an important tool and can provide very important insights, we have to remember that differences in definitions or methodologies in each of the studies can also introduce error. We should also be cautious about generalizing the occurrence of long COVID in ten countries to the rest of the world, in identifying long COVID cases by three major symptom clusters (they use the three major groups of symptoms identified by WHO, but we will need to keep in mind that long COVID patients often will not fit nicely into one of these three symptom clusters because many will have overlapping symptoms and others will have symptoms that don’t fit neatly in any of the symptom clusters) and their reference to COVID cases (which raises the concern that they are only looking at symptomatic cases that were identified, diagnosed and reported, which will exclude cases that occurred, but were not diagnosed or reported as well as asymptomatic cases unless we see that they identified cases based upon serologic testing).

They defined their symptom clusters based upon the WHO clinical case definition (so that is good) and they came up with fatigue, cognitive problems and shortness of breath as their three clusters (so this could leave out many patients who do not have these symptoms, but have symptoms or conditions that we do currently believe are the result of SARS-CoV-2 infection (e.g., new-onset diabetes, postural orthostatic tachycardia syndrome, etc.), unless they also identify as having one of these other three symptoms. The authors also use in their criteria for inclusion, the duration of symptoms for at least three months. I don’t find that overly problematic, other than keep in mind, many other studies use one month or two months, so this will simply create some difficulties in comparing studies if there are a significant number of cases of long COVID or PASC that resolve themselves in this time-frame.

The results are based on “detailed information” on 1906 community infections (a really low number from 10 countries during this almost two year period) plus 37,262 cases published in the literature (total 39,168) and “detailed information” on 10,526 hospitalized patients (so, we can see that the results are going to be skewed towards sicker (and likely older) patients, when we have a lot of information to suggest that many patients with long COVID had “mild” infections and were not hospitalized) plus 9,540 published hospitalized cases (total 20,066). In addition, the authors indicate that they had medical record information data concerning 1.3 million infections. So, ultimately, the authors do get to a large number of cases.

The authors find that in 2020 and 2021, there were 144.7 million cases of long COVID fitting into one of the three symptom clusters, corresponding to 3.69% of all infections, with 51.0% of these people with long COVID suffering from fatigue, 60.4% suffering from respiratory symptoms and 35.4% suffering from cognitive problems (so, we see that the long COVID patients identified in this study do have symptoms that overlap among clusters since the total adds up to > 100%).

Interestingly, the authors find that those with milder acute COVID-19 infections recovered from their long COVID symptoms (median 3.99 months) than those with long COVID following hospitalization (median duration 8.84 months). However, at one year, 15.1% of those with long COVID continued to experience symptoms.

Interestingly, these authors also found what has been previously reported in terms of a female predominance in long COVID – 63.2% (see below why this is interesting).

The risk for long COVID after COVID-19 that did not require hospitalization was:

  • 2.73% in children
  • 4.76% in adult males
  • 9.88% in adult females

Alarmingly, the peak ages for developing long COVID-19 were in those young adults who probably were not concerned about risk for hospitalization or death from COVID-19 – those ages 20 – 29 (this is lower than some earlier studies, which seemed to find the highest risk among those in their thirties and early 40s).

However, do not be deceived by the references to the symptoms, which for those unaffected, might think, these are no big deal. The average disability score reported was 0.231 – equivalent to moderately severe traumatic brain injury!

Despite the limitations of this study, we once again can see that for many people, COVID-19 is not merely a cold or the flu, and that they can suffer significantly for extended periods of time. Unfortunately, this study was not designed to answer the question as to how much protection the COVID-19 vaccines provided against long COVID. It also does not answer the questions as to whether infections with different variants are more or less likely to result in long COVID and whether early treatment (with antivirals or monoclonal antibodies) was effective in reducing the risk for long COVID. Notice also, that this study was not designed or intended to assess health outcomes for this population over time.

So, now let’s proceed with our discussion about the pathogenesis of long COVID. First, let me point out that SARS-CoV-2 is not the first virus to cause a post-acute infection syndrome. There is a nice review of post-acute infection syndromes at https://doi.org/10.1038/s41591-022-01810-6. While we do not fully understand the pathogenesis of these post-acute infection syndromes (PAISs), there are some similarities in many cases caused by very different pathogens, suggesting that perhaps there are common etiologies at play.

While PAISs appear to affect only a minority of patients who suffer acute infection, that can still be a huge number when you consider how many people the pathogen infects, and we also know that many patients go undiagnosed due to the nonspecific nature of their symptoms, inadequate access to expert medical care, imprecise case definitions for the specific PAIS, and the fact that most of these PAISs do not have an identified marker of disease (in other words, a specific test that confirms or rules out the presence of the PAIS in question).

Common shared symptoms among sufferers of PAISs include exertion intolerance, disproportionate levels of fatigue, neurocognitive and sensory impairments, flu-like symptoms, unrefreshing sleep, myalgia (muscle pains)/arthralgias (joint pains) and a plethora of nonspecific symptoms, however, the relative frequencies of these symptoms following different acute infections appears to vary in a manner that may reflect the underlying tropism of the pathogen causing the infection and/or the pathogenesis of the acute infection.

One condition that has now been recognized as a PAIS from certain infections including SARS-CoV-2 is myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). I remember being in practice and seeing patients that would ultimately fit this diagnosis, but before this condition was identified or it was understood what was causing it, though we suspected many were experiencing this as a consequence of Epstein Barr virus infection. The patients I saw had their lives upended, both in the normal activities of life that most of us take for granted, but also their ability to work or work as effectively as they previously did. Characteristically, these patients will have systemic exertion intolerance along with chronic fatigue that is unresolved by rest or sleep. Importantly, whereas we often prescribe physical therapy, rehabilitation and conditioning for persons who are recovering from many conditions in a weakened state, these patients often experience a worsening of their symptoms following physical, cognitive and emotional exertion and exercise actually poses the risk of a decline in their condition.

Patients with ME/CFS may have other prominent features of their illness including neurocognitive impairments (such as impaired memory, impaired concentration or what is colloquially referred to as “brain fog”), pain, sensory disturbances and various forms of dysautonomia (we’ll discuss this in a later blog post).

One can understand that given the pandemic with COVID-19 is still unfolding and changing, we might not have good data on prevalence and the prognosis of long COVID, which is certainly the case. But, we don’t really have good data on any of the PAISs, despite having seen these cases for decades. This may be for many reasons – no precise case definitions or diagnostic tests, no required reporting to centralized data bases, and likely, no significant funding devoted to research of this kind. This is unfortunate, because given our suspicion that there are likely common etiologies of the pathogenesis resulting in these PAISs, since we tend to see similar PAISs with differing pathogens, had there been more robust research over the past decades, we might have a better understanding of the pathogenesis (and therefore potential treatments) of long COVID by now, as well as answers to a very important question as to why some people recover from these illnesses apparently just fine, but others develop these PAISs.

We do have some data from adolescents and young adults who developed ME/CFS following infectious mononucleosis (these are most often the result of Epstein Barr virus infection; but in a small number of cases can be due to cytomegalovirus infection). Some studies showed that of approximately 30-40 percent of patients with persisting symptoms following infectious mononucleosis, most would recover over time with a drop to 8 – 14 percent still symptomatic at 6 months and 7 – 9 percent at 1 year. Another study showed that 4 percent were still symptomatic at 2 years, but we have no idea why those in these studies developed ME/CFS, why most improve, and why some remain symptomatic.

West Nile virus can also lead to persistent symptoms. A study that followed persons infected in Texas over 8 years found that the frequency of persistent symptoms seemed to depend upon which form of disease people got – West Nile-related fever vs. West Nile meningitis or encephalitis. Again, there tended to be a number of patients whose symptoms resolved over a 2-year period, but with this infection, there was a much higher level of patients with persistent ongoing symptoms – 40 – 70% of those with persistent symptoms following their initial infection remained symptomatic past the 2-year mark.

On the other hand, we do see PAISs in some infections, such as Q fever and Lyme disease where we see little improvement, if any, over many, many years.

Fortunately, as reported above, as well as in a number of other studies, although we do see patients with thus far persistent long COVID, we do see improvement, and in some cases, resolution of their symptoms in many patients over the course of months to a year or so.

So, what do we know about the pathogenesis of other post-acute infection syndromes? Not much. Mostly, we just have hypotheses (educated guesses). What are those hypotheses:

  1. Persistence of the pathogen that either is in such low levels as to escape our currently available tests or the residence of these pathogens is in places of the body where they can escape our detection. (This is one of the potential etiologies for long COVID and there is some evidence that we will discuss in the next blog post). Persistence of pathogens, or even remnants of the pathogen (in the case of SARS-CoV-2, RNA from the virus, which is no longer infectious – this is why a PCR test may remain + for weeks or months after your acute infection has resolved and you are no longer contagious) may provide antigenic stimulation for the body’s immune system. The residual virus or remnants of the virus that are still recognized as antigens generate pathogen-associated molecular patterns (PAMPs), which can continue to stimulate the innate immune system, which in turn leads to ongoing inflammation, as well as chronic stimulation of lymphocytes as part of the cellular immune system, that can lead to T-cell exhaustion and a diminishment of the immune modulation role that T-cells play in preventing the immune response from becoming overly exuberant and causing more harm than good.
  2. Autoimmune reactions. When a pathogen enters our body, our immune system tries its best to specifically target the pathogen with the antibodies it produces and the T-cells that are activated. However, infections involving certain tissues may induce local innate immune responses that can trigger T-cells to be directed at so-called “self-antigens,” antigens that belong to our own cells and tissues and not the pathogen. Other pathogens exhibit “molecular mimicry,” that is to say that the antigens belonging to the pathogen are so similar in their molecular structure to naturally occurring antigens in our own bodies that our immune system is tricked into attacking our own cells believing that they are those of the pathogen (this is believed to be one possible mechanism by which insulin-producing cells of the pancreas are destroyed resulting in diabetes). There is evidence that autoimmunity plays a role in the development of severe COVID-19 and thus, reason to believe it could be playing a factor in the development of long COVID. Interestingly, for reasons unknown to me and I think others, women seem to be at higher risk than men for the development of autoimmune disorders (conditions like lupus, scleroderma and rheumatoid arthritis), and it is then interesting to consider that most studies do show a female predominance among those that develop long COVID. My suspicion is that there are genetic predispositions accounting for some or all of this, though the influence of hormones has not been ruled out. We will discuss the evidence for autoimmune antibodies caused by COVID-19 in my next blog post.
  3. Another hypothesis is that the pathogen and/or our treatments of it disrupt the normal balance of bacteria and viruses in our body, causing disruption of various physiologic processes in our bodies. We do see cases where infection with one pathogen disrupts the normal immune processes that keep other latent viruses in check such that they are reactivated. Generally, these latent viruses are DNA viruses such as Epstein Barr virus, cytomegalovirus, and herpes simplex virus (remember that SARS-CoV-2 is a RNA virus). Many people who have been plagued by recurrent sores and blisters on their lips, tongue, roof of their mouths and gums have herpes simplex virus type 1. They will tell you that it erupts, then comes under control and then can erupt again weeks, months or years later. Often, they will note that reactivation occurs at a time of another illness (leading many to call these cold sores, or at a time of significant stress, both situations that can temporarily weaken our immune systems). Another example, in those of us who were infected with chickenpox as children, is that we never really get rid of that virus (varicella zoster virus), rather it becomes what we call latent (basically hanging out in our peripheral nervous system, but not actively reproducing and causing the chickenpox lesions on the skin) and our immune system helps keep it in check. However, as we age and our immune system becomes “senescent” or if we develop an illness that causes compromise to our immune system or we are treated with medication that can suppress our immune system, the varicella zoster virus can reactivate and when it does, it is manifested as shingles. The same thing can happen with certain infections. They may cause our immune system to be so focused on this new infection, that it lets up its guard against these latent viruses and they can reemerge. This is another potential etiology in long COVID, as we have been able to demonstrate that in some cases of COVID-19, the Epstein Barr virus (EBV) that most of us were infected with when we were young, and our immune systems brought under control, but never fully cleared from our bodies, with the virus becoming latent or dormant, has become reactivated in some long COVID patients. We will review that evidence in the next blog post, but keep in mind, chronic fatigue resembling ME/CFS is common in long COVID and is also something we saw as a PAIS with EBV infections.
  4. Another proposed etiology is the tissue damage itself caused by the infection. Our bodies are amazing in their ability to heal, but not all injury can be healed. For example, while some cells and tissues can be repaired or replaced with new cells, others become scarred and non-functional. Certain of the variants of SARS-CoV-2 have had the ability to inflict such severe damage on lung tissue that some people have developed a disabling condition called pulmonary fibrosis, basically lung scarring. When this happens, the lung tissue cannot do its primary function sufficiently of transporting oxygen from the air we breathe into the capillaries of the lung beds that will then transport oxygen to our other tissues. In many cases, these people will require supplemental oxygen and you have probably seen some of these patients who require a portable tank of oxygen with tubing that fits around their ears going to their nose. In other even more severe cases, we have had patients have such bad pulmonary fibrosis from their COVID-19 that they required double lung transplantation.

Let’s look at the list of putative etiologies for long COVID:

  • Persistence of the virus in certain sanctuaries of the body (failure of the body to clear all of the virus produced during the acute infection resulting in an overly exuberant immune response).
  • Immunopathology (damage to the immune system itself) – either resulting from the initial infection or due to the persistence of the virus in the body and the resulting persistent antigenic stimulation.
  • Autoantibodies (damage caused to tissues by an aberrant immune response)
  • Micro-clotting and the resultant damage to tissues by reducing oxygen delivery to those tissues.
  • Reactivation of latent viruses, such as EBV.
  • Damage to the nervous system and other tissues resulting from direct infection and the resulting immune response.

What remains unclear is whether all of these play a role in all persons or whether different etiologies or combinations of etiologies occur in different people that in turn account for the myriad presenting symptoms we see in patients with long COVID. Further, we don’t yet know whether the risks for long COVID are additive with each reinfection, or potentially orders of magnitude increased by reinfection.

In my next blog piece, we will examine the evidence that we have for these etiologies and discuss some ways that these abnormal reactions have impacted some patients with long COVID.

Pathogenesis and Pathophysiology of COVID-19 and Long Term COVID-19 Health Consequences

We are well into my blog series dedicated to my mother (Hi Mom!) about the long-term health consequences that may face those who were infected by the SARS-CoV-2 virus and survived – a topic on which there is little discussion in the lay press and media. And, to some extent this is understandable, because frankly, there is much we don’t know, and much of what we do know just keeps raising more questions. Oftentimes, doctors and scientists are reluctant to wade into these areas where we have more questions than answers because they are worried about being proved wrong with time or being labelled a fear monger. I, too, share some of this reluctance, however, I believe that people need to understand all the risks and potential risks as we know them so that they can make their own risk calculations as to what precautions they feel they should take to protect themselves and others. Unfortunately, the focus only on hospitalizations and deaths has caused many people to take risks that they might not have had they fully understood the long-term consequences to their health that might be possible even with relatively mild infection. I also believe that my readers are capable of understanding the limits to the information that I am providing to them, and we will discuss some of those limits below.

We started with mini-tutorials on virology, immunology and clinical studies. This will help prepare you to understand the rest of this blog series at a deeper level. In the last blog piece, we discussed what is Long COVID and the potential magnitude of that problem. Now we are going to discuss the pathogenesis (how an infection results in disease and how that disease manifests itself) and pathophysiology (the biologic processes by which the virus is able to cause disease) of COVID-19. We will start with what we currently understand about how the SARS-CoV-2 virus causes COVID-19 and then in the next blog piece, we will turn to what goes wrong that appear to be factors in why some people develop long-term consequences to their health following what seems to be recovery from the initial infection, including Long COVID or PASC.

Before digging in, let’s cover my disclaimers:

  1. We are learning more every day about these subjects. I have trouble keeping up with all of the developments myself, even with all the time I dedicate to reading articles and clinical studies each and every day. So, keep in mind that new studies may provide more light on what I am going to cover below, which is based on what we know today, literally today. That new light may correct, modify or further elucidate the information below.
  2. I am going to do my best to assimilate huge amounts of data and clinical studies together for you below, but I cannot cover everything, and some of the information is just so complicated that I may choose to not cover it if I don’t think it will be of general interest, or I may have to simplify it a bit in order to not loose my audience, but as you can understand, when I simplify complicated material, there will be some lost nuances and risk for some technical inaccuracies. Afterall, my goal is not to make you experts, but rather to make you more informed with a much better grasp of this information for which there is little public awareness.
  3. When we discuss pathogenesis and pathophysiology, it is important to understand some of these disease processes are different in different aged people. I am a general internist- that means an expert in diagnosing and treating diseases in adults. I learned a long time ago that kids are not little adults, medically speaking. They are a completely different species. Most of what we know about pathogenesis and pathophysiology is from studying adults. Some of this information will apply to children; some will not. When I do not specify otherwise, the information below is what happens in adults, and it may or may not occur the same way in children.
  4. In addition, as you will learn, if you didn’t already know it, disease processes can also be different in the elderly compared to young adults in their 20s, 30s and 40s. One explanation for this is that the immune system ages- so-called immunosenescence – and this plays a huge role, though not the only role, in why we have seen the worst COVID-19 outcomes (hospitalization and death) impact the elderly disproportionately.
  5. Besides age, disease processes are also different in different people depending on their general health, the presence or absence of other chronic medical conditions, their pre-infection functional status, and can even be different based on which variant they have been infected with and how much virus they were infected with (a story largely missed is that one of the greatest benefits of wearing a mask may merely be the reduction in the amount of virus that you inhale, which appears to result in milder illness, at least for our earlier variants). Further, your prior exposures and your genetics may greatly influence the disease you get and the way it manifests for better or for worse. There are hundreds of proteins, cytokines, chemokines, receptors, and cells involved in the response to the entry of SARS-CoV-2 virus into your body. Many of these trigger genes that comprise your genetic make-up to be turned on or off, and a genetic defect that you would be unlikely to know about can impact how and how effectively your body reacts to the virus. We also must appreciate that there are millions of Americans who have an immune deficiency (e.g., their bodies may not make certain types of antibodies or immune cells) or who are otherwise immunocompromised (cannot mount a normal and effective immune response due to an underlying disease or because of medications used to treat the underlying disease). Their disease processes will also be very different, and I will not be going into depth on how those disease processes are different in this blog piece.
  6. Finally, a warning. In medical school, we joked about “sophomore-itis.” That is to say that in our second year of medical school, as we began to get much more into the study of diseases, it was not unusual for students to begin thinking they might have that disease we were studying. I know many readers are looking for understanding of their own health issues following COVID-19. I just want to be clear that what we will review may or may not apply to your individual situation. This will especially be true as we get further into this blog series where we are discussing specific conditions resulting from COVID-19. In a blog, I simply cannot provide you with the depth of information that a physician must use to make actual diagnoses. Please do not diagnose yourself, especially from merely reading my blog. Instead, use this to better inform yourself and better inform the questions that you want to discuss with your physician when you see him or her for evaluation and follow-up.

Here we go. We are starting with the pathogenesis and pathophysiology behind the development of COVID-19 (the acute infection).

So, it all begins with someone being infected with the SARS-CoV-2 virus, whether they know it or not. Keep in mind that one of the reasons this pandemic has taken off and been so difficult to control is the fact that people can be infected and shedding infectious virus from their mouth and nose for up to several days prior to the development of symptoms or testing positive for COVID-19. The person who has infectious virus in their nose and throat will expel that virus into the air with breathing, talking, laughing, yelling, singing, coughing and/or sneezing. If a susceptible person is in a room, choir hall, auditorium, lecture hall, office, lunch or break room, restaurant, classroom, or other indoor area that is served by the same air supply and ventilation system, very small aerosols of the infectious virus will be suspended in air and carried across the room from the source (infected person) to the air return. When you have heard of super-spreader events, it is almost always this mechanism of transmission at play. (Super-spreader events can also occur outdoors when people are crammed closely together such as a sporting event, concert or rally.)

With very poor ventilation and air circulation, the virus can remain suspended in air for more than an hour. We can greatly mitigate this risk of so-called aerosol transmission by increasing the number of air exchanges per hour so that the virus is not allowed to remain suspended in the air so long. In addition, we can decrease the chances of infection by not recirculating the air, or if the air is recirculated, by adding filtration designed to trap virus particles, such as HEPA filters.

Another way to be infected is through larger respiratory droplets. This can occur when you are in close proximity to the infected person and this can be either indoors even with fairly good ventilation and filtration or outdoors. Obviously, the closer you are and the longer amount of time you are in contact, the higher the chance of transmission. However, do not get confused by the CDC definition of close contact, which is criteria (less than 6 feet for at least 15 minutes over a 24-hour period) for who would be subject to contact tracing – these are not the criteria for determining whether someone is at risk for being infected. You can be infected in far less than 15 minutes (the time can vary, but if someone has a high viral load [the amount of virus in their nose and throat] and you are indoors in the same room unmasked or not wearing a high-quality mask correctly or in close proximity to that person either indoors or outdoors, transmission may take place in less than a minute, especially with our more recent highly transmissible variants of concern). You also can be infected at a greater distance, especially if the infected person is coughing vigorously, yelling, singing, or otherwise projecting their voice.

As the virus enters a person’s nose or throat (and reportedly the conjunctivae of the eyes), the virus will seek out cells that have the appropriate receptor that will allow it access to the inner workings of the cell. We sometimes describe viruses by the tissues that contain the necessary receptors that will allow the virus cell entry and are targets for infection as tropism. For example, rabies, polio and California encephalitis viruses are neurotropic, in that they can infect the brain and cause disease with neurologic features. Some viruses have very limited tropism and cause characteristic diseases that are limited to a specific tissue or organ of the body. On the other hand, we shall see that SARS-CoV-2 has wide-reaching and varying tropism that allows it to infect many different tissues and organs resulting in a variety of disease manifestations. Of course, just because a virus has a number of tropisms, does not mean it will cause those infections and disease manifestations in everyone. For example, the polio virus enters the gastrointestinal system, and in most people causes asymptomatic or minor illness. However, in some unfortunate individuals, the poliovirus does make its way to the nervous system and can cause paralysis, weakness and disability. We will find that the same multi-tropism is true for SARS-CoV-2.

As we discussed in the virology and immunology tutorials, when we encounter a new virus for the first time, it is our innate immune system that does the heavy lifting in trying to fight the virus, providing the adaptive immune system (humoral [antibodies] and cellular) time to develop and design precision weapons. Recall that it takes 1 – 2 weeks to generate the full range of antibody response. Also recall that the antibodies cannot enter cells to combat the viruses that have already entered cells (we have to rely on our cellular immunity for that).

This is where vaccinated individuals have a huge advantage when they are encountering the SARS-CoV-2 virus for the first time. Vaccinated individuals already have a range of antibodies, including neutralizing antibodies, that can bind to the virus. In the case of the neutralizing antibodies, they target the receptor binding domain on the spike protein making it difficult, if not impossible, for the virus to attach to the ACE-2 receptor on a cell in order to enter the cell. In addition, you have heard a lot about T-cells, but there is another part of the cellular immune system called B-cells, cells that can be turned on to produce huge amounts of antibodies to a specific invader. When vaccinated, some of these B-cells become memory B-cells that will then already be primed with the instructions and machinery to produce large amounts of these specific antibodies, so while it can take a week or 10 days for an unvaccinated person to make these new antibodies in response to encountering the virus, these memory B-cells can crank out these specific antibodies in just a few days to augment what antibodies are already circulating.

Now when the virus is breathed in your nose or throat and does reach cells that have the ACE-2 receptors in your airways, the receptor binding domain on the spike protein will align itself with the ACE-2 receptor on the cell surface (imagine a space shuttle docking to the international space station). We believe that the better the fit and the stronger the binding between the virus’ receptor binding domain and the cell’s surface ACE-2 receptor (we call this binding affinity), the more the newly infected person will be able to infect others and the more severe disease the infected person is likely to get. Once attached, the membrane of the SARS-CoV-2 virus will fuse to the membrane of the cell and the cell will essentially engulf and swallow the virus. Think of a cell like an egg that you have cracked open and poured into a skillet. The yellow part of the egg would be the analogy to the nucleus of the cell. The white part of the egg is the analogy to the cytoplasm of the cell. The virus is now in the cytoplasm of the cell. This is where the cell keeps its machinery to produce proteins, in ordinary conditions according to instructions that originate in the DNA in the nucleus of the cell that are copied by RNA and then the cell’s messenger RNA (mRNA) will take that message from the nucleus to the cytoplasm to the cell’s machinery (ribosomes, endoplasmic reticulum and Golgi apparatus) that will produce proteins needed by the cell according to those instructions.

However, once the cell is infected, the virus takes control of the cell’s protein-making equipment and instructs it according to the RNA of the virus, to make viral proteins and particles. As these come off of the production line of the cell’s machinery, the pieces are assembled to create new complete viruses that can be released from the cell to go out and infect other cells. Since each time a virus successfully enters a cell, it results in the production of many progeny, you can begin to see why minimizing the time we are in proximity to someone who is infected and shedding infectious virus, being outdoors or having good ventilation indoors to minimize the number of virus particles suspended in air that we might breathe in and wearing a well-fitting high grade mask will all serve to help protect us from getting infected, but even if we do get infected, it will minimize the number of invading viruses (the viral dose). With a lower viral dose, we have a better fighting chance. Our tears, our nasal secretions and saliva all play roles in decreasing the numbers of virus particles that get through to invade our bodies. Then, our innate immune system kicks in, and you can see how we are advantaged if we have already been vaccinated and have antibodies at the ready that can attach to the spike protein and prevent or impede the ability of the virus particles to successfully bind to the cell surface ACE-2 receptors. The more virus particles that are prevented from entering cells, the fewer new virus particles produced. Remember from above, even if the antibodies don’t completely block the virus from entering the cell, if they just make the fit less tight between the spike protein (receptor binding domain) and the ACE-2 receptor on the cell due to the physical interference from the attached antibody, it appears that the newly infected person will be less likely to transmit the virus to others and is likely to have milder disease.

Now, we are going to back and fill in some more details, because in many cases, it appears that the hyper-inflammatory and dysregulated immune response to the infection may be causing more of the damage to the body than the direct viral infection of cells. This likely helps to explain why we see such a range in illness from those who are asymptomatic or mildly ill to those who end up on ventilators in the ICU and even die. Of note, though co-infections have been reported (e.g., infection with both SARS-CoV-2 and influenza virus or SARS-CoV-2 with Respiratory Syncytial Virus), we will not be discussing the impact of co-infection in this pathophysiology review. Further, another complication of severe COVID-19 and its treatment can be superinfection (i.e., a subsequent bacterial or fungal infection that occurs during the treatment of the COVID-19 infection – the latter was a big problem in India), and similarly, this pathophysiology review will not explore the implications of such an additional infection.

To further understand how SARS-CoV-2 infection can result in severe COVID-19 in some people, we must examine more closely the hyper-inflammatory state that can be induced and the immune dysregulation that can occur. First, we examine the innate immune system reaction to the virus.

Our innate immune system is on guard for either bacterial or viral invaders. You likely have experienced the consequences of the former if you have ever had an infected cut or strep throat – pain, swelling, and soreness – evidence of our body’s innate immune system reacting to the bacterial invader and trying to stop it. We have already discussed the ACE-2 receptor on the cell surface to which the SARS-CoV-2 virus binds in order to enter cells. Humans have at least 10 different “toll-like” receptors (TLRs) that bind to various types of molecules that are commonly associated with bacteria, viruses, fungi and protozoal parasites. One in particular (TLR 4), binds to lipopolysaccharide (LPS) (a common structural component of bacterial cell walls made up of a fat and a sugar), and when LPS binds to it, it signals the release of inflammatory chemicals (cytokines – a wide variety of pro- and anti-inflammatory factors such as interleukins (I will refer to those as IL followed by a number to indicate which specific interleukin), tumor necrosis factor (TNF), and interferons (I will refer to those as IFN followed by a Greek letter to indicate the specific interferon) and chemokines – a subset of cytokines that have the special function of “chemotaxis” – attracting specific white blood cells to come to the site of invasion to assist in killing the invaders). Keep in mind that the SARS-CoV-2 virus enters the body at sites that already have bacteria lining the surfaces (nose, throat, and perhaps the gastrointestinal tract), and as I mentioned above, some people, especially when they require treatment in the hospital with steroids can develop superinfections with bacteria. Further, there can be LPS in the blood due to the fact that our bodies are constantly fending off bacterial would-be invaders. It turns out that the spike protein of the SARS-CoV-2 virus can bind to LPS and together this can interact with TLR 4 to cause release of cytokines and chemokines that can cause inflammation and recruitment of certain white blood cells that cause further damage to the cells and tissues where the virus is invading. https://pubmed.ncbi.nlm.nih.gov/33295606/ and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347018/.

As you will see with this blog series, the immune system is made up of many components that under normal circumstances, strive to maintain a balance between responding enough to successfully thwart an invader, but not too much that an overexuberant response will harm the host (the body’s effort to ensure that the “cure” is not worse than the disease). There are many ways in which the SARS-CoV-2 virus can tip the scales in terms of promoting overreaction by the immune system, and this binding of the SARS-CoV-2 virus with LPS that stimulates an exuberant reaction is just one example. The one good thing that comes from this release of cytokines is that they specifically activate helper T-cells (CD4+), which enable the development and production of more and better SARS-CoV-2 specific antibodies.

Unfortunately, this is not the only mechanism whereby pro-inflammatory cytokines are released, and in fact, when excessive, we refer to this as cytokine storm, a condition of excessive inflammation that renders patients critically ill. This “cytokine storm” or similar phenomenon is common in our COVID-19 ICU patients and in children that develop MIS-C (Multi-System Inflammatory Syndrome – Children), except that it occurs with the acute infection in those in the ICU and occurs weeks to months following the acute infection in children.

I made reference to certain white blood cells above. There are many kinds of white blood cells and they have differing functions, but there are four types that are important for our discussion in this blog series – lymphocytes (these include, among others, T-cells and B-cells), monocytes (specialized cells that play a large role in attacking invading viruses, bacteria, fungi and protozoal parasites, breaking them down and ridding the body of them), neutrophils (white blood cells that we typically associate with bacterial infections, but ones that get recruited to the scene of infection with SARS-CoV-2 in certain instances in response to specific chemokines and then wreak havoc) and macrophages (cells that detect, engulf [phagocytose] invaders and present the antigens of the invader to T-cells to assist with the cellular immune response to the invading would-be pathogen).

We all have macrophages in our lungs to clean up debris and to go after any bacteria or viruses that get past our upper airway defenses to settle into our lungs and attempt to cause infection of the lungs. Within the cytoplasm (remember, that is the white of the egg in our analogy of a cell) of the macrophages are inflammasomes – sensors that trigger the release of pro-inflammatory cytokines and proteases (enzymes that degrade certain proteins, such as elastase, collagenase, cathepsin and metalloproteinase). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519035/.

Initially, we focused on the cells in our nose, throat, nasopharynx, airways and lungs as sites of infection where the SARS-CoV-2 virus was entering and causing all this damage directly or indirectly. Then we became aware that the virus was invading many other cells, including those of many of our organs, but also endothelial cells (the cells that line our blood vessels). Most recently, we have learned that the virus can even infect the immune cells that are responding to fight the virus! Few other viruses do this. (I hope you are beginning to see that COVID-19 is not just like a cold or the flu).

This is likely difficult for you to understand (but I will help you over the course of the remainder of the blog series), but as a consequence of all of this, in some patients with COVID-19 (and it appears that parts of this are not just limited to those who get severely ill), there are paradoxically two things going on at the same time – the immune system goes into overdrive trying to fight off the invading virus, while the immune system also becomes somewhat dysfunctional resulting in potential harm to the body. (more on this latter)

Now, back to our macrophages (these are those scavenger white blood cells that are attracted to sites of infection by chemokines (https://pubmed.ncbi.nlm.nih.gov/25359998/). As mentioned above, there are some macrophages that take up residence in our lungs and stay on duty, cleaning up debris and fighting any infection that can bypass the defenses of our upper airways.

A recent study (https://www.nature.com/articles/s41586-022-04802-1) describes a cascade of events that begins with infection of these lung macrophages by the SARS-CoV-2 (this was very surprising to me), but fortunately little replication of the virus within macrophages occurs (probably because unlike lung cells that can efficiently produce virus when infected; macrophages are designed to engulf and destroy viruses and the inflammasome pathway is a critical piece of this ability to do so). However, the viral replication that does occur within the macrophages activates inflammasomes within the macrophages (remember, these are the sensors that in turn trigger the release of pro-inflammatory cytokines (including IL-1β and IL-18, the latter has been associated with severe COVID-19) and proteases (enzymes that degrade certain proteins). Another unfortunate consequence of this exuberant response to infection is that this kind of inflammation actually triggers a programmed cell death of the macrophages (pyroptosis) – in essence, the cell being pre-wired with explosives to blow itself up if the enemy takes it over. While the inflammasome activation is important to fighting viruses that get down to the lungs, the excessive inflammation that results may be one of the keys to the excessive inflammation that typifies Long COVID as well as the lung damage that can result in lung scarring (fibrosis) and has resulted in so much damage that some people have even required lung transplantation following their recovery from the acute infection.

Macrophages are not the only immune cell that can be infected by the SARS-CoV-2 virus https://www.nature.com/articles/s41586-022-04702-4. I mentioned above in the short list of types of white blood cells that we will discuss because of their role in the pathogenesis of COVID-19 – monocytes. Monocytes are another type of white blood cell that plays an important role in innate immunity, being on the prowl for evidence of an invading virus. They, too, form inflammasomes that signal infection, trigger pyroptosis and lead to the release of potent cytokines, but rather than being stationed in tissues, like the lungs, monocytes circulate in the blood. The authors of this study demonstrated that up to 10% of monocytes were infected with SARS-CoV-2 in patients presenting to the emergency room for evaluation of their COVID-19.

The mechanism by which the virus enters monocytes is different than the mechanism by which it infects cells lining the airways and lungs (monocytes do not have ACE-2 receptors on their cell surface). Monocytes have different receptors that recognize antibodies attached to the virus, which causes the monocytes to attach to the virus-antibody complex in their effort to kill the virus and clear it from the body. However, with SARS-CoV-2, this binding could result in the monocytes themselves becoming infected. This is a form of antibody-mediated disease enhancement (ADE). Ironically, some physicians who spread disinformation have alleged that ADE is a significant risk with COVID-19 vaccination (which it is not), but in fact, we do see this phenomenon in these cases of infection.

This may be important not only for its role in further aggravating the inflammatory state by triggering the release of many more cytokines, but we have wondered how the SARS-CoV-2 virus gets to so many internal organs once it enters the lungs. Some viruses have a viremic phase (transient period of actual virus circulating in the blood). That may be the case for SARS-CoV-2, but as far as I am aware, we have never identified that. An alternative explanation may be that the virus is being carried by these infected immune cells that do circulate in the blood, do travel to various organs and in some cases, do take up residence in lymphoid tissues (such as your tonsils, gut and lymph nodes).

There is another remarkable thing these investigators discovered. The monocytes only took up the virus that was attached to antibodies from infection (the range of antibodies resulting from infection and from vaccination are very different); not when the antibodies were generated by the mRNA vaccines. This may be another reason why those who develop severe COVID-19 tend to be the unvaccinated. I have a relative who told me that his antibodies resulting from infection were much better than mine resulting from vaccination. Turns out, he may be wrong for several reasons.

Cytokines, and especially IL-8, attract neutrophils, a type of white blood cell that we typically see attack and kill bacteria. In the case of the cytokine storm, we see many neutrophils attracted to the sites of infection, like the lungs. IL-17 then activates the neutrophils. Activated neutrophils can release proteins that promote programmed cell death of the lung cells (apoptosis) and that contribute to immunological stimulation of blood clotting.

There are other changes to immune cells that we will discuss later in this blog series, but the direct infection of certain immune cells, as well as the resulting pyroptosis, may contribute to decreases in white blood cell counts that have been associated with more severe disease and worse outcomes. Lymphopenia (low lymphocyte count) is particularly associated with these worse outcomes and recall that lymphocytes encompass T-cells, B-cells and natural killer cells, among others.

Another key mediator of the body’s defense in fighting invading viruses is interferon. Interferon is very important to controlling the spread of the virus. Entry into certain cells by the virus will induce genes within the cell to produce and release this chemical messenger to surrounding cells. In essence, imagine thieves breaking into a house with the intent to go house-by-house up the street in the neighborhood to break into them, as well. When the first house (cell in this case) gets broken into (entered by the virus), an alarm system is triggered (release of Interferon) that notifies all its neighbors to lock their doors and windows, secure all entry points and put the deadbolts on. It doesn’t mean that those other houses (cells) can’t be entered, but it makes it much more difficult and slows the thieves (virus) down.

In addition, interferons can also interfere (get it?) with viral replication in the infected cell, this being a good thing to reduce the viral load that a patient is dealing with. Interferons, a type of cytokine, can also activate macrophages, cytotoxic T-cells (CD8+, these are the T-cells that attack and kill infected cells to prevent further replication of the virus as part of the cellular immune response) and natural killer cells (we haven’t discussed these yet. They are a specialized type of white blood cells – a subset of lymphocytes – that kill infected cells as part of the innate immune response. They do not need to be pre-programmed like the CD8+ cells of the cellular immune response by having seen and processed the antigens (the proteins that antibodies are designed to attach to) of the virus (e.g., the spike protein in the case of SARS-CoV-2). The natural killer cells recognize that cells are infected and they in essence puncture the cell wall of the infected cell and introduce a powerful enzyme causing the infected cell to implode.)

When you got a fever in the past with a viral infection, you probably have your interferons to thank for it. (In case you are interested, fever is itself a defense against many organisms that cannot survive higher temperatures or are slowed down in their replication by higher temperatures).

Interferons also play a major role in modulating the immune response (i.e., tying to make sure we kill the bad guy with the attack, but not all the surrounding innocent people and buildings). But, like most everything else we have discussed or will discuss, when anything in the immune response is too little or too late, we are in danger of the infection being uncontrolled; and when anything in the immune response is too much or too long, we are in danger of the immune response harming us. In fact, one of the hallmarks of severe COIVD-19 is a delayed, and then sustained interferon response. The delayed interferon response appears to be due to the replicating virus being packaged in membrane covered vesicles and spherules that prevent the innate immune sensors in the infected cells from recognizing the virus and also due to proteins on the virus, but not associated with the spike protein that suppress interferon production and hamper signaling to other cells. An appropriate interferon response is critical to limiting viral replication and dissemination and to limiting the programmed destruction of infected cells (apoptosis) in order to protect the host. https://journals.sagepub.com/doi/full/10.1177/10760296211021498 So, the next time you hear someone tell you that they think they are building up their immunity to COVID-19 by repeatedly getting infected with SARS-CoV-2 variants, you can now cringe like I do!

We still have a few more concepts we need to cover on COVID-19 pathogenesis. We will save the discussion about the pathogenesis of Long COVID and other health consequences of infection for the next blog piece, as all of this lays the ground work for that discussion.

We have discussed how the SARS-CoV-2 virus can trigger the release of an excessive amount of pro-inflammatory cytokines (e.g., IL-6, IL-8, IL-17, TNF-α and IFNϒ). These levels (as well as IL-2, IL-7, IL-10, granulocyte colony stimulating factor (G-CSF) https://www.ncbi.nih.gov/pmc/articles/PMC8311250/), have correlated with disease severity in COVID-19 and even death. Unfortunately, in those who develop severe illness, we find that some of the cytokines that are anti-inflammatory (IFNα/β) and IFNϒ are diminished and delayed in their release. Another marker in the blood of severe COVID-19 patients that we commonly test for in hospitalized patients is lactate dehydrogenase (LDH). LDH is commonly elevated when cells are destroyed and it can be evidence of pyroptosis that we discussed above.

Another element of the pathology of COVID-19 that has been vexing and unlike what we have generally seen with viral infections has been the development of both microclots (microthrombosis) and large blood clots that have in some cases blocked arteries (when you hear about a friend or family member having blood clots prior to COVID-19, these are almost always clots in veins. The difference is that if you block a vein, in many cases, your body will build redundancy around it so that it doesn’t threaten the viability of the extremity, but in the case of a clot to an artery, these can threaten the loss of the extremity in a matter of hours. Unfortunately, this has caused the need for amputation of limbs in some young adults with severe COVID-19). These larger blood clots have caused strokes, heart attacks, pulmonary emboli (blood clots that travel to the lungs) and even sudden death (often a massive pulmonary embolus).

When we have looked at lungs from patients who have died of COVID-19, it is not just the infection of the lung cells and the eventual destruction of the cells and resultant scarring (fibrosis) of the lungs, we see these very unusual microclots throughout the lungs. This is really important because your lungs are designed to breathe in oxygen from the air and then have that oxygen cross the thin air sacs of the lungs (called alveoli) into the blood vessels that abut them in order to oxygenate your blood. But, these microclots impede that oxygenation of the blood and this in turn can pose the risk that the organs of your body don’t get enough oxygen and are harmed.

We have covered a lot, but we need to explore one more concept and then we can move on in the next blog piece to discuss what may be the pathogenesis and pathophysiology leading to Long COVID and other post-COVID health consequences.

This last concept relates to the fact that there is a sequence of amino acids in the spike protein of the SARS-CoV-2 virus that functions as a “superantigen.” Antigens are the structural components of a foreign substance or pathogen that are recognizable by our immune system and that trigger the development of antibodies that are specific to those antigens. Normally, an antigen will stimulate the development of a single clone of B-cells and T-cells, and these clones will represent only a small fraction of all the B-cells or T-cells. However, “superantigens” stimulate 5 – 20% or more of all the T-cells. This large-scale T-cell activation and proliferation results in hyperinflammation and cytokine storm. Unfortunately, superantigens are also implicated in the development of autoimmunity (the production of an immune response against parts of the patient’s own body) by triggering self-reactive T-cells.

Summary

  1. COVID-19 can manifest itself differently in different people due to age, underlying health conditions, the particular variant involved, the viral dose, prior infection history and genetics.
  2. The infection is transmitted by aerosols and respiratory droplets.
  3. The virus first tries to make its way into the cells lining the nose, throat and nasopharynx by attaching to the ACE-2 receptors on the cell surface. If not stopped, the virus can move down the airways into the lungs. Vaccination plays a huge role in limiting the replication and dissemination of the SARS-CoV-2 virus, and thus, helping protect against severe disease.
  4. Infected immune cells prompt a massive inflammatory response that helps contain the SARS-CoV-2 infection, but can inflict harm on the host at the same time. Antibodies generated in response to prior infection, but not vaccination, can facilitate the entry of virus into monocytes, and these cells may play a role in transporting the virus to other parts of the body.
  5. We have known that hospitalization lags infection by about a week since early in the pandemic. The association of worsening clinical progression during a time in which we generally see declining viral loads, and the development of critical illness occurring at the time we generally see the adaptive immune response kicking into full gear and a significant increase in inflammatory markers (cytokines, chemokines, LDH and C-reactive protein) all support an exuberant immune response and inflammation as playing a significant role in the pathogenesis of severe COVID-19.
  6. Another key factor in the development of severe COVID-19 and organ damage is the development of blood clots, both large and small. These blood clots can be life threatening (heart attacks, strokes and pulmonary emboli) when larger, but lead to organ damage when small by blocking small vessels that are important for delivering oxygen to the organs or other parts of the body.
  7. SARS-CoV-2 is different from many viruses, and all the previous coronaviruses that we have known to infect humans in that it contains a superantigen. This superantigen can trigger massive amounts of the body’s T-cells further contributing to hyperinflammation, an overly exuberant immune response to infection, and potentially to the development of autoimmunity.

Health Consequences from SARS-CoV-2 Infection

With our two tutorials out of the way, we are ready to dig into this very complicated topic. Several reminders as we begin this journey:

  1. We are looking at early data and early studies. I have no doubt that we will learn much more over the next few years that may change some of this information or confirm it and build upon it. Remember, our understanding of science evolves. So, too, will our knowledge and understanding of the health consequences from SARS-CoV-2 infection.
  2. It does seem clear that health consequences can be highly variable and that Long COVID is not one disease process or syndrome, but likely many different pathophysiological processes that may operate alone or in concert with each other in different people leading to different manifestations of disease. No doubt many people who are struggling with long-term health effects from COVID-19 infection are looking for answers. I caution those so affected not to conclude that anything we review over this blog series must necessarily be the explanation for your personal health issues. It may or may not be, but that is a question to take up with your treating physician.
  3. Finally, as I pointed out in the introductory blog piece to this blog series- I know a little about a lot of things, but I don’t know everything about anything. I am not an expert in all the disciplines and fields of study that we are going to review. I certainly can be mistaken at times, and I am happy for those who do have more expertise than me to please comment and let me know of things that I get wrong and I will then try to correct my mistakes in a future blog piece or the comment section. We are all learning through this time.
  4. Finally, I will be pulling information from more than 100 studies for this blog series. Although I make an effort to be well read on these subjects, I am certain there are studies out there that I have missed. If I have missed an important one, please submit a comment and provide me with a citation or link to the study and I will then try to review it and add points that I have not previously made to a future blog post.
  5. Long COVID encompasses a lot of long-term health effects from SARS-CoV-2 infection, but not all long-term health consequences. Thus, while I will devote a lot of time and effort in addressing Long COVID, I will be including all health consequences that I have seen studied, whether or not they fit under the umbrella of “Long COVID.”

Okay, with that stated, let’s dig in.

What is Long COVID?

There are a variety of names that have been used to refer to the long-term health effects resulting from COVID-19 – post-acute COVID-19, long-term effects of COVID, long COVID, post-acute COVID syndrome, chronic COVID, long-haul COVID, late sequelae, and others. One of the difficult things about gathering data and reviewing studies related to Long COVID (formal name post-acute sequela of SARS-CoV-2 infection or PASC in the U.S. or post COVID-19 condition by the WHO) is that a universal case definition for this illness has not been accepted. A case definition is what physicians use to make a diagnosis, e.g., the blood pressure levels we use to diagnose hypertension or the blood sugar levels we use to diagnose diabetes. Thus, some studies may include study subjects that would not be included in a different study due to differing criteria that may be used.

The World Health Organization (WHO) did come up with its case definition on October 6, 2021. Of course, many of the studies had already selected their study subjects by then, and even since then, not all researchers have accepted that definition, especially because neither the CDC nor the NIH have established a case definition, which are the agencies to whom American physicians and researchers would generally be looking to for that case definition.

Here is the WHO clinical case definition:

“Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time.”

As you can see, this definition is very broad and is still a bit subjective. One feature that differs from many other commonly used study criteria is the duration of symptoms. The WHO definition requires persistence of symptoms for at least 2 months. Many others use 1 month. On the other hand, in some ways, this case definition may be more limiting than others in that it does not account for persons who had asymptomatic COVID-19 infection and it does not account for those who are experiencing aggravation of preexisting symptoms as their post-COVID condition as some other case definitions do.

Another problem in identifying Long COVID patients is that they may not have evidence of a SARS-CoV-2 infection. We now know that Long COVID can follow a mild case of COVID-19. That infection may have been so mild that the person did not realize that they were sick, did not realize that the symptoms might be related to COVID-19, or may have assumed that they did have COVID-19, and because it was mild that there was no need to get tested. There were also people infected during surges at which time it was difficult to find testing, so they did not get tested. Finally, we know that not everyone forms the tell-tale antibodies that we can test for to determine whether they may have had infection in the past, and others have antibody responses, but those antibodies fall below detectable limits with time, so when these patients are seen for evaluation of their Long COVID symptoms, we may not be able to establish with certainty that they had COVID-19, a precondition for the development of Long COVID.

The WHO definition attempts to account for the fact that many people with Long COVID may not have evidence of prior infection by including those with a probable infection. Of course, even this terminology can be subject to different interpretations. We often use the label “probable” when someone had close contact with a known infected person and developed symptoms consistent with COVID-19 within the typical timeframe for development of infection following exposure. Of course, this remains inadequate because there are many who are suffering with symptoms typical of Long COVID that not only did not realize that they had a prior COVID-19 infection, but also do not recall a close contact with a person known to have COVID-19. Similarly, studies have different criteria for who they include – some including only subjects with confirmed prior infection (+ PCR test), some including those with confirmed infection by PCR or antibody testing, and others with other criteria.

The CDC uses the term post-COVID conditions to describe health issues that persist more than four weeks after a person is first infected with SARS-CoV-2. https://www.cdc.gov/washington/testimony/2021/t20210428.htm. (Notice the CDC uses persistence of symptoms for more than 1 month versus the WHO criteria of 2 months.)

As I mentioned previously, not all health consequences following SARS-CoV-2 infection are generally considered Long COVID. For example, we have seen cases where a person appears to have recovered fully from their infection, but then suddenly has a heart attack or a massive pulmonary embolus (blood clot to the lungs). I just heard of another such case today involving a seemingly otherwise healthy person who appeared to have recovered from COVID-19 three months ago and then died of a massive heart attack today. We generally don’t refer to those cases as Long COVID. The CDC has come up with 3 categories of post-COVID-19 conditions, but acknowledges that these are not black-and-white and there certainly can be overlap between categories.

The first, called Long COVID, involves a range of symptoms that can last for months after first being infected with SARS-CoV-2 or can even first appear weeks after the acute phase of infection has resolved. Long COVID can happen to anyone infected with SARS-CoV-2, even if the illness was mild or entirely asymptomatic. People with Long COVID report experiencing varied symptoms, including tiredness or fatigue, abnormal sleep patterns, difficulty thinking or concentrating (sometimes referred to as “brain fog”), headache, loss of smell or taste, fast- beating or pounding heart (also known as heart palpitations), chest pain, shortness of breath, cough, joint or muscle pain, depression, anxiety, and fever. The causes of Long COVID are still unclear, although there are several hypotheses, including damage to blood vessels, autoimmune effects, and ongoing infection and there may be different causes in different people and even more than one cause at play in some patients. We will discuss these potential causes in much greater detail during this blog series.

Multiorgan effects of COVID-19 are the second type of post-COVID condition as described on the CDC’s website. COVID-19 can affect and cause long-term damage in multiple body systems including those involving the heart, lung, kidney, and brain. We will be reviewing all of these, and more, during the course of this blog series. These effects can include conditions that occur shortly after the acute phase of SARS-CoV-2 infection, like multisystem inflammatory syndrome (MIS) and autoimmune conditions. MIS is a condition where different body parts can become inflamed causing severe illness and even death. The CDC is studying inflammatory symptoms in both children (called MIS-C) and adults (called MIS-A). COVID-19 illness can also precede the development of autoimmune responses which cause the immune system to attack healthy cells by mistake and damage different parts of the body. Multiorgan effects include reports of neurological conditions, kidney damage or failure, diabetes, cardiovascular damage, fibrosis of the lungs (in some cases even requiring lung transplantation) and skin conditions.

Finally, post-COVID conditions also include the longer-term effects of COVID-19 treatment or hospitalization. Some of these longer-term effects for those who were hospitalized are similar to those seen in people hospitalized for other reasons, such as severe respiratory infections caused by other viruses or bacteria. Effects of COVID-19 treatment and hospitalization can also include post-intensive care syndrome, which refers to psychological and physical health effects that remain after a critical illness. Post-intensive care syndrome includes severe weakness, brain dysfunction, and mental health problems like stress disorders. Some of these symptoms can overlap with those observed with Long COVID.

As I write the blog series, I may occasionally describe findings related to one of these three categories, but most often, especially because of the arbitrariness of these distinctions, I will lump them altogether in our discussions as health consequences of COVID-19 or post-COVID conditions or some other more general description.

How many people are afflicted with Long COVID?

There are many reasons why this is a difficult question to answer. First, obviously it is difficult to quantify this number if we don’t even have a clear definition of what Long COVID is. Second, without a clear case definition, we cannot look to a common method we use to quantify illness – medical records and billing codes. And, unfortunately, with the relative newness of this condition, and the lack of a case definition, there are some doctors who have been dismissing these symptoms and failing to diagnose this condition. Thus, we are often left to surveys and self-reporting. Of course, when these studies are done, we often miss people who are in lower socioeconomic conditions, who in the case of COVID-19 have been disproportionately impacted, so these studies will often undercount the number of cases. Further, there are some people who are very hesitant to admit their symptoms, perhaps because of guilt in getting infected because they did not take steps to protect themselves or others, perhaps because of the fear of being stigmatized by friends, co-workers or even from family members, perhaps because of fear that it might impact their employment status and there are likely other reasons.

So, another way we can get to these numbers is by sampling and then extrapolating. For example, if we can sample a large enough group to determine what percentage of infections result in Long COVID, then we can apply that percentage to the general population to come up with estimates of the numbers of people with Long COVID. Of course, there are limitations to this methodology, as well. Not knowing what factors contribute to the development of Long COVID, we might select a group that will result in overestimating or underestimating the incidence of Long COVID. It is also complicated because we don’t know whether Long COVID might occur more or less often with changes in the variants, so the timing of this sampling may cause us to over- or underestimate the incidence. Further, although Long COVID can occur in children, it appears to be less common than in adults, so if we use a group of adults only, we might overestimate the incidence of Long COVID in the general population. On the other hand, if we our sample group is people of all ages, then we might underestimate the risk for Long COVID when adults try to make their personal risk decisions.

Another challenge is that if we try to apply a percentage of people that get Long COVID to a population based on the number of infections, we also may get an artificially low number because we know that Long COVID can develop in people who had mild COVID, people who didn’t get tested and therefore wouldn’t be counted in reported numbers, and people who didn’t ever realize they were infected. This problem has become even greater since at home tests became available and in much greater use. Recently, it is estimated that only 1 in 7 to 1 in 9 of all cases of COVID are currently diagnosed by a PCR test and reported to the state and CDC. Thus, if we use reported cases, we will undercount Long COVID cases.

Another way around that is to take a large population and test them for antibodies to determine who has previously had COVID-19 and determine what percentage of people have Long COVID. We can then apply that percentage to a larger population to determine the total number of Long COVID cases. However, even this methodology has limitations because of the fact that there are people who were infected in 2020, who developed Long COVID, but no longer have detectable antibodies. Therefore, this methodology may still underestimate the true incidence of Long COVID, though it should capture more cases than the method of just applying a percentage to the reported cases.

And, of course all of this fails to answer another question. We are now realizing that more and more people are getting reinfected. We know that our case counts significantly undercount reinfections and antibody testing does not distinguish between those who have been infected once and those who have had multiple reinfections. However, we are beginning to see evidence that those who are reinfected may have even higher risk for developing Long COVID. If true, this complicates applying whatever percentage of persons with Long COVID from those with a reported case of COVID or antibody evidence of prior infection to a general population.

Finally, it is also becoming clear that vaccination does not eliminate the risk of Long COVID, but it does decrease the risk of getting infected by 2.8 – 3.5-fold. And, it appears that if vaccinated and then infected, the risk for developing Long COVID is roughly half of the risk for those who are unvaccinated and get infected. https://www.bmj.com/content/376/bmj.o407. Therefore, if we determine the percentages of those infected who go on to develop Long COVID without regard to vaccination status, we may overestimate the risk in the general population for those who are vaccinated and underestimate the risk for those who are unvaccinated.

So, now understanding all of these limitations, let’s discuss what estimates currently are. First, we can look to a study done in the first year of the pandemic (so, this means no one was vaccinated and this would have been prior to the circulation of variants of concern). The authors concluded, “In this random sample of adults with a recent history of confirmed COVID-19, one third of participants reported post-acute sequelae 2 months after their SARS-CoV-2 positive test result, with higher odds among persons aged 40–54 years, females, and those with preexisting conditions. Persons aged ≥40 years, females, those with preexisting conditions, and Black persons also reported higher rates of post-acute sequelae.” https://www.cdc.gov/flu/weekly/index.htm.

A study that attempts to adjust for many of the limitations I mentioned above is the Long Covid Impact on Adult Americans: Early Indicators Estimating Prevalence and Cost by the Solve Long Covid Initiative www.solvelongcovid.org. In their white paper issued on April 5, 2022, they attempt to quantify the number of Americans with Long COVID, the proportion of those who are experiencing disabling Long COVID and the financial burden of disease. For their purposes, they defined Long COVID from the patient’s perspective of experiencing lingering or new symptoms following a suspected or confirmed case of COVID-19.  They considered disabling Long COVID as a patient’s experience of disabling or disruptive symptoms following a suspected or confirmed case of COVID-19. Disabling symptoms were considered to be those that resulted in the person being unable to fully function at their pre-infection level and experience of lingering or new symptoms resulting in disability or reduced ability to work, such that they could no longer work full-time or at their pre-illness work level.

These researchers used both the case model and the seroprevalence model (testing for antibodies) that I discussed above. The time period of their study ended January 31, 2022, so we would expect these estimates to undercount the number of persons today, both from the fact that our Omicron surge had not yet ended, but also the fact that those infected during January would not yet have been considered to have symptoms of a duration to constitute Long COVID.

Even so, using the seroprevalence model, they estimated that 43 million Americans (13.4% of the adult population have Long COVID, and another 14 million Americans (4.4% of adults) have disabling Long COVID. The financial burden (lost wages, lost savings and medical expenses) was estimated to total $511 billion.

The researchers do a very good job of explaining their methodology and how they make adjustments for many of the limitations of these kinds of studies that I wrote about above. For their reported case model (i.e., using confirmed cases reported to states and the CDC), they estimate 30% of those who were unvaccinated develop Long COVID, with 10% of those cases being severe enough to be classified as disabling Long COVID. They use lower rate calculations for those who have been vaccinated. In their seroprevalence model, using these percentages, they examine the cases and financial impacts for each state. For Idaho, they estimate 237,000 cases of Long COVID and 79,000 cases of disabling Long COVID, with a financial impact of $2.8 billion. These numbers are truly staggering, and keep in mind, they almost certainly undercount the true numbers of impacted people.

Of course, as we often have to remind some, this pandemic is not over. Unfortunately, many do not understand the potential for these long-term health consequences from getting infected at a time when many are abandoning almost all of the public health measures that we have to avoid infections, and many remain concerned that the harms of vaccination promoted by a group of doctors who spread disinformation that are not supported by science or evidence outweigh the real harms that we are seeing the evidence of in those who have been infected. Thus, I remain concerned about the amount of needless death and suffering, but also just the long-term economic implications of increased health care costs and decreased employee productivity, especially since Long COVID impacts many at the prime of their lives.

In my next blog piece, we will explore the pathophysiology of SARS-CoV-2 infection, i.e., the various disturbances to the body’s normal functioning that may result in death for some and long-term health consequences for others.

Virology and Immunology Tutorial

I am beginning my blog series on what is known about the medical and health consequences of COVID-19. Before jumping in, I indicated that readers would need two tutorials in preparation. The first we covered in the last blog piece. That covered different types of clinical trials and a brief tutorial on the statistics that we use to interpret the results of clinical studies.

Today, we will complete the other tutorial – a basic understanding of virology and immunology, one that is so brief and basic that it is sure to offend microbiologists, virologists and immunologists, because in being so basic, there is much that we won’t cover and do justice to, but also, we won’t be able to cover all the intricacies and the exceptions to general principles that a non-scientist will not need to know in order to gain an understanding of the health effects from infection with the SARS-CoV-2 virus.

So, let’s take on virology first. Let me first confess and let you know that in explaining viruses, I will do two things that are wrong, but I don’t know a better way to help non-scientists understand viruses. First, I will lead you to believe that viruses are living things. They are not. I will write things that discuss “killing” the virus, which would lead one to believe then, prior to killing, they must have been alive. It probably would be better for me to be more precise by stating that the virus is “inactivated” or “altered” to render it no longer capable of infecting a cell, but I find it a lot easier to just say the virus is killed, even though that is not technically correct. I am also in good company, because most of the virologists and microbiologists I talk to also use this phraseology, even though they know this is not technically correct. In fact, we even refer to “live” virus and “killed” virus vaccines as a simplistic reference to whether the vaccine can or cannot cause infection. (By the way, we do not use “live” vaccines for prevention of COVID-19).

The other thing I will do is give you the impression that viruses are intentional beings, which they are not. It is common when we discuss how viruses evolve to use language that suggests the virus is getting smarter and craftier, with the impression that the virus is purposefully trying to preserve its ability to transmit and infect its host. Certainly, we do see many viruses evolve in this manner, but there is no mind, consciousness or intent with respect to viruses. Again, it simply is a bit easier to understand and converse about these evolutionary changes by thinking about what is best for the virus and how it might choose to act if it could do so, because obviously, if a virus doesn’t evolve in a manner that preserves its ability to transmit and infect, then it is not going to pose much of a threat to us and we are not going to spend a lot of time worrying about those viruses.

With my confessions out of the way, we can begin. What is a virus? There are a number of ways we can divide viruses up into categories -the size of the virus, plant vs. animal viruses, human vs. non-human viruses, the family of viruses to which it belongs (e.g., coronaviruses), whether the virus has an envelope or not (SARS-CoV-2 does) and a number of other ways, but one common way is to divide them up according to the make-up of their genetic material – DNA viruses and RNA viruses. SARS-CoV-2 is an RNA virus. DNA and RNA contain the genetic instructions for the production of protein and new viruses. But, having the genetic code is not enough, and this is a big problem for viruses. (You may be wondering what does it matter whether a virus is a DNA virus or an RNA virus. The majority of examples of viruses that have a latent phase in humans, i.e., you get infected, but then the virus can hide out relatively dormant until manifesting itself years later are DNA viruses. As we will see, SARS-CoV-2 may be one of the exceptions to this rule. RNA viruses generally undergo much more rapid replication and often do not have the mechanisms that help prevent errors or repair these mistakes in the replication process. This leads to mutations, which can change the properties of the virus and may make antibodies formed to the version of the virus prior to the mutations less effective (immune escape or evasion). We have seen many examples of this with the SARS-CoV-2.)

Viruses need the machinery contained within a cell to make the proteins and to assemble all the pieces of newly reproduced viral particles into virus progeny. In other words, viruses can only replicate when they infect a cell so that they can take over the cell’s machinery. If a virus is airborne or on a surface like a countertop, it may or may not be able to infect a cell if it comes into contact with a host, but it is not replicating while in the air or on the surface. When the virus does infect a cell, instead of the cell’s machinery making proteins coded for by the cell’s DNA, the cell is now hijacked to use the virus’ genetic material to make the proteins needed to assemble new viruses. The virus has two more challenges, though.

First, if our immune systems are working properly, they are not going to welcome the virus into the body. As soon as our bodies recognize an invader, our immune systems launch an attack. From the time the virus enters our nose, mouth, lungs, gastrointestinal tract or blood until the time that it can invade a cell, it is particularly vulnerable to this attack. We’ll talk a lot more about this when we get to the immunology primer below, but keep in mind that before the virus enters a cell, antibodies can attack it. Once inside the cell, antibodies can’t get to the virus. (Keep in mind that there are millions of Americans who have immune deficiencies or states of immunocompromise where various portions of the immune system may not work well or work at all. For example, there are conditions where people don’t make certain antibodies or any antibodies. Also, many people have underlying health conditions for which the treatment has the effect of weakening the immune response. These folks can all be much more susceptible to infection than the rest of us, and if they get infected, they may be unable to clear the virus on their own.)

The second challenge for the virus is that it can’t just invade any old cell it wants to (see how I make it sound like viruses have minds and intentions!). Just like when we check into a hotel, we will get a room key that works just on one door and allows us to enter one room, the virus can only enter and infect cells that it has a “key” for, but in this case, we refer to the lock on the door as a receptor on a cell surface. With SARS-CoV-2, this is why you have heard so much about the ACE-2 receptor. This is the door lock to the cell for which the SARS-CoV-2 spike protein (specifically, something called the receptor binding domain or RBD) serves as the key. Now, this is where my analogy falls apart because unlike the single hotel room for our key, there are many, many cells that have the ACE-2 receptor, and thus they may all possibly be vulnerable to infection. In fact, this is in large part why we see so many different possible manifestations of SARS-CoV-2 infection.

The other way my analogy fails is that the SARS-CoV-2 virus also has a trick up its sleeve (see again how I am giving you the impression that the virus is alive, cognizant and tricky!) in that it has an alternative way into cells, kind of like if we forgot the key to our house, we might still be able to get in through an unlocked window. Nevertheless, knowing that the receptor for SARS-CoV-2 is the ACE-2 receptor and knowing which cells have ACE-2 receptors on their surface will help us a lot to understand all the ways the SARS-CoV-2 virus can wreak havoc on our bodies and why we see so many different manifestations of COVID-19 among people who get infected.

Above is a depiction of the SARS-CoV2 virus. First notice the red projections. These are the spike proteins that are able to bind to the ACE-2 receptor on cells that the virus can infect. This is the protein that the mRNA in the Pfizer and Moderna vaccines code for. That means that you can receive the genetic instructions that tell your cells to make the spike protein (but no other parts of the virus, so no infection can result), but your body will recognize the spike protein as an invader and form antibodies against it that will be at the ready should you be exposed and infected by the actual SARS-CoV-2 virus. Remember from above that the antibodies can only stop the virus before it enters the cell, so having premade antibodies (a process that can take 5 – 10 days) is a real advantage in fighting the virus and preventing significant infection.

There are other proteins besides the S or spike protein, including the E, M and N proteins. You will recall from above that I indicated that the SARS-CoV-2 virus has an envelope (not all viruses do). An envelope is the outermost layer of the virus and it serves to help protect the virus’ genetic material. The E protein is part of that envelope. The M protein is associated with the virus membrane. The N protein relates to the nucleocapsid.

So, a person who has been infected with the virus will often have antibodies against most or all of these proteins, whereas someone who has been vaccinated, but not infected, will only have antibodies to the spike protein, since there is no viral membrane, envelope or nucleocapsid in the vaccines approved for use in the U.S.

So, here is a look at the SARS-CoV-2 virus in a clinical specimen from the first patient known to be infected in the U.S. using a special kind of electron microscope and a stain that turns the virus particles blue. The virus particles are the blue circles, most of which are inside cells that they are infecting:

In this case, the viruses that are inside of cells would no longer be susceptible to antibodies.

Here is another image from the same patient. In this case, the virus is not stained blue, but you can see them as the small black circles. But, notice that most of these have not yet entered a cell to infect the cell:

In this case, antibodies can bind to the virus and when those antibodies are effective in preventing the virus particle from entering a cell, we call those neutralizing antibodies. Not all antibodies are neutralizing; some bind to the virus, but don’t block the virus’ entry into the cell. That doesn’t mean that those antibodies don’t sill serve a purpose, but they may not be enough to prevent infection of cells.

Okay, just a little bit more and we will move on to the immunology tutorial. We will refer to viral load which is a reference to how many virus particles are in your nose or throat or wherever we are measuring it. But, what we are often more interested in is “infectious” viral load, something much more difficult to measure, but an indicator of not just how many viruses are present, but how many of those virus particles are infectious to someone else. Remember that if you are normal, you will begin attacking the viruses in your nose, throat, lungs, etc., so some of those viruses are rendered incapable of infecting someone else, and while they would be detected as part of the viral load, they would not be part of the infectious viral load.

Conversely, we talk about viral dose when we try to quantify how many viruses do you have to get in your nose or throat or lungs to cause infection or what amount were you exposed to. Oftentimes, being exposed to a higher amount of virus can produce more severe disease. This is where masks come in and the public has missed some of the nuance here. Masks don’t have to filter out every virus particle in order to help protect you. If they filter out enough of a virus, it may mean that you are exposed to so few virus particles that you do not become infected (although for SARS-CoV-2, a recent study shows that it doesn’t take many virus particles to cause infection), but even if you do get infected, having blocked a lot of the virus so that you received a low dose may make it more likely that you will only have a mild or moderate infection.

Now for a bit of immunology.

The immune system is actually very complex. Most often, people equate antibodies with immunity to something, but antibodies are just one part of a very complicated system, and having antibodies to something doesn’t always mean you are immune to it. I had a teacher ask me to explain the immune system as if I was teaching one of her 5th grade students. That is not easy to do, but here is some of what we know about the immune response to SARS-CoV-2 for a 5th or 6th grader:

If a bacteria or virus invades your body, and you have never been exposed to that invader before, the first response of your body is to send in ground troops that will try to stop these invaders at your border (your skin or just under your skin if you get cut, or your nose and throat if it is trying to invade your body there, or your gut, if it is trying to make entry there).

The ground troops with their rifles are called white blood cells (or white cells, but not all white cells. We are going to talk about other white cells that are critical, but aren’t major players in this initial (innate) immune response later), and they don’t care who the enemy is, they just attack and try to shoot anyone (in this case a bacteria or virus) who doesn’t have the same uniform as the rest of the body (in this case, features that these white cells recognize as being your own body as opposed to an invader).

Just like we have different military forces (Army, Marines, Navy, Air Force, Coast Guard, National Guard, etc.), so too these white blood cells all have slightly different roles and tactics to attack an enemy. We have many different types of white cells in our blood, and they each conduct different kinds of warfare against these bacteria and viruses.

Just like our ground troops can throw a hand grenade or fire a cannon and blow up our enemies as well as things around them that we might otherwise not want blown up (like innocent bystanders or buildings, etc.), our white cells start releasing chemical warfare (chemokines, cytokines, etc.) against these invaders of our bodies and they cause some indiscriminate inflammation and surrounding tissue damage, as well, but as an attempt to kill these invaders or at least slow them down (if you got a cut in the past that got infected, you saw the redness and swelling that resulted, which is a result of this process).

What our ground troops (white cells) are trying to do is prevent these invaders, in this case a virus, from crossing that boarder (our nasal passages and throat in the case of SARS-CoV-2) and entering into our towns and cities (in this case our cells), where they can take over our food supplies and manufacturing plants that will allow them to make more invaders (viruses) that can then increase their attack on us.

This chemical attack is what makes us feel bad – fever, aches, cough, runny nose, etc.

Now, all this time that our ground troops (white cells) are fighting the invaders (virus) off at our borders with their rifles, hand grenades and cannons, they have already sent the message back to headquarters that we have invaders, a sample of what they look like, and a request that we need some weapons that will specifically target these invaders to stop them before they get into our towns and cities (cells) where they will make more invaders (virus). These weapons will be very specifically targeted to this invader (think like drones and laser-directed missiles) so that they only kill the invader and don’t cause all the collateral damage (destruction of property and injury or death to our own body’s cells and tissues as friendly fire, although like a drone, sometimes we target something we think is the enemy, but is not. In the case of our antibodies, this can mean that a part of our body becomes the target of the antibodies and this can result in auto-immune disease and we refer to those antibodies as autoantibodies).

HQ then revs up the manufacturing plant and starts making these highly targeted bombs (antibodies) that recognize something that is different that makes up these invaders that is not present in our normal body cells and tissues. This different thing is called an antigen and HQ manufactures these special bombs (antibodies) that only blow up anything that has that particular antigen and leaves everything else alone. It ordinarily takes HQ 5-14 days to make these specialized bombs (antibodies).

In the meantime, our ground troops (white cells) have to hold off the invaders. Sometimes they do, but often times, some of the invaders get into our towns and take over the food supply and start manufacturing new viruses.

Now, if you get an antibody test while you are sick (in this case, COVID-19), but before HQ has had time to make antibodies, the test will be negative, even though you are infected. This is called a false negative. It is also possible that you had some left-over antibodies from a prior invasion (COVID-19 infection), but you already defeated that invader, and perhaps now when the antibody test is measured, you were suffering from a cold virus or influenza virus. This positive test for SARS-CoV-2 antibodies would not indicate that you have acute SARS-CoV-2 virus infection at this particular time.

Now, these bombs (antibodies) come in a number of different kinds. Antibodies do often defeat invaders, but not always. We have examples of other virus invaders where HQ makes plenty of antibodies, but the invaders march on and take over our cities and don’t seem to be slowed down by the antibodies. In the case of this coronavirus, we think antibodies are important, but they are not the only thing that is important, and we still do not know how many antibodies you need to be protected from infection, which kinds of antibodies are needed, and if you have them, how long they will protect you.

Now, back to the types of bombs (antibodies). It turns out that you need one kind of antibody if the invader is crossing the skin (IgG) and you likely need a different antibody (IgA) if the invader is crossing a mucosal border (your nose or gut). Polio was a gut invader. We developed two different vaccines – a shot and a sugar cube, and it turned out that the sugar cube worked the best, because it caused HQ to make IgA better than the shot did. Everyone talks about IgG and that is what the COVID-19 antibody tests check for (much less commonly tests will include IgM levels), but it may be that IgA is very important in preventing SARS-CoV-2 – we don’t know (or at least I don’t). The good news is that in one of the first vaccine trials to be reported, it appears that the vaccine does stimulate a robust response of both IgG and IgA.

Okay, back to the types of bombs HQ is making. In addition to different types of antibodies like IgG and IgA (and there are others), some of these bombs are really powerful killer bombs called neutralizing antibodies, because in a test tube, they keep the enemy from entering into our towns and cities (cells), and if the invaders can’t get into our cells, they can’t make more invaders, so, when we shoot or bomb all of the invaders at our borders, its over because there are no more invaders.

Let me add that we don’t know that an antibody is truly a neutralizing antibody in someone’s body just because it is in a test tube, but in the case of the SARS-CoV-2, it does appear that these neutralizing antibodies are very important in our protection and that they do tend to be effective, though we saw that with omicron, these antibodies were less neutralizing than with prior variants. So, while neutralizing antibodies do seem to be important in the immune response to SARS-CoV-2 (this was not a given because there are other examples of viruses that induce lots of neutralizing antibodies to be produced, yet they don’t slow or stop the infection), other antibodies that bind to parts of the virus but don’t prevent cell entry (called binding antibodies) also seem to play an important role in our defense against SARS-CoV-2. It turns out that some of these other bombs (binding antibodies) are like paint balls/pellets, where you shoot the invader and it doesn’t kill them, but they are now marked. Marking these invaders can help other parts of our immune system go after them. This other part of the immune system is called the cellular immune system.

In this case, HQ is not only making highly specific bombs (antibodies – for extra credit, this part of the immune system is called humoral immunity and for credit to skip a grade, that part of the immune system with our troops on the ground at our borders is called innate immunity. It is innate because we are born with it and it does not require ever having been exposed to something to fight it. It is ready to fire on sight), but also plays a key role in messaging to HQ that we need to make highly specialized tanks (T-cells).

Remember, the humoral immunity – antibodies – takes time if you have never been exposed to that invader before. We have to get the body part to HQ, HQ has to design a blueprint for the bombs, and then we have to manufacture the bombs (antibodies) and that all takes about 5 – 14 days.

While HQ is mass producing bombs (antibodies), they have also been producing highly specialized tanks (T-cells – part of what we call cellular immunity).

These specialized tanks (T-cells) also come in several types. As, I mentioned previously, the goal of our innate immune system (our troops at the border) is to kill the invaders, or at least hold the invaders from getting to our towns and cities (our cells, where they can take over our manufacturing plants and make more invaders) until HQ has time to produce the specialized bombs (antibodies). Once an invader gets into a city, our innate immune system is not very effective and our specialized bombs (antibodies) generally can’t get inside to capture the invaders. It’s like ISIS getting into a town or city where they can create a stronghold and many barriers of protection as opposed to being out in the open in the unoccupied land by our borders.

So, HQ makes these T-cell tanks while they are making the antibodies. One of these tanks has the ability to find pieces of the invaders and it amplifies the attack in those areas (helper T-cells). Another type of tank can identify which towns or cities (our cells) have been invaded, and while our antibodies can’t penetrate the invader’s hold on the towns, these tanks just blow up the cell and kills all the invaders who are occupying the town (our cells) (these are called cytotoxic or killer T-cells – in the studies we are going to look at, these will often be referred to as CD8+ cells reflecting that we can identify these specific cells based on them having the CD8 marker on them). And, thinking ahead, HQ makes tanks with advanced radar, infrared detection capabilities and other abilities to quickly detect these same invaders again should they ever try to cross our border again once we have defeated them (memory T-cells – these are often referred to as CD4+ T-cells because they are positive for this marker). The long-lasting antibodies and the helper and memory T-cells are useful, because while the first time we face an invader, the entire range of our arsenal (humoral- antibodies- and cellular – T-cells) takes 5 – 14 days to mount our full response, the next time we see the invader, all of these parts of our immune response can be called to duty almost immediately, so much so, that we often will not get sick or have any symptoms, or if we do, with some unusual exceptions (like Dengue fever- due to a phenomenon called antibody-dependent enhancement or ADE, something you may have heard about early in 2020 when we feared this might also be the case with SARS-CoV-2, but we were relieved to find does not happen contrary to some doctors who still suggest it does in their disinformation campaigns), we will only have a mild case.

What we also found out is that while the antibody response to SARS-Co-V-2 infection is not always robust or long-lasting, the cellular response in nearly everyone was. Not only did those who did not mount a very good antibody response develop a good cellular response, but even family members who lived with someone who was infected, but to the best of our knowledge, did not get infected themselves, still developed a good cellular immune response! And, for many viruses, we know that the cellular immune response tends to be more important for viruses, because there are diseases that you don’t produce antibodies, and these patients tend to get serious bacterial infections, but not severe viral illnesses; while there are other diseases for which patients have problems with their T-cells and they tend to get bad and prolonged viral infections, like shingles that will occur in multiple locations (whereas shingles tends to occur only in a single area in those with otherwise healthy immune systems). COVID-19 appears to be a disease for which both the humoral (antibody) and cellular (T-cells) responses are important.

Vaccines can often be engineered to trigger specific antibody responses that we want (like neutralizing antibodies against a specific part of the virus that appear to be especially protective against viruses getting into cells), but they also often trigger the cellular immune response. Even if the antibody response declines over a few months, we have many examples (e.g., measles) where the memory cells specific for that virus can persist for many decades, if not the remainder of your life. With COVID-19, the immune response thus far, to the currently available vaccines, does not appear to be long-lasting (certainly not life-time), but it does appear that the cellular immune protection may outlast the humoral (antibody) immune response, which may explain why, over time, we may be more prone to breakthrough infections (if previously vaccinated) or reinfections (if previously infected), but yet don’t seem to be as likely to become severely ill. However, as you will see, recent studies are showing that some people who get infected are developing immune disturbances that can result in those people having more severe disease with reinfection, despite the common misinformation that infections build up your immune system. We have to remember that the immune system is a delicate balance between many different chemicals, antibodies and cells that can all work together in the right balance to protect us, but call also easily become out of balance and actually cause harm in an uncontrolled and overly exuberant response which appears to be playing a role in why certain children develop MIS-C (Multisystem Inflammatory Syndrome – Children) and certain adults develop critical illness with manifestations of cytokine storm.

I think this is enough for now. In my next post, we will dig into what health effects we are seeing in those who survive COVID-19.