A COVID Cautionary Tale

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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