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.