COVID-19: The Looming Challenge of Long COVID

by Raywat Deonandan, PhD
Epidemiologist & Associate Professor
University of Ottawa
(I add my credentials to these COVID-19 blog posts in case they get shared. I want readers to know that my opinion is supposedly an educated and informed one)

In 2020, Harvard economist Dr David Cutter estimated that the cost to American society of so-called Long COVID would be a staggering $2.6 trillion, representing 17% of GDP.  For comparison, total US health care spending historically is around 18% of GDP.

This post-viral condition is poised to be one of, if not the, most impactful health conditions for coming years and possibly decades.  Some believe that the pandemic is over. (It’s not.) But COVID will continue to render its horrors upon us for some years to come.

Later today, I will join Fahad Razak and Jennifer Frontera on a panel discussion on TVOntario’s The Agenda, about some of the challenges posed by Long COVID. In preparation for that session, I’ve decided to briefly jot down a summary of what is known about this syndrome.

1. Is Long COVID an Unusual Post-Viral Condition?

Zeynep Tufekci pointed out in the NY Times that after the 1889 and 1918 pandemics, many people suffered from post-infection conditions, poorly defined and described. Conflation with the woes of WWI prevented a proper investigation of the extent and nature of the post-viral epidemic that followed the Spanish Flu.

Post-viral misery is not unexpected for a proportion of people who become infected. According to one study, though, Long COVID symptoms do not appear to occur more frequently than longer-lasting symptoms of other viral respiratory infections. With COVID-19, though, so many people have been infected… and continue to be re-infected that the risk of such post-viral complication being a large burden on the population might be considerable

But I think it’s important to remember that post-viral illnesses are not uncommon. It might be time to expand coverage of this reality in medical schools. Just because it’s not unique to COVID doesn’t mean this is not a serious concern. On the contrary; I feel that we as a society should be quite concerned about the potential impacts of Long COVID, both individually and on society as a whole.

2. What Are the Symptoms of Long COVID?

Oh, man. There are so many symptoms associated with the phenomenon.  One study identified at least 50. The most commonly reported ones are fatigue and attention deficit. The actual list of symptoms is probably over 200, affecting multiple organs.

Recently, there’s been more open discussion of the more serious cardiovascular implications of prior COVID infection, with the risk of hear attack higher among all age groups of people who have had COVID, though highest among the 25-44 year age group. Understandably, then, there is an emerging special research focus on this particular category of Long COVID, even though it’s not the most common.

While heart effects are getting most of the media attention, the condition affects multiple organs. One study found that 4% of recovered COVID patients were shedding viral RNA in their feces and reporting gastrointestinal symptoms 7 months after infection, suggesting that there was lingering infection in that particular part of their bodies.  But lingering viral presence is not the only possible mechanism for this condition.

A magnificent paper published last month included this graphic that well summarizes the organs affected:

Long COVID symptoms and the impacts on numerous organs with differing pathology. [source:]

3. What is the Mechanism of Long COVID?

Again, no one knows yet. Not fully. And frankly, it’s unlikely to be just one thing. There are at least three possible mechanisms at play:

  1. Tissue damage incurred during the acute phase of COVID infection
  2. Some lingering presence of either the virus or an antigen associated with the virus
  3. A prolonged immune response to infection, possibly localized inflammation

Some have also suggested that immune dysregulation (infection somehow impairing the body’s ability to fight off other diseases), an autoimmune reaction, or infection somehow having triggered or reactivated dormant pathogens already lingering in the body.

As a result of these various possible pathways to Long COVID, doctors are compelled to approach it as a syndrome. It seems unlikely a single therapy could remove the cause outright.

Here’s a visual summary of possible mechanisms, taken from an excellent recent paper:

Hypothesized mechanisms of long COVID pathogenesis [source:]

4. How Common is Long COVID?

Well, it’s impossible to answer this question accurately without first having a solid definition of what constitutes Long COVID. (More on that later).  But let’s take a stab at it anyway.

In a 2021 study, out of 1000 adults with confirmed COVID, 40% had “issues” 3 months later. A clever Dutch matching study concluded that 12.7% of COVID patients had lingering symptoms that were likely attributable to infection. Rounding that estimate down to 10%, other authors have applied that figure to the 651 million known COVID cases worldwide to suggest that 65 million people are or will be experiencing Long COVID shortly.

A study of 4.5 million people treated at US Veterans Affairs hospitals suggests that the prevalence is 7%. Frankly, attempts at guessing prevalence range from 5% to 50%.  But I think 10% is a safe place to start the conversation.

5. Does Vaccination Lower the Risk of Long COVID?

A systematic review concluded that there is a “low level of evidence” that vaccination lowers the risk of Long COVID.  Keep in mind that all this means is that the studies investigating this question are exclusively observational studies, with no clinical trials (RCTs).  So I would challenge whether the evidence truly is low level.

One study of infected persons found that a single dose of vaccine lowered the risk of Long COVID by 12.8%, while a second dose lowered those odds by an additional 8.8%. Perhaps the most sobering and powerful investigation of this question so far was a 2022 paper that found that vaccination reduced the likelihood of the syndrome among infected people by about 15%.

It’s unclear, though, whether 3rd, 4th, and 5th boosters reduce that likelihood further, whether the bivalent vaccines offer additional protection, and whether non-mRNA vaccines perform differently in this regard than mRNA ones.

It’s important to remember, though, that the best way to avoid Long COVID is to avoid getting infected in the first place. While the power of vaccines to do prevent infection and transmission has waned considerably, booster shots restore much of that power, at least for a few weeks (possibly much longer), and bivalent doses do so even better.  So it stands to reason that a population with higher uptake rates of booster shots will be one less affected by Long COVID.

6. Who Is Most Likely to Get Long COVID?

According to the CDC, the people more likely to experience Long COVID (however you want to define that) are:

  • People who have experienced more severe COVID-19 illness, especially those who were hospitalized or needed intensive care
  • People who had underlying health conditions prior to COVID-19
  • People who did not get a COVID-19 vaccine
  • People who experience multisystem inflammatory syndrome (MIS) during or after COVID-19 illness.

Another study found that those aged >45 years and with at least 15 COVID-19 symptoms were 5.55 and 6.02 times, respectively, more likely to acquire severe long COVID-19. The same study identified obesity as a significant predictor.

7. Are There Treatments for Long COVID?

There are no validated treatments for Long COVID. But there are many symptom-specific pharmacological options for the various components of the syndrome. By definition, these treat the symptoms or the outcomes of the phenomenon. As noted above, attention deficit is among the most common symptoms reported. So neurologists are using the existing tools in their kits to attack the symptoms, not the cause. Guanfacine (an ADHD drug) and N-acetylcysteine, or NAC (an antioxidant used for lung diseases) are being explored at the clinical level. But the evidence for this is at the case report level, which is the very early stages of wisdom.

For the interested clinician, here is an impressive list of treatments available for the various symptoms associated with Long COVID:

Paxlovid (nirmatrelvir) is being robustly investigated as a more wide-spectrum treatment. Remember, paxlovid is the primary treatment for COVID. It works by preventing virus replication. A statistical signal has been observed that people who took paxlovid for the COVID were less likely to develop long-lasting symptoms at 3 months. But can it work as a therapy for people who are no longer infected, but are experiencing Long COVID? Well, a clinical trial is underway to answer that question. The antiviral molnupiravir is also being investigated in that trial.

8. How Do We Define Long COVID?

Now we get into the administrative heart of the problem. Diagnostic tools exist for components of Long COVID (like the regular tools to detect heart damage). But there are no validated tools or tests to diagnose Long COVID per se. The definition must be syndromic.

In 2021, the WHO offered a definition: “…a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.”

A 2021 paper proposed an “integrative classification model” to better suggest different underlying mechanisms. They suggested three categories of post-COVID symptom syndrome:

  • acute (symptoms 5-12 weeks after infection)
  • long (symptoms 12-24 weeks after infection)
  • persistent (symptoms >24 weeks after infection)

Defining it is very important. A definition leads to diagnosis. From diagnosis flows therapeutic options. Getting a diagnosis is important for insurance purposes, among other things. And depending on how a definition is phrased, research funds will flow.

Definitional challenges are many. They include:

  • Symptoms are often subjective. There’s no blood test for “brain fog.”
  • Must we confirm COVID diagnosis before labelling someone as having Long COVID? Most people get infected now without ever getting a PCR test. Do we trust a rapid test for this purpose?  Or a syndromic diagnosis?
  • The spectre of attribution error always lingers. In the weeks between COVID infection and presentation with post-COVID symptoms, has the patient been exposed to other factors, like other viruses, that might have contributed to the issue?
  • What is timeframe? How long after infection should be set the timer for defining Long COVID? 3 months? More?


9. What Are the Administrative Implications?

My MD spouse was quick to say to me, “the worst thing for a family doctor to deal with is a diagnosis without a treatment.” Doctors will struggle to have conversations with patients who are suffering with no recourse. And at present there is no OHIP billing code for Long COVID, so administratively structuring such conversations can be challenging. Yes, these are real concerns.

Absent a proper definition, the best that doctors can do is to stream patients to the specialists who can deal with specific symptoms. But treating individual symptoms might miss the multisystem nature of the problem. What’s needed are Long COVID clinics with interdisciplinary teams capable of managing multiple issues with related causes.

Some writers have suggested that now is the time to create national institutes of post-viral syndromes. In Canada, I don’t think we have the resources or bandwidth for such a move. But I do think dedicated clinics, research funding streams, and research chairs committed specifically to Long COVID are not unwarranted.

In this country, we’re currently seeing about 30 COVID deaths per day. Each death is one too many, but this rate is down considerably from where we were months ago, by virtue of the awesome life-saving power of our vaccines. The societal threat posed by COVID is no longer a mortal one, as most of us have every expectation of surviving infection.

But the looming threat of Long COVID is dire indeed. As reinfections continue to mount, and a risk of lingering post-COVID hovering around 10%, it is glaringly obvious that this syndrome presents a serious challenge to our health care infrastructure and, via economy and quality of life, to society as a whole.  It’s a pretty important topic.

Government needs to take notice and to take action:

  • Create appropriate billing codes so that family doctors have a place to start, and so we can monitor the clinical presentation issue from a billing database perspective. This is an easy start at the provincial level.
  • Establish dedicated Long COVID clinics in large urban centres.
  • Direct funding bodies to stream research funds toward Long COVID investigation.
  • Endow research chairs specifically in this area.
  • Reinvigorate medical schools with a better foundation in post-viral syndromes.
  • In partnership with professional colleges, prepare clinical guidelines to assist clinicians in managing Long COVID patients.
  • Push harder for better bivalent booster uptake.
  • Expand eligibility of bivalent boosters.
  • Subsidize development of mucosal vaccines, which will better prevent infection and transmission.

What have I missed? Let me know in the comments below.