A Recipe for Uncertainty: Long COVID

Key Takeaways

• Long COVID is difficult to study, owing to a lack of standard definition of symptoms and duration
• Long COVID may be explained by persistent activation of immuno-inflammatory responses by a retained viral reservoir
• No treatments for long COVID exist, but vaccination against SARS-CoV-2 reduces its risk

What is a symptomatic disease that has no clearly defined symptoms, is persistent but can be intermittent for an unknown duration, and follows an infection but may or may not be an infectious disease? Add to the riddle a pinch of unclear prevalence, a few shakes of undetermined etiologic mechanisms, and a dollop of no proven treatments. If you answered myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), you get some credit—plus style points for using the new name—but it is the more topical postacute sequelae of COVID-19, also known as long COVID, that takes the cake.

Three years on since what seems like the biggest thing to hit our planet since the comet that took out the dinosaurs, we are emerging from the explosive start of the SARS-CoV-2 pandemic realizing, like our small mammalian ancestors, things are not going to be the same going forward. COVID-19 will always be with us in one form or another. Although the anxiety of acute COVID-19 infection and its immediate consequences is fading with rising immunity due to vaccines and prior SARS-CoV-2 infections, some are warning of a looming threat: that long COVID could affect the lives of millions of people, some of whom may suffer significant debility.

Limitations to Studying Long COVID
The amorphousness of long COVID makes it difficult to study. Foremost, there is no agreement on how to define the myriad persistent symptoms experienced by some following acute COVID-19. Overlap with diagnostic criteria formulated for ME/CFS—especially the postinfection impairment of functioning and, perhaps, orthostatic hypotension—may be applied, although the postexertional malaise and unrefreshing sleep of ME/CFS do not seem as central to long COVID.

In addition to the problem of defining the syndrome is the problem of measurement. Absent objective markers, surveys are used to detect post–COVID-19 symptoms, but these are crude, often seeking the presence of a symptom at a point in time with limited understanding of their presence before acute infection or alternative causes. It is through the lens of these serious limitations that we have to consider emerging long COVID data.

Most long COVID investigators are seeking to address 2 questions: 1) How common is long COVID and 2) what might be causing it?

Prevalence, Symptoms
To understand long COVID prevalence, we can look at 2 studies, both from Europe, where universal healthcare not only makes for better medicine but better emerging infections research.

The first is an analysis of questionnaires completed at least monthly from March 2020 to August 2021 as part of a longitudinal general health study by 76,422 people living in the north of the Netherlands. Uniquely, the study looked at symptoms in the 4231 (5.5%) who during study follow-up were diagnosed with COVID-19 and had symptoms that were persistent for at least 90-150 days. These cases were matched 2:1 to controls without a COVID-19 diagnosis. Of the cohort with diagnosed COVID-19, 21.4% had persistent symptoms not present before the COVID-19 infection, as did 8.7% of controls, leading to the summation that 12.7% of people with COVID-19 experienced long COVID.  The most common long COVID symptoms included chest pain, difficulty with or pain when breathing, lump in throat, painful muscles, heavy arms or legs, ageusia or anosmia, feeling hot and cold alternately, tingling extremities, and general tiredness.

A more generalized assessment of the burden of long COVID is provided by a survey conducted by the British government of respondents representative of the population of the United Kingdom. As of July 31, 2022, an estimated 2 million people, a remarkable 3.1% of the overall UK populace, reported symptoms related to COVID-19 for more than 4 weeks after acute infection; 45% had symptoms for at least 1 year. Almost three quarters of those with self-reported long COVID—1.5 million—indicated that their symptoms adversely affected daily life. Fatigue, shortness of breath, ageusia, and myalgias were most commonly reported symptoms.

Causes
Research on the causes of long COVID is a wild west of expeditions far and wide seeking to strike biomechanism gold. A tantalizing vein is suggested in a study that looked at cellular immune responses of 99 people with long COVID, 40 healthy controls without known infection, 39 who had prior SARS-CoV-2 infection but no lingering symptoms, and 37 healthcare workers with prior SARS-CoV-2 infection. Those with a history of COVID-19 were, on average, a year post acute infection. Participants with long COVID were observed to have heightened immune activation involving T-cells and B-cells, relative to the other groups, as well as elevations in antibodies to herpes viruses, including Epstein-Barr virus (EBV) and varicella zoster virus (VZV).

These findings are not too surprising and fit with assumptions that long COVID could be explained by persistent activation of immuno-inflammatory responses; an attendant reactivation of latent herpesviruses can explain the high antibody levels to EBV and VZV.

However, when applying machine learning models to their data, the investigators found that the strongest association with the immune-profile of long COVID was low levels of cortisol without compensatory elevations in adrenocorticotropic hormone, raising the possibility of a dysfunctional hypothalamic-pituitary axis in long COVID.

A different path was followed in an analysis of serial blood collections from 63 people with a history of SARS-CoV-2 infection, 37 of whom were diagnosed with long COVID, that relied on sensitive assays to detect SARS-CoV-2 antigens, including spike and nucleocapsid. Among those with long COVID, 60% had full-length spike antigen detected in 1 or more samples compared with none in the cohort without lingering symptoms.

This is a small study, but with huge implications as the possibility of a retained reservoir that is feeding the flames of long COVID has led some to promote use of antivirals in these patients, a still unstudied intervention. Of interest, persistent compartmentalized virus has also been posited to lead to a similar persistence of symptoms in Ebola survivors.

Can We Prevent or Treat Long COVID?
Currently, therapeutic approaches to long COVID have been limited to supportive care. Innovative techniques are helping some to regain their sense of smell, and it is likely that similar targeting of symptoms may be necessary given the variety of long COVID symptoms and their likely disparate mechanisms. It has been hypothesized that early treatment of COVID with antivirals may prevent long COVID, but we need more data to know if this is true. With treatment lacking, prudent mask wearing and remaining up to date on COVID-19 vaccinations are effective at reducing the risk of infection. Of importance, in those with a breakthrough infection, there are lower rates of long COVID compared with unvaccinated people. The best way to avoid long COVID is to not get COVID-19.

Your Thoughts?
What has been your biggest challenge in diagnosing long COVID in your patients? What treatments have been helpful for your patients experiencing long COVID? Join the discussion by posting a comment below.