The puzzle of long COVID

SARS-CoV-2 is the virus that can cause the disease called COVID-19. This virus belongs to a family of viruses called coronaviruses.

Most people infected with SARS-CoV-2 have mild symptoms or none at all. However, a minority of people can develop severe symptoms, including difficulty breathing and pneumonia, and require hospitalization. And then there are some people infected with SARS-CoV-2 who have mild or serious initial symptoms and later develop a long-lasting disorder commonly called “long COVID.”

People with long COVID can experience a wide range of symptoms because different organs and systems in the body appear to be affected. Due to the serious and even debilitating nature of long COVID, some affected people may be unable to do normal everyday activities and have difficulty working.

As SARS-CoV-2 and COVID-19 are relatively new, and long COVID is even newer, there is much that remains unknown. Major research institutions such as the U.S. National Institutes of Health are beginning to invest in research on long COVID. However, it will take time for scientists and doctors to understand the many issues that bedevil people with long COVID, such as the following:

  • Why do some people infected with SARS-CoV-2 develop long-term complications?
  • How long will post-COVID-19 complications last?
  • What can be done to help people with long COVID get better?

Scientists must be able to firmly understand the cause of long COVID before it is possible to find effective remedies. In this issue of TreatmentUpdate, we report on a limited range of research associated with long COVID.

More than one syndrome?

Because so many different organ systems can be affected in long COVID, some scientists think that long COVID is not one disorder but instead may represent a syndrome, with different people developing different manifestations of it.

Is autoimmunity an issue?

Scientists at several research centres, including Yale University, have found that infection with SARS-CoV-2 seems to cause the immune system to attack itself (a phenomenon called autoimmunity). Specifically, the immune system attacks a key molecule that plays a role in the early defence against viruses and other germs. This molecule is called interferon-alpha.  By causing the immune system to attack interferon-alpha with its own antibodies, SARS-CoV-2 is better able to infect people.

Not just interferon-alpha

In addition, emerging research has found that people who develop COVID-19 tend to have antibodies that attack a wide range of the body’s proteins and organs. These antibodies can interfere with how organs communicate and function, particularly the brain. The full implications of this emerging research are not clear (and require confirmation). However, one example provided by scientists at Yale University is that these antibodies attack a receptor called orexin that plays a role in “regulating wakefulness and appetite.”

Hopefully, additional research will uncover other cellular communication pathways that are affected by long COVID. Identification of such pathways could potentially explain why so many different organ systems are affected and give rise to interventions to help people recover. However, it is important to note that the immune system turning on the body might not explain all aspects of long COVID. This suggests that the drivers of long COVID may be complex.

Inflammation and the immune system

There is a high level of inflammation and activation of the immune system in people with COVID-19. Initially, this can be useful in helping to contain an infection. However, persistent inflammation can injure tissues.

Some cells of the immune system circulate throughout the body and while on patrol for germs and tumours can take up residence within an organ system. If these roving cells of the immune system are not functioning normally, they can release chemical signals that incite inflammation in organ systems. Some researchers think that lingering inflammation and immune activation may contribute to the symptoms that manifest in long COVID.

Fragments of a virus

There may be pieces of SARS-CoV-2 (viral RNA) or certain proteins from this virus that linger deep within some organs and tissues. This could be another potential contributor to long COVID. It does not mean that people with long COVID are infectious with SARS-CoV-2, as there is zero evidence for that.

Experiments with mice infected with other coronaviruses have found that viral RNA lingers in the brains of these animals after acute infection. This viral RNA persists without any infectious coronavirus present in the mice. Scientists are not certain why this virus persists.

At the National Institutes of Health (NIH)

NIH virologist Dr. Avi Nath, MD, is one of many leading scientists who are starting research on long COVID. In an interview with the journal Nature Methods, he discusses his preliminary findings after reviewing data from more than 200 people with long COVID. He says that people with long COVID can be divided into three broad groups based on grouping their symptoms:

1. Problems with the autonomic nervous system (dysautonomia)

The autonomic nervous system connects parts of the brain with many important organs and systems. Usually, the autonomic nervous system functions without most people being aware of it. This system affects functions such as heart rate, breathing, digestion, urination, and so on. In cases of dysautonomia, the autonomic nervous system does not function normally. Symptoms of dysautonomia can include the following: dizziness upon sitting up or standing up as blood pressure temporarily falls, erectile dysfunction in men, and difficulty digesting food.

2. Brain fog

In people with long COVID who have this condition, Dr. Nath has found that “they are unable to remember names of people and objects, and they lose a sense of time. They can recount what they had for breakfast but fail to recall if it was today’s breakfast or last week’s.” Some people may also experience changes in mood, including the development of severe depression.

3. Exercise intolerance

There may be many reasons for an intolerance to exercise, ranging from injury to the lungs, heart and blood vessels to other issues. Exercise intolerance can sometimes also arise from injury to the autonomic nervous system (dysautonomia). Dr. Nath gave the example of a cardiologist with long COVID. She becomes exhausted after climbing a flight of stairs and has to spend the rest of the day in bed recovering. He said that after extensive investigation her doctors were unable to find any obvious causes to explain her symptoms.

Hiding in the brain

Many viruses attack and live inside cells in the brain. As mentioned earlier, another coronavirus that can infect mice persists in their brains. Coronaviruses belong to a larger family of viruses called RNA viruses. Other RNA viruses, including dengue virus, Zika virus and HIV, can also invade the brain. So, it is plausible that SARS-CoV-2 can also enter the brain.

Measles virus can infect unvaccinated children (causing measles). Dr. Nath notes that “months, even years, after recovering from measles, some children develop a deadly condition called subacute sclerosing panencephalitis (SSPE).”  While scientists can’t find measles virus in the blood of affected children at autopsy, Dr. Nath says, “you look in the brain, it’s loaded with virus.” He says that in such cases the measles virus has mutated significantly and does not behave like the strain of measles that originally infected the child. It can’t form new viruses, just some proteins and viral RNA. This severely mutated virus causes infection within the brains of children with SSPE in a limited form, moving from one brain cell to another. 

Based on these findings with measles, Dr. Nath says that it is possible that SARS-CoV-2 may have mutated significantly within the brains of people with long COVID. This significantly mutated virus is not infectious to other people. However, the virus has adapted to living in the brain (or another organ) of an affected person and slowly replicates there. Note that this idea of fragments of SARS-CoV-2 lurking in the brain is a theory, as Dr. Nath and his team attempt to make sense of why some people have long COVID. One proposed NIH study will use powerful magnetic resonance imaging (MRI) technology to try to detect traces of SARS-CoV-2 in the brains of people with long COVID.

For the future

Long COVID represents a puzzle to scientists as they race to find its cause and possible treatments. The ideas and associated research reported in this section of TreatmentUpdate are preliminary. Much more research lies ahead as scientists try to confirm their preliminary findings on long COVID.

—Sean R. Hosein


  1. Marshall M. The four most urgent questions about long COVID. Nature. 2021 Jun;594(7862):168-170.
  2. Marx V. Scientists set out to connect the dots on long COVID. Nature Methods. 2021 May;18(5):449-453.
  3. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nature Medicine. 2021 Apr;27(4):601-615.
  4. Subbaraman N. US health agency will invest $1 billion to investigate “long COVID.” Nature. 2021 Mar;591(7850):356.
  5. Editorial. Long COVID: Understanding the neurological effects. Lancet Neurology. 2021 Apr; 20(4):247.
  6. Wang EY, Mao T, Klein J, et al. Diverse functional autoantibodies in patients with COVID-19. Nature. 2021; in press.
  7. Rodrigues TS, de Sá KSG, Ishimoto AY, et al. Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients. Journal of Experimental Medicine. 2021 Mar 1;218(3):e20201707.
  8. Wallukat G, Hohberger B, Wenzel K, et al. Functional autoantibodies against G-protein coupled receptors in patients with persistent long-COVID-19 symptoms. Journal of Translational Autoimmunity. 2021;4:100100.
  9. Talla A, Vasaikar SV, Lemos MP, et al. Longitudinal immune dynamics of mild COVID-19 define signatures of recovery and persistence. bioRxiv [Preprint]. 2021 May 26:2021.05.26.442666.
  10. Mazza MG, Palladini M, De Lorenzo R, et al. Persistent psychopathology and neurocognitive impairment in COVID-19 survivors: Effect of inflammatory biomarkers at three-month follow-up. Brain, Behavior and Immunity. 2021 May;94:138-147.
  11. Woo MS, Malsy J, Pöttgen J, et al. Frequent neurocognitive deficits after recovery from mild COVID-19. Brain Communications. 2020 Nov 23;2(2):fcaa205.
  12. Ferreira-Gomes M, Kruglov A, Durek P, et al. SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself. Nature Communications. 2021 Mar 30;12(1):1961.
  13. Boldrini M, Canoll PD, Klein RS. How COVID-19 affects the brain. JAMA Psychiatry. 2021 Jun 1;78(6):682-683.
  14. Komaroff AL and Lipkin WI. Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of post-acute COVID-19 syndromes. Trends in Molecular Medicine. 2021; in press.