Estimates suggest that as many as 20 to 30 per cent of patients with COVID develop long lasting symptoms, what’s been called “long COVID.”

Initially many were asymptomatic or had mild symptoms, only to develop much more troublesome and persistent symptoms weeks later.

Those later symptoms often include shortness of breath, fatigue, weakness, irregular heartbeat, trouble concentrating and focusing (brain fog), headaches and persistent loss of taste and smell.

Long COVID defies precise definition because of the diversity and complexity of its symptoms. The range and variety of the symptoms associated with long COVID are similar to other disorders such as myalgic encephalomyelitis (chronic fatigue syndrome), chronic Barr-Epstein virus infection and the persistent symptoms that follow acute Lyme disease.

When I first reviewed this subject in June 2021, the cause of long COVID was a mystery – and it remains so. Despite the mystery there has been progress.

For example, Oxford University and the Imperial College in London collaboratively posted online comparative MRI and functional MRI (fMRI) studies of volunteers who a few years earlier were studied as part of the U.K. Biobank program, some of whom later developed COVID. Others who did not, acted as controls.

The authors posited that the SARS-CoV-2 virus might gain access to the brain through the olfactory and gustatory systems. Both are intimately connected to structures in the temporal lobe and elsewhere in the brain and play major roles in memory, mood and emotion, as well as smell and taste.

Their findings were striking. Abnormalities were found in many of the latter regions of the brain, mostly on the left side, and were more widespread in the small subgroup of patients, usually older, who were hospitalized.

But for me, the most important observation was finding abnormalities in the brains of COVID patients, most of whom were not hospitalized (only 15 of a total of 379 subjects). This study strongly suggests the virus reaches the brain through the olfactory system, as suspected.

Unfortunately, the study made no mention of which subjects developed symptoms and if so, what symptoms? But given the localization of the findings, it wouldn’t be much of a stretch to suggest that some symptoms such as troubles with focusing and remembering, as well as impaired smell and taste, could well have been related to the MRI findings.

The hypothesis that lesions in the brain might be far more common than we thought and possibly related to long COVID symptoms is worth further study.

But it needs a bevy of psychological and other tests to complement the imaging studies. And that would only be the beginning.

Consensus is emerging on what might underlie all the symptoms in the long COVID syndrome. Some scientists suggest tiny blood clots in the lungs might contribute to the shortness of breath, and even fatigue, by impairing oxygen transfer in the lungs.

There is some evidence for this, based on SPECT-CT (single photon emission computed tomography) studies of children several months following mild COVID infections. They developed shortness of breath and “crushing” fatigue.

Based on that working hypothesis, some children with SPECT-CT positive scans were treated with an anticoagulant and improved enough to return to school.

Other scientists suggest that persisting high interferon levels mean the immune system in long COVID patients may remain overactive.

There is also evidence that the virus remains in the body for many months and, possibly, years. Indeed, all three factors may be operative.

Persistent functional COVID viruses or parts of the virus, long after the clinical phase of the disease, could well explain a continuing hyperactive immune system and possibly, the continuing formation of micro-sized blood clots in the lungs, brain, muscles, bowel and kidneys – and hence some or all of the symptoms reported by patients long after the initial infection.

There are other wrinkles to the long COVID puzzle. Some patients develop COVID two or more times based on evidence from repeated testing and their clinical histories. More worrisome is recent evidence the virus continues to evolve in the bodies of patients with long COVID.

In most patients with acute SARS-CoV-2, the virus is cleared by the immune system within a few weeks and thus the virus has little chance to mutate.

But for chronic infections, such as some cases of long COVID, the virus might last several months or longer, giving the virus plenty of opportunity to evolve and new, possibly worrisome mutations to appear.

Perhaps persisting low-grade infection explains some patients with repeated infections in much the same way herpes simplex (cold sores) can do.

What’s obvious is that this virus is still evolving. That’s reason enough to keep vaccines up-to-date and repeated vaccination as indicated by worldwide surveillance.

Dr. William Brown is a professor of neurology at McMaster University and co-founder of the InfoHealth series at the Niagara-on-the-Lake Public Library.