Update on Long COVID

The full implications of the COVID-19 pandemic are still being grappled with by scientists. Studying the effects of the SARS-CoV2 virus is a moving target because it continues to evolve and produce new strains. The high rate of hospitalizations and deaths is concerning, and what is frequently offered as the primary reason to get vaccine. It is now well-established that an infection with COVID-19 can cause long-term symptoms that persist after the acute infection.

The post-acute sequelae of COVID-19 are called long COVID. There are a lot of symptoms that persist after the acute infection has been resolved. The symptoms are an indication that COVID is a systemic disease. The largest study to date was conducted by PASC.

Among COVID-19 survivors (mean [SD] age: 46.3 [19.8], 55.6% female), 57.00% had one or more long-COVID feature recorded during the whole 6-month period (i.e., including the acute phase), and 36.55% between 3 and 6 months. The incidence of each feature was: abnormal breathing (18.71% in the 1- to 180-day period; 7.94% in the 90- to180-day period), fatigue/malaise (12.82%; 5.87%), chest/throat pain (12.60%; 5.71%), headache (8.67%; 4.63%), other pain (11.60%; 7.19%), abdominal symptoms (15.58%; 8.29%), myalgia (3.24%; 1.54%), cognitive symptoms (7.88%; 3.95%), and anxiety/depression (22.82%; 15.49%).

There are more reasons for concern from recent studies. A paper presented at the European Congress of Clinical Microbiology and Infectious Diseases suggests that long COVID symptoms may be different for different versions of the virus. This is a study of hospitalized patients, so we would expect a higher incidence of long COVID.

At least three-quarters 325/428 (76%) of patients reported at least one persistent symptom. The most common reported symptoms were shortness of breath (157/428; 37%) and chronic fatigue (156/428; 36%) followed by sleep problems (68/428; 16%), visual problems (55/428; 13%), and brain fog (54/428; 13%).

The researchers found that when they divided the patient into those with and without the original variant of the virus, it was different than when the alpha variant was dominant. The later alpha variant was associated with a higher incidence of brain fog, myalgia, fatigue, anxiety, and depression. It is not known what effect the Delta and Omicron variant had on COVID.

A recent study in Nature looked at brain scans in patients before and after they were hospitalized with COVID. The UK Biobank collects data on subjects including brain scans and health questionnaires. The benefits of large numbers of subjects combined with detailed information make this a very useful resource. The database provided brain scans before the subjects were exposed to COVID, something that would not be available in large numbers of subjects. The researchers found that those who were notinfecting with COVID were more likely to have it.

(i) greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, (ii) greater changes in markers of tissue damage in regions functionally-connected to the primary olfactory cortex, and (iii) greater reduction in global brain size.

The differences were present even after removing the hospitalized subjects. The areas most affected were in the limbic region. It makes sense that the virus may be entering the brain through the nose and olfactory nerve. The effects were not limited to these regions.

This result is concerning. All of the data I have been discussing is observational. We can't randomize subjects to be exposed to COVID so we only have that data on the clinical effects. The data is fairly robust because it is easy to control for premorbid conditions and large numbers. We don't know what the long-term effects of reduced brain volume will be. Will brain volumes return to baseline after 1-2 years? We need more research to correlate these findings with clinical outcomes.

According to the data we have so far, long COVID is very common in those who contract it, and it lasts for at least 3-6 months in about a third of all those who have it. The risk of long COVID is higher for those with more severe infections and vulnerable populations, but it can occur even with mild infections in those who are young and healthy at baseline. Long COVID can be tied to biological changes in the brain and is not just a subjective persistence of symptoms.

The long-term health burden of the COVID-19 pandemic may be much greater than is currently understood. It will take years to fully appreciate the health care costs and long-term disability, but early indications are that they will be substantial.

We can't look only at hospitalizations and deaths when calculating the risk vs benefit of interventions. The long-term burden of long COVID needs to be considered. This is one more reason for everyone to get fully vaccine and boosted.

• Steven Novella is an academic clinical neurologist at the Yale University School of Medicine. He is the host and producer of the popular weekly science show, The Skeptics, Guide to the Universe, and also the author of the daily neuroscience website, Neuro LogicaBlog. The Skeptics Guide to the Universe was published by Dr. Novella, as well as two courses with The Great Courses.

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