Scientists are still grappling with the full implications of the COVID-19 pandemic. One of the challenges is that the SARS-CoV2 virus continues to mutate and produce new strains, so studying the virus and its effects is a moving target. The relatively high rate of hospitalizations and deaths are of course extremely concerning, and what is frequently offered as the primary reason to get vaccinated. However it is now well-established that infection with COVID-19 can also produce so-called “long COVID” with chronic symptoms that persist long after the acute infection.
The technical term for long COVID is post-acute sequelae of COVID-19 (PASC). These are any of a long list of symptoms that persist after the acute infection has completely resolved. The symptoms are an indication that COVID is a systemic infection, not just a pulmonary infection. The largest study to date of PASC showed:
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%).
More recent studies provide further reasons for concern. A paper presented at this year’s European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) suggests that long COVID symptoms may be different for different variants of the virus. This is a study of hospitalized patients, so we would expect a higher incidence of long COVID, and that is what they found:
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%).
Further the researchers found that when they divided the patient into those infected while the original variant of the virus was dominant were different than when the alpha variant was dominant. The later alpha variant was associated with a greater incidence of brain fog, myalgia, fatigue, anxiety, and depression, with a lower incidence of loss of smell (anosmia), altered taste, and decreased hearing. It remains to be seen what effect the Delta and Omicron variants had on long COVID.
More concerning is a recent study published in Nature looking at brain scans in patients before and after infection with COVID. The study takes advantage of the UK Biobank, which collects data on subjects including brain scans and health questionnaires. This is an extremely useful resource because it combines the benefits of large numbers of subjects with detailed information. In this case the database provided brain scan before being infected with COVID, something that would otherwise not be available in large numbers of subjects. When comparing those infected with COVID vs those not infected the researchers found:
(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.
These differences were present even after removing those subjects who were hospitalized, so they can be see even with relatively mild COVID. The authors also point out that the areas most affected were in the limbic region, which includes olfactory sense – smell. This suggests that the virus may be entering the brain through the nasal passages and the olfactory nerve, which makes sense. However, effects were not limited to these regions and were present globally.
This result is extremely concerning. Of course, all of the data I have been discussing is observational. That is the only kind of data we will have on the clinical effects of COVID because we obviously cannot randomize subjects to be infected with COVID. But it is easy enough to control for premorbid conditions and other variables, and the large numbers make the data fairly robust. In the case of reduced brain volume, we also don’t know what the long-term effects will be. After 1-2 years, for example, will brain volumes return to baseline? We also need further research to correlate these anatomic findings with specific clinical outcomes, such as cognitive function on standardized neuropsychological testing.
The data we have so far, however, strongly indicates that long COVID is extremely common in those who contract COVID, persisting for at least 3-6 months in about a third of all those infected. The risk of long COVID is greater for those with more severe infections and in vulnerable populations, but they can occur even with mild infections in those who are young and healthy at baseline. Further, long COVID is not merely a subjective persistence of symptoms but can be tied to biological changes in organs, most notably the brain.
All this means that the long-term health burden of the COVID-19 pandemic may be far greater than is currently apparent. A full accounting of the health care costs and long-term disability will takes years to fully appreciate, but early indications are that they are likely to be substantial.
When calculating the risk vs benefit of interventions, such as vaccines and mask mandates, we cannot look only at hospitalizations and deaths. We also need to consider what the long-term burden of long COVID is likely to be. At the very least this is one more reason for everyone to get fully vaccinated and boosted.
