A National Institutes of Health (NIH) study published on 25 May 2023 in the Journal of the American Medical Association¹ found the risk of Long Covid after infection by SARS-CoV-2 variant Omicron is approximately 10%. It also found the risk of Long Covid after reinfection by Omicron is almost 20%. The results of this study were widely reported^2,3 but seem to have had little impact on policy or public attitudes.

This lack of concern is partly down to the barrage of messaging from politicians and some public health leaders that SARS-CoV-2 is “just another respiratory virus” and that COVID-19 will “become like the flu"⁴. Many people already believe COVID-19 is now no more serious than a cold or a flu, thanks to immunity derived from vaccines or prior infection, but this is not the case. We’ve written before about the reality gap: the difference between the perception of the risks of COVID-19 and what the evidence actually tells us.

The NIH study is in line with a recent study of Long Covid in children, which found increased risk of developing Long Covid on reinfection⁵ and these findings might explain recent advice from the US government to avoid reinfection because of the cumulative risks.

There are some who seek to downplay Long Covid by saying the list of 200 possible symptoms makes it impossible to accurately diagnose and that it could be encompassing illnesses people might have gone on to develop anyway, but there are sound biological reasons for this condition to affect the body in so many different ways.

Angiotensin-converting enzyme receptor 2 (ACE2) is the socket SARS-CoV-2 plugs into to infect human cells^6-8. The virus can use other mechanisms to enter cells⁹, but ACE2 is the most common method. ACE2 is widely expressed in the human body, with highest levels of expression in small intestine, testis, kidneys, heart, thyroid, and adipose (fat) tissue, but it is found almost everywhere, including the blood, spleen, bone marrow, brain, blood vessels, muscle, lungs, colon, liver, bladder, and adrenal gland¹⁰.

Given how common the ACE2 receptor is, it is unsurprising SARS-CoV-2 can cause a very wide range of symptoms. Viral persistence is a possible cause of Long Covid^11,12 and since the receptor used by SARS-CoV-2 is widely expressed, we should expect diversity of long-term impact, from the young child with a persistent fever¹³ to the adult with new onset hypothyroidism¹⁴, from the child who develops diabetes^15,16 to the adult who suffers acute kidney injury^17,18, from a child with new onset gastro-intestinal illness^{19, 20} to the adult who develops a new vascular or cardiac condition^21-23.

In the simplest terms, when a coronavirus infects a cell, it usually destroys the cell as part of replication, or the cell is destroyed by the immune system. Destruction of the cell causes damage to the affected organ. In addition, prolonged immune activation can mean the body continues to destroy cells after the virus has cleared, but some people seem unable to entirely clear the virus, which continues to persist^24-27, driving an ongoing immune response.

When one considers the widespread distribution of the ACE2 receptor and the mechanisms by which SARS-CoV-2 can cause damage directly or by prompting an immune response, it is not surprising that the risk of developing long-term symptoms increases with each reinfection. An infection that causes diabetes will not necessarily prevent harm from a future infection that targets the kidneys or the heart, particularly as it seems some SARS-CoV-2 variants are better adapted for different organs^{28, 29}. With enough reinfections, it is plausible people will develop multiple long-term complications of COVID-19. The clinical significance of reinfection should be obvious if one considers the biological mechanisms that are at play.

Given the continued rapid rate of mutation of SARS-CoV-2³⁰, reinfection is likely to be relatively common, and if the results of the NIH study hold true for subsequent infections, we should not be surprised to observe a cumulative risk of long-term harm with each instance of COVID-19.

If you’d like to reduce your risk of catching or transmitting COVID-19, check out our advice here.