Quick Question: Do We Know What Causes Long COVID?

Akiko Iwasaki, PhD: There’s been so much progress that’s been made in this area of Long COVID research. And there are hypotheses that we’re testing, both at the basic science level and through collaboration with Harlan [Krumholz, MD, SM] using randomized clinical trials and other sorts of human investigation methods.

So there’s the persistent virus idea, where SARS-CoV-2, even though it was thought to be an acute respiratory infection, is able to infect multiple organs and remain and replicate in some people.

There’s also the autoimmunity hypothesis where infections can trigger bystander or cross-reactive antibodies and T cells that can target the host cells and that can be mediating chronic conditions in some people.

And then there’s the reactive herpes virus hypothesis where latent viruses like the herpes virus family members can reactivate in response to SARS-CoV-2 infection, and now that may be causing the pathology.

And finally, there is also the tissue damage that’s not repaired. Chronic inflammation is persisting in patients, and that may be triggering the disease.

These are not mutually exclusive hypotheses; all of these could be happening in some patients while one of them or two of them are happening in others. And so the challenge in the field is to identify patients who suffer from one or two or more of these root causes so that we can diagnose and treat them properly.

We believe that further research will lead to some actionable things that we can do to help people, especially identifying these root causes and utilizing either existing or new medicines that target these root causes. For example, we are collaborating with a company called Invivyd, which has a next-generation monoclonal antibody that targets the SARS-CoV-2 spike protein. We’d love to be able to do a randomized clinical trial of patients with Long COVID with persistent virus antigen to see if that eliminates the cause of the disease, in which case this would dramatically improve the health of individuals.

I remain hopeful because I think the reason why some trials have failed is that the medication or the drugs being used did not change the root cause of the disease. And I think the four hypotheses that I raised, remain very plausible. There are so many papers demonstrating evidence for these things. I think it’s just a matter of doing the right trial with the right drugs for the right duration to be able to see an effect.