The American Medical Association's AMA Update video podcast from April 7, 2025, spoke with Akiko Iwasaki, PhD, Sterling Professor of Immunobiology at Yale University about Long Covid research, emerging treatments, and the latest from the Yale Long Covid Clinic.
Some of the key points from the discussion with Dr. Iwasaki.
Rather, Long Covid is an umbrella term that encompasses multiple distinct endotypes that's triggered by acute SARS-CoV-2 infection. Recent studies have identified at least 4 potential root causes:
It's these different root causes and mechanisms that help explain the wide array of symptoms that are seen in Long Covid presentations, such as neurocognitive, cardiovascular, and gastrointestinal presentations. Studies also found evidence of hormonal changes, such as lower levels of cortisol. and differences in sex hormones (eg. lower levels of testosterone in females). Research is currently trying to identify biomarkers that can classify patients into these different endotypes, so that patients can be diagnosed and treated more effectively.
Because the range and severity of symptoms are so broad, it can be difficult to pinpoint the cause as SARS-CoV-2 infection. This is especially the case when the symptoms can also be associated with other diseases or conditions, including normal aging process and other pre-existing health conditions. Some of these conditions, such as postural orthostatic tachycardia syndrome, or POTS, and post-exertional malaise, are common manifestations of Long Covid, but many clinicians are not aware of this and may not attribute those symptoms to Long Covid.
There is also a huge lack of awareness of Long Covid. Over one third of Americans have never heard of Long Covid. In this case, these individuals are likely to place blame elsewhere for their symptoms. And since symptoms and their intensity can wax and wane over time, many individuals may not realize that what they are experiencing is Long Covid. The CDC estimates that approximately 6% of Americans currently have Long Covid and that 8% have experienced it at some point. Considering, those would only be for individuals who have diagnosed Long Covid, the numbers are likely significantly higher.
The risks of Long Covid appear to be increasing cumulatively with each subsequent COVID-19 infection. So preventing COVID-19 infection in the first place is the most effective way to prevent Long Covid. Preventative strategies such as wearing high-quality masks indoors and increasing ventilation in crowded spaces are vital, along with continuing to get updated COVID-19 vaccines. If you do get infected, taking antivirals such as Paxlovid can mitigate the risks of developing Long Covid. There are also pre-exposure prophylaxis for immunocompromised individuals, that potentially can decrease the risk of developing Long Covid, however research still needs to be done on this.
Since Long Covid's root cause are a variety of endotypes, randomized controlled trials on emerging drugs should focus on the specific endotypes. For example, for the root cause of persistent viral replication, clinical trials on antivirals and neutralizing monoclonal antibodies that target SARS-CoV-2 should be investigated.
Latent herpes virus reactivation caused by SARS-CoV-2 needs trials focused on antivirals like valacyclovir, that target herpes viruses. There are currently RCTs underway trialing antivirals such as Truvada and Maraviroc for Long Covid.
And for chronic inflammation, trials should focus on things like immunomodulators, JAK inhibitors and checkpoint inhibitors that target inflammation.
Lastly, to target autoimmunity, clinical trials should be looking to things like FCRN inhibitors to reduce circulating antibodies, or B cell depletion therapies.
But as you can see, these interventions must be targeted to the particular root cause of disease. Otherwise, it will not be effective.
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