Potential Mechanisms of Long COVID
Long COVID (also known as post-acute symptoms of COVID-19, or PASC) refers to the persistent, worsening or emergence of new symptoms at least 4-12 weeks following an initial SARS-CoV-2 infection (CDC; Subramanian, July 2022; Thaweethai, May 2023). The underlying causes of long COVID remain uncertain, though they may relate to direct viral damage and/or dysregulated immune response to initial infection, as well as potential responses to persistent viral components in the body (Davis, January 2023). Suggested mechanisms include circulating autoantibodies, dysregulated immune cell signaling, hormonal changes such as low cortisol, reactivation of latent herpesviruses and clotting abnormalities (Mehandru, February 2022).
Avoiding or mitigating SARS-CoV-2 infections via nonpharmacological interventions and vaccination remains the clearest method to avoid development of long COVID, given infection is the prerequisite for developing complications of COVID-19. However, in addition to many persons already suffering from long COVID, additional infections in the community may result in more cases of long COVID moving forward. Therefore, therapeutic interventions to reduce or treat long COVID remain important frontiers.
Potential Treatments for Long COVID
Many therapies to reduce development of long COVID are under investigation, though none has yet been authorized for clinical use (Chee, January 2023). For example, early treatment with antiviral or immunomodulatory therapies during infection might reduce risk of developing subsequent long COVID, such as use of nirmatrelvir/ritonavir (Paxlovid) (Xie, November 2022 – preprint, not peer-reviewed), molnupiravir (Lagevrio) (Xie, April 2023), or metformin (Bramante, March 2023 – preprint, not peer-reviewed) in high-risk individuals.
For people who already have long COVID, many trials are underway including rehabilitation-based interventions, antiviral drugs such as longer-course nirmatrelvir/ritonavir and drugs targeting autonomic or neuropsychiatric pathways. Additionally, a small study found some improvement in select fatigue scores with use of a metabolism-targeted therapy in people with long COVID (Finnigan, May 2023).
Ultimately, variability in long COVID clinical phenotype and underlying mechanisms has key implications for the targeting of potential therapies to prevent or reduce this condition (Reese, December 2022; Subramanian, July 2022; Thaweethai, May 2023).