Dear Professor Cao,

I am Liu Yaxue. After watching the online lecture of Akiko Iwasaki from Yale University, I gained some insight into long COVID. 

It is now clear that COVID-19 can lead to long-term disease—often referred to as Long Covid syndrome or post-acute sequelae of SARS-CoV-2 infection (PASC) even in a proportion of asymptomatic or mild COVID cases. Even worse, long COVID can affect multiple organ systems and cause tissue damage.

The existing hypotheses on the pathogenesis of long COVID include persistent viral reservoirs/viral PAMPs, activation of autoimmunity, dysbiosis/reactivation of other previously infected viruses (e.g., EBV), and tissue damage. Several possible causes of long COVID among these have been identified by scientists. For some, SARS-CoV-2 infection exerts unique prolonged residual effects on the innate and adaptive immune systems. A study showed that IFN-β and IFN-λ1 remained elevated in the LC group at month 8 after initial infection, while their levels began to resolve in MCs, which provides evidence that SARS-CoV-2 virus may persist in the body and cause symptoms. For others, COVID-19 may cause the body to produce an antibody that mimics SARS-CoV-2 and triggers an autoimmune response in which the immune system attacks its own antibodies. For example, functionally active autoantibodies targeting G-protein coupled receptors were found in LC patients.

We do still not yet fully understand the risk factors, consequences and treatments of long COVID. A longitudinal investigation of 309 COVID-19 patients from initial diagnosis to 2 to 3 months after identified four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein–Barr virus viremia, and autoantibodies. Prof. Akiko Iwasaki introduced their work on mild respiratory-only SARS-CoV-2 infection leading to prolonged changes in the CNS. Prof. Iwasaki also suggests that microclots and mitochondria dysfunction are the possible downstream drivers of long COVID. Obviously, the search for detailed molecular mechanisms of long COVID in which different concurrent mechanisms could be involved is far away but significant.

Whether vaccination for COVID-19 reduces an infected person's risk of developing long COVID is unclear. Some reports have suggested that vaccination improved the long COVID symptoms by up to 50 percent, while others have found no reduction in risk. Vaccines may improve long COVID symptoms by eliciting robust antiviral antibodies to clear the viral reservoir, or divert autoimmune lymphocytes through innate and adaptive cytokines. Maybe we need more data to answer this question in a long term.

Currently, we don't have a reliable way to diagnose and treat with long COVID. What we really need to do is to understand these different endotypes that underlie long COVID. If there are four distinct endotypes that are caused by different things, we need to treat them differently. Biomarkers can help identify endotypes and mark these specific groups of patients as suitable candidates for targeted biological therapies. So, for each endotype, we need a biomarker or biomarkers, and then we can separate the patients into the right kind of disease treatment pathways. 

Thank you for your time.

Sincerely yours,

Liu Yaxue