Summary of the talk “The Latest on Long Covid Research with Dr. Iwasaki”

It has been noticed that unrecovered covid patients do decline over time, but the percentage never reaches 0, which is similar to the issue of EBV infection. Currently, the definition of "Long Covid" has not been universally acknowledged. WHO defines it as a post-COVID-19 condition occurring 3 months from the onset and lasting for at least 2 months, while in CDC’s definition the condition happens four or more weeks after the first infection and NICE explains Post-COVID-19 syndrome as persistent symptoms for more than 12 weeks after the start of acute symptoms.

~50% of the severe covid patients after being discharged from the hospital end up having long-term symptoms. 5~30% of asymptomatic or mild covid turns to long covid. The risk factors for these two cohorts are different. The former group is older and male represented, while the latter is more female and younger aged. People who start with more symptoms show a tendency to have prolonged symptoms, whereas people with fewer symptoms recover within 90 days. More interestingly, three distinct sets of symptoms come up over time.

There are many hypotheses against the mechanism of long covid. Mains ones were listed in the talk. The first hypothesis is about the reservoir of viral antigen and viral PAMPs which could result in chronic stimulation of B cells and T cells. The second one is autoimmunity triggered by the viral infection through molecular mimicry or bystander activation of autoreactive adaptive immunity.

Immune responses toward long covid:

-        Interferon β was particularly maintained at a high level in long covid patients, but reduced by eight months in the matched controls, suggesting the existence of viral PAMPs.

-        Auto-antibodies against GPCRs were found in some patients with neurologic long covid.

-        There are four long covid anticipating risk factors, type 2 diabetes, SARS-Cov-2 RNAemia, EBV viremia, and autoantibodies.

-        A reduced cortisol level was found in long-covid patients presenting with viral respiratory disease because of the disturbed function of the hypothalamic-pituitary adrenal axis. Interestingly, it’s also found in ME/CFS and other non-viral diseases.

-        A mouse model where hACE2 encoding AAV vector was introduced intratracheally to limit the SARS-Cov-2 infection within the respiratory tract was utilized to study the influence of remote infection on the CNS. The respiratory-only infection caused by a low dose of the virus could cause the upregulation of cytokines and chemokines in the serum and CSF, elevated levels of ccl11 in the CSF, and elevated reactive microglia in the brain even at seven weeks post-infection. In the case of SARS-Cov-2 infected people, the issue has been similar, whose autopsies showed increased reactive microglia in the white matter, though some of them had no covid symptoms leading to death.

Possible downstream drivers of long covid symptoms:

-        Microscopic blood clots (micro clots) have been seen in long covid patients, but their root is unknown.

-        Mitochondrial dysfunction causes severe impairment in oxygen extraction and utilization by tissues

Dr. Iwasaki’s ongoing research:

-          Analyze what's going on in terms of the immune and physiological factors in patients who were infected in the early phase of the pandemic by integrating symptoms and electronic medical records, doing real-time flow cytometry analyses, multiplex proteomics analyses, and reap.

-          Study how the vaccine might impact the immune responses of long-covid patients. As ~60% of patients felt better after the vaccine and it didn't matter what kind of vaccine they were getting, it’s hypothesized that the vaccines might induce robust immune responses such as T cells and antibodies that can clear the viral reservoir and will be zapping the root cause of disease, which therefore would be a permanent cure.

-          Generate knowledge from participants who are suffering from similar symptoms and provide peer-to-peer support.

-          Investigate what correlates with long covid development during the acute phase of the infection. The workflow includes a real-time flow cytometry analysis to analyze cell types and different activation statuses, deep profiling, reap to look at autoantibodies T cell receptor sequencing metabolomics, hormone profiling, and then a multi-modal data analysis to understand the predictive diagnostic and predictive factors of different symptoms.

Gaps and thoughts

The main questions about long covid include what characterizes the disease, what differentiates it from acute covid symptoms, how to diagnose long covid, how long is its duration, what determines the time of persisting symptoms, and how to cure and relieve the symptoms. They are all open to research and if we have the answer of one question, it would also make sense to other problems. A few studies that could be carried out are listed below:

1.        The lack of a general definition of long covid would possibly affect the collection of patient data and the meta-analysis of data from different hospitals and institutions. The exact “turning point” when we should consider the symptoms as long covid instead of acute covid could match the transition of the three clusters of clinical manifestation and the pathophysiologic changes. The labor put into defining long covid would also help establish a clear diagnostic criterion of long covid.

2.        The different hypotheses of the causes of long covid each have their supportive evidence, indicating that these could all happen in long covid patients. However, it is not clear how these mechanisms relate to the diseases. Do they work independently to drive different downstream symptoms, or some combined to determine the results? Long covid patients should be classified as different groups based on either clinical or immune features for further investigation. Immune features are seemingly more informative as CNS symptoms could be traced back to a mild local infection in the lung.

3.        Concerning the remote influence of local inflammation in other organs, attention should be put on the circulating immune molecules and cells, as well as hormones, particularly those that penetrate the blood-brain barrier and cause changes of CSF for CNS damage.