SARS-CoV-2 was identified as the causative agent of Corona Virus Disease 19 (COVID-19) in January 2020 and has rapidly spread throughout the world, causing an ongoing pandemic. Unfortunately, the number of SARS‐CoV‐2‐infected patients and related deaths continue to increase despite the continuous fight against COVID-19. According to the statistical report of the World Health Organization (WHO), nearly 525 million infection cases of COVID‐19 infections have been reported until May 18, 2022. In the past two years, people have had a deep understanding of the clinical features and pathogenesis of COVID-19. However, there are many unanswered questions in the face of such a fast-spreading viral disease.
As the number of infections has increased, so has the number of recovered people. However, not all people who have recovered from SARS-CoV-2 infection are asymptomatic. Protracted symptoms, termed as ‘Long COVID’ in some recovered patients, have been increasingly recognized. Recently, research on ‘Long COVID’ have been published one after another. Through the explanation of Dr. Akiko Iwasaki, the professor of immunology at Yale University, I have a better understanding of the definition, symptoms, probability of occurrence and pathogenic mechanism of ‘Long COVID’.
Above all, for the definition of ‘Long COVID’, Dr. Akiko Iwasaki said that there is currently no general consensus on the definition of Long COVID. The CDC defines it as a series of new, recurring, or persistent health problems that develop 4 weeks or more after the first infection with SARS-CoV-2. While the WHO defines it as a condition that occurs in people with confirmed or probable SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.
Dr. Akiko Iwasaki said that patients with Long COVID experience dyspnea and multiple organ involvement, usually with overlapping symptoms, leading to a substantial effect on their quality of life. And the most common manifestations are systemic, respiratory, gastrointestinal, cardiovascular, and neurological. Similarly, our group systematically and comprehensively characterized the longitudinal evolution of health and functional outcomes in survivors of COVID-19 of varying severity over the first 2-year period. We found that 2 years after acute infection, those with previous COVID-19 infection remained in poorer physical health than controls. At 2 years of follow-up, the burden of restrictive ventilatory disorders and pulmonary diffusion disorders was significantly higher in critically ill patients than in controls. In addition, Dr. Akiko Iwasaki said that for severe patients, the incidence of Long COVID after recovery is as high as 50%; while the incidence of Long COVID in mild patients is between 5% and 30%.
It is no accident that the virus has been found to cause serious long-term sequelae by affecting the immune system. For example, a recent study confirmed the relationship between Epstein-Barr virus (EBV) and multiple sclerosis (MS). EBV is a human herpesvirus with mild symptoms in the acute phase of infection. However, EBV can exist in B lymphocytes in a latent form throughout the life cycle after host infection, therefore continuing to cause damage to the body. Experts then focused on the immunobiology of Long COVID currently under investigation. The main hypotheses include (i) persistent virus or viral antigens and RNA in tissues that drive chronic inflammation, (ii) the triggering of autoimmunity after acute viral infection, (iii) dysbiosis of the microbiome or virome, and (iv) unrepaired tissue damage, each of these hypotheses is supported by varying degrees of evidence. Many studies show that SARS-CoV-2 viral proteins and/or RNA have been detected throughout respiratory, cardiac, renal, and reproductive systems, as well as in the brain, muscles, eyes, GI tract, and lymph nodes months after infection. And the persistence of viral components may result in chronically elevated IFNs and cytokines. Moreover, certain autoAbs may provide permissive conditions for such viral persistence.
Dr. Akiko Iwasaki mentioned a study published in collaboration with Dr. Michelle Monje. They found that survivors of SARS-CoV-2 infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing, and memory. And the findings presented here underscore profound multi-cellular dysregulation in the brain caused by even mild respiratory SARS-CoV-2 infection. They speculate that abnormal cytokine levels activate microglia, which in turn lead to neuroinflammation, and this mechanism is similar to brain fog in chemotherapy patients. It is known that SARS-CoV-2 is not a neurotropism virus, but it can cause the neurological symptoms described above. Therefore, I think this is a very important discovery that explains why SARS-CoV-2 can cause a large number of neurological symptoms without directly entering the brain.
Dr. Akiko Iwasaki indicated that another possible mechanism for Long COVID is microclots. Plasma samples from COVID-19 patients in the recovery period still contained large amounts of anomalous amyloid deposits (microclots). At the same time, extensive fibrin amyloid microclots can entrap other proteins, which may lead to the production of various autoantibodies. The researchers believe that these microclots can block up capillaries, thereby restricting the passage of red blood cells and, in turn, O2 exchange, which can underpin the various symptoms of Long COVID. Consistent with this, in a preliminary report, appropriate and closely monitored 'triple' anticoagulant therapy has been shown to remove microclots and remove other symptoms. Therefore, fibrin amyloid microclots represent a novel and potentially important target for understanding and treating Long COVID and related disorders.
Another question is whether the vaccine can reduce Long COVID. Current research suggests that COVID-19 vaccines may affect Long COVID symptoms in a subset of individuals. In addition, some researchers believe that the vaccine can probably reduce the proportion of Long COVID by half. However, how exactly the vaccine prevents or treats Long COVID is currently unclear. Therefore, the immune response to vaccines in patients with Long COVID needs to be assessed to reveal potential protective mechanisms.
At present, there are people who advocate living with the virus, but personally, I don't agree to do nothing, because we still don't fully understand the harm of Long COVID. Moreover, it has been found that even the patients with mild COVID -19 may have an incidence of Long COVID. Therefore, for protection, I will definitely wear a mask for a long time in the future. In addition, I believe it is necessary to pay attention to the follow-up of patients recovering from COVID-19, even years after the initial infection, and to develop effective interventions to reduce the risk of Long COVID.
