Long COVID, also known as post-acute COVID-19 syndrome (PACS), is manifested by Long lasting symptoms involving multiple organs such as systemic, neuropsychiatric[1], HEENT, endocrine, cardiovascular[2, 3], pulmonary, musculoskeletal [4, 5] and gastrointestinal. According to WHO, the Long-term symptoms of COVID-19 refer to the symptoms that occur within 3 months after infection and last for at least 2 months in patients with COVID-19 or suspected novel coronavirus infection and cannot be explained by other diagnosis. It was reported that 80% of the infected patients with COVID-19 developed one or more Long-term symptoms, and the five most common symptoms are fatigue(58%)，headache（44%），attention disorder（27%），hair loss（25%）and dyspnea（24%）[6]. One study in 2021 shows there are more than half of COVID-19 survivors experienced PASC 6 months after recovery[7]. These symptoms create a bad influence on patients’ daily life long time after infection[8].

 Like autoimmune disease，Long COVID is more likely to appear in older, higher BMI and female population[9]. Thus, understanding Long COVID can help us explain the post-infection symptoms of COVID-19.

According to the introduction made by Professor Akiko, there are a few of hypotheses for Long COVID pathogenesis:

(1)    viral reservoir/viral PAMPs (Pathogen Associated Molecular Pattern): triggers innate immunity responses, stimulating T and B lymphocytes chronically, and there may be some virion that hide in some tissues.

(2)    Autoimmunity: molecular mimicry/ activates autoreactive T and B lymphocytes

(3)    Dysbiosis/reactivation

(4)    Tissue damage: tissue damage caused by virus ang immune system that can’t be impaired.

(5)    Other pathogens（such as EBV）that potentially infect the human body are activated by COVID-19 infection

(6)    Intestinal flora imbalance

Hypotheses above are just some of presumption raised by scientists. There are more and more probable causes being found recently about Long COVID.

According to the introduction of Professor Akiko, there are some discoveries in patients with Long COVID:

（1）      Higher levels of some cytokine, such as IFN-β,IFN-λ

（2）      Autoantibodies to various GPCRs

（3）      4 Post acute sequelae of COVID-19 (PASC) anticipating risk factors at the time of initial COVID-19 diagnose: Type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, Autoantibodies

（4）      Active microglia increase in autopsies of patients’ white matter

（5）      Elevated levels of CCL11 in the CSF of mice and human serum with brain fog

（6）      Direction infection of the CNS is not required to induce significant CNS pathology

  Those introduction helps explain part of the changes take place in patients. To our surprise, scientists found that CNS pathology can occur without any direction infection in CNS itself. This finding suggests there may be some other mechanisms between infection and CNS pathology. Another research also indicated the possible role of reactive gliosis following SARS-CoV-2 CNS injury, and the potential role of the hypothalamus network in PCS manifestations[10].

There are some probable drivers of Long COVID:

(1)    Micro clots

(2)    Mitochondria dysfunction

(3)    Oxidative Stress and Hyper-Inflammation[11]

  There are more and more researches in regarding to the Long-lasting post-infection symptoms, from appearance to mechanism, basic researches to clinical trials. What puzzles me most is why we only find this phenomenon in COVID-19 infection, rather than in normal uncomplicated influenza or severe influenza. Further study on the immune mechanism of COVID-19 in vivo may be the key to answer how the Long COVID occurs, as well as how can we deal with it.

  Due to the unclear cause of Long COVID and the complex situations it leads to, there is not specific short for Long COVID. At present, taking two dose of vaccines seems to be an approach to dropping incidence of Long COVID for about 50 percent. Rehabilitation interventions[12] and exercise training[13] are also probable ways to accelerate recovery, and nutrient intake may also plays a role[14], these findings also provide us with new thinkings about the mechanism of Long COVID.

  Immune response, which contains innate immunity and adaptive immunity, plays a significant role in virus and bacterium infections. The more profound understanding we have on immune response during COVID-19 infection[15], the more effective measures we can take to treat patients with Long COVID. In addition, mental health of patients with Long COVID is also worth paying attention to[16].

References

1.         Stefanou, M.-I., et al., Neurological manifestations of long-COVID syndrome: a narrative review. Therapeutic Advances In Chronic Disease, 2022. 13: p. 20406223221076890.

2.         Martínez-Salazar, B., et al., COVID-19 and the Vasculature: Current Aspects and Long-Term Consequences. Frontiers In Cell and Developmental Biology, 2022. 10: p. 824851.

3.         Raman, B., et al., Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus. European Heart Journal, 2022. 43(11): p. 1157-1172.

4.         Dos Santos, P.K., et al., The Musculoskeletal Involvement After Mild to Moderate COVID-19 Infection. Frontiers In Physiology, 2022. 13: p. 813924.

5.         Silva, C.C., et al., Muscle dysfunction in the long coronavirus disease 2019 syndrome: Pathogenesis and clinical approach. Reviews In Medical Virology, 2022: p. e2355.

6.         Lopez-Leon, S., et al., More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. Scientific Reports, 2021. 11(1): p. 16144.

7.         Groff, D., et al., Short-term and Long-term Rates of Postacute Sequelae of SARS-CoV-2 Infection: A Systematic Review. JAMA Network Open, 2021. 4(10): p. e2128568.

8.         Fugazzaro, S., et al., Rehabilitation Interventions for Post-Acute COVID-19 Syndrome: A Systematic Review. Int J Environ Res Public Health, 2022. 19(9).

9.         Sudre, C.H., et al., Attributes and predictors of long COVID. Nature Medicine, 2021. 27(4): p. 626-631.

10.        Mohamed, M.S., et al., Dissecting the Molecular Mechanisms Surrounding Post-COVID-19 Syndrome and Neurological Features. International Journal of Molecular Sciences, 2022. 23(8).

11.        Vollbracht, C. and K. Kraft, Oxidative Stress and Hyper-Inflammation as Major Drivers of Severe COVID-19 and Long COVID: Implications for the Benefit of High-Dose Intravenous Vitamin C. Frontiers in pharmacology, 2022. 13.

12.        Fugazzaro, S., et al., Rehabilitation Interventions for Post-Acute COVID-19 Syndrome: A Systematic Review. International Journal of Environmental Research and Public Health, 2022. 19(9).

13.        Cattadori, G., et al., Exercise Training in Post-COVID-19 Patients: The Need for a Multifactorial Protocol for a Multifactorial Pathophysiology. Journal of Clinical Medicine, 2022. 11(8).

14.        Motti, M.L., et al., The Role of Nutrients in Prevention, Treatment and Post-Coronavirus Disease-2019 (COVID-19). Nutrients, 2022. 14(5).

15.        Merad, M., et al., The immunology and immunopathology of COVID-19. Science (New York, N.Y.), 2022. 375(6585): p. 1122-1127.

16.        Zürcher, S.J., et al., Post-viral mental health sequelae in infected persons associated with COVID-19 and previous epidemics and pandemics: Systematic review and meta-analysis of prevalence estimates. Journal of Infection and Public Health, 2022. 15(5): p. 599-608.