As more people become infected with SARS-CoV-2, there is increasing concern for patients who develop one or more symptoms after acute COVID-19, known as long COVID or post-COVID-19 condition. In addition to focusing on the diagnosis, prevalence, risk factors, and susceptible populations of long COVID, in-depth research on pathogenesis is also crucial. Viral antigens and components of SARS-CoV-2 were still found in the gut and brain more than 200 days after infection and closely related with symptoms of long COVID. By comparing whether patients recovered completely after infection, patients with long COVID had higher levels of inflammatory cytokines, suggesting that the persistent inflammatory may contribute to the occurrence of long COVID. Hyperinflammatory responses can lead to irreversible lung fibrosis that severely compromises respiratory function, and biomarkers for persistent neutrophil activation (lipocalin-2), fibrosis signaling (matrix metalloprotease-7) and alveolar epithelial repair (hepatocyte growth factor) strongly associate with the impaired pulmonary function tests. Pulmonary diffusing capacity is impaired months after COVID-19 infection, even 2 years later, suggesting that lung damage persists, which may be caused by an imbalance in lung immune homeostasis. Alveolar macrophages are essential for maintaining lung tissue integrity by removing damaged cells, but in bronchoalveolar lavage fluid from severe COVID-19 patients, alveolar macrophages are greatly reduced due to replace by inflammatory monocytes. Single-cell analyses of lungs from individuals with fatal COVID-19 revealed that AT2 cells failed to fully transition into AT1 cells, depriving alveolar macrophages of AT2 cell support and nutrition, resulting in impaired lung regeneration and abnormal immune homeostasis.
Autoantibodies associated with connect tissues disease and cytokines were detected in many COVID-19 patients at early phase, anti-cytokines antibodies were more common. Autoantibodies targeting type I IFNs are enriched in sever COVID-19 patients, and in vivo validation of the presence of this antibody makes mice more susceptible to SARS-CoV-2 infection, and increased severity. The cytokine autoantibodies against IL-1β, IL-21 and GM-CSF were identified in patients with COVID-19, all of which exert antiviral effects. The use of neutralizing antibodies against IL-1β, IL-21 and GM-CSF in mice increases susceptibility to SARS-CoV-2. Autoantibodies that target components of the interleukin-18 (IL-18) pathway (in particular, IL-18Rβ) have the same effect, which plays a critical role in antiviral responses of natural killer and CD8 T cells+. Anti-cytokines antibodies were also identified in > 50% of patients infected with influenza, other non-SARS-CoV-2 viruses and pathogens, including patients with pneumonia attributed to bacterial causes. Whether these antibodies are unique to COVID-19 patients, whether viral RNA triggers pre-existing immune abnormalities in their bodies, and the dynamic changes of antibodies in different patients during recovery, the impact of different types of vaccines on autoantibodies are still needed to further explore.
A study of COVID-19 patients from acute phase to 3-month after infection indicated that the presence of type 2 diabetes, SARS-CoV-2 RNAemia, Epstein–Barr virus viremia, and autoantibodies in the early stage of COVID-19 increased the risk of developing long COVID. Recently study has demonstrated that infection with Epstein–Barr virus (EBV) will increase the risk of multiple sclerosis (MS) 32-fold. Researchers have been trying to prove for more than a century that various chronic diseases have roots in infection, such as Helicobacter pylori bacteria for stomach ulcers, EBV for MS, and perhaps SARS-CoV-2 for long covid or other diseases. The mechanism of long COVID is complicated, the similar syndrome can be observed after other acute infections such as SARS, MERS, Ebola, influenza, etc. Certain symptoms of long COVID are not particular, but it does not mean that research on it is meaningless. Making a profound study of long covid is beneficial for us to deal with possible infectious diseases in the future.
The COVID-19 pandemic has been going on for more than 2 years, although there are many studies on long COVID, the definition of long COVID is not clear because the detailed symptoms, organ function impairment, and the timepoint of diagnosis have not been unified. There is no agreement on how to classify the severity and phenotype of this new disease, and what relevant outcomes should to measure in practice. There is an urgent need to optimize and standardize outcome measures for this important patient group both for clinical services and for research.
Chief Medical Officer for England and Head of the NIHR, Professor Chris Whitty said, “Good research is absolutely pivotal in understanding, diagnosing and then treating any illness, to ease symptoms and ultimately improve lives.” Elucidating the phenotypes of long COVID and finding subtypes that have the greatest impact on patients, whether these phenotypes have different underlying mechanisms and warrant different treatments and clinical pathways needs to be determined. Identifying the most common and disturbing symptoms, determining the extent of organ damage by objective tests, and self-assessment of quality of life or work status are all necessary for prognostic assessment in long COVID patients. To explore its mechanism and finding possible interventions to maximize the relief of patients' symptoms, improve their quality of life, and delay organ function impairment can better solve the problem of long COVID.
张慧
