Review
Copyright ©The Author(s) 2024.
World J Gastroenterol. Oct 7, 2024; 30(37): 4104-4114
Published online Oct 7, 2024. doi: 10.3748/wjg.v30.i37.4104
Table 1 Summary of evidence on the pathophysiological mechanisms related to long coronavirus disease
Proposed etiology
Available evidence
Ref.
Immune dysregulationThe immune profiling of patients recovering from acute COVID-19 shows an up-regulation of immunological signaling molecules associated with inflammation, including ESR, CRP, TNF-α, IL-4, and IL-6Haunhorst et al[28]
Auto-immunityBoth latent autoimmunity and PolyA have been observed in a high percentage of patients (83% and 62% of cases, respectively). The delayed resolution resulting from low-grade inflammation is evidenced by elevated levels of IL-1β, IL-6, IL-8, and TNF-α. The detection of circulating ANA/ENAs further reinforces this hypothesisRojas et al[31], Son et al[32]
Viral antigen persistenceThe SARS-CoV-2 NP has been detected in different organs and structures of the body of patients who recovered from COVID-19, such as the gallbladder, lymph nodes, colon, appendix, ileum, hemorrhoid, and liver. In some of these cases, the presence of the viral antigen was observed in all the tissues evaluated, which may therefore predispose to the occurrence of a possible widespread involvement of multiple organs and structuresCheung et al[33]
Latent virus reactivationMarked differences in viral reactivities against non-SARS-CoV-2 antigens have been detected in patients with long COVID. In this respect, different herpesvirus antigens, such as the EBV minor viral capsid antigen gp23, the EBV fusion-receptor component gp42, and the varicella zoster virus glycoprotein E can be found in elevated levels in these patientsKlein et al[34]
End-organ damageThe invasive potential of SARS-CoV-2 has been shown to cause damage to different organs. A study that included a sample of young adults, most of whom were free of risk factors for severe COVID-19, found that 66% of the subjects had at least one radiological abnormality in various organs, such as the lungs, liver, pancreas, among others, thus demonstrating the possibility of multisystemic involvement. Organ damage has also been reported in the nervous system (brainstem)Yong[18], Dennis et al[35]
EndotheliopathyThe levels of different biomarkers of endothelial damage have been observed to be changed in patients with long COVID, including Ang-1, Ang-2, sP-selectin, sICAM-1, VEGF, and vWf, demonstrating an important correlation to the presence of related symptomsVassiliou et al[36]
Mitochondrial dysfunctionIncreased levels of blood biomarkers together with mitochondrial damage and oxidative stress have been evidenced in cases of long COVID. For example, increased levels of F2-isoprostanes, malondialdehyde, with a respective reduction in the levels of antioxidants (coenzyme Q10). Results from genomic studies have provided additional evidence in this respect. Patients with COVID-19 may exhibit altered gene expression associated with both mitochondrial function and the cellular response to viral infectionsMolnar et al[37]
Microbiome dysbiosisIn addition to reduced bacterial diversity, the SCFA-producing salutary commensal bacteria are also significantly reduced in patients with previous COVID-19 history. SCFAs play a key role in regulation of the immune system responseZhang et al[38]
Metabolic dysregulationMetabolomic and proteomic profiling of patients with long COVID can aid in determining whether the symptoms of long COVID may be attributed to metabolic dysregulation. In this connection, higher levels of lactate, pyruvate, and total triglycerides, and significantly lower Apo-A1 and A2 levels have been observed in patients with long COVID compared to healthy individualsBerezhnoy et al[39]
Autonomic nervous system dysfunctionDifferent mechanisms, such as, direct tissue damage, immune dysregulation, hormonal disturbances, persistent low-grade infection, invasion of SARS-CoV-2 into the brain, and elevated levels of cytokines have been proposed as pathways with potential to lead to reduced levels of vagal activity in patients with COVID-19. Patients with long COVID presenting neurological symptoms have been shown to exhibit higher levels of NfL and glial fibrillary acidic protein, which may be related to persistent axonal damage in such patientsGiunta et al[40], Marchegiani et al[41]