Discussion
In our study, it was observed that laboratory parameters that have been observed to have prognostic importance in COVID-19 patients increased in correlation with the severity of the disease. In the evaluation of suPAR and KIM-1 levels, it was observed that suPAR level was low compared to moderate patients in severe patients, while KIM-1 level increased in line with the severity of the disease. In the correlation of PaO2/FiO2 level with the parameters subject to our research, positive directional correlation was observed with suPAR level, while negative directional correlation was found with KIM-1 level.
SARS-CoV-2 is closely related to SARS-CoV and MERS-CoV, which are responsible for past outbreaks with significant morbidity and mortality. The rapid spread of COVID-19 has caused the pandemic and is now spreading globally. So far, the number of people infected due to COVID-19 is said to be over a hundred million, and the number is increasing day by day 11.
Observing lymphopenia in most patients in the examination of laboratory parameters of COVID-19 patients suggested that 2019nCoV similar to SARS-CoV could have an effect on lymphocytes, especially T lymphocytes. Virus particles emanating from the respiratory mucosa and infecting other cells cause abnormal cytokine discharge in the body, which is called a cytokine storm. T lymphocyte damage is also important in cytokine storm formation 12. After the cytokine storm, many proinflammatory cytokines, especially TNF-alpha, IL-1, IL-2, IL-6, nitric oxide, are released. These cytokines can cause increased vascular permeability, causing deterioration in tissue perfusion, as well as endothelial damage and microtombus formation. This increase in vascular permeability causes fluid accumulation in lung tissue and the interstitial area, resulting in an acute setting of respiratory failure. Positive results have been reported that IL-1 and IL-6 antagonists can be used to control this setting 13, 14.
The dense presence of the KIM-1 molecule in T cells gave it a different name: T cell/transmembrane, immunoglobulin, and mucin (TIM-1). The interaction of KIM-1/TIM-1 with T cells has played an important role in immune response, allergy, asthma, autoimmune diseases and response to viral infections 5. In the preliminary evaluation of clinical interaction between KIM-1/TIM-1 and COVID-19 patients, the relationship with acute kidney damage was evaluated in the foreground15. Kim-1/TIM-1 has been observed to facilitate the entry of the virus into the cell, such as ACE-2 receptors via IgV. It has been observed that increased proinflammatory cytokine levels as a result of increased virulence may cause further progression of kidney damage 6. In studies with SARS-CoV and MERS-CoV, it was also determined that the IgV unit provides ease of entry for other members of the family 16. In another publication, which is also in the evaluation phase, it has been suggested that KIM-1/TIM-1 receptors are high in the lungs and kidneys and that the observed TW-37 molecule, which can inhibit anth-KIM-1/TIM-1 antibody and endocytosis, can be used as a therapeutic target 5.
Humoral immunity plays an important role in controlling infection after the development of viremia. One of the chemotactic agents that plays an important role in the migration of these cells is uPAR. uPAR and its serum-dissolved form, suPAR, mediate the transformation of plasminogen into a plasmin.
By enabling a number of proteolytic activities to take place in the placenum extracellular matrix, it facilitates the migration of cells that play a role in the immune response 8. Studies investigating the relationship of suPAR level with inflammatory diseases found that the level of diabetes mellitus, coronary artery disease, community origin, ventilator-related pneumonias, smoking, acute enflaming of chronic obstructive pulmonary disease and sepsis increased compared to the healthy control group 17, 18, 19, 20, 21, 22, 23, 24, 25. It has also been shown that early mortality may have an important place in the pre-examination and survey in patients with sepsis. In the study evaluating patients with COVID-19, it was also assessed that there may be an early biomarker in patients who may require hospitalization in intensive care 26.
In our study, it was observed that the laboratory parameters examined in hospitalization such as NLR, LDH, prothrombin time, CRP, PaO2/FiO2, D-Dimer, ferritin and fibrinogen levels were higher in severe patients in line with previous studies conducted in patients with COVID-19. It was also observed that the KIM-1 level taken care of during hospitalization was high compared to moderately ill patients compared to severely ill patients. This can be assessed as the KIM-1, which mediates the endocytology of the virus in the cell, increases viremia.
In addition, increased viremia may have led to the development of MAS with abnormal cytokine discharge in these patients later on. In the evaluation of suPAR levels, we obtained a different observation with previous studies. Compared to the healthy control group, it was observed that the rising suPAR level in both moderate and severe COVID-19 patients was lower in severely ill patients than in moderate COVID-19 patients. SuPAR, which plays an important role in the migration of cells involved in body defense, can be evaluated as aggravating the disease due to the inability to create a low level adequate immune response in severe patients. In addition, the decreased level of this molecule, which plays a role in fibrinolytic activity, may have led to hypofibrinolytic activity, causing acute respiratory distress.
The most important limit observed in our study was that the number of our severely ill patients was small compared to the number of moderately ill patients. However, due to the effects of the level of parameters subject to our research on comorbidities, the exclusion of these patients caused our number to be small.
As a result, KIM-1/TIM-1 acts as an important gateway to the entry of the virus into the cell and its increased level of severely ill patients seems to confirm this. Treatments for this gateway can play an important role in treatment in COVID-19. In addition, the falling level of suPAR, which plays a role in body defense and fibrinolisis, with the weight of the disease may be the cause of parenchymal fibrosis development in patients, increased predisposition to thromboembolic events and increased virulence. This issue seems to need to be confirmed through more extensive research.