Discussion
In this study, we observed that levels of MCP-1 and SP-A in COVID-19 patients were higher than those in the control group and decreased during follow-up. High MCP-1 and SP-A levels were strongly associated with the development of ARDS and MAS. We also found that nonsurviving COVID-19 patients had higher MCP-1 and SP-A levels compared to patients who survived. SP-A was positively correlated with levels of MCP-1, CRP, LDH, and D-dimer, which are important parameters in the clinical course and follow-up of COVID-19, and negatively correlated with lymphocyte count and PaO2/FiO2 ratio.
The novel coronavirus that causes COVID-19 was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses 8. SARS-CoV-2 is closely related to SARS-CoV and MERS-CoV, which were responsible for smaller outbreaks with substantial morbidity and mortality. The pathophysiology underlying the unusually high pathogenicity of SARS-CoV2 compared to SARS-CoV or MERS-CoV has not been fully elucidated. Initial studies showed that increased serum levels of pro-inflammatory cytokines (e.g., IL-1B, IL-6, IL-12, IFN, and MCP1) were associated with pulmonary inflammation and extensive lung damage in patients with SARS3,5,9. Studies of patients infected with MERS-CoV showed that this virus also induced production of pro-inflammatory cytokines such as IFNγ, TNF-α, IL-15, and IL-17 10,11. As in MERS, studies on COVID-19 demonstrated significant increases in IL-1B, IFNγ, and MCP-1 levels 12,13. Moreover, it was found that MCP-1 and TNF-α levels were higher in patients who needed intensive care compared to patients who did not. Consistent with previous studies, our results showed that MCP-1 level was significantly higher in patients admitted to intensive care due to ARDS14.
One of the important underlying causes of morbidity and mortality in COVID-19 is cytokine storm syndrome. A cytokine storm involves the release of many proinflammatory cytokines, mainly TNF-α, IL-1, IL-2, IL-6, and nitric oxide. Increased vascular permeability due to these cytokines can lead to impaired tissue perfusion, endothelial damage, and microthrombus formation 15,16. This increase in vascular permeability also leads to fluid accumulation in the lung tissue and interstitial space, which consequently causes acute respiratory failure. In the present study, we also observed higher MCP-1 levels in patients who developed MAS compared to patients without MAS17.
Endothelial damage plays an important role in the development and exacerbation of hypoxemic respiratory failure in patients with acute respiratory failure. Type 2 epithelium is involved in surfactant production, and type 2 epithelial damage in the alveoli disrupts surfactant production and leads to the development of microatelectasic areas. In addition to facilitating alveolar expansion, surfactant plays an important role in the innate immune response 18. SP-A is a member of the collectin protein family, which plays an important role in innate immunity. SP-D and MBL are other members of this family 19,20. The primary aim of these proteins is to facilitate microbial clearance by enabling the agglutination, opsonization, and modulation of alveolar macrophages, dendritic cells, and T-lymphocytes to damaged cells. Studies on SP-A level in patients with acute respiratory failure showed that SP-A level increased with the duration of mechanical ventilator use, and high SP-A level in on the onset of ARDS was associated with poor prognosis and clinical course18,21.
In our study evaluating the follow-up of SARS-CoV-2 (COVID-19) patients, we observed that prothrombin time, CRP, troponin-I, MCP-1, and D-dimer levels were associated with clinical course and prognosis and were all initially high and decreased over time. ARDS is one of the leading causes of mortality in COVID-19 patients and, consistent with the literature, we found that patients who developed ARDS had high SP-A levels at admission that decreased with treatment. Considering the emphasis on the anti-inflammatory effect of SP-A, these findings may be interpreted as showing that SP-A plays a less significant role due to mitigation of the inflammatory response as a result of treatment. In our study, patients who developed MAS had higher levels of both MCP-1 and SP-A. Although MCP-1 was previously shown to play an important role in the pathogenesis of COVID-19, our study is the first to evaluate the relationship between SP-A and COVID-19/MAS. This suggests that these patients have a stronger inflammatory response, which is consistent with ARDS pathogenesis, and that SP-A level increases in an attempt to balance. The considerably higher MCP-1 and SP-A levels in the nonsurviving COVID-19 patients compared to those who survived suggests that these two biomarkers may be important markers of mortality.
The main limitation to identifying the relationship between MCP-1 and SP-A and mortality is the small number of deceased patients in our study. However, our analysis included all nonsurviving patients from two pandemic hospitals in our region, making it the most important reference that could be used in the evaluation of fatal cases.
In conclusion, high admitting MCP-1 and SP-A levels in COVID-19 patients may be parameters that can help predict the development of ARDS, MAS, and mortality and guide early planning and treatment accordingly. In future studies, SP-A may be a pneumoprotein that could be used in the planning of treatment for COVID-19 patients.