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.