In this study, we analyzed the laboratory examination of COVID-19 patients, especially hematological and inflammatory parameters both at admission and after discharge and evaluated the relationship with LVGLS in follow-up. The remarkable findings of our study are as follows:
(i)Among the inflammatory markers, only serum ferritin levels both at hospital admission and after discharge were found to be significantly associated with the severity of pneumonia.
(ii)LVGLS values after discharge were significantly lower in the group with severe pneumonia than those without pulmonary involvement (see Table 2).
(iii)As the most interesting findings of our study, the patients recovering from the COVID-19 infection who had higher serum ferritin and LDH levels in control laboratory analysis after discharge demonstrated reduced LVGLS values in follow-up visits. We consider that these patients may benefit from close monitoring of long term outcomes such as heart failure and left ventricular dysfunction. Therefore, clinicians should pay close attention to early identification of subclinical myocardial injury by measurements of LVGLS in patients with high serum ferritin and LDH levels after discharge.
To our knowledge, this study is the first to specifically demonstrate the relationship between the biochemical, hematological parameters and LVGLS in patients recovered from COVID-19 in follow-up visits.
COVID-19 infection may present various hematological and biochemical changes according to the severity of inflammatory response. Wan et al demonstrated that cytokine storm is crucial in the progression from mild to severe disease, leading to ARDS and even death. .
Due to the monocyte and macrophage system activation and inflammatory cytokine storm, marked variabilities are observed in inflammatory parameters. Therefore, it is crucial to identify the inflammatory markers associated with the prognosis and outcomes of the disease.
Zeng et al found that inflammatory markers, particularly CRP, PCT, IL-6 and ferritin were positively correlated with the severity of COVID-19 . In a meta-analysis by Henry et al, in particular, IL-6 and serum ferritin were strong discriminators for severe and fatal COVID-19 disease . Likewise, Qin et al found CRP, ferritin and LDH higher in severe and critically ill patients than those with non-severe . In another study, Guan et al. presented several biochemical findings so that CRP and elevated LDH showed a more marked increase in more severe cases compared with the non-severe ones .
Serum ferritin is a key mediator in immune system by pro-inflammatory effects. It increases in inflammation and contributes to the cytokine storm . Prior studies found serum ferritin levels associated with disease severity and mortality in COVID-19 infection [19, 20]. Besides, Wu et al. found high serum ferritin levels associated with the development of ARDS in COVID-19 .
LDH is an intracellular enzyme and is present in cells in almost all organ systems with highest levels in heart, lungs, liver, kidneys, muscles and blood cells. LDH has been used as a marker of acute and chronic tissue damage and is considered an inflammatory marker . Previous studies demonstrated that there was an association between LDH values and worse outcomes in COVID-19 patients. Li et al found that elevated serum LDH at admission remained a more independent risk factor among the other inflammatory markers for COVID-19 severity and mortality . Therefore, we suggest that elevated serum LDH levels in both acute and chronic phase may be used as an important tool in determining clinical outcomes and prognosis in COVID-19.
In the present study, there was a significant association between the COVID-19 pneumonia and serum ferritin levels both at admission and after discharge. Serum ferritin increased in patients with COVID-19 pneumonia compared to those without pulmonary involvement. Although serum LDH levels in both visits were higher in patients with severe COVID-19 pneumonia, statistical significance was weak. Serum ferritin and LDH levels after discharge were significantly higher in the study group than the control group. CRP, D-dimer, PCT and fibrinogen have been found significant markers in assessing disease severity in many studies, whereas we found no significant association between them in our study. These findings may be related to the small sample size, especially in the severe pneumonia group. We suggested that serum ferritin may be a more sensitive and potent inflammatory marker in the prediction of the disease severity among the others in both acute and chronic stages of the disease.
Neutrophilia and lymphocytopenia occur as physiological responses of the innate immune system to systemic inflammation. In COVID-19 disease, inflammatory cytokines may accelerate lymphocyte apoptosis  and further trigger the migration of blood lymphocytes to lymph nodes and into inflamed tissues; leading to inflammatory lymphopenia. Recently, NLR, a composite index of systemic inflammation has been proposed as a novel prognostic marker in both cardiac and non-cardiac diseases [25, 26]. In many studies, NLR was found to be significantly higher in severe COVID-19 disease . NLR has been suggested as an independent risk factor for predicting COVID-19 infection and it may determine the prognosis .
However, our study demonstrated no statistical difference between NLR and pneumonia severity in both visits. On the other hand, lymphocyte and WBC counts slightly increased in patients with severe pneumonia in follow-up visits. This was an interesting finding in the present study and this may potentially suggest that the increase in WBC and lymphocyte counts may have occurred as a compensatory response to systemic inflammatory changes in the chronic phase.
COVID-19 disease can affect multiple organ systems, however the higher mortality in patients with COVID-19 may be attributed to cardiovascular involvement with worsening prognosis. The mechanisms of cardiovascular injury may be due to multiple factors.
Myocardial injury may occur through direct and indirect mechanisms in COVID-19 patients. Direct cardiotoxicity may occur by viral infiltration of myocardium as direct mechanism. Indirect mechanisms may involve stress-induced cardiomyopathy through respiratory failure and hypoxemia and myocardial inflammation by pro-inflammatory cytokines . Activation of the immune response with cytokine storm leads to myocardial inflammation and myocardial suppression . Morever, hypercytokinemia causes endothelial damage, generating a state of hypercoagulability, plaque instability and thromboembolic events [29, 30]. However, the main components of the myocardial injury are inflammatory mechanisms in COVID-19 .
The early identification of myocardial injury is crucial to prevent poor clinic outcomes and mortality . LVGLS analysis by STE demonstrates myocardial deformation earlier and may determine subclinical left ventricular myocardial dysfunction in case of preserved LVEF. Recently, GLS analysis using STE is a sensitive and reliable method for determining occult myocardial injury and has additional prognostic information [32, 33]. For this reason, both in the acute setting and the follow-up period, LVGLS analysis may be an important imaging tool for management, risk stratification and prognosis of COVID-19 patients.
In this study, the patients with a low LVEF were excluded and subclinical myocardial injury was determined by LVGLS analysis in patients affected by COVID-19 with preserved LVEF.
The present study showed that serum ferritin, LDH and pro-BNP values after discharge were significantly higher in patients with impaired LVGLS. There was a significant correlation between serum ferritin, LDH levels and LVGLS at a median 6 months after discharge. Serum ferritin and LDH levels were negatively correlated with LVGLS values in patients recovered from COVID-19 in follow up visits. We found no statistical difference between LVGLS and the other inflammatory markers both at admission and after discharge. Additionally, we found higher hemoglobin values and lower platelet counts in patients with impaired LVGLS than those with preserved. These results may be related to the outcomes of the severe COVID-19 disease in the chronic settings.
Herein, we may deduce that patients- once recovered from the COVID-19 infection with higher serum ferritin and LDH levels after discharge should be observed closely for future cardiac events such as left ventricular dysfunction, heart failure or arrhythmia in long term follow-up.