In December 2019, a novel β-coronavirus emerged in Wuhan, China that caused pneumonia- and flu-like illness. This virus was later named as the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV2) and the diseases Coronavirus Disease 2019 - COVID-19. The reported mortality rate ranged from to 2.3% in China to 7.2% in reported in Italy. On August 1st, 2020, the total number of infected people globally passed 20 million, with more than 770 thousand deaths. On the same date, Bosnia and Herzegovina (B&H) reported 16.025 individuals with COVID-19, of which 571 people have deceased (1, 2). The first registered case of COVID-19 at Tuzla University Clinical Center, Northeastern Bosnia and Herzegovina was on the 28th of March 2020 (3).
The vast majority of individuals with COVID-19 (~ 80%) report having no or mild symptoms, whereas minor part develops more severe symptoms that demand hospital admission. Most common first symptoms in confirmed COVID-19 infected patients are cough, dyspnea, and fatigue, fever as well as myalgia and headache; while gastrointestinal symptoms include nausea, vomiting, abdominal pain, and diarrhoea; some patients report loss of olfactory sensation as well (4).
From the start of the pandemic, several risk factors have that contributed to the development of a severe type of COVID-19 infection were reported such as old age, obesity, chronic kidney diseases, diabetes and black ethnicity among others (5). Nevertheless, the area that is still under research is what are the laboratory and inflammatory markers that could be used in the assessment of the severity of COVID-19 infection and outcome and differentiate COVID-19 from other viral infections.
So far it has been reported that several laboratory markers are deranged in COVID-19 such as d-dimer, lactate dehydrogenase (LDH), interleukin-6 (IL-6), C-reactive protein (CRP), and ferritin (6). These derangements are also seen in other infections, with certain variations, with potential to provide insight into the disease severity as well as in predicting the outcome. Recent studied have investigated the impact of biomarkers that are used for identification of hyperinflammation syndrome (HI-S) in COVID-19 such as ferritin and CRP. It has been shown that fatal outcome from COVID-19 infection closely associated with HI-S development, suggesting that disease severity is associated with increase in specific inflammatory markers (7). However, other markers of inflammation that are more systemic such as LDH and AST have not been yet extensively researched and used in predictive models. Furthermore, cut-off values have been set on the basis higher than normal rather than establishing a new level that could be more accurate in predicting survival or eventual diseases progress.
The exact origin of elevated serum ferritin seen in infectious diseases (hyperferritinemia) is still matter of debate; macrophage activation syndrome and de nuovo biosynthesis of ferritin could explain these elevated levels, also there is evidence that ferritin is released by necrosis or cell damage and subsequent leakage. Probably both pathways are responsible for the elevated levels of ferritin in inflammatory states and this issue needs further research (8). The role of increased ferritin is another matter of debate; its primary role in a healthy organism is in iron storage. At the same time, in inflammation, it seemingly has a role as a mediator between various cells involved in the immune response. Also, it may prevent over extensive damage to the tissue by free radicals and prevent iron being utilized by the pathogen (9).
In other coronavirus outbreaks in the last twenty years (SARS, MERS) the levels of ferritin have not been reported as a predictor or significant marker of inflammation (10, 11). On the other side, in dengue fever, Ebola and Crimean-Congo hemorrhagic fever, elevated levels of serum ferritin have been observed and reported. Interestingly, patients with influenza virus B infection have a low correlation with serum elevation of ferritin (8).
Recently it has been reported that part of the patients with COVID-19 develop hyperinflammatory syndrome (HI-S) which is associated with increased mortality and morbidity. One of the inflammatory markers that are necessary in order to diagnose HI-S in COVID-19 infection is ferritin, and the cut-off level of ferritin for diagnosis is set at 1500 ng/mL and higher (12). Additionally, one study reported that in patients who died from COVID-19 infection, ferritin levels were higher upon hospital admission and during the hospital stay; with median values of serum ferritin levels after day 16 of hospitalization surpassing the upper limit of detection, indicating that ferritin levels were elevated throughout hospitalization (13). Patients, in one study, with a severe form of COVID-19 reported elevated levels of serum ferritin when compared to patients in the non-severe disease group. Therefore, it was assumed that serum ferritin levels were closely linked to the severity of COVID-19 infection (14). Lastly, laboratory findings in patients with severe COVID-19 showed data compatible with the development of cytokine storm with raised inflammatory markers, among them elevated serum ferritin levels. (15). This may strengthen the argument that hyperferritinemia is linked specifically with inflammation in SARS-CoV-2 infection, and consequently, ferritin could be a useful parameter to predict disease severity (9).
Increased serum levels of LDH have been associated with more severe outcome in other virus infections, such as in acute respiratory distress, viral community-acquired pneumonia, and dengue fever (where levels closer to 1000 U/J were correlated with development of a more severe form of the diseases). These findings are consistent with the current medical understanding that high LDH levels are associated with tissue breakdown occurring in various infectious diseases. (16, 17) In previous studies on patients who had been affected in previous coronavirus outbreaks (SARS and MERS), elevated levels of LDH were reported (18). Furthermore, LDH is present in lung tissue and its is one of the primarily affected sites in COVID-19, hence elevated levels of LDH could be the result of lung tissue breakdown (19, 20). Pooled statistical analysis of the impact of increased levels of LDH on severity and outcome in COVID-19 infection have shown an increase of 6-fold in odds of severe COVID-19 disease and a 16-fold increase in a lethal outcome. Elevated levels of LDH were found > 95% In patients with lethal outcome, while < 60% in the survivor group (21). However, the levels of LDH indicative for increased odds of morbidity and mortality have not been thoroughly researched in COVID-19 patients.
This study aims to establish levels of serum ferritin and LDH upon admission and used them as predictors of COVID-19 mortality as well as try to establish independent cut-off levels of ferritin and LDH that have the most significant impact on the survival of COVID-19 patients in Bosnia and Herzegovina (B&H). This is the first study of its kind in B&H that has analyzed these inflammatory markers and tried to make a prognostic model of mortality for COVID-19 patients based serum levels of ferritin and LDH upon admission to the hospital. It is the first study of its kind that has been conducted in B&H and provides information as well as an update on the nature of COVID-19 pandemic in this part of Europe and adds to the body of knowledge regarding COVID-19 that could facilitate further research with providing relevant data.