Discussion
In our study, we found that procalcitonin and lactate levels were higher in patients with severe CCHF when compared to patients with mild and moderate CCHF. In the differentiation of severely ill patients from mild/moderately ill patients, a lactate cut-off value of 1.9 mmol/L had 77.8% sensitivity and 76.9% specificity, whereas a procalcitonin cut-off value of 0.61 ng/mol had 83.3% sensitivity and 89.7% specificity. Both procalcitonin and lactate levels were positively correlated with AST and ALT, which are frequently used parameters in CCHF follow-up.
As in all viral hemorrhagic fevers, the basis of CCHF pathogenesis is viral infection of various cell types, primarily endothelial cells, mononuclear cells, and hepatocytes, followed by proliferation and systematic spread 11. Increased endothelial permeability and consequent endothelial damage is the main pathogenetic process leading to death. This endothelial damage has been attributed to two main mechanisms. The first is a direct viral effect on the endothelial cells, and the second is damage caused indirectly by the cytokines secreted from infected tissues 9,12,13.
The most important of these cytokines are tumor necrosis factor alpha, interleukin (IL)-1, and IL-6, which are synthesized by type 1 helper T cells and are involved in monocyte activation. The activation of monocytes by cytokines impairs platelet activation and degranulation and leads to an abnormal coagulation cascade in CCHF. Monocyte activation is considered one of the main causes of hemophagocytic lymphohistiocytosis, which leads to cytopenia and liver dysfunction in CCHF. Serum AST, ALT, LDH, and creatine kinase (CK) are liver function indicators that are frequently used parameters in clinical follow-up and have been associated with poor prognosis 14-16.
Serum lactate level is another parameter frequently used in the clinical practice, and although it may increase secondary to tissue hypoperfusion, elevation may also occur due to causes unrelated to hypoperfusion 17. Lactate, which can be synthesized in many of the body’s tissues, is eliminated primarily by the liver and to a lesser extent by the kidneys. A substantial proportion of studies evaluating the relationship between lactate level and clinical course and prognosis have observed that hypoperfusion increases lactate level due to sepsis and septic shock 18. Our literature search yielded no studies in which lactate level was associated with the clinical course of CCHF. In the present study, serum lactate level was found to increase in correlation with clinical severity in CCHF patients. This may be attributed to the inadequate elimination of lactate by the liver in CCHF, as liver dysfunction due to hemophagocytic lymphohistiocytosis plays an important role in the clinical course of this condition. Moreover, the increased cytokine levels seen in CCHF due to the indirect effect of the virus might have led to muscle dysfunction and higher levels of creatine kinase as well as lactate. This is corroborated by the fact that muscle and joint pain are among the most common presenting symptoms.
High serum procalcitonin level is often observed in bacterial infections rather than viral infections. However, it has been found that increased cytokine levels also increase amount of procalcitonin synthesized by thyroid C cells in viral infections, independent of bacterial superinfections 8,19. Procalcitonin level was reported to be higher in patients with fatal CCHF and correlated with CRP level, which is frequently used in routine practice 20. None of the patients in our study died after clinical follow-up, and in line with previous studies, we also found that procalcitonin levels were higher in severely ill patients. This level also correlated with liver function markers and serum lactate level. The lack of growth in blood, urine, and sputum cultures performed after the increase in procalcitonin levels suggest that this was due to high cytokine level.
The main limitation of our study was the inability to detect an association between lactate and procalcitonin levels and mortality. This was primarily due to the fact that during the study period, our hospital was designated as a COVID-19 pandemic hospital during the pandemic, and as a result there was a sharp decline in the number of patients we followed due to CCHF in our hospital.