1. Introduction
Crimean-Congo Hemorrhagic Fever (CCHF) is a severe viral infection with substantial implications for public health in a wide range of countries in Asia, Africa, Southern Europe and the Middle East. CCHF is caused by CCHF virus (CCHFV) belonging to the genus of Orthonairovirus, and the family of Nairoviridae being one of deadliest viruses of its kind with reported mortality rate of 3-30% (1). CCHFV is transmitted to humans through tick bites of infected ticks, contact with blood or tissues of infected livestock, or contact with infected patients (2). The exact course of pathogenesis of CCHF is not clearly known however it is divided into four phases: incubation, pre-haemorrhagic, haemorrhagic and convalescence (2, 3). CCHF is classified as a severe hemorrhagic fever with a short incubation period of 1-3 days although longer incubation periods have been documented (3, 4). The onset of infection is often sudden and includes symptoms, fever, diarrhea, vomiting, nausea, myalgia, back and abdominal pain followed by an hemorrhagic phase where severe bruises, uncontrollable bleeding at the body orifices are observed and in severe cases, deterioration of kidneys, liver and lungs (5). Deaths associated with the infection mostly occur between 5-14 days from the start of the viremic phase (6, 7). In terms of treatment, early hospitalizations and early administration of therapeutics are shown to reduce both severity and mortality of CCHF (8). Hence, lack of early detection of CCHF is one of the leading factors causing the particular high mortality rate of CCHF.
There are several challenges of diagnosing CCHF infection particularly before the hemorrhagic phase of the infection and patients who are not suspected of being bitten by infected ticks or contacted with infected livestock. CCHF is relatively rare in certain areas, so healthcare providers may not consider CCHF as a possible diagnosis at first. Likewise, there are documented cases of difficulties diagnosing CCHF, both because of the latter but also the absence of a universally applicable diagnostic kit for surveillance and diagnosis of all CCHFV strains (9). Standard blood tests such as hemogram, biochemical analysis and physical examination at the beginning of hospitalization is applied on all patients who are suspected to be infected with CCHF although the results are often relevant for short term prognostic factors as biochemical values change often quickly. More comprehensive tests such as viral antigen and nucleic acid amplification tests are used as standard diagnostic methods (10). The initial symptoms of CCHF, such as fever, headache, and muscle aches, are rather non-specific hence diagnosing CCHF early by differential diagnosis can be difficult. (3,6) Biomarkers, essentially biomolecules, provide a measure of specific diseases or their stages due to their varying concentrations. They are instrumental in diagnosing and monitoring the progression of viral infections. The associated changes in their levels, often indicative of the disease, are typically attributed to the host’s immune reaction and the disturbance of key biochemical routes in reaction to the infectious process. In this sense, omics studies and biomarkers could be used for both analysis and diagnosis of CCHF and for characterizing better treatment strategies of hospitalized patients swiftly is crucial to pinpoint optimal treatment strategies for treating CCHF (11).
So far there is only one omics study which investigates host-viral response and pathogenesis of CCHF utilizing transcriptomics and proteomics methods (12). Led by this gap in the literature, we conducted a nationwide analysis of metabolomes of patients hospitalized due to CCHF. Turkey has over 10,000 cases of CCHF with an average fatality rate of 5%, making it a critical public health concern affecting people living in rural areas as ticks are widespread in these regions (13). In our present investigation, we employed Nuclear Magnetic Resonance (NMR) spectroscopy exploratory metabolomics to investigate the overall temporal variations in plasma metabolites during a seasonal outbreak of CCHF infection. We employed PLS-DA statistical analysis of the blood serum metabolome of CCHF patients and categorized certain metabolomes linked to metabolic dysregulation caused by CCHF. Preliminary results from our study suggest that specific metabolic markers can be identified in the serum of CCHF patients pointing to metabolic dysregulation, which may allow for earlier diagnosis and more targeted treatment strategies. Additionally, being the first study to categorize alterations of patient metabolome during CCHF viremic phase may be valuable for efforts to develop therapeutics or targeted treatment strategies to reduce the severity and high mortality rate of CCHF.