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.