[Investigation of hsa-miR-1908 and hsa-miR-144 Expression Levels in Crimean-Congo Hemorrhagic Fever Patients]. / Kirim-Kongo Kanamali Atesi Hastalarinda hsa-miR-1908 ve hsa-miR-144 Ifade Düzeylerinin Arastirilmasi.

Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne zoonotic viral disease. MicroRNAs (miRNAs), which play an important role in the regulation of gene expression, are involved in many processes essential for cell life such as development, differentiation, survival, apoptosis and aging. If miRNAs fail to fulfill their functions, they cause susceptibility to many diseases, including viral infections or cause the disease to be experienced in different clinical situations, such as severe or mild. In this study, we aimed to determine the expression levels of hsa-miR-144 and hsa-miR-1908 in CCHF patients and to compare the results in different clinical courses of CCHF disease. In this study, expression levels of hsa-miR-144 and hsa-miR-1908 were detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in blood samples obtained from 60 CCHF patients and 40 healthy individuals. We also investigated the differences in the expression levels of the microRNAs between patients with severe and non-severe disease or between patients who died and survived. Quantitative polymerase chain reaction data were uploaded to the "Data Analysis Center" (Qiagen, Germany) and analyzed using the ΔΔCq (ΔΔCt) method. p value was calculated according to Student's t test for genes in the study groups. The expression level of hsa-miR-144 decreased (fold change= 0.09) and the expression level of hsa-miR-1908 increased 1.44-fold in CCHF patients compared to the control group. The expression of hsa-miR-144 and hsa-miR-1908 increased 2 and 2.36-fold, respectively, in severe patients compared to non-severe patients. The expression levels of hsa-miR-144 and hsa-miR-1908 were 16.3- and 14.3-fold higher, respectively, in fatal cases compared to surviving patients and these results were statistically significant. In addition, the expression level of hsa-miR-144 was significantly decreased in patients with low leukocyte counts and the expression level of hsa-miR-1908 was significantly increased in patients with prolonged prothrombin time (PT). This is the first study in the literature investigating the expression level of hsa-miR-1908 in CCHF patients. In conclusion, the data of this study suggest that hsa-miR-144 and hsa-miR-1908 may be important biomarkers in predicting the prognosis and clinical course of CCHF disease.

Long noncoding RNA expression analysis in Crimean Congo hemorrhagic fever patients.

Crimean Congo hemorrhagic fever (CCHF) is an acute viral infection that can cause death. The detection of host transcriptome is important for understanding differences in the pathogenesis of the disease. Long noncoding RNAs (lncRNAs) regulate gene expression in different biological processes. They have also emerged as key molecules for therapeutic targets. We investigated the lncRNA gene expression profiles by utilizing the microarray for the first time in CCHF. LncRNAs were determined by the comparisons between case-control, fatal case-control, and fatal case-nonfatal cases. Quantitative polymerase chain reaction was applied to validate the microarray results of some lncRNAs. In our study, 39 lncRNAs (5 downregulated and 34 upregulated) were found to be significantly regulated in the cases when compared to the controls (p < 0.05; FC ≥ 2). One hundred ten lncRNAs exhibited a statistically significant difference between fatal cases and controls. FER1L4, ECRP, and LOC100133669 are important lncRNAs in both case and fatal case groups compared with controls. These lncRNAs may be considered important therapeutic targets for the CCHF in further studies.

Which scoring system is effective in predicting mortality in patients with Crimean Congo hemorrhagic fever? A validation study.

We aimed to decide which scoring system is the best for the evaluation of the course of Crimean-Congo Hemorrhagic Fever (CCHF) by comparing scoring systems such as qSOFA (quick Sequential Organ Failure Assessment), SOFA (Sequential Organ Failure Assessment), APACHE II (Acute Physiology and Chronic Health Evaluation II) and SGS (Severity Grading System) in centers where patients with CCHF were monitored. The study was conducted with patients diagnosed with CCHF in five different centers where the disease was encountered most commonly. Patients having proven PCR and/or IgM positivity for CCHF were included in the study. The scores of the scoring systems on admission, at the 72nd hour and at the 120th hour were calculated and evaluated. The data of 388 patients were obtained from five centers and evaluated. SGS, SOFA and APACHE II were the best scoring systems in predicting mortality on admission. All scoring systems were significant in predicting mortality at the 72nd and 120th hours. On admission, there was a correlation between the qSOFA, SOFA and APACHE II scores and the SGS scores in the group of survivors. All scoring systems had a positive correlation in the same direction. The correlation coefficients were strong for qSOFA and SOFA, but poor for APACHE II. A one-unit rise in SGS increased the probability of death by 12.818 times. qSOFA did not provide significant results in predicting mortality on admission. SGS, SOFA and APACHE II performed best at admission and at the 72nd and 120th hours.

MicroRNA analysis from acute to convalescence in Crimean Congo hemorrhagic fever.

Crimean Congo hemorrhagic fever (CCHF) is one of the most important viral infections and is caused by Crimean Congo hemorrhagic fever orthonairovirus (CCHFV). Severity of CCHF can vary from a mild and nonspecific illness to a severe disease with fatal outcomes. MicroRNAs (miRNAs) have an increasing impact on the different pathways of viral infections. Within the transition process from acute phase to convalescence with 18 CCHF patients, we investigated the impacts on miRNA via microarray for the first time. We also compared miRNA gene expression in 16 severe and 15 mild cases. We identified Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathways associated with significant miRNAs utilizing DIANA TOOLS mirPath v.3. In this study, miR-15b-5p and miR-29a-3p were significantly downregulated in statistical terms; miR-4741, miR-937-5p, miR-6068, miR-7110-5p, miR-6126, and miR-7107-5p were upregulated in acute cases in comparison with convalescent patients (p ≤ .05). In total, 28 miRNAs (8 downregulated, 20 upregulated) were differentially expressed in severe CCHF patients as compared with mild cases (p ≤ .05). Whereas miR-6732-3p, miR-4436b-5p, miR-483-3p, and miR-6807-5p had the highest downregulation, miR-532-5p, miR-142-5p, miR-29c-3p, and let-7f-5p had the highest upregulation in severe patients in comparison with mild cases. Consequently, we determined that CCHF-induced miRNAs are associated with antiviral and proinflammatory pathways in acute and severe cases. In comparison with convalescence, these miRNAs in acute period may be therapeutic targets.

Investigation of NEAT1, IFNG-AS1, and NRIR expression in Crimean-Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever (CCHF), whose causative agent is CCHF orthonairovirus (CCHFV), demonstrates different symptoms in patients. Long noncoding RNAs (lncRNAs) take part in various pathological processes of viral diseases. They are prominent regulators of antiviral immune responses. To our knowledge, this study is the first study to investigate nuclear paraspeckle assembly transcript 1 (NEAT1), interferon (IFN) gamma antisense RNA 1 (IFNG-AS1), and negative regulator of IFN response (NRIR) expression in CCHF in the literature. We selected these lncRNAs because they are related to IFN signal or IFN-stimulated genes. We investigated NEAT1, IFNG-AS1, and NRIR gene expression in patients with CCHF. Total RNA was extracted from blood samples of 100 volunteers and NEAT1, IFNG-AS1, and NRIR expression were measured using a quantitative real-time polymerase chain reaction. NRIR expression was statistically significant in cases versus controls (p < .001), fatals versus controls (p < .001), and fatals versus nonfatals (p = .01). Furthermore, NRIR was found statistically significant at some clinical parameters including alanine aminotransferase (p = .03), international normalized ratio (p = .03), prothrombin time (p = .02), and active partial thromboplastin time (p = .01) in CCHF cases. NEAT1 and IFNG-AS1 expression were downregulated in the case and fatal groups which were compared with controls. Our results demonstrate that NRIR may be important in CCHF pathogenesis and the target of CCHF treatment.

Glutamine depletion in patients with Crimean-Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever (CCHF) is a viral disease. There is not enough knowledge about plasma amino acid levels in CCHF. Therefore, we investigated plasma amino acid levels in patients with CCHF and the association between the levels of these amino acids and disease severity. The plasma amino acid levels (including glutamate [Glu], aspartate [Asp], glutamine [Gln], asparagine [Asn] and gamma-aminobutyric acid [GABA]) in CCHF patients and controls were measured by using liquid chromatography-mass spectrometry. Plasma levels of Gln were lower while Asp, Glu, and GABA levels were higher in patients. In fatal CCHF patients, we found the plasma level of Asn was increased whereas the plasma level of GABA was decreased. This study is the first in the literature to evaluate the plasma Gln, Glu, Asn, Asp, and GABA levels in CCHF patients. We found that the plasma Gln levels were significantly lower in CCHF patients while Asp, Glu, and GABA levels were elevated. Considering that these amino acids are important for immune cells, the plasma amino acid levels of CCHF patients may contribute to the understanding of the pathophysiology of disease and it can be important for supportive treatment of CCHF.

An Evaluation of the Different Serum Markers Associated with Mortality in Crimean-Congo Hemorrhagic Fever.

BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne viral disease with a high mortality rate. Although CCHF has been widely investigated over the past decade, a review of the literature indicated no data on the prognostic capacity of the mean platelet volume-to-platelet count ratio (MPVPCR) and the red cell distribution width-to-platelet count ratio (RDWPCR) for the systemic inflammatory response in patients with CCHF. This study aimed to evaluate the prognostic ability of MPVPCR and RDWPCR on mortality in patients with CCHF. METHODS: A total of 807 patients that were admitted to the Cumhuriyet University Hospital's Emergency Department from January 2010 to December 2018 were involved. The RDWPCR and MPVPCR were separately calculated via absolute blood red cell and platelet counts at the time of admission. Before performing receiver-operating characteristic (ROC) curve analysis to define the optimum cut-off values of MPVPCR and RDWPCR stepwise logistic regression analysis was used to determine the predictive factors related to mortality in CCHF patients. RESULTS: Values of both MPVPCR and RDWPCR were significantly lower in survivors than in non-survivors (MPVPCR: 0.20±0.23 versus 0.55±0.55, P<0.001; RDWPCR: 0.27±0.32 versus 0.77±0.77, P<0.001, respectively). The MPVPCR (odds ratio [OR], 5.95; P=0.048) was an independent predictor for the prognosis of mortality in CCHF patients. The area under the curve in the ROC curve analysis for MPVPCR was 0.876 with a cut-off of 0.21 (sensitivity 87%, specificity 76%). CONCLUSION: At the time of admission, MPVPCR might be a useful predictor of mortality in patients with CCHF.

Identification of potential microRNA markers related to Crimean-Congo hemorrhagic fever disease.

Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease caused by the arbovirus Crimean-Congo hemorrhagic fever virus (CCHFV). The CCHFV has a single-stranded RNA genome of negative sense. MicroRNAs (miRNAs) are key players in virus-host interactions and viral pathogenesis. We investigated the miRNA gene expression profiles in patients with CCHF using microarray for the first time in the world. Microarray analysis was performed using mirBase Ver 21 (Agilent Technologies, Santa Clara, CA). All statistical analyses were performed across the case-control, fatal-control, and fatal-nonfatal case groups using Genespring (Ver 3.0). Fifteen miRNAs were statistical significant in patients with CCHF compared with the controls (5 were upregulated, 10 were downregulated). Seventy-five and sixty-six miRNAs are in fatal compared with control and nonfatal case, respectively (fold change ([FC] ≥50) were statistically significant. In this study, the target genes of important miRNAs were identified and Gene Ontology analyses were performed across all groups. As a result of this study, we propose that the detection of miRNAs in patients with CCHF will allow the determination of therapeutic targets in diseases. CCHF is an important public health problem that can often be fatal. In this study, we investigated miRNA expression in case-control, fatal-control, and fatal-nonfatal case groups. Significant miRNAs associated with fatality were detected in CCHF. This study will serve as a source of data for the development of an antagomir-based therapy against CCHF using miRNAs in the future.

Apoptosis and its relation with clinical course in patients with Crimean-Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever (CCHF) is a tick-mediated viral infection. Patients with CCHF may show various clinical presentations. The cause of this difference in the clinical course is not completely understood. Apoptosis is programmed cell death and plays an important role in regulating the immune system. Our knowledge of the role of apoptosis in CCHF disease is limited. We investigated the role of apoptosis and their relationship with the severity of the disease in CCHF. Thus, in 30 patients with CCHF and 30 healthy individuals, we analyzed the serum levels of cytochrome C, apoptotic protease activating factor-1 (Apaf 1), caspase 3, caspase 8, caspase 9, sFas, sFasL, perforin, granzyme B, and CK18 by enzyme-linked immunosorbent assay. This is the first study that research the serum levels of the mentioned apoptosis markers in adult patients with CCHF. We found that the serum levels of sFasL, cytochrome C, Apaf 1, caspase 3, caspase 8, caspase 9, perforin, granzyme B, and M30 were statistically significantly different in the acute phase of the disease compared with healthy individuals and patients in convalescent period. There was no association between the clinical severity of the disease and apoptosis markers. In conclusion, the results of our study suggested that the extrinsic and intrinsic apoptosis pathway play an important role in CCHF.

HULC and 7SL RNA expression levels in patients with Crimean-Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease caused by the Crimean-Congo hemorrhagic fever virus. Long non-coding RNAs (lncRNAs) are generally classified as transcripts longer than 200 nucleotides (nt). The various lncRNAs expressed in infected cells are responsible for regulating the expression of viral and host genes. This is the first study to investigate hepatocellular carcinoma upregulated long non-coding RNA (HULC) and 7SL RNA expression levels in patients with CCHF. Blood samples were taken from 100 individuals (60 patients and 40 controls), and total RNA isolation was performed. Quantitative polymerase chain reaction (qPCR) was performed using the SYBR Green method to determine HULC and 7SL RNA expression levels in the study population. Compared the patient and control groups, HULC was upregulated statistically significantly (P = 0.04) and 7SL RNA was downregulated (P = 0.93) in patients. Also, there was a statistically significant difference between fatal cases and surviving patients for HULC and 7SL RNA (P < 0.01 and P = 0.03, respectively). In addition, HULC expression was increased statistically significantly in fatal cases compared with surviving patients in terms of clinical parameters such as aspartate aminotransferase (P < 0.01), alanine aminotransferase (P < 0.01), international normalized ratio (P = 0.05), prothrombin time (P = 0.01), active partial thromboplastin time (P < 0.01), and lactate dehydrogenase (P < 0.01). These findings highlighted that HULC and 7SL RNA could be important mediators for studying the pathogenesis of CCHF and significant therapeutic targets of the disease.

Is the brain spared in Crimean-Congo haemorrhagic fever? An MR-SWI study to reveal CNS involvement.

OBJECTIVES: The aim of this prospective study is to investigate the central nervous system involvement in Crimean-Congo haemorrhagic fever (CCHF) with magnetic resonance imaging (MRI) in conjunction with clinical and laboratory findings. METHODS: Between July 2015 and August 2016, 36 patients with CCHF were undergone brain MRI including SWI. Two MRIs, one at the time of admission and the second in the convalescent period, were performed for each patient in order to see if there is any sign of central nervous system (CNS) involvement, especially in terms of intracranial haemorrhage or viral encephalitis. Clinical severity scoring was also done and laboratory findings were noted in order to correlate with clinical and imaging findings. RESULTS: None of the 36 patients showed any MRI findings of an acute intracranial event during the course of the disease. There was a significant difference between mild cases and moderate cases in terms of some laboratory parameters (p < 0.05). CONCLUSIONS: Although CCHF is a highly lethal disease which involves multiple organs and systems, CNS involvement seems to be extremely rare in mild and moderate cases. KEY POINTS: • MRI is the imaging method of choice to diagnose microbleeds and encephalitis • Although CCHF causes multisystem bleeding, intracranial haemorrhage seems to be very rare • CNS complications are uncommon, even in the setting of suggestive symptoms • Death usually results from extracranial bleeding and multiorgan failure • Severity scoring is associated with some laboratory abnormalities in CCHF.

The protective effect and diagnostic performance of NOX-5 in Crimean-Congo haemorrhagic fever patients.

INTRODUCTION: Crimean-Congo haemorrhagic fever (CCHF) is an acute viral haemorrhagic disease. Reactive oxygen species that are mainly generated by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) enzyme family have a pivotal role in the pathophysiology of many diseases. The serum levels of NOX isoforms in patients with CCHF have yet to be assessed. METHODS: This prospective study was conducted at Cumhuriyet University, Turkey. Only patients with CCHF confirmed by the National Reference Virology Laboratory were enrolled in the study. The study subjects comprised 67 CCHF patients and 70 healthy control subjects. The quantitative sandwich ELISA technique was used for the determination of serum NOX 1, 2, 4 and 5. RESULTS: Higher median median NOX-1 (P=0.001) and NOX-5 (P<0.001) levels were found in patients compared to the control group. Higher median serum NOX-5 levels were found in the low-grade disease group compared to the intermediate-high disease group according to two different severity scores (P=0.003). Negative correlations were also found between the serum NOX-5 levels and the severity scores [(P<0.05, r=-0.259), (P<0.01, r=-0.417)]. The area under the curve (AUC) values for the NOX-1 and NOX-5 were 0.67 (confidence interval: 0.58-0.75) and 0.99 (confidence interval: 0.95-1.00), respectively. Lower NOX-5 levels were found in patients receiving thrombocyte suspension (P=0.004)Conclusions. NOX-5 may have a protective effect on CCHF patients and the measurement of serum NOX-5 levels may be used as a novel biochemical test in the diagnosis of CCHF.

Pasteurella aerogenes as an Asymptomatic Bacteriuria Agent.

'Asymptomatic bacteriuria' (ASB) is isolation of a specified quantitative count of bacteria in an appropriately collected urine specimen obtained from a person without symptoms or signs referable to urinary infection. Catheterized specimens are less likely to be contaminated compared with voided specimens; therefore, positive cultures of catheterized specimens are more likely to reflect true bladder bacteriuria even with low colony counts. The common pathogens for ASB are Escherichia coli, Klebsiella and Streptococcus spp. Pasteurella spp. was not previously reported as an ASB agent. ASB is important for pregnant women, children, individuals with obstructive uropathy, chronic renal failure and neutropenia, before the urologic procedures and after renal transplantation. Treatment of ASB is required for above situations. We report an 11-year-old-girl with neurogenic bladder who made clean intermittent catheterization and had Pasteurella aerogenes as an ASB agent.

Effect of TLR10 (2322A/G, 720A/C, and 992T/A) polymorphisms on the pathogenesis of Crimean Congo hemorrhagic fever disease.

Crimean Congo hemorrhagic fever (CCHF) is a tick-borne disease caused by the Crimean Congo hemorrhagic fever virus (CCHFV). Toll-like receptors (TLRs) are type 1 transmembrane proteins of immune cells that play a critical role in innate and adaptive immunity. The present study first time aims to investigate the relation between TLR10 gene polymorphisms (720A/C, 992T/A, and 2322A/G), severity/non-severity, fatality/non-fatality, and CCFH disease by using PCR-RFLP assay in a Turkish population. TLR10 720A/C polymorphism was determined to be statistically significant both genotype and allele frequency (P = 0,011, P = 0.015, respectively). TLR10 992T/A polymorphism was found statistically significant relationships between patient and control (P = 0.026) and individual with AA genotype have approximately three times greater risk than TT genotype (OR = 2.93). There was not a significant difference in 2322A/G genotype distribution (P = 0.152). There were also statistically significant associations between both TLR10 992T/A and 2322A/G polymorphism and patient mortality (P = 0.001 and P = 0.008, respectively). We have not found statistically any linkage among TLR10 haplotype, but individual AAA and GAT haplotype have higher risk than individual AAT haplotype (OR = 3.22, OR = 1.93, respectively). Consequently, this study shows that pathogenesis of CCHF disease is associated with the TLR10 720A/C and 992T/A polymorphisms. There is a statistically significant association in fatal/non-fatal patients with TLR10 720A/C and 992T/A. The TLR10 992AA genotype might increase and TLR10 720CC genotype might decrease susceptibility to pathogenesis of CCHF disease. TLR 10 polymorphisms may be also an important biomarker for CCHF susceptibility and fatality rate.

Determination of nasal mucociliary clearance time and nasal symptom in patients with Crimean-Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever (CCHF) is an important health problem in Turkey. Number of studies on symptoms of ear nose throat system and indicating whether or not the organs are affected in patients with CCHF is limited. The aim of the present study was to investigate whether CCHF infections caused any change in nasal physiology in adult patients or not by using saccharin transit time (STT) and nasal symptom scoring. Twenty subjects with laboratory-confirmed diagnosis of CCHF and 28 healthy control subjects were included in the present study. A saccharin test was used to evaluate nasal mucociliary clearance time (NMCT) and the nasal symptom scoring used in allergic rhinitis was modified and used to examine the symptoms of the patients. The average STT of CCHF and control groups were 472.70 ± 151.58 and 276.07 ± 89.65 sec, respectively. The difference between them was statistically significant (P = 0.00, P < 0.05). When those in CCHF group were classified according to timing of the test, STT average of those undergoing the test on the 1st-3rd days (n = 10) and 4th-6th (n = 10) days was 547.00 ± 154.37 and 398.40 ± 111.39 sec, respectively. The difference between them was statistically significant (P = 0.024; P < 0.05). The results of the present study showed that NMCT prolonged in adult patients with CCHF compared to those in the control group despite the fact that it was within normal limits. For these reasons, clinicians should follow-up CCHF patients more closely for respiratory tract diseases and sinonasal and middle ear infections. J. Med. Virol. 89:960-965, 2017. © 2016 Wiley Periodicals, Inc.

Retrospective analysis of the microbiological spectrum of pneumonia in Turkish patients with lung cancer.

AIM OF THE STUDY: The spectrum of pulmonary infections in patients with lung cancer is wide, and tools for target-oriented infection control measures are necessary. In this retrospective study we report the microbiological spectrum of pneumonia (based on the results of sputum culture) in a case series of Turkish patients with lung malignancies. MATERIAL AND METHODS: Between 2010 and 2011 a total of 119 patients (111 males and 8 females, mean age: 59.8 ±9.6 years) with lung cancer and pneumonia were identified at the Department of Medical Oncology of two Turkish Universities (Uludag University, Bursa and Cumhuriyet University, Sivas). Expectorated sputum samples were collected in sterile specimen containers and processed immediately in the hospital bacteriology laboratory. RESULTS: Of the 119 study patients, 92 (77.3%) had positive isolates from sputum cultures. The most frequent isolate from the sputum of lung cancer patients with pneumonia was Aspergillus fumigatus (n = 22), followed by Haemophilus influenzae (n = 13) and Pseudomonas aeruginosa (n = 12). The likelihood of having a positive Aspergillus fumigatus sputum culture was significantly and independently associated with febrile neutropaenia (OR = 1.32, 95% CI: 1.17-3.68, p < 0.05) and the development of pneumonia within the first 10 days of chemotherapy initiation (OR = 1.78, 95% CI: 1.37-4.12, p < 0.01). CONCLUSIONS: We conclude that Aspergillus fumigatus was the most frequent isolate, but the high diversity of pathogens clearly challenges the empirical use of antimicrobial drugs.

Is there any relationship between Toll-like receptor 3 c.1377C/T and -7C/A polymorphisms and susceptibility to Crimean Congo hemorrhagic fever?

Crimean-Congo hemorrhagic fever (CCHF) is an infectious disease that is caused by CCHF virus. A family of transmembrane receptors called as Toll-like receptors (TLRs) selectively acts in recognizing a wide range of microbial components and endogenous molecules released by damaged tissue and have been preserved throughout evolution. TLRs initiate some signaling cascades which activate the innate immune system. Mainly four TLRs act in protection against viral infections; TLR3 is one of them. TLR3 identifies dsRNA. By producing inflammatory cytokines and type I interferons, it generates an antiviral immune response. Proper response to TLR ligands may be impaired by single nucleotide polymorphisms (SNPs) within TLR genes in some indviduals, and this can cause varied susceptibility to infections. In the present work, polymerase chain reaction-based restriction fragment length polymorphism is used to analyze the frequencies of TLR3 (c.1377C/T and -7C/A) polymorphisms in 149 CCHF patients and 171 healthy adults as controls, in Cumhuriyet University, Sivas/Turkey. We also investigated the relation between these polymorphisms and severity or mortality of CCHF disease. This is the first study investigating the TLR3 SNPs in patients with CCHF. In the present study, the frequency of the TLR3 (c.1377C/T and -7A/C) genotypes in fatal and non-fatal cases were comparable, however, the homozygous mutant (TT) genotype frequency of TLR3 c.1377C/T in CCHF patients was significantly higher than that of the healthy controls. In conclusion, presence of TLR3 c.1377 TT genotype may have a role in the susceptibility to CCHF. J. Med. Virol. 88:1690-1696, 2016. © 2016 Wiley Periodicals, Inc.

Relationship between IFNA1, IFNA5, IFNA10, and IFNA17 gene polymorphisms and Crimean-Congo hemorrhagic fever prognosis in a Turkish population range.

Crimean-Congo hemorrhagic fever (CCHF) is a fatal emerging acute viral infection. Not much is known regarding the pathogenic mechanisms and the reasons behind severe or mild disease courses in CCHF. IFN-alpha (IFNA) is one of the essential cytokines in the immune system. Existence of single nucleotide gene polymorphisms (SNPs) in cytokines can cause susceptibility or resistance to viral agents and different clinical courses. Hence, the relationship between SNPs in genes encoding cytokines (IFNA1 -1823G/A (rs1332190), IFNA5 -2529T/A (rs758236), IFNA10 Cys20stop (rs10119910), and IFNA17 Ile184Arg (rs9298814) SNPs and disease susceptibility were investigated. The associations between SNPs and CCHF prognosis were also studied. Total 150 patients with CCHF and 170 healthy individuals were enrolled. Genotyping was performed by PCR-RFLP methods. The frequency of IFNA1 -1823 (rs1332190) GG genotype was significantly higher in control subjects than CCHF patients (20% vs. 8%; P = 0.01). For IFNA17 Ile184Arg (rs9298814) polymorphism, CCHF patients having TG genotype had a higher frequency than the control subjects (38% vs. 32.4%; P = 0.039). The distribution of TT + TG genotype frequencies was also significantly higher in CCHF group than the controls (97.3% vs. 91.8%; P = 0.049). Genotype and allele frequencies for IFNA subtypes between fatal and survivors were the same (P > 0.05). Genotype and allele frequencies between severe and mild/moderate CCHF patients were also the same (P > 0.05). The results show that IFNA1 rs1332190 and IFNA17 rs9298814 SNPs may play an important role in CCHF susceptibility. Determining the existence of other connections for IFNA SNPs and CCHF severity and fatality requires further investigations.

Relationship of plasma cell-free DNA level with mortality and prognosis in patients with Crimean-Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever (CCHF) is a viral infection. Circulating plasma cell-free DNA (pcf-DNA) is a novel marker indicating cellular damage. So far, the role of pcf-DNA did not investigate in CCHF patients. In the current study, pcf-DNA levels were investigated in CCHF patients with different clinical severity grades to explore the relationship between circulating pcf-DNA level, virus load, and disease severity. Seventy-two patients were categorized as mild, intermediate, and severe based on severity grading scores. The pcf-DNA level was obtained from all participants on admission and from the survivors on the day of the discharge. The controls consisted of 31 healthy. Although the pcf-DNA level at admission was higher in patients than in the controls, the difference was not statistically significant (P = 0.291). However, at admission and in the convalescent period, the difference between pcf-DNA levels in mild, intermediate, and severe patient groups was significant. The pcf-DNA level in severe patients was higher than in the others. Furthermore, compared to survivors, non-survivors had higher pcf-DNA levels at admission (P = 0.001). A direct relationship was found between the pcf-DNA level and the viral load on the day of discharge in surviving patients. ROC curve analysis identified a pcf-DNA level of 0.42 as the optimal cut-off for prediction of mortality. The positive predictive value, negative predictive value, specificity, and sensitivity for predicting mortality was 100%, 72%, 100%, and 79%, respectively. In summary, our findings revealed that pcf-DNA levels may be used as a biomarker in predicting CHHF prognosis.