Predictors of Mortality in Crimean-Congo Hemorrhagic Fever Patients Admitted at a Tertiary Care Hospital in Pakistan over the Last 10 Years: A Case-Control Study.

The objective was to identify predictors of mortality in hospitalized patients with Crimean-Congo hemorrhagic fever (CCHF). A case-control study was conducted on patients hospitalized with CCHF from 2012 to 2022. Risk factors for mortality in CCHF patients were analyzed using logistic regression. A total of 86 patients with a median age of 36 years (interquartile range [IQR], 27-36 years) were included, and the majority were males (78, 90.7%). Thirty-one patients (36%) were cases, whereas 55 (64%) were control patients. Based on univariate logistic regression analysis, patients who were in an age group of ≥40 years (odds ratio [OR]: 4.85; 95% CI: 1.8-12.4) or with presence of gum bleeding (OR: 2.66; 95% CI: 1.0-6.8), unit increase in white blood cell count (WBC) (OR: 1.09; 95% CI: 1.00-1.07), serum glutamate-pyruvate transaminase of ≥500 U/L (OR: 3.68; 95% CI: 1.4-9.3), serum glutamic-oxaloacetic transaminase (SGOT) of ≥1,000 U/L (OR: 8.72; 95% CI: 2.6-28.3), prothrombin time (PT) of ≥120 seconds (OR: 9.85; 95% CI: 3.2-29.8), international normalized ratio of ≥5 (OR: 15.8; 95% CI: 2.0-125.3), or acute respiratory distress syndrome (ARDS) (OR: 28.27; 95% CI: 5.84-136.9) were found to be significantly associated with mortality in CCHF. Factors found to be independently associated with mortality on multivariate analysis included ARDS (adjusted OR [aOR]: 27.7; 95% CI: 4.0-190.5), unit increase in WBC (aOR: 1.02; 95% CI: 1.02-1.26), SGOT of ≥1,000 U/L (aOR: 23.6; 95% CI: 2.32-241.7), and PT of ≥120 seconds (OR: 10.2; 95% CI: 2.00-52.4). CCHF is a rare but fatal disease, and patients with ARDS and increased WBC, high SGOT level, and increased PT indicative of liver injury and coagulopathy at the time of hospitalization are at high risk for mortality.

Worldwide epidemiology of Crimean-Congo Hemorrhagic Fever Virus in humans, ticks and other animal species, a systematic review and meta-analysis.

There are uncertainties about the global epidemiological data of infections due to Crimean-Congo hemorrhagic fever virus (CCHFV). We estimated the global case fatality rate (CFR) of CCHFV infections and the prevalence of CCHFV in humans, ticks and other animal species. We also explored the socio-demographic and clinical factors that influence these parameters. In this systematic review with meta-analyses we searched publications from database inception to 03rd February 2020 in Pubmed, Scopus, and Global Index Medicus. Studies included in this review provided cross-sectional data on the CFR and/or prevalence of one or more targets used for the detection of CCHFV. Two independent investigators selected studies to be included. Data extraction and risk of bias assessment were conducted independently by all authors. Data collected were analysed using a random effect meta-analysis. In all, 2345 records were found and a total of 312 articles (802 prevalence and/or CFR data) that met the inclusion criteria were retained. The overall CFR was 11.7% (95% CI = 9.1-14.5), 8.0% (95% CI = 1.0-18.9), and 4.7% (95% CI = 0.0-37.6) in humans with acute, recent, and past CCHFV infections respectively. The overall CCHFV acute infections prevalence was 22.5% (95% CI = 15.7-30.1) in humans, 2.1% (95% CI = 1.3-2.9) in ticks, and 4.5% (95% CI = 1.9-7.9) in other animal species. The overall CCHFV recent infections seroprevalence was 11.6% (95% CI = 7.9-16.4) in humans and 0.4% (95% CI = 0.0-2.9) in other animal species. The overall CCHFV past infections seroprevalence was 4.3% (95% CI = 3.3-5.4) in humans and 12.0% (95% CI = 9.9-14.3) in other animal species. CFR was higher in low-income countries, countries in the WHO African, South-East Asia and Eastern Mediterranean regions, in adult and ambulatory patients. CCHFV detection rate in humans were higher in CCHFV suspected cases, healthcare workers, adult and hospitalized patients, ticks of the genus Ornithodoros and Amblyomma and in animals of the orders Perissodactyla and Bucerotiformes. This review highlights a significant disease burden due to CCHFV with a strong disparity according to country income levels, geographic regions, various human categories and tick and other animal species. Preventive measures in the light of these findings are expected.

Efficacy of therapeutic plasma exchange in patients with Crimean-Congo hemorrhagic fever.

OBJECTIVE: To examine the efficacy of therapeutic plasma exchange (TPE) in patients critically ill with Crimean-Congo hemorrhagic fever (CCHF). METHODS: Patients with CCHF received supportive treatment (ST) or TPE. After laboratory and clinical evaluations, the patients were divided into mild, moderate, and severe CCHF groups according to the severity score index (SSI). To assess the efficacy of TPE, the incubation period, time of admission to hospital, hospitalization duration, mortality rate and times to recovery of the platelet count and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were compared between patients receiving ST and TPE. RESULT: A total of 119 confirmed CCHF cases was analyzed. The median SSIs were 7 in the TPE group and 5 in the ST group. The SSI stages, median incubation times and admission times were similar in the two groups. However, the duration of hospitalization was longer in the TPE group. The overall mortality rates were 9% (3 of 33 patients) in the TPE group and 16% (5 of 31 patients) in the ST group; the difference was significant. The platelet count recovered after a median of 6 (4-7) days in the ST group. CONCLUSION: The mortality rate was lower in the TPE group than in the ST group, but the duration of hospitalization and the time to platelet recovery were longer in the TPE group than in the ST group. TPE did not contribute significantly to the prognosis of patients with intermediate-severity CCHF. However, TPE might be efficacious in patients with severe CCHF.

Comparison of the Predictive Performances of qSOFA, APACHE II, and SGS for Evaluation of the Disease Prognosis of CCHF Patients at the Emergency Department.

In this study, we compared the predictive performances of quick sequential organ failure assessment (qSOFA), the acute physiology and chronic health evaluation (APACHE II) scores, and the severity grading score (SGS) for evaluation of the disease prognosis of patients with Crimean-Congo hemorrhagic fever (CCHF) at the emergency department. We recorded the qSOFA, SGS, and APACHE II scores at admission and at the 72nd and 120th hour in 97 patients admitted to the emergency department and diagnosed with CCHF. In our study, the area under a receiver operating characteristic curve values of qSOFA, SGS, and APACHE II at admission were found to be 0.640, 0.824, and 0.576, respectively. No statistical significance was found for a qSOFA score ≥ 2 at admission as a predictor of mortality. The use of qSOFA score for diseases with a mortal prognosis such as CCHF is insufficient in predicting the prognosis.

Structure and Characterization of Crimean-Congo Hemorrhagic Fever Virus GP38.

Crimean-Congo hemorrhagic fever virus (CCHFV) is the causative agent of the most widespread tick-borne viral infection in humans. CCHFV encodes a secreted glycoprotein (GP38) of unknown function that is the target of a protective antibody. Here, we present the crystal structure of GP38 at a resolution of 2.5 Å, which revealed a novel fold primarily consisting of a 3-helix bundle and a ß-sandwich. Sequence alignment and homology modeling showed distant homology between GP38 and the ectodomain of Gn (a structural glycoprotein in CCHFV), suggestive of a gene duplication event. Analysis of convalescent-phase sera showed high titers of GP38 antibodies indicating immunogenicity in humans during natural CCHFV infection. The only protective antibody for CCHFV in an adult mouse model reported to date, 13G8, bound GP38 with subnanomolar affinity and protected against heterologous CCHFV challenge in a STAT1-knockout mouse model. Our data strongly suggest that GP38 should be evaluated as a vaccine antigen and that its structure provides a foundation to investigate functions of this protein in the viral life cycle.IMPORTANCE Crimean-Congo hemorrhagic fever virus (CCHFV) is a priority pathogen that poses a high risk to public health. Due to the high morbidity and mortality rates associated with CCHFV infection, there is an urgent need to develop medical countermeasures for disease prevention and treatment. CCHFV GP38, a secreted glycoprotein of unknown function unique to the Nairoviridae family, was recently shown to be the target of a protective antibody against CCHFV. Here, we present the crystal structure of GP38, which revealed a novel fold with distant homology to another CCHFV glycoprotein that is suggestive of a gene duplication event. We also demonstrate that antibody 13G8 protects STAT1-knockout mice against heterologous CCHFV challenge using a clinical isolate from regions where CCHFV is endemic. Collectively, these data advance our understanding of GP38 structure and antigenicity and should facilitate future studies investigating its function.

Identification of the crucial parameters regarding the efficacy of ribavirin therapy in Crimean-Congo haemorrhagic fever (CCHF) patients: a systematic review and meta-analysis.

OBJECTIVES: Recently, ribavirin has been suggested as a therapeutic approach in Crimean-Congo haemorrhagic fever (CCHF) patients; however, there are controversial findings about its efficacy. In the current study, a meta-analysis was systematically performed to assess the effectiveness of ribavirin administration regarding CCHF patient survival and to explore the most important influential parameters for its efficacy. METHODS: All of the outcomes of the clinically studied CCHF patients who were treated with ribavirin were included in the meta-analysis. RESULTS: Overall, 24 studies met our criteria. Although the studies did not have high quality there was no heterogeneity and publication bias across studies. The results indicated that the administration of ribavirin to CCHF patients significantly decreased the mortality rate (by 1.7-fold) compared with those who did not receive this medication. Furthermore, it was found that the prescription of ribavirin in the initial phase of disease was more effective, and a delay in the start of treatment resulted in a 1.6-fold increase in mortality rate. In addition, interventional therapy resulted in an ∼2.3-fold reduction in the mortality rate of those who received ribavirin along with corticosteroids compared with those who were treated with ribavirin monotherapy. CONCLUSIONS: This meta-analysis reveals that ribavirin should be considered as a crucial antiviral drug in the therapeutic approach used for CCHF patients, especially in early phases of the disease. Additionally, it seems that the administration of corticosteroids alongside ribavirin can play an effective role in alleviation of the disease status, particularly in haemorrhagic phases.

Crimean-Congo Haemorrhagic Fever: Case study analysis of a sporadic outbreak from Chakwal, Pakistan.

Crimean-Congo Haemorrhagic Fever (CCHF) is a deadly viral zoonotic disease, which is endemic in Pakistan. We report a case study analysis of three cases of CCHF which occurred in Chakwal, Pakistan in 2016. The disease was suspected in three patients exhibiting clinical symptoms suggestive of CCHF; two of the three patients died. The presence of CCHF was detected by seroconversion (IgG) from the surviving patient, while the antigen was detected in Hyalomma ticks originating from animals in the vicinity. This report indicates increase threat emergence of CCHF in Pakistan and highlights its zoonotic implications requiring immediate interventions under the "One-Health" concept.

The relationship with clinical course and prognosis of serum endothelin-1, angiopoietin-2, and tie-2 levels in Crimean-Congo hemorrhagic fever

Background/aim: Crimean-Congo hemorrhagic fever (CCHF) is a serious illness characterized by fever and hemorrhage. Endothelin-1 (ET-1), angiopoietin-2 (Ang-2), and endothelial cell-specific receptor tyrosine kinase (Tie-2) are believed to be important markers of the pathogenesis, clinical course, and prognosis of the disease. The aim of this study was to determine ET-1, Ang-2, and Tie-2 levels in adults with CCHF and investigate the associations between these markers and pathogenesis and disease course. Materials and methods: Sixty CCHF patients were included in the study. The patients were classified according to disease severity criteria and Ang-2, Tie-2, and ET-1 levels were compared. Results: Mean serum ET-1 level was 36.62 ± 27.99 pg/mL in the patient group and 3.70 ± 4.71 pg/mL in the control group (P = 0.001). Mean serum Ang-2 levels were 2511.18 ± 1018.64 pg/mL in the patient group and 3570.76 ± 209.52 pg/mL in the control group (P = 0.001). Mean serum Tie-2 levels were 7.35 ± 7.75 ng/mL in the patient group and 0.67 ± 1.26 ng/mL in the control group (P = 0.001). Conclusion: Elevated ET-1 and Tie-2 levels were associated with more severe disease course, while Ang-2 level was negatively correlated with severity in adult CCHF patients. ET-1, Tie-2, and Ang-2 levels are important prognostic parameters in CCHF and may contribute significantly to treatment and follow-up.

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.

Factors related to fatalities and clinical progression of Crimean-Congo hemorrhagic fever patients and the effects of IL 28-B gene polymorphism.

Mortality rates of Crimean-Congo hemorrhagic fever (CCHF) vary from 5% to 80%. However, there is no clear information available about why this disease is fatal for some people while others recover. In this study, the factors related to fatalities and serious clinical progression of CCHF patients and the correlation between serious prognosis and IL 28-B gene polymorphism were investigated. The study included 107 patients with a preliminary diagnosis of CCHF, and the patients were found positive for CCHFV RNA based on polymerase chain reaction (PCR) analysis. The IL 28-B rs12979860 polymorphism was identified by PCR "restriction fragment length polymorphism" (PCR-RFLP) analysis using blood samples from the patients. In addition to the IL 28-B analysis results, a variety of data along with laboratory records obtained during the hospital stay were evaluated using statistical analysis. Of the 107 cases, nine were fatal (8.4%), while the other patients recovered and were discharged. Twenty-four patients had the CC genotype (22.43%), 64 had the CT genotype (59.81%), and 19 had the TT genotype (17.76%). Of the nine patients who died, three had the CC genotype (33.33%) and six had the CT genotype (66.67%). None of the patients who died had the TT genotype. Symptoms and findings of diarrhea, abdominal pain, hemorrhage, and rash were more common in fatal cases than in non-fatal cases. The IL 28-B rs12979860 polymorphism was not found to have a statistically significant correlation with fatality or symptoms indicating serious clinical progression in CCHF patients. As has been observed in previous studies, our study showed that leukocytosis, abdominal pain and diarrhea were more common in fatal cases.

Effects of Paraoxonase-1 variants on course of severity and mortality of Crimean-Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever (CCHF) is an acute viral hemorrhagic fever caused by Crimean Congo hemorrhagic fever virus (CCHFV). Paraoxonase-1 (PON1) is a high density lipoprotein (HDL)-binding protein which defense the body against oxidative stress. To investigate the role of the PON1 gene in CCHF, we screened the genotypes of two single nucleotide polymorphisms (Q192R [rs662] and L55M [rs854560]) in CCHF patients stratified according to course of severity and mortality by using PCR-based RFLP assay. Overall, 132 patients diagnosed as CCHF were enrolled in this study. The frequencies of the three genotypes and two alleles of Q192R and L55M polymorphisms didn't show any statistically significant differences in terms of mortality and disease severity (p > 0.05). Any statistically significant differences were not found between severe and mild and fatal and non-fatal CCHF patients according to seven composite genotypes (p > 0.05). When we analyzed the clinical characteristics of CCHF patients stratified according to PON1gene polymorphisms, any statistically significant differences were not also observed (p > 0.05). Our study showed no possible association between genotypes of PON1 gene Q192R and L55M polymorphisms and CCHF.

Effects of platelet function on the haemorrhagic manifestations and mortality in Crimean-Congo haemorrhagic fever.

Crimean-Congo haemorrhagic fever (CCHF) is a viral zoonotic disease which can lead to life-threatening with haemorrhagic manifestations. We aimed here in this study was to evaluate the effect of the platelet count and volume-related indices, such as the mean platelet volume (MPV), platelet distribution width (PDW) which is a measure of platelet anisocytosis and plateletcrit, in the haemorrhagic manifestations and mortality seen in CCHF cases. We retrospectively examined data derived from 173 patients. The age, gender, alanine transaminase (ALT), aspartate transaminase (AST), platelet counts and MPV, PDW and PCT values upon admission (MPV1, PDW1 and PCT1) and those values measured at the time when the PLT was at the lowest level (MPV2, PDW2 and PCT2), haemorrhagic manifestations and the mortality status of patients diagnosed with CCHF were recorded. ALT and AST values were higher among the haemorrhagic patients when compared with the others (p<0.001), while platelet 1 (PLT1), platelet 2 (PLT2), plateletcrit 1 (PCT1), plateletcrit 2 (PCT2) and platelet distribution width 2 (PDW2) values were significantly lower (p=0.001, p<0.001, p=0.002, p<0.001 and p=0.003, respectively). A negative correlation was documented between haemorrhage and the PLT1, PLT2, PCT1, PCT2 and PDW2 (r=-0.255, r=-0.415, r=-0.241, r=-0.377, r=-0.223, respectively); however, there was a positive correlation between haemorrhage and mortality (r=0.34). This was the first study evaluating the platelet functions in CCHF, such as the PLT, PDW and PCT, in CCHF correlated with the mortality and haemorrhagic manifestations. The platelet functions contribute as much to the prediction of haemorrhage and mortality as the PLT. The present study suggests that the PCT and PDW values could be beneficial in anticipating the inclination toward haemorrhage and mortality.

Systematic Review and Meta-analysis of Postexposure Prophylaxis for Crimean-Congo Hemorrhagic Fever Virus among Healthcare Workers.

We performed a systematic review and meta-analysis on the effectiveness of ribavirin use for the prevention of infection and death of healthcare workers exposed to patients with Crimean-Congo hemorrhagic fever virus (CCHFV) infection. Splashes with blood or bodily fluids (odds ratio [OR] 4.2), being a nurse or physician (OR 2.1), and treating patients who died from CCHFV infection (OR 3.8) were associated with healthcare workers acquiring CCHFV infection; 7% of the workers who received postexposure prophylaxis (PEP) with ribavirin and 89% of those who did not became infected. PEP with ribavirin reduced the odds of infection (OR 0.01, 95% CI 0-0.03), and ribavirin use <48 hours after symptom onset reduced the odds of death (OR 0.03, 95% CI 0-0.58). The odds of death increased 2.4-fold every day without ribavirin treatment. Ribavirin should be recommended as PEP and early treatment for workers at medium-to-high risk for CCHFV infection.

Cutaneous Findings of Crimean-Congo Hemorrhagic Fever: a Study of 269 Cases.

Crimean-Congo hemorrhagic fever (CCHF) is a zoonotic viral disease. We aimed to investigate the cutaneous manifestations of CCHF and reveal their associations with fatality. Two hundred and sixty-nine patients diagnosed with CCHF were assessed. Skin findings were observed in 170 (63.2%) patients. A facial rash was the most common cutaneous finding (n = 82, 30.5%). In severe cases, hemorrhagic cutaneous manifestations (petechiae and ecchymoses) were recognized. A statistically significant correlation was obtained between cutaneous manifestations and fatality, and it was determined that there was a strong positive correlation between fatality and ecchymosis (r = 567, p < 0.001). In addition, a logistic regression analysis was performed, and death occurred 4.69 times more in those with skin signs than in those without. We hypothesize that CCHF patients with ecchymosis are at the highest risk and that cutaneous findings can contribute to the prognosis of 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.

Ribavirin for treating Crimean Congo haemorrhagic fever.

BACKGROUND: Crimean Congo haemorrhagic fever (CCHF) is a tick-borne disease that occurs in parts of Asia, Europe and Africa. Since 2000 the infection has caused epidemics in Turkey, Iran, Russia, Uganda and Pakistan. Good-quality general supportive medical care helps reduce mortality. There is uncertainty and controversy about treating CCHF with the antiviral drug ribavirin. OBJECTIVES: To assess the effects of ribavirin for treating people with Crimean Congo haemorrhagic fever. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (OVID); Science Citation Index-Expanded, Social Sciences Citation index, conference proceedings (Web of Science); and CINAHL (EBSCOHost). We also searched the WHO International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for trials in progress. We conducted all searches up to 16 October 2017. We also contacted experts in the field and obtained further studies from these sources. SELECTION CRITERIA: We evaluated studies assessing the use of ribavirin in people with suspected or confirmed Crimean Congo haemorrhagic fever. We included randomised control trials (RCTs); non-randomised studies (NRSs) that included more than 10 participants designed as cohort studies with comparators; and case-control studies. DATA COLLECTION AND ANALYSIS: Two review authors assessed eligibility, risk of bias, and extracted data. For non-randomized studies we used the ROBINS-I tool to assess risk of bias. The main effects analysis included all studies where we judged the risk of bias to be low, moderate or high. We summarized dichotomous outcomes using risk ratios (RRs) and continuous outcomes using mean differences (MDs), and used meta-analyses where appropriate. We carried out a subsidiary appraisal and analysis of studies with critical risk of bias for the primary outcome, as these are often cited to support using ribavirin. MAIN RESULTS: For the main effects analysis, five studies met our inclusion criteria: one RCT with 136 participants and four non-randomized studies with 612 participants. We excluded 18 non-randomized studies with critical risk of bias, where none had attempted to control for confounding.We do not know if ribavirin reduces mortality (1 RCT; RR 1.13, 95% confidence interval (CI) 0.29 to 4.32; 136 participants; very low-certainty evidence; 3 non-randomized studies; RR 0.72, 95% CI 0.41 to 1.28; 549 participants; very low-certainty evidence). We do not know if ribavirin reduces the length of stay in hospital (1 RCT: mean difference (MD) 0.70 days, 95% CI -0.39 to 1.79; 136 participants; and 1 non-randomized study: MD -0.80, 95% CI -2.70 to 1.10; 50 participants; very low-certainty evidence). We do not know if it reduces the risk of patients needing platelet transfusions (1 RCT: RR 1.23, 95% CI 0.77 to 1.96; 136 participants; very low-certainty evidence). For adverse effects (including haemolytic anaemia and a need to discontinue treatment), we do not know whether there is an increased risk with ribavirin in people with CCHF as data are insufficient.We do not know if adding ribavirin to early supportive care improves outcomes. One non-randomized study assessed mortality in people receiving ribavirin and supportive care within four days or less from symptom onset compared to after four days since symptom onset: mortality was lower in the group receiving early supportive care and ribavirin, but it is not possible to distinguish between the effects of ribavirin and early supportive medical care alone.In the subsidiary analysis, 18 studies compared people receiving ribavirin with those not receiving ribavirin. All had a critical risk of bias due to confounding, reflected in the mortality point estimates favouring ribavirin. AUTHORS' CONCLUSIONS: We do not know if ribavirin is effective for treating Crimean Congo haemorrhagic fever. Non-randomized studies are often cited as evidence of an effect, but the risk of bias in these studies is high.

A cynomolgus macaque model for Crimean-Congo haemorrhagic fever.

Crimean-Congo haemorrhagic fever (CCHF) is the most medically significant tick-borne disease, being widespread in the Middle East, Asia, Africa and parts of Europe 1 . Increasing case numbers, westerly movement and broadly ranging case fatality rates substantiate the concern of CCHF as a public health threat. Ixodid ticks of the genus Hyalomma are the vector for CCHF virus (CCHFV), an arbovirus in the genus Orthonairovirus of the family Nairoviridae. CCHFV naturally infects numerous wild and domestic animals via tick bite without causing obvious disease2,3. Severe disease occurs only in humans and transmission usually happens through tick bite or contact with infected animals or humans. The only CCHF disease model is a subset of immunocompromised mice4-6. Here, we show that following CCHFV infection, cynomolgus macaques exhibited hallmark signs of human CCHF with remarkably similar viral dissemination, organ pathology and disease progression. Histopathology showed infection of hepatocytes, endothelial cells and monocytes and fatal outcome seemed associated with endothelial dysfunction manifesting in a clinical shock syndrome with coagulopathy. This non-human primate model will be an invaluable asset for CCHFV countermeasures development.

Evaluation of epidemiological, clinical, and laboratory characteristics and mortality rate of patients with Crimean-Congo hemorrhagic fever in the northeast region of Turkey.

BACKGROUND & OBJECTIVES: : Crimean-Congo hemorrhagic fever (CCHF), an illness characterized by fever and hemorrhage, is caused by a CCHF virus (CCHFV). It is an important public health problem in Turkey. The objective of this study was to evaluate the demographic, clinical, and laboratory characteristics and mortality rates of CCHF patients in the northeast region of Turkey. METHODS: : A total of 206 patients, diagnosed with CCHF, from northeast region of Turkey were included and evaluated between 2011 and 2017. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence (IFA) methods were used for the diagnoses. RESULTS: : Of the patients included in the study, 77.2% were farmers/livestockers, while 22.8% had other occupations. The incidence of tick bite or tick contact with bare hands was 52.9%. About 94.2% of the patients were living in rural areas and 5.8% in city centers. However, all the patients living in city centers had a history of visit to rural areas. The disease was more common in May, June, and July months. The most common symptoms at the time of admission included fatigue, fever, and widespread body pain, while laboratory findings were thrombocytopenia, leukopenia, and anemia. Bleeding, tachycardia, and rash were the most common findings on physical examination. Of all the patients, 95.6% were identified by RT-PCR and 4.4% by IFA methods. Severe cases constituted 22.3% (46) of the included patients. Throughout the course of this study, 7 (3.4%) patients died, and the remaining 96.6% (199) patients were discharged with a full recovery. Disease severity was significantly correlated with mortality rate and duration of hospitalization (p <0.001 and p = 0.013). INTERPRETATION & CONCLUSION: : In this study, the mortality rate observed was lower than that reported in the literature because of accessibility of early supportive therapy. It would be beneficial in CCHF treatment to recognize the disease at an early stage, begin supportive treatment quickly, and educate the people living in high-risk areas as well as health care personnel working in these areas.

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.

Dynamics of viral load in Crimean Congo hemorrhagic fever.

Crimean Congo hemorrhagic fever (CCHF) is a viral zoonotic disease with high mortality rate. There are only a few studies on viral load in CCHF. In our study, we revealed the dynamics of viral load and its relationship with mortality in early phase of the disease. A total of 138 serum samples were collected from 23 patients. All patients had positive PCR for CCHF on admission. Serum samples were obtained daily from all patients for the first 6 days of hospitalization and stored at -80°C for viral load measurement. We found statistically significant difference between mean number of viremic serum samples of fatal and non-fatal patients. Furthermore, non-fatal cases' viral loads demonstrated statistically significant decreases over time; however, we could not observe a similar trend in viral loads of fatal cases. Limited number of studies on CCHF indicate that score of the contest between CCHF virus and immune system determines the survival in CCHF and viral load is found to be the most prognostic factor. In our study, we found that there is a notable decrease trend in viral loads of non-fatal patients over time and this clearance of CCHF virus is significantly related with survival.