Looking Beyond the Lens of Crimean-Congo Hemorrhagic Fever in Africa.

Crimean-Congo hemorrhagic fever (CCHF) is a lethal viral disease that has severe public health effects throughout Africa and a case fatality rate of 10%-40%. CCHF virus was first discovered in Crimea in 1944 and has since caused a substantial disease burden in Africa. The shortage of diagnostic tools, ineffective tick control efforts, slow adoption of preventive measures, and cultural hurdles to public education are among the problems associated with continued CCHF virus transmission. Progress in preventing virus spread is also hampered by the dearth of effective serodiagnostic testing for animals and absence of precise surveillance protocols. Intergovernmental coordination, creation of regional reference laboratories, multiinstitutional public education partnerships, investments in healthcare infrastructure, vaccine development, and a One Health approach are strategic methods for solving prevention challenges. Coordinated efforts and financial commitments are needed to combat Crimean-Congo hemorrhagic fever and improve all-around readiness for newly developing infectious illnesses in Africa.

Animal Exposure Model for Mapping Crimean-Congo Hemorrhagic Fever Virus Emergence Risk.

To estimate the determinants of spatial variation in Crimean-Congo hemorrhagic fever virus (CCHFV) transmission and to create a risk map as a preventive public health tool, we designed a survey of small domestic ruminants in Andalusia, Spain. To assess CCHFV exposure spatial distribution, we analyzed serum from 2,440 sheep and goats by using a double-antigen ELISA and modeled exposure probability with environmental predictors by using generalized linear mixed models. CCHFV antibodies detected in 84 samples confirmed low CCHFV prevalence in small domestic ruminants in the region. The best-fitted statistical model indicated that the most significant predictors of virus exposure risk were cattle/horse density and the normalized difference vegetation index. Model validation showed 99.7% specificity and 10.2% sensitivity for identifying CCHFV circulation areas. To map CCHFV exposure risk, we projected the model at a 1 × 1-km spatial resolution. Our study provides insight into CCHFV ecology that is useful for preventing virus transmission.

Accelerated DNA vaccine regimen provides protection against Crimean-Congo hemorrhagic fever virus challenge in a macaque model.

Crimean-Congo hemorrhagic fever virus (CCHFV) is widely distributed throughout Africa, the Middle East, Southern Asia, and Southern and Eastern Europe. Spread by Hyalomma ticks or by contact with infected animals, CCHF begins non-specifically but can rapidly progress to severe, sometimes fatal, disease. Due to the non-specific early symptoms and often unrecognized infections, patients often present to healthcare systems exhibiting later stages of disease, when treatment is limited to supportive care. Consequently, simple vaccines are critically needed to protect populations at risk of CCHFV infection. Currently, there are no widely approved vaccines for CCHFV. We have previously reported significant efficacy of a three-dose DNA-based vaccination regimen for CCHFV in cynomolgus macaques (Macaca fasicularis). Here, we show that in cynomolgus macaques, plasmid-expressed CCHFV nucleoprotein (NP) and glycoprotein precursor (GPC) antigens elicit primarily humoral and cellular immunity, respectively. We found that a two-dose vaccination regimen with plasmids expressing the NP and GPC provides significant protection against CCHFV infection. Studies investigating vaccinations with either antigen alone showed that plasmid-expressed NPs could also confer protection. Cumulatively, our data show that this vaccine confers robust protection against CCHFV and suggest that both humoral and cellular immunity contribute to optimal vaccine-mediated protection.

Can we predict bleeding at admission in Crimean-Congo hemorrhagic fever?

BACKGROUND: In Crimean-Congo hemorrhagic fever, bleeding has a significant impact on the prognosis of the disease. In our study, we aimed to identify independent risk factors for the development of bleeding in Crimean-Congo hemorrhagic fever and to contribute to the management of the disease. METHODS: Cases with a definitive diagnosis of Crimean-Congo hemorrhagic fever were divided into two groups: those who developed bleeding and those who did not. Demographic, clinical and laboratory parameters were subjected to logistic regression analysis in terms of risk factors for bleeding development. Cut-off values for numerical variables were determined by receiver operating characteristics. RESULTS: A total of 74 patients diagnosed with CCHF were included in the study. Bleeding occurred in at least one defined focus in 21 patients. In the multivariate logistic regression model, procalcitonin, days from symptom onset to admission, platelet count, and d-dimer were identified as independent risk factors for bleeding development. Procalcitonin had the most significant effect, with an approximately 5.3-fold increase in bleeding risk for each unit increase in its level. For discriminate bleeding, LDH and ferritin exhibited the highest sensitivity, while procalcitonin showed the highest specificity. CONCLUSION: This study demonstrates the potential use of specific clinical and laboratory variables to predict bleeding development in CCHF patients. Procalcitonin elevation and the time from symptom onset to hospital admission have a significant effect in predicting bleeding.

Changing Disease Course of Crimean-Congo Hemorrhagic Fever in Children, Turkey.

Crimean-Congo hemorrhagic fever (CCHF), endemic in certain regions of the world, is listed as a priority disease with pandemic potential. Since CCHF was first identified in Turkey, children have been known to experience milder disease than adults. However, during the COVID-19 pandemic, we observed an unusually severe disease course, including hemophagocytic lymphohistiocytosis (HLH). We examined cytokine/chemokine profiles of 9/12 case-patients compared with healthy controls at 3 time intervals. Interferon pathway-related cytokines/chemokines, including interleukin (IL) 18, macrophage inflammatory protein 3α, and IL-33, were elevated, but tumor necrosis factor-α, IL-6, CXCL8 (formerly IL-8), and cytokines acting through C-C chemokine receptor 2 and CCR5 were lower among case-patients than controls. Interferon pathway activation and cytokines/chemokines acting through CCR2 and CCR5 improved health results among children with severe CCHF. Children can experience severe CCHF, including HLH, and HLH secondary to CCHF can be successfully treated with intravenous immunoglobulin and steroid therapy.

In silico formulation of a next-generation multiepitope vaccine for use as a prophylactic candidate against Crimean-Congo hemorrhagic fever.

BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF) is a widespread disease transmitted to humans and livestock animals through the bite of infected ticks or close contact with infected persons' blood, organs, or other bodily fluids. The virus is responsible for severe viral hemorrhagic fever outbreaks, with a case fatality rate of up to 40%. Despite having the highest fatality rate of the virus, a suitable treatment option or vaccination has not been developed yet. Therefore, this study aimed to formulate a multiepitope vaccine against CCHF through computational vaccine design approaches. METHODS: The glycoprotein, nucleoprotein, and RNA-dependent RNA polymerase of CCHF were utilized to determine immunodominant T- and B-cell epitopes. Subsequently, an integrative computational vaccinology approach was used to formulate a multi-epitopes vaccine candidate against the virus. RESULTS: After rigorous assessment, a multiepitope vaccine was constructed, which was antigenic, immunogenic, and non-allergenic with desired physicochemical properties. Molecular dynamics (MD) simulations of the vaccine-receptor complex show strong stability of the vaccine candidates to the targeted immune receptor. Additionally, the immune simulation of the vaccine candidates found that the vaccine could trigger real-life-like immune responses upon administration to humans. CONCLUSIONS: Finally, we concluded that the formulated multiepitope vaccine candidates would provide excellent prophylactic properties against CCHF.

Leukotriene metabolism and proiflammatory cytokines in Crimean Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever (CCHF) is an emerging acute viral infection disease, yet its pathophysiology remains largely uncharacterized. Lipid mediators are molecules that play numerous roles in the physiologic and pathophysiologic conditions in certain viral diseases. No previous study evaluated the status of cysteinyl leukotrienes (CYSLT) and 5-lipoxygenase (5-LO) and their relationship with proinflammatory cytokines in CCHF. A total of 90 subjects including 60 CCHF patients and 30 healthy controls were enrolled the study. Serum CYSLT, 5-LO, interleukin-6 (IL-6), and ferritin levels were determined in the study population. Lower median 5-LO level was determined in patients compared to healthy controls (p = 0.0004). Higher ferritin (p < 0.001) and IL-6 (p < 0.001) levels in patients than healthy controls. No statistically significant difference was observed between patients and controls in terms of CYSLT levels. No statistically significant differences were observed between mild, moderate, and severe groups in terms of both 5-LO and CYSLT levels. IL-6 and ferritin levels were higher in severe group compared mild and moderate groups. In conclusion, changes in 5-LO enzyme and increased inflammation are related with the disease molecular mechanism. Higher inflammatory status contributes to the impaired hemostatic balance in CCHF. Thus, treatment strategies to reduce inflammation may help to prevent bleeding and DIC in patients. IL-6 and ferritin can be used to as an additional biomarker in the estmation of the prognosis and diagnosis of the patients.

Status of Crimean-Congo haemorrhagic fever virus in ticks in Iran: A systematic review with meta-analysis.

Crimean-Congo haemorrhagic fever (CCHF) is a re-emerging viral haemorrhagic fever causing outbreaks in Iran in the last 15 years. In this systematic review and meta-analysis, the status of Crimean-Congo haemorrhagic fever virus (CCHFV) in ticks would be evaluated. PubMed, Google Scholar and Web of Science were searched for peer-reviewed original papers published between 2000 and 1 July 2022. We included papers that evaluated the prevalence of CCHFV in individual ticks using reverse transcription polymerase chain reaction (RT-PCR). The pooled prevalence of CCHFV was 6.0% (95% confidence interval [CI]: 4.5-7.9%), with heterogeneity (I2 = 82.706; P < 0.0001). The prevalence of CCHFV was higher related to regions with above sea level of 1001-1500m (6.4%; 95% CI: 4.3-9.5%), an average temperature of ≤15 °C (8.3%; 95% CI: 5.6-12.0%), latitude of ≥36° (8.1%; 95% CI: 5.2-12.3%), an annual rainfall of 101-300 mm (9.8%; 95% CI: 6.1-15.4%) and humidity of ≥61% (10.2%; 95% CI: 5.1-19.3%). Due to the importance of CCHF, it is better to do new epidemiologic studies on ticks by related organizations and adjacent regions of some provinces in which human cases have been previously reported.

Cases of Crimean-Congo haemorrhagic fever in North Macedonia, July to August 2023.

The last report of Crimean-Congo haemorrhagic fever (CCHF) in North Macedonia was more than 50 years ago in the northwest. We report on a fatal CCHF case following a Hyalomma tick bite in the east of the country in July 2023. Tracing of 67 contacts identified CCHF in one healthcare worker (HCW) providing care for the patient. Monitoring of contacts is concluded (including further 11 HCW contacts), thus far 28 days after the death of the case no additional cases were identified.

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.

Retrospective Identification of Early Autochthonous Case of Crimean-Congo Hemorrhagic Fever, Spain, 2013.

Before this report, 7 autochthonous human cases of Crimean-Congo hemorrhagic fever had been reported in Spain, all occurring since 2016. We describe the retrospective identification of an eighth case dating back to 2013. This study highlights that the earliest cases of an emerging disease are often difficult to recognize.

Hotspot of Crimean-Congo Hemorrhagic Fever Virus Seropositivity in Wildlife, Northeastern Spain.

We conducted a serosurvey for Crimean-Congo hemorrhagic fever virus antibodies in various wildlife species in Catalonia, northeastern Spain. We detected high seroprevalence in southern Catalonia, close to the Ebro Delta wetland, a key stopover for birds migrating from Africa. Our findings could indicate that competent virus vectors are present in the region.

Identification of a novel lineage of Crimean-Congo haemorrhagic fever virus in dromedary camels, United Arab Emirates.

Crimean-Congo haemorrhagic fever virus (CCHFV) is a tick-borne virus causing Crimean-Congo haemorrhagic fever (CCHF), a disease reported to have a high fatality rate in numerous countries. The virus is geographically widespread due to its vector, and numerous wild and domestic animals can develop asymptomatic infection. Serological and limited molecular evidence of CCHFV has previously been reported in Camelus dromedarius (the dromedary, or one-humped camel) in the United Arab Emirates (UAE). In this study, 238 camel samples were screened for CCHFV RNA where 16 camel samples were positive for CCHFV by RT-PCR. Analysis of full-length CCHFV genome sequences revealed a novel lineage in camels from the UAE, and potential reassortment of the M segment of the genome.

Knowledge, attitude and perceptions about Crimean Congo Haemorrhagic Fever (CCHF) among occupationally high-risk healthcare professionals of Pakistan.

BACKGROUND: Crimean Congo Haemorrhagic Fever (CCHF), a tropically neglected infectious disease caused by Nairovirus, is endemic in low middle-income countries like Pakistan. Emergency health care professionals (HCPs) are at risk of contracting nosocomial transmission of CCHF. We, therefore, aim to analyze the knowledge, attitudes, and perceptions (KAP) of at-risk physicians, nurses, and pharmacists in Pakistan and the factors associated with good KAP. METHOD: A validated questionnaire (Cronbach's alpha 0.71) was used to collect data from HCPs in two CCHF endemic metropolitan cities of Pakistan by employing a cross-sectional study design. For data analysis percentages, chi-square test and Spearman correlation were applied by using SPSS version 22. RESULTS: Of the 478 participants, 56% (n = 268) were physicians, 37.4% (n = 179) were nurses, and 6.5% (n = 31) were pharmacists. The proportion of HCPs with good knowledge, attitude, and perception scores was 54.3%, 81, and 69%, respectively. Being a physician, having more work experience, having a higher age, working in tertiary care settings, were key factors for higher knowledge (p < 0.001). The correlation coefficient showed significant positive correlation between attitude- perception (r = 0.560, p < 0.001). CONCLUSION: We have observed average knowledge of HCPs. Therefore, we recommend time to time education campaigns and workshops in highly endemic CCHF regions to be launched by health ministries and HCPs, in particular nurses, encouraged to follow authentic academic sources of information to prevent nosocomial transmission.

Crimean-Congo hemorrhagic fever virus nucleocapsid protein harbors distinct RNA-binding sites in the stalk and head domains.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne Nairovirus that causes severe hemorrhagic fever with a mortality rate of up to 30% in certain outbreaks worldwide. The virus has wide endemic distribution. There is no effective antiviral therapeutic or FDA approved vaccine for this zoonotic viral illness. The multifunctional CCHFV nucleocapsid protein (N protein) plays a crucial role in the establishment of viral infection and is an important structural component of the virion. Here we show that CCHFV N protein has a distant RNA-binding site in the stalk domain that specifically recognizes the vRNA panhandle, formed by the base pairing of complementary nucleotides at the 5' and 3' termini of the vRNA genome. Using multiple approaches, including filter-bonding analysis, GFP reporter assay, and biolayer interferometry we observed an N protein-panhandle interaction both in vitro and in vivo The purified WT CCHFV N protein and the stalk domain also recognize the vRNA panhandle of hazara virus, another Nairovirus in the family Bunyaviridae, demonstrating the genus-specific nature of N protein-panhandle interaction. Another RNA-binding site was identified at the head domain of CCHFV N protein that nonspecifically recognizes the single strand RNA (ssRNA) of viral or nonviral origin. Expression of CCHFV N protein stalk domain active in panhandle binding, dramatically inhibited the hazara virus replication in cell culture, illustrating the role of N protein-panhandle interaction in Nairovirus replication. Our findings reveal the stalk domain of N protein as a potential target in therapeutic interventions to manage CCHFV disease.

Prevalence of Antibodies to Crimean-Congo Hemorrhagic Fever Virus in Ruminants, Nigeria, 2015.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly transmissible human pathogen. Infection is often misdiagnosed, in part because of poor availability of data in disease-endemic areas. We sampled 150 apparently healthy ruminants throughout Nigeria for virus seropositivity and detected virus-specific IgG in cattle (24%) and goats (2%), highlighting the need for further investigations.

Crimean-Congo Hemorrhagic Fever Virus in Humans and Livestock, Pakistan, 2015-2017.

We detected Crimean-Congo hemorrhagic fever virus infections in 4 provinces of Pakistan during 2017-2018. Overall, seroprevalence was 2.7% in humans and 36.2% in domestic livestock. Antibody prevalence in humans was highest in rural areas, where increased contact with animals is likely.

Ixodid tick species and two tick-borne pathogens in three areas in the Sudan.

Ticks are important parasites from economic and public health points of view because of their ability to reduce farm animals' productivity and transmit zoonotic diseases. We conducted this cross-sectional study between January and March 2016 and between March and April 2017 to identify tick species in West Darfur, Al-Jazeera, and the River Nile states in the Sudan and to investigate whether these ticks carry Rickettsia spp. and Crimean-Congo hemorrhagic fever (CCHF) virus. In total, 1593 ticks were collected from 207 animals and identified based on morphology or 16S rRNA gene and tested for Rickettsia spp. and CCHF virus either individually or as pools containing 2 to 10 pooled ticks using molecular methods. Overall, 14 tick species belonging to three genera, namely Amblyomma, Hyalomma, and Rhipicephalus, were identified. Hyalomma anatolicum and Rhipicephalus evertsi evertsi were the most frequent ticks. A total of 561 tests comprised of individual or pooled ticks were conducted and 13.7% (77/561) were positive for Rickettsia spp. which were mostly Rickettsia aeschlimannii and R. africae. The highest positivity was noticed among H. rufipes collected from cattle and camels in West Darfur. However, none of the screened Hyalomma ticks harbored CCHF viral RNA. These findings suggest that there might be a risk of zoonotic transmission of Rickettsia spp. by ticks but zoonotic transmission of CCHF virus is apparently doubtful. An in-depth and a country-wide epidemiological study is needed to better understand the dynamic of Rickettsia spp. and CCHF virus in the Sudan.

Monitoring Crimean-Congo haemorrhagic fever virus RNA shedding in body secretions and serological status in hospitalised patients, Turkey, 2015.

IntroductionCrimean-Congo haemorrhagic fever (CCHF) is a tick-borne disease in Africa, Asia, the Balkan peninsula, the south-east of Europe and the Middle East, with mortality rates of 3-30%. Transmission can also occur through contact with infected animals or humans.AimThis observational, prospective case series aimed to investigate detectable viral genomic RNA in whole-body fluids and antibody dynamics in consecutive daily samples of patients diagnosed with CCHF until discharge from hospital.MethodsWe tested 18 patients and 824 swabs and sera with RT-PCR and 125 serum samples serologically.ResultsThe longest duration until clearance of viral RNA was 18 days from serum collection and 18, 15, 13, 19 and 17 days, respectively, from nasal, oral, genital (urethral or vaginal) and faecal swab, and urine. In seven patients, viral load decreased in serum at the same time as it increased in urine or persisted at the same logarithmic values. Despite clearance in serum, viral RNA was detected in faeces and genital swabs in two and three patients, respectively. Viral clearance from body fluids occurred earlier than from serum in eight patients on ribavirin treatment. The shortest seroconversion time was 3 days after symptom onset for IgM and IgG. Seroconversion of IgG occurred until Day 14 of symptoms.ConclusionWe report persistence of viral RNA in urine, faeces and genital swabs despite serum clearance. This may indicate a need for extending isolation precautions, re-evaluating discharge criteria and transmission risk after discharge, and considering oral swabs as a less invasive diagnostic alternative.

Crimean-Congo haemorrhagic fever (CCHF) virus-specific antibody detection in blood donors, Castile-León, Spain, 2017 and 2018.

BackgroundCrimean-Congo haemorrhagic fever virus (CCHFV) is considered an emerging or even a probable re-emerging pathogen in southern Europe. Presence of this virus had been reported previously in Spain in 2010.AimWe aimed to evaluate the potential circulation of CCHFV in western Spain with a serosurvey in asymptomatic adults (blood donors).MethodsDuring 2017 and 2018, we conducted a CCHFV serosurvey in randomly selected asymptomatic blood donors from western Spain. Three assays using specific IgG antibodies against CCHFV were performed: the VectoCrimea ELISA test, an in-house ELISA and indirect immunofluorescence (EuroImmun) test with glycoprotein and nucleoprotein.ResultsA total of 516 blood donors participated in this cross-sectional study. The majority of the study participants were male (68.4%), and the mean age was 46.3 years. Most of the participants came from rural areas (86.8%) and 68.6% had contact with animals and 20.9% had animal husbandry practices. One in five participants (109/516, 21.1%) were engaged in at-risk professional activities such as agriculture and shepherding, slaughtering, hunting, veterinary and healthcare work (mainly nursing staff and laboratory technicians). A total of 15.3% of the participants were bitten by ticks in the days or months before the date of sampling. We detected anti-CCHFV IgG antibodies with two diagnostic assays in three of the 516 individuals and with one diagnostic assay in six of the 516 individuals.ConclusionSeroprevalence of CCHFV was between 0.58% and 1.16% in Castile-León, Spain. This is the first study in western Spain that showed circulation of CCHFV in healthy people.