Crimean-Congo Hemorrhagic Fever (CCHF) in Pakistan: The Daunting Threat of an Outbreak as Eid-ul-Azha Approaches.

The Crimean-Congo hemorrhagic fever (CCHF) virus is a tick-borne virus that can spread from infected people and other animals, including cattle and ticks of the Hyalomma genus. People who are infected describe symptoms that range from flu-like manifestations to severe multi-organ failure. With a death rate between 10% and 30%, the virus is undoubtedly a disease of high concern. With 10,000-15,000 cases/y, it is endemic in parts of Asia, Africa, and South-Eastern Europe. There has been a recent CCHF outbreak in Iraq, with 212 cases documented, 80% of which were reported between April and May and led to 27 fatalities.

Potentially Zoonotic Viruses in Wild Rodents, United Arab Emirates, 2019-A Pilot Study.

The majority of emerging viral infectious diseases in humans originate from wildlife reservoirs, such as rodents and bats. We investigated a possible reservoir, namely wild gerbils and mice trapped in a desert reserve within the emirate of Dubai, United Arab Emirates (UAE). In total, 52 gerbils and 1 jird (Gerbillinae), 10 house mice (Mus musculus), and 1 Arabian spiny mouse (Acomys dimidiatus) were sampled. Oro-pharyngeal swabs, fecal samples, attached ticks, and organ samples (where available) were screened by (RT-q)PCR for the following viruses: Middle East respiratory syndrome-related coronavirus, Crimean-Congo hemorrhagic fever orthonairovirus, Alkhumra hemorrhagic fever virus, hantaviruses, Lymphocytic choriomeningitis mammarenavirus, Rustrela virus, poxviruses, flaviviruses, and herpesviruses. All of the samples were negative for all investigated viruses, except for herpesviruses: 19 gerbils (35.8%) and seven house mice (70.0%) were positive. The resulting sequences were only partly identical to sequences in GenBank. Phylogenetic analysis revealed three novel betaherpesviruses and four novel gammaherpesviruses. Interestingly, species identification of the positive gerbils resulted in eight individuals clustering in a separate clade, most closely related to Dipodillus campestris, the North African gerbil, indicating either the expansion of the geographic range of this species, or the existence of a closely related, yet undiscovered species in the UAE. In conclusion, we could not find evidence of persistence or shedding of potentially zoonotic viruses in the investigated rodent cohorts of limited sample size.

[The Importance of Differential Diagnosis During Pandemic: A Case Report with Coexistence of COVID-19, Brucellosis and Crimean-Congo Hemorrhagic Fever]. / Pandemi Döneminde Ayirici Taninin Önemi: COVID-19, Bruselloz ve Kirim-Kongo Kanamali Atesi Birlikteligi Olan Bir Olgu Sunumu.

The coronavirus disease-2019 (COVID-19) pandemic, which affects millions of people around the world, has been affecting our country since March 2020. The fact that the symptoms such as fever, myalgia, headache, joint pain which are common in COVID-19 patients are quite similar to the symptoms of diseases such as Crimean-Congo hemorrhagic fever (CCHF) and Brucellosis. This may cause a diagnostic confusion in regions where these diseases are seen as endemic. In this report, a patient hospitalized with a pre-diagnosis of COVID-19 and diagnosed with acute Brucellosis, CCHF and COVID-19 during followup was presented. A 31-year-old female patient living in a rural area admitted to the emergency service with complaints of fever, weakness, headache, and body/joint pain. Physical examination revealed a temperature of 38.3°C, a pulse rate of 102/minute, and a peripheral capillary oxygen saturation of 97% in room air. The system examination was normal. In the laboratory findings, an increase in liver enzymes and acute phase reactants was observed and the platelet count was at the lower limit of the normal range. In terms of COVID-19, no involvement compatible with COVID-19 was detected in the thorax computed tomography (CT) of the patient whose nasopharyngeal and oropharyngeal mixed swab samples were taken.The patient was transferred to our infectious diseases service with a pre-diagnosis of COVID-19 and CCHF. Serum samples were sent to the Public Health Agency Microbiology Reference Laboratory Department (PHA-MRLD) for CCHF diagnostic tests and supportive treatment was started. Brucella Rose Bengal and Coombs' immuncapture (1/1280 titer) tests were found as positive in the patient, who was examined for brucellosis because of living in a rural area and having a history of consuming fresh dairy products. In the tests performed at PHA-MRLD, CCHF-specific IgM positivity and the presence of viral RNA were detected. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reverse-transcriptase polymerase chain reaction (RT-PCR) test was negative. For Brucellosis, doxycycline and rifampicin were added to the treatment of the patient whom was given supportive therapy for CCHF. In the followup, the patient's fever was persisting and loss of taste and smell complaint developed. In this context, COVID-19 test was repeated and resulted as positive. Upon this, hydroxychloroquine sulfate treatment was started due to the recommendation of the current Ministry of Health Scientific Committee Guide. No new infiltration was detected in the chest radiography of the patient. The patient's fever subsided during follow-up and laboratory findings improved. The treatment of brucellosis was completed to eight weeks at the outpatient clinic. No problems were detected in the follow-up. This report was prepared because of a case with simultaneous brucellosis, CCHF and COVID-19 infections which could not be encountered in the literature review. As a result; in regions such as our country where both brucellosis and CCHF are seen as endemic, it is very important to keep these diseases in mind in the differential diagnosis of COVID-19 infection.

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.

The Prevalence of Viral Pathogens among Bats in Kazakhstan.

Bats carry thousands of viruses from 28 different families. To determine the presence of various pathogens in bat populations in Kazakhstan, 1149 samples (393 oropharyngeal swabs, 349 brain samples, 407 guano) were collected. The samples were collected from four species of bats (Vespertilio murinus, Nyctalus noctula, Myotis blythii, Eptesicus serotinus) in nine regions. The Coronavirus RNA was found in 38 (4.75%) samples, and the rabies virus in 27 (7.74%) samples from bats. Coronaviruses and the rabies virus were found in bats in six out of nine studied areas. The RNAs of SARS-CoV-2, MERS, TBE, CCHF, WNF, influenza A viruses were not detected in the bat samples. The phylogeny of the RdRp gene of 12 samples made it possible to classify them as alphacoronaviruses and divide them into two groups. The main group (n = 11) was closely related to bat coronaviruses from Ghana, Zimbabwe and Kenya. The second group (n = 1) was closely related to viruses previously isolated in the south of Kazakhstan. The phylogeny of the N gene sequence from a bat from west Kazakhstan revealed its close relationship with isolates from the Cosmopolitan group of rabies viruses (Central Asia). These results highlight the need for a continuous monitoring of volatile populations to improve the surveillance and detection of infectious diseases.

Crimean-Congo Hemorrhagic Fever Outbreak in Refugee Settlement during COVID-19 Pandemic, Uganda, April 2021.

Crimean-Congo hemorrhagic fever (CCHF) was detected in 2 refugees living in a refugee settlement in Kikuube district, Uganda. Investigations revealed a CCHF IgG seroprevalence of 71.3% (37/52) in goats within the refugee settlement. This finding highlights the need for a multisectoral approach to controlling CCHF in humans and animals in Uganda.

Degenerate sequence-based CRISPR diagnostic for Crimean-Congo hemorrhagic fever virus.

CRISPR (clustered regularly interspaced short palindromic repeats), an ancient defense mechanism used by prokaryotes to cleave nucleic acids from invading viruses and plasmids, is currently being harnessed by researchers worldwide to develop new point-of-need diagnostics. In CRISPR diagnostics, a CRISPR RNA (crRNA) containing a "spacer" sequence that specifically complements with the target nucleic acid sequence guides the activation of a CRISPR effector protein (Cas13a, Cas12a or Cas12b), leading to collateral cleavage of RNA or DNA reporters and enormous signal amplification. CRISPR function can be disrupted by some types of sequence mismatches between the spacer and target, according to previous studies. This poses a potential challenge in the detection of variable targets such as RNA viruses with a high degree of sequence diversity, since mismatches can result from target variations. To cover viral diversity, we propose in this study that during crRNA synthesis mixed nucleotide types (degenerate sequences) can be introduced into the spacer sequence positions corresponding to viral sequence variations. We test this crRNA design strategy in the context of the Cas13a-based SHERLOCK (specific high-sensitivity enzymatic reporter unlocking) technology for detection of Crimean-Congo hemorrhagic fever virus (CCHFV), a biosafety level 4 pathogen with wide geographic distribution and broad sequence variability. The degenerate-sequence CRISPR diagnostic proves functional, sensitive, specific and rapid. It detects within 30-40 minutes 1 copy/µl of viral RNA from CCHFV strains representing all clades, and from more recently identified strains with new mutations in the CRISPR target region. Also importantly, it shows no cross-reactivity with a variety of CCHFV-related viruses. This proof-of-concept study demonstrates that the degenerate sequence-based CRISPR diagnostic is a promising tool of choice for effective detection of highly variable viral pathogens.

Multi-omics insights into host-viral response and pathogenesis in Crimean-Congo hemorrhagic fever viruses for novel therapeutic target.

The pathogenesis and host-viral interactions of the Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV) are convoluted and not well evaluated. Application of the multi-omics system biology approaches, including biological network analysis in elucidating the complex host-viral response, interrogates the viral pathogenesis. The present study aimed to fingerprint the system-level alterations during acute CCHFV-infection and the cellular immune responses during productive CCHFV-replication in vitro. We used system-wide network-based system biology analysis of peripheral blood mononuclear cells (PBMCs) from a longitudinal cohort of CCHF patients during the acute phase of infection and after one year of recovery (convalescent phase) followed by untargeted quantitative proteomics analysis of the most permissive CCHFV-infected Huh7 and SW13 cells. In the RNAseq analysis of the PBMCs, comparing the acute and convalescent-phase, we observed system-level host's metabolic reprogramming towards central carbon and energy metabolism (CCEM) with distinct upregulation of oxidative phosphorylation (OXPHOS) during CCHFV-infection. Upon application of network-based system biology methods, negative coordination of the biological signaling systems like FOXO/Notch axis and Akt/mTOR/HIF-1 signaling with metabolic pathways during CCHFV-infection were observed. The temporal quantitative proteomics in Huh7 showed a dynamic change in the CCEM over time and concordant with the cross-sectional proteomics in SW13 cells. By blocking the two key CCEM pathways, glycolysis and glutaminolysis, viral replication was inhibited in vitro. Activation of key interferon stimulating genes during infection suggested the role of type I and II interferon-mediated antiviral mechanisms both at the system level and during progressive replication.

Crimean-Congo hemorrhagic fever (CCHF) is an emerging disease that is increasingly spreading to new populations. The condition is now endemic in almost 30 countries in sub-Saharan Africa, South-Eastern Europe, the Middle East and Central Asia. CCHF is caused by a tick-borne virus and can cause uncontrolled bleeding. It has a mortality rate of up to 40%, and there are currently no vaccines or effective treatments available. All viruses depend entirely on their hosts for reproduction, and they achieve this through hijacking the molecular machinery of the cells they infect. However, little is known about how the CCHF virus does this and how the cells respond. To understand more about the relationship between the cell's metabolism and viral replication, Neogi, Elaldi et al. studied immune cells taken from patients during an infection and one year later. The gene activity of the cells showed that the virus prefers to hijack processes known as central carbon and energy metabolism. These are the main regulator of the cellular energy supply and the production of essential chemicals. By using cancer drugs to block these key pathways, Neogi, Elaldi et al. could reduce the viral reproduction in laboratory cells. These findings provide a clearer understanding of how the CCHF virus replicates inside human cells. By interfering with these processes, researchers could develop new antiviral strategies to treat the disease. One of the cancer drugs tested in cells, 2-DG, has been approved for emergency use against COVID-19 in some countries. Neogi, Elaldi et al. are now studying this further in animals with the hope of reaching clinical trials in the future.

Inactivation of three emerging viruses - severe acute respiratory syndrome coronavirus, Crimean-Congo haemorrhagic fever virus and Nipah virus - in platelet concentrates by ultraviolet C light and in plasma by methylene blue plus visible light.

BACKGROUND: Emerging viruses like severe acute respiratory syndrome coronavirus (SARS-CoV), Crimean-Congo haemorrhagic fever virus (CCHFV) and Nipah virus (NiV) have been identified to pose a potential threat to transfusion safety. In this study, the ability of the THERAFLEX UV-Platelets and THERAFLEX MB-Plasma pathogen inactivation systems to inactivate these viruses in platelet concentrates and plasma, respectively, was investigated. MATERIALS AND METHODS: Blood products were spiked with SARS-CoV, CCHFV or NiV, and then treated with increasing doses of UVC light (THERAFLEX UV-Platelets) or with methylene blue (MB) plus increasing doses of visible light (MB/light; THERAFLEX MB-Plasma). Samples were taken before and after treatment with each illumination dose and tested for residual infectivity. RESULTS: Treatment with half to three-fourths of the full UVC dose (0·2 J/cm2 ) reduced the infectivity of SARS-CoV (≥3·4 log), CCHFV (≥2·2 log) and NiV (≥4·3 log) to the limit of detection (LOD) in platelet concentrates, and treatment with MB and a fourth of the full light dose (120 J/cm2 ) decreased that of SARS-CoV (≥3·1 log), CCHFV (≥3·2 log) and NiV (≥2·7 log) to the LOD in plasma. CONCLUSION: Our study demonstrates that both THERAFLEX UV-Platelets (UVC) and THERAFLEX MB-Plasma (MB/light) effectively reduce the infectivity of SARS-CoV, CCHFV and NiV in platelet concentrates and plasma, respectively.

Crimean-Congo Hemorrhagic Fever Virus: Current Advances and Future Prospects of Antiviral Strategies.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a widespread, tick-borne pathogen that causes Crimean-Congo hemorrhagic fever (CCHF) with high morbidity and mortality. CCHFV is transmitted to humans through tick bites or direct contact with patients or infected animals with viremia. Currently, climate change and globalization have increased the transmission risk of this biosafety level (BSL)-4 virus. The treatment options of CCHFV infection remain limited and there is no FDA-approved vaccine or specific antivirals, which urges the identification of potential therapeutic targets and the design of CCHF therapies with greater effort. In this article, we discuss the current progress and some future directions in the development of antiviral strategies against CCHFV.

The Integration of Human and Veterinary Studies for Better Understanding and Management of Crimean-Congo Haemorrhagic Fever.

Outbreaks that occur as a result of zoonotic spillover from an animal reservoir continue to highlight the importance of studying the disease interface between species. One Health approaches recognise the interdependence of human and animal health and the environmental interplay. Improving the understanding and prevention of zoonotic diseases may be achieved through greater consideration of these relationships, potentially leading to better health outcomes across species. In this review, special emphasis is given on the emerging and outbreak pathogen Crimean-Congo Haemorrhagic Fever virus (CCHFV) that can cause severe disease in humans. We discuss the efforts undertaken to better understand CCHF and the importance of integrating veterinary and human research for this pathogen. Furthermore, we consider the use of closely related nairoviruses to model human disease caused by CCHFV. We discuss intervention approaches with potential application for managing CCHFV spread, and how this concept may benefit both animal and human health.

[COVID-19 Co-infection in a patient with Crimean Congo Hemorrhagic Fever: A Case Report]. / Kirim Kongo Kanamali Atesi Hastasinda COVID-19 Ko-enfeksiyonu: Bir Olgu Sunumu.

Crimean-Congo Hemorrhagic Fever (CCHF) is an acute viral zoonotic disease. Coronavirus disease-2019 (COVID-19) is a newly emerging viral disease and it is caused by "severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)". In this article, a case diagnosed with CCHF and COVID-19 coinfection confirmed by the polymerase chain reaction (PCR) method and its management was presented. A thirtyfive years old female patient admitted to the hospital with the complaint of fever for one day and common body pain. It was learned that three days before the onset of her complaints, she removed a tick adhering to the anterior abdominal wall with no precaution. Her body temperature was 38°C degrees and her respiratory rate was 22 per minute. The leucocyte count was 3660/mm³ and the platelet count was 138.000/mm³. It was determined that prothrombin time was 15.4 seconds, international normalized ratio (INR) was 1.35 seconds, and D-dimer level was 1310 ng/ml. The patient was hospitalized with prediagnosis of CCHF. Supportive treatment was started. On the second day at the clinical follow-up of the patient, complaints of sore throat and cough without sputum started. A combined nasopharyngeal and throat swab sample was taken from the patient because of the suspicion of COVID-19. COVID-19 PCR test result was reported as positive. Favipiravir treatment was started. The CCHF-PCR test, which was studied from the serum sample sent to the Microbiology Reference Laboratories was reported as positive. From the third day of favipiravir treatment; the patient did not have a fever and her complaints regressed. On the ninth day of her hospitalization, she was discharged. In this case; it is important to show that both diseases, especially in regions where CCHF disease is endemic, can be confused due to the similarity of the clinical picture with COVID-19 and to know that they can coexist.

Association Between Severity Grading Score And Acute Phase Reactants In Patients With Crimean Congo Hemorrhagic Fever.

As the COVID-19 pandemic continues, countries still have to struggle with their endemic diseases such as Crimean-Congo hemorrhagic fever (CCHF). Severity grading score (SGS) is a practical approach and may shed light on the course of the CCHF, whose pathogenesis is not clearly understood, and have no effective treatments. It is aimed to assess the association between SGS and acute phase reactants (APR). Laboratory-confirmed patients were categorized by severity scores, and the relationship between APR and SGS was evaluated. A significant correlation between SGS and C-reactive protein (CRP) was found (p < 0.001). High SGS was associated with mortality and high CRP levels were used to predict the mortality at the beginning of the hospital admission. To predict the outcome of the disease and for appropriate patient management, SGS and APR can be used simultaneously.

Novel Broad-Spectrum Antiviral Inhibitors Targeting Host Factors Essential for Replication of Pathogenic RNA Viruses.

Recent RNA virus outbreaks such as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus (EBOV) have caused worldwide health emergencies highlighting the urgent need for new antiviral strategies. Targeting host cell pathways supporting viral replication is an attractive approach for development of antiviral compounds, especially with new, unexplored viruses where knowledge of virus biology is limited. Here, we present a strategy to identify host-targeted small molecule inhibitors using an image-based phenotypic antiviral screening assay followed by extensive target identification efforts revealing altered cellular pathways upon antiviral compound treatment. The newly discovered antiviral compounds showed broad-range antiviral activity against pathogenic RNA viruses such as SARS-CoV-2, EBOV and Crimean-Congo hemorrhagic fever virus (CCHFV). Target identification of the antiviral compounds by thermal protein profiling revealed major effects on proteostasis pathways and disturbance in interactions between cellular HSP70 complex and viral proteins, illustrating the supportive role of HSP70 on many RNA viruses across virus families. Collectively, this strategy identifies new small molecule inhibitors with broad antiviral activity against pathogenic RNA viruses, but also uncovers novel virus biology urgently needed for design of new antiviral therapies.