In this study, we systemically searched for relevant literature published on CCHF/CCHFV in humans, animals, and ticks in the 22 Arab countries using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol (26) (Figure 1). Our search strategy was based on searching different databases such as Google Scholar, Science Direct, Web of Science, Scopus, and PubMed for retrieving relevant articles published in the Arab countries, from 1978 to 2021. Search terms, “CCHF,” “CCHFV,” “humans” or “patients,” “tick” or “ticks,” “tick vectors,” “animals,” “livestock,” “wildlife,” “small mammals,” and the name of the concerned country were used for retrieving data. The filters were used such as time line (1978–2021) and Arab world/Arab countries.

The CCHF/CCHFV detection, prevalence, and distribution studies on animals, tick vectors and human case reports with fatality rate were analyzed carefully and reviewed systematically. NP retrieved the data, screened each record/report. GK checked and verified each record/report on the basis of inclusion criteria to avoid duplications and errors to enhance the quality of extracted data. We did not use automation tool. Details are given in PRISMA flow chart diagram (Figure 1). Non-duplicate published records were identified and titles and abstracts were screened. A total of 57 relevant studies specifically on CCHF/CCHFV in Arab countries were identified. For data extraction and qualitative assessment, CCHF case reports, CCHFV screening, prevalence, and distribution studies were analyzed, and duplicates removed. For documentation, we used original research studies and case reports. Letters to the editor and commentaries were excluded. All articles with relevant data according to our searches are summarized in Table 1. Out of all published papers, studies on human cases/clinical reports were more common compared to studies on tick vectors, and serological detection of CCHFV in animals. Some studies were multidimensional and included CCHFV detection from more than one source, for example, ticks, animals, and humans, and these studies were included in data.

CCHFV is a Nairovirus belonging to the family Bunyaviridae that also includes genera Orthobunyavirus, Hantavirus, Phlebovirus, and Tospovirus (75). All these genera are known to include human pathogens except Tospovirus which infects plants (76). Nairoviruses are tick-borne viruses (77, 78) and they are distinguished from other bunyaviruses by their large genome L segments (75, 79). CCHFV is an RNA enveloped virus with a diameter of ~80–100 nm (79) (Figure 4). Its lipid envelope is specked with spikes comprising of the glycoproteins (Gn and Gc), which are responsible for the binding of the virus to cellular receptors. The genome consists of single-stranded RNA with negative polarity, contains three segments, small (S), medium (M), and large (L), encapsidated by the nucleoprotein (NP), and the RNA-dependent RNA polymerase (RdRp), which is required for transcription and genome replication in the host cell (75, 79) (Figure 4).

CCHFV is genetically diverse arbovirus and analysis of complete and partial S segment sequences revealed the seven genetic lineages of CCHFV correlated with the geographical area of virus detection including Asia 1, Asia 2, Africa 1, Africa 2, Africa 3, Europe 1, and Europe 2 (80–82). Reassortment and recombination of segments that occurs with concurrent infections of vectors with viral strains of different lineages may lead to the emergence of new genetic variants of CCHFV (83–85).

Ticks become infected with CCHFV during their blood meal on an infected animal. The virus replicates in the tick midgut, disseminates to the hemocoel, and then spreads to the salivary glands to be transmitted to the next host through saliva. As compared to mosquitoes, ticks feed for a longer period on the host and ingest a greater volume of blood. Ticks digest blood in the acidic intracellular compartments of the gut epithelium (86). Therefore, the virus does not need to bind to a receptor in the tick's midgut to infect and replicate in the cells of the midgut and to spread to different parts of the body such as the salivary glands and reproductive organs (87). The virus passes through several barriers within ticks during the process of replication and transmission. Viral replication is stimulated by the attachment of the tick to the host during the feeding period (6). CCHFV can be associated with the vector for an extended period by persistent infection through the trans-ovarial transmission to the next generation and trans-stadial transmission to the next life stage (6). However, the frequency of both of these transmission processes requires further investigations. For example, ticks can survive long periods without feeding; consequently, tick vectors serve as reservoirs of CCHFV infection even in the absence of vertebrate hosts. For example, in H. marginatum, CCHFV was detectable up to 700 days after an infectious blood meal (88). Moreover, ticks have been reported to transmit the virus by biting the vertebrates even after storage at 4 °C for up to 10 months (88).

CCHF infections are enzootic and mostly asymptomatic in various animals (89). The CCHF virus can be transmitted to humans via contact with infected humans and animal tissues/blood or by tick bites (90) (Figure 5). Nosocomial outbreaks in hospitals are associated with resource-poor settings (43). For example, a nosocomial outbreak was reported in Al-Fulah, Kordufan, Sudan in 2008 when a 60 years old male patient who had worked as a butcher was admitted to hospital. Due to the lack of personal protective equipment (PPE) and implementation of stringent infection control measures, the virus was transmitted to nurses who had provided care to the index patient (43). The majority of CCHF cases however, have occurred in people associated with the livestock industry, slaughterhouse/abattoir, and veterinary practice (91, 92). In the Arab world, the virus has been shown to circulate in many tick genera (Table 1). However, ticks belonging to the genus Hyalomma are the main source of human infections, perhaps due to both immature and adult ticks feeding on host blood that they requires at each stage of their maturation (75). Hyalomma ticks act as both reservoirs and vectors for CCHFV (93). The Hyalomma tick larvae and nymphs feed on small mammals or/and birds, or reptiles whereas the adults feed on ungulates, and maintain CCHFV in nature through trans-ovarian and trans-stadial transmission (6, 27, 35). The role of reptiles as competent host for CCHFV transmission and as reservoirs needs to be determined. The transmission of CCHFV to animals occurs through a bite of an infected tick. Subsequently, the virus transmits to non-infected ticks while taking blood meal from the infected host. Ticks can also acquire infection during co-feeding of infected and non-infected ticks on same host and viral substances present in the saliva of ticks accelerate the viral transmission (94). However, all mammals are equally susceptible to CCHFV infection (95). Birds are considered poor hosts for CCHFV replication and transmission because birds are commonly resistant to becoming viremic (96). Humans are generally considered as incidental, dead-end host for CCHFV. People predominately get infected through tick bites, contact with tissues and blood of viremic animals, and though tissues and body fluid/blood of infected humans (75). Travel and trade of infected livestock from infected areas to new areas can also lead to CCHFV transmission (97). The threat of CCHFV transmission can be reduced through changes in land use, and by controlling the travel and trade of infected livestock. In the Arab world, during various outbreaks, the most common mode of CCHFV transmission was found to be contact with contaminated blood of carcasses through wounds or mucous membranes of infected animals and patients (Table 1).

CCHF first caught attention during an outbreak in Crimea in 1944 when 200 Soviet military personnel were infected while assisting farmers (27). It later emerged that the same virus infected a 13-year-old male patient in Congo in 1956, giving the virus its current name (27). It was designated as arbovirus in 1962 (98, 99). CCHF is endemic in Africa, Asia, Eastern Europe, and the Middle East (8, 100). The CCHFV distribution covers the maximum geographic range of any tick-borne virus in the MENA Region. Many Arab countries of the MENA Region have reported CCHF cases. The CCHF geographic distribution overlaps with that of Hyalomma ticks (Figure 2). These ticks feed on several animals including livestock and wildlife that could serve as asymptomatic reservoirs of CCHFV in the transmission cycle in endemic areas (89). A wide range of hosts and favorable climatic and ecological conditions in several Arab countries bordering each other could upsurge the incidence of CCHF in the region in the future. Ecological settings and human behavior can also play a crucial role in the maintenance and occurrence of CCHFV within region (101). Furthermore, changes in land-use, urbanization, transportation and trade of infected livestock can also impact the risk of CCHFV transmission. Limitations in surveillance and diagnostic capacities are important impediments in the estimation of the CCHF burden in many countries (102). In the following section we will discuss the epidemiology of CCHFV in specific countries in the Arab world.

CCHFV infection can be broadly grouped into four phases: Incubation period, pre-hemorrhagic, hemorrhagic, and convalescent (110). The incubation period is the asymptomatic phase, which persists for 3–7 days after infection. The second is a pre-hemorrhagic phase that lasts for 4–5 days and is characterized by symptoms such as high fever, headache, abdominal pain, myalgia, and hypotension (27). The third phase involves severe symptoms, such as epistaxis, hemoptysis, ecchymosis, diarrhea, neuropsychiatric and cardiovascular changes (7). Severely ill patients can progress to multi-organ failure and death. Those who survive, recovery starts around 10–20 days after the onset of the illness (78). Full recovery can take almost a year in CCHF survivors (13). However, some patients were reported with dramatic recovery in much shorter time (14).

CCHFV causes severe disease in humans with a high fatality rate, up to 50% (111) and up to 80% for nosocomial transmission (112). In Arab countries, mortality rate varied from 24–61% during different outbreaks. Early diagnosis is critical for patient support and for preventing the spread of infection through well-documented human-to-human transmission (113). Ribavirin has been used extensively as an antiviral treatment (113). Table 2 documents CCHF cases and fatality rates reported in different countries in the Arab world over the last four decades.

CCHF is a disease with a high potential of an outbreak with high fatality rate. Hyalomma ticks are present across the Arab countries. Climate change and anthropogenic factors could contribute to an extension of the geographic range of CCHFV. Continuous surveillance of tick vectors and animals is required to monitor the CCHF burden and epidemiological trends. Considering the high case fatality rate of CCHF, early detection and diagnosis are critical to allow quick interventions at all levels, including patient, hospital, and community level. Further, the development of a vaccine and new drugs against CCHFV is of major importance. Ribavirin efficacy should be evaluated through well-designed clinical protocols. Awareness about the mode of transmission of CCHF to the general public is essential to curtail the spread in the area. In many rural areas in Arab countries, backyard slaughtering is common practice and this can result in transmission of the virus to humans (8). Similarly, auxiliary staff should be well trained to recognize and act accordingly to avoid nosocomial spread of the infection. High biosafety level laboratories (BLS4) are crucial for rapid confirmation of suspected cases. Tests need to be reliable and affordable. Climate change and anthropogenic factors that may affect the epidemiology of CCHF should be further studied. Risk assessment in CCHF endemic areas is important for devising tick-control strategies. Therefore, multidisciplinary collaboration is required at the local and regional levels to identify relevant gaps and work in an integrated fashion for the prevention and control of CCHF.

This study has a number of limitations. We only included studies/reports published in English. It is possible that some studies may have been published in Arabic which we did not include. Furthermore, we could not find published data on CCHF/CCHFV for some countries. Moreover, reliable and good quality data on CCHF, such as demographics, clinical data, and incidence/fatality rates are not always available or accessible in some of the countries in the region. These limitations can clear impact the analysis.