Explore the complexities of Crimean-Congo hemorrhagic fever, a tick-borne viral disease with a high mortality rate. This comprehensive overview covers the virus’s transmission, symptoms, epidemiology, management challenges, and recent impacts in regions like Pakistan, especially following environmental crises.
It is a tick-borne viral disease caused by the arbovirus, also known as Crimean Congo Hemorrhagic Fever Virus (CCHFV). It is a member of the Nairovirus genus (family Bunyaviridae). These nairoviruses are present in two types of tick genera, Hyalomma ticks and ixodid ticks (these are large and have scaly bodies). The virus is transmitted to the animals when these ticks suck blood from animals during their stage of maturation. It spreads in vertical and horizontal cycles due to both of these tick’s general presence on the bodies of most of the domestic and wild vertebrates in which they don’t show the signs of illness.
Introduction
The CCHF virus causes outbreaks of very viral hemorrhagic fever with a case mortality rate of 10-40%. The CCHF is endemic to the south of the 50th Parallel North in Africa, the Balkans, the Middle East and Asian countries – these are the geographical ranges of the main tick vector.
The disease was first found in Crimea in 1944 and was named Crimean Hemorrhagic Fever. This was later recognized as the cause of the disease in Congo in 1969, thus resulting from the current name of the disease.
The incubation period ranges from 2 to 14 days. According to a survey, 88% of injuries are all clinical. The percentage of cases in which death occurs is 15%. The most common symptoms include:
Sudden fever, chills, tremors, myalgia, headache, vomiting, abdominal pain, joint pain; After a few days: bleeding from the mucous membranes, bruising, Melena, hematuria, nosebleeds, vaginal bleeding, bradycardia, thrombocytopenia, leukopenia.
The percentage of circulating blood serum in animals is a good indicator of the local circulation of viruses, for example, the study revealed areas with a high risk of human infection. Slaughter Employees, veterinarians, breeders and other persons associated with the breeding site must be informed. They should take practical measures to reduce or prevent contact with fresh blood and exposed skin of other animals. To prevent tissue cutting, use ticks and fleas. The experience of South Africa shows that: Those who clean animals before slaughter can reduce the number of infected workers in the slaughterhouse.
In general, veterinary treatment can reduce the number of ticks on these animals. The fight against these fleas is possible with the use of acericides. Not much, but in harsh agricultural conditions it can be difficult to use it. The passive mouse brain The vaccine was used to prevent infection in humans and is being used on a limited scale for the first time in eastern Europe. The development of the Soviet vaccine against the emerging coronavirus continues to use some Proven ways to overcome existing problems
CCHF History
A physician in the 12th century from the region that is presently Tadzhikistan of all told of its presence. Then it spread out from Western China to Middle East and Southern Europe to most of Africa.
Epidemiology
Commonly it is caused in agricultural laborers as a result of a tick bite and to a lesser extent, in the slaughter house workers as they come in contact with infected animals blood and body fluids and also in the medical staff in hospitals due to contact with body fluids of contaminated patients
Deciphering the Complex Pathogenesis of CCHF
The pathogenesis of CCHF is poorly understood because it occurs sporadically, and in areas where clinical pathology facilities are limited, complete autopsies are seldom performed on patients who die from the disease. Additional factors that hamper studies on CCHF include the need for specialized laboratories (i.e., biosafety level-4 (BSL-4)) and lack of available animal models of disease. Therefore, limited knowledge of pathogenesis is often obtained from blood changes and liver. The typical course of CCHF has been noted by some authors as progressing through three distinct phases, i.e., incubation, prehemorrhagic, and hemorrhagic.
CCHFV is generally not only a single microbe in ticks; endosymbionts and many pathogens may also be involved. Metagenomics studies showed that the microbiome has an effect on tick fitness and pathogen infection and transmission. As an example, Francisella-like endosymbionts have also been identified in Hyalomma spp. ticks. The presence of these extra pathogens or endosymbionts may affect the physiology and immune response of the ticks.
Viral infections in ticks affects their life span, gene expression and many other life changes occur.
Tick-host Interactions
The general issues concerning tick-host interactions likely apply to CCHFV. The first interaction between the tick and the host occurs during the tick bite and then a complicated process of the tick feeding on the host. The involvement of salivary gland secretions into the feeding lesion is the major route via which pathogens and toxins access the vertebrate host and mediate the host reactions. Despite the host’s hemostatic, inflammatory and immune responses, the tick manages to remain attached for blood-feeding. Anticoagulants, cytolytic substances, vasoactive mediators (such as prostaglandins), and cement, which anchors the mouthparts to the skin, are the substances that are secreted in saliva.
Saliva activated transmission, subsequently renamed saliva-assisted transmission (SAT), SAT is thought to play an additional critical role facilitating the infection of uninfected tick. There are no reports on the role of SAT on CCHFV. Because the salivary glands are the most important route for pathogen transmission by arthropod vectors, it is expected that the volume of saliva secreted into the host is a major factor in determining the efficiency of transmission. Time of attachment may also affect the level of tick-host interaction.
Abiotic (environmental and climatic) factors are involved indirectly in the tick-host interactions by playing a role in the abundance and aggressiveness of ticks, thus affecting the chance of a host to be bitten by ticks. By a bloody meal, CCHFV enters the tick’s humoral and cellular immune responses and replicates in the lining of the tick’s midgut; then it is disseminated to the hemolymph and infects various tissues, with the highest viral titers being observed in the proliferating tissues. The minimum virus titer necessary to infect the ticks varies among tick species.
Following intracoelomic inoculation of CCHFV, virus titer is not affected by tick’s sex and feeding status, but it is positively related with blood feeding. CCHFV replication in tissues of an infected tick may be stimulated by tick attachments and feeding. The molecular events at the tick-pathogen interface are not known. Most likely, the first step is the interaction of CCHFV envelope glycoproteins and the epithelial cells of the ticks. The glycoprotein Gc was shown to be a class II viral fusion protein.
Ticks do not present adaptive immunity, and they rely on innate immune response consisting of phagocytosis, encapsulation, nodulation, and secretion of humoral factors in the hemolymph. An additional important mechanism of innate antiviral defense of arthropods against arboviruses, RNA interference, was investigated on Hazara nairovirus, which is considered as a surrogate CCHFV model. It was shown that small interfering RNAs targeting Hazara nairovirus N protein mRNA inhibited virus replication, and the antiviral effect was stronger when siRNAs were combined with ribavirin. The exact role of RNA in tick-CCHFV interactions remains to be elucidated.
Transmission Pathway of Crimean Congo Hemorrhagic Fever
Transmission of CCHF virus in people either by tick bites or through contact with the blood or tissues of infected animals during and immediately after slaughter. Most cases have been among people involved in the livestock industry, such as agricultural workers, slaughterhouse workers and veterinarians. Human-to-human transmission can occur as a result of close contact with blood, secretions, organs or body fluids of those affected. Incorrect sterilization of medical devices, reuse of needles and poor cleaning of medical equipment can also lead to hospital-acquired infections. The reservoir and a vector for the CCHF virus is Ixodid (hard) ticks, especially the genus Hyalomma. Numerous wild and household animals, such as cattle, goats, sheep and rabbits, serve as enhancing hosts for the virus.
Clinical Symptoms
The length of the incubation period depends on the mode of acquisition of the virus. The incubation period is usually one to three days after infection with a tick bite, with a maximum of nine days. The incubation period is usually five to six days after contact with infected blood or tissues, with a maximum of 13 days documented.
Symptoms have no sign at the beginning, with fever, myalgia, dizziness, neck pain and stiffness, back pain, headache, eye pain and photophobia. There is a very early possibility of developing nausea, vomiting, diarrhoea, abdominal pain, and a sore throat, while over time there may be a sharp change in mood and confusion. After some three or four days, the provocation can be replaced by sleep, depression, and lastoid, and abdominal pain can be local pain in the upper right quadrant, in which liver enlargement can be assessed.
As well as medical symptoms include tachycardia (rapid heart rate), enlarged lymph nodes, and a rash caused by bleeding on the inner surfaces of the mucosa, such as in the throat and mouth, and on the skin. Petechia can give way to large rashes called ecchymosis and other bleeding phenomena, which usually have symptoms of hepatitis, and seriously ill patients may experience rapid kidney failure, sudden liver failure, or lack of pulmonary function after the fifth day of illness. The mortality rate is about 30% from CCHF, while death occurs in the second week of illness.
In recovered patients, improvement usually begins on the ninth or tenth day after the onset of the disease. Patients may have mild nonspecific febrile synthesis, vascular leak, multi-organ failure, shock and haemorrhage, blood in the urine, rectum, gums, vomitus, sputum, and abdominal cavity, which is caused by a louse or tick, which normally parasitizes a blackbird. Onset of fever, accompanied by weakness, headache and muscular pains, vomiting, marked hyperemia of the face and oropharynx, a hemorrhagic rash with development of ecchymoses and bleeding from the nasopharynx, gastrointestinal tract and other sites.
Difficulties And Troubles
Pakistan has grown endemic to this severe virus, which has a high case death rate, since the first case of CCHF was reported there in 1976. There are multiple reasons for the rising prevalence of CCHF throughout time.
Distribution both geographically and chronologically
Since the CCHF virus is spread through tick bites, the most important component of the equation is the ideal habitat in which tick vectors are cultivated. Ticks can thrive and proliferate in Pakistan due to the country’s ideal climate and other environmental factors. Due to the fluctuating temperatures during these months, there is a biennial spike in CCHF infections from March to May and from July to September. Despite reports of illnesses from all around the nation, Sindh and Balochistan account for the majority of cases. Afghanistan and Iran, where CCHF is also endemic, border Balochistan.
Keeping of animals
Pakistan is an agricultural nation where the majority of the rural populace raises cattle. The majority of the time, animals do not receive animal vaccinations or routine health checkups by veterinary professionals due to poverty and lack of education, which allows the virus to spread uncontrolled. Furthermore, because animals and their carcasses are handled carelessly during Eid-ul-Azha, there is a heightened demand for animals, which exacerbates infection outbreaks.
Pakistan’s Healthcare System
The widespread CCHF epidemics in Pakistan are currently beyond the capabilities of the country’s healthcare system. Both adequate surveillance systems and CCHF diagnostic tests are in short supply, making it difficult to identify cases early. Healthcare personnel have a low index of suspicion, which exacerbates the situation. A survey found that over 40% of medical professionals don’t know enough about CCHF.
Management Difficulties of Crimean Congo Hemorrhagic Fever
There is currently no authorized vaccination against the Crimean-Congo hemorrhagic virus (CCHV) that may be used to treat or prevent infections in humans. Patients are primarily treated with supportive care after diagnosis. As of right now, no particular antiviral medication has been created to combat CCHV. Although ribavirin has demonstrated some efficacy, more effective pharmaceutical treatments are still required to address the CCHF. The no placebo nature of the ribavirin trials has led some meta-analyses to classify them as low quality trials. Because they raise ethical concerns, randomized control trials to determine the effectiveness of ribavirin are still lacking. There is no evidence of the effectiveness of other experimental medications, such as favipiravir, chloroquine, chlorpromazine, and interferon type-1, in people.
Congo Fever In The Setting Of Recent Pakistan Floods
Over 33 million people and 75% of the nation’s districts have been affected by the monsoon-related flooding in Pakistan. Pakistan’s public health system was already criticized for being deficient before to the floods, and millions of people still lack access to care. The crisis has exacerbated disease epidemics such as acute watery diarrhoea, dengue fever, malaria, polio, and COVID-19, particularly in camps and locations where the infrastructure for water and sanitation has been weakened. In particular, mosquito-borne illnesses like dengue fever may become more prevalent after flooding in endemic areas. A mosquito breeding habitat could be created by standing water.
Changes in the climate have an impact on disease transmission and alter the geographic distribution of vector-borne infections. A potential avenue for this is to modify the effectiveness of current therapies. In a similar vein, while flooding may drown ticks, the warm, humid weather that follows can increase tick populations and increase the risk of tick fever. Thus, it is important to keep an eye out for cattle that may be harboring tick-borne diseases following floods.
Genetic Diversity of Crimean Congo Hemorrhagic Fever
Crimean-Congo hemorrhagic fever virus is a circular, negative-sense single-stranded RNA virus. Many early studies, primarily based on serological testing, suggested that there are very few significant differences among strains of CCHFV. For instance, investigations using modified agar gel diffusion precipitation, neutralization, cell culture interference, and complement fixation tests revealed no apparent antigenic differences among strains collected from various geographic locations within the former Soviet Union and Africa. In 1973, researchers first described the morphology of CCHFV in the brains of infected newborn mice, noting its similarity to members of the Bunyaviridae family.
Geographic range
Crimean-Congo hemorrhagic fever is primarily transmitted through tick bites, with ticks acting as carriers of the virus. Studies conducted on ticks collected from the field, as well as laboratory experiments assessing their ability to transmit the virus, confirm that ticks are responsible for spreading the disease. Migratory birds and international livestock trade have also contributed to the dispersion of the virus. Since 2000, cases of Crimean Congo Hemorrhagic Fever have increased in countries like Turkey, Iran, India, Greece, the Republic of Georgia, and the Balkan states. In Spain, viral RNA linked to CCHF has been found in Hyalomma ticks recovered from deer. The first recorded human case of CCHF occurred in the Soviet Union in 1944, with Turkey reporting its first case in 2002. Over the next decade, 6,300 cases were recorded in the country. The earliest known human infection dates back to 1999.
CCHF originates suddenly, with symptoms including headaches, high fever, back pain, joint pain, abdominal pain, and vomiting. Red eyes, a flush face, a red throat, and red spots are common on the palate. Jaundice can also occur, and in a dangerous state, mood and sensory perception change.
As the disease continues to grow, large areas of serious injury, nosebleeds and uncontrolled bleeding can be seen at the injection sites, starting on the fourth day of the disease and lasting about two weeks. In the documented outbreak of CCHF, the mortality rate among hospitalized patients has risen from 9% to 50%.
Life Cycle of Crimean Congo Hemorrhagic Fever
The virus circulates in the tick-vertebrate-tick cycle, but the tick can also spread horizontally and vertically within the population. Hyaloma ticks affect a wide range of different wildlife species. Many birds are resistant to infections, such as deer and rabbits, and free cattle animals, such as goats, cattle, and sheep, but ostriches appear more sensitive. Varemia in cattle is short-lived and of low intensity. These animals play an important role in the life cycle of ticks and in the transmission and enhancement of viruses and are therefore in the eyes of veterinary public health. Since clinical symptoms do not arise in animals, CCHFV infection has no effect on the economic burden with respect to livestock production. Unlike animals, if it comes to humans, human infections can result in the development of a severe disease, Crimean Congo hemorrhagic fever.
Natural cycle CCHFV also includes transureal and transstadial transmission between ticks and tick-vertebrate cycles involving a variety of wild and domestic animals. The infection can also be transmitted between infected and uninfected ticks during Co-feeding on the host. The so-called’ non-veramic transmission ‘ phenomenon. Hyaloma ticks feed on a variety of domestic infants and wild vegetarians, rabbits, hedgehogs, and some rodents. CCHFV infection was evaluated in animals by Nalka & White House (2007).
Spengler and others examined experimental infections of wild animals and livestock with CCHFV (2016). Although animal infections are usually subclinical, associated varemia levels are sufficient to enable the transmission of the virus to uninfected ticks. Many birds are resistant to infection, but ostriches appear to be more susceptible than other bird species. Although they do not appear to be veramic, ground-feeding birds can act as a vehicle for the spread of CCHFV-infected ticks. The results of serological surveys conducted in Africa and Eurasia indicate a wide circulation of the virus in cattle and wild vertebrates.
Handling of CCHFV
Infection of CCHFV with boiling or autoclaving and low availability of formalin or beta-prolactone we can eliminate. This virus is very sensitive to lipid solvents. It is labelled in infected tissues after death, possibly due to a decrease in hydrogen ions, but the infection persists for a few days at ambient temperature in the serum and for 3 weeks at 4°C. The infection is stable at temperatures below -60 °C. CCHFV with defined appropriate biocontainment measures must be handled by risk analysis standard for biological risk management in veterinary laboratory and animal facilities.
Diagnosis of CCHFV
Initial laboratory evaluations for Crimean-Congo hemorrhagic fever typically reveal leukopenia (low white blood cell count), thrombocytopenia (low platelet count), and elevated serum levels of AST and ALT (liver enzymes). A specific diagnosis can be confirmed by testing a serum specimen for viral RNA using reverse transcriptase polymerase chain reaction (RT-PCR) and for virus-specific IgM antibodies. Other diagnostic methods include enzyme-linked immunosorbent assay (ELISA), antigen detection, serum neutralization, RT-PCR assays, and virus isolation through cell culture.
Treatment of Crimean Congo Hemorrhagic Fever
Mostly asymptomatic, but in nonspecific febrile illness, patient should be hospitalized when they feel the symptoms of hypotension, hemorrhage and a fall in blood pressure due to increased vascular permeability.
So the treatment in these is largely supportive measures such as volume replacement by intravenous fluids
Treatment options for Crimean Congo Hemorrhagic Fever are limited. Early remedies included giving rutin (a bioflavonoid compound found in buckwheat), ascorbic acid, and calcium chloride for the treatment of the hemorrhagic syndrome. It was also suggested that with extensive blood loss, transfusions and blood substitutes such as polyglutin, plasma, and hemodes were necessary and intravenous injections of gelatin and aminocaproic acid were also indicated. Much emphasis was also placed on preventing reinfection.
Prevention
An inactivated, mouse-brain derived vaccine against CCHF has been developed and is used on a small scale in Eastern Europe. However, there is no safe and effective vaccine currently available for human use. Further research is needed to develop these potential vaccines as well as determine the efficacy of different treatment options including ribavirin and other antiviral drugs.
General strategy to control CCHF outbreaks
Controlling Crimean-Congo hemorrhagic fever outbreaks requires a multifaceted approach that includes clinical case management, behavioral and social interventions, and the control of vectors and reservoirs in nature. Effective coordination among health authorities and stakeholders is crucial, along with efficient logistics to ensure timely responses. Additionally, thorough epidemiological investigation, surveillance, and laboratory work are essential for monitoring and understanding the spread of the disease. These combined efforts are vital for effectively managing and mitigating CCHF outbreaks.
Potential Bioterrorism Concerns
The highly pathogenic nature of the CCHFV has led to the fear that it might be used as an agent of bioterrorism and/or bio warfare and has resulted in its inclusion as a CDC/NIAID Category C Priority Pathogen.
CCHFV can be transmitted from person to person, has a high case-fatality rate, and may be transmissible by small-particle aerosol; but, its inability to replicate to high concentrations in cell culture is cited as a major impediment to its development as a mass casualty weapon. The disease now occurs sporadically throughout much of Africa, Asia, and Europe and results in an approximately 30% fatality rate after a short incubation period.
Vaccines for Crimean Congo Hemorrhagic Fever
The virus is sensitive in vitro to the antiviral drug ribavirin. In 1944, a formalin-inactivated mouse-brain vaccine for Crimean-Congo hemorrhagic fever was utilized in the Soviet Union.
Transmission of Crimean Congo Hemorrhagic Fever virus in people either by tick bites or through contact with the blood or tissues of infected animals during and immediately after slaughter. Most cases have been among people involved in the livestock industry, such as agricultural workers, slaughterhouse workers and veterinarians. Human-to-human transmission can occur as a result of close contact with blood, secretions, organs or body fluids of those affected. Incorrect sterilization of medical devices, reuse of needles and poor cleaning of medical equipment can also lead to hospital-acquired infections.
The reservoir and a vector for the CCHF virus is Ixodid (hard) ticks, especially the genus, Hyalomma. Numerous wild and household animals, such as cattle, goats, sheep and rabbits, serve as enhancing hosts for the virus.
This article is co-authored by Muhammad Faizann, Ahram Hussain, and Muhammad Hussain from the University of Veterinary and Animal Sciences.