Crimean-Congo hemorrhagic fever: Pathogenesis, transmission and public health challenges

Abstract

The dangerous Crimean-Congo hemorrhagic fever virus (CCHFV), an encapsulated negative-sense RNA virus of the family Nairoviridae, is transmitted from person to person via ticks. With a case fatality rate between 10% to 40%, the most common ways that the disease may spread to humans are via tick bites or coming into touch with infected animals' blood or tissues. Furthermore, the transfer of bodily fluids between individuals is another potential route of infection. There is a wide range of symptoms experienced by patients throughout each stage, from myalgia and fever to extreme bruising and excess bleeding. Tick management measures include minimising the spread of ticks from one species to another and from people to animals via the use of protective clothing, repellents, and proper animal handling. In order to prevent the spread of illness, healthcare workers must adhere to stringent protocols. Despite the lack of an authorised vaccine, the main components of treatment now consist of preventative measures and supportive care, which may include the antiviral medicine ribavirin. We still don't know very much about the virus's mechanisms, even though advances in molecular virology and animal models have improved our understanding of the pathogenesis of CCHFV. A critical need for vaccination that is both safe and effective, as well as for quick diagnosis and efficient treatments to lessen the disease's impact in areas where it is most prevalent. Important steps towards lowering Crimean-Congo hemorrhagic fever mortality and morbidity rates were to anticipatethe future availability of immunoglobulin products.

Key Words: Crimean-congo haemorrhagic fever; Tick-borne illness; Immunoglobulins; Viral hemorrhagic fever; Antiviral therapy

Core Tip: This review provides a comprehensive overview of Crimean-Congo hemorrhagic fever (CCHF), a severe tick-borne viral disease with significant public health implications. The article discusses the virus's transmission dynamics, clinical manifestations, current diagnostic techniques, and available treatments, including the use of antiviral therapy. It emphasizes the urgent need for vaccine development, better diagnostic tools, and efficient therapies. By addressing gaps in knowledge and highlighting the importance of a one health approach, this review serves as a critical resource for researchers and healthcare professionals seeking to improve CCHF control and prevention strategies.

INTRODUCTION

Between 10%-40% of infected people die during Crimean-Congo hemorrhagic fever virus (CCHFV) outbreaks of severe viral hemorrhagic fever. As a febrile sickness, the disease was first known as Crimean haemorrhagic fever when it was initially discovered in 1944 among troops on the Crimean Peninsula (near the Black Sea)[1]. The present name of the disease was given to it in 1969 when the same bacterium was identified as the cause of febrile sickness in the Congo Basin. The main vector and reservoir of CCHFV are ticks of the species Hyalomma[2]. The species of Hyalomma tick that causes Crimean-Congo hemorrhagic fever (CCHF) depends on the geographic region. Hyalomma marginatum is the primary vector of CCHF in Europe and the Balkans where as Hyalomma anatolicum in Iran, Pakistan, Turkmenistan, and Tajikistan, Hyalomma asiaticum in Central Asia and China and Hyalomma rufipes in Africa.

Many non-domesticated animal species, including ostriches, buffalo, tiny rodents, hares, and rhinoceroses, may be infected with CCHFV, according to serological investigations. Important amplifying hosts for the transmission of tick-borne diseases include animals that ingest infected ticks or co-feed with them[3]. Tick bites or coming into contact with sick animals during slaughter are the most common ways for humans to get the disease. In humans, an infection usually manifests as a fever, which may later develop into a hemorrhagic condition and could be deadly. Particularly in areas without access to high-containment facilities, molecular testing have allowed for safe and quick diagnosis. Sheep, goats, and cattle are just a few of the many domestic and wild animal species that may harbour the CCHFV[4].

Although most birds can withstand infections, ostriches aren't immune and may have a high infection rate in regions where it is common. The tick-borne disease stays in an infected animal's bloodstream for around seven days after infection[5]. When another tick bites the sick animal, the tick-animal-tick cycle might resume. Hyalomma ticks are the most common vectors of the CCHFV (Figure 1), however infections may occur in other tick genera as well.

Figure 1 Lifecycle and vector role of Hyalomma ticks in Crimean-Congo hemorrhagic fever transmission. A.Larval stage of the Hyalomma tick; B: Nymphal stage attached to a host; C: Adult Hyalomma tick, the main vector for Crimean-Congo hemorrhagic fever virus; D: Close-up of the tick attachment to host skin for blood-feeding; E: Transmission cycle from animal to human through tick bites and handling infected animals.

Although CCHF is common in many regions of the globe, including the Indian subcontinent, northwest China, Africa, the Balkans, and Eastern Europe, there is no vaccine that can protect people or animals against this disease at this time[6].

The four families of viruses known to cause viral hemorrhagic fevers are Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae which cause severe systemic febrile diseases (Table 1). The arenaviridae family of viruses includes both Old World and New World Strains, and they are known to cause infections transmitted by rodents. Europe, Asia, and Africa are just a few of the numerous regions where rats are susceptible to viral infections[7]. Urine or droppings from rodents are a common vector for infection. A 50% case mortality rate has been reported in West African epidemics caused by the arenavirus Lassa. Insects and rodents may transmit viruses that belong to the Bunyaviridae family, which can cause mild to severe illness[8]. Rift Valley fever, hemorrhagic fever in the Crimean-Congo region, and hantavirus infections are among the most prominent ailments. The Ixodid tick is the vector for the virus. The family Filoviridae includes the Ebola virus and Marburg hemorrhagic sickness, both of which have been found in African bats. The danger of transmission from person to person is considerable for human infections, particularly among those in care takers[9]. In low-income nations, the case fatality rate for Marburg hemorrhagic fever may reach 82%, while in the Democratic Republic of Congo, it can reach 80% to 90%. Various forms of infections are carried by the flavivirus family, which is carried by arthropods[10]. Dengue fever affects more than a hundred nations throughout Europe, Asia, Australia, Africa, and the Pacific Islands. It is a global health crisis. The mosquitoes Aedes aegypti and Aedes albopictus are vectors for the flavivirus that causes dengue fever. The disease can progress through three stages: (1) Mild; (2) Moderate; and (3) Severe[11].

Table 1 Different types of viral haemorrhagic fevers and causative agents.

Family	Causative virus	Disease	Symptoms	Treatment
Arenaviridae	Lassa virus	Lassa fever	Fever, weakness, and haemorrhage	Supportive care and ribavirin
	Junin virus	Argentine haemorrhagic fever	Fever, malaise, and haemorrhage	Supportive care
	Chapare virus	Chapare hemorrhagic fever	Fever, malaise, headache, vomiting and diarrhoea	Supportive care and early diagnosis
	Guanarito virus	Venezuelan hemorrhagic fever	Confusion, convulsions, coma, and bleeding from body orifices	No specific anti-viral treatment is available
	Lujo virus	Lujo hemorrhagic fever	Fever, headache, vomiting, diarrhea, arthralgia, and myalgia	Supportive care
	Lymphocytic choriomeningitis virus	Lymphocytic choriomeningitis	Fever (38.5 °C to 40 °C), malaise, myalgia, retro-orbital headache, photophobia, and anorexia	Supportive care and ribavirin
	Machupo virus	Bolivian hemorrhagic fever	Fever, malaise, fatigue headache, dizziness, myalgias, and severe lower back pain	Supportive care
	Sabia virus	Brazilian hemorrhagic fever	High fever, fatigue, maculopapular/petechial rash bleeding and haemorrhage	Supportive care and ribavirin antiviral drug
Bunyaviridae	Crimean-Congo haemorrhagic fever virus	Crimean-Congo haemorrhagic fever	Fever, myalgia, and haemorrhage	Supportive care and ribavirin
	Hantan virus	Hantavirus pulmonary syndrome	Fever, muscle pain, and pulmonary edema	Supportive care
	Dobrava-Belgrade virus	Hemorrhagic fever with renal syndrome	Intense headache, back and abdominal pain, fever, chills, and blurred vision	Supportive therapy, renal dialysis. Treatment with ribavirin
	Seoul virus	Hemorrhagic fever with renal syndrome	Intense headache, back and abdominal pain, fever, chills, and blurred vision	Supportive therapy, renal dialysis. Treatment with ribavirin
	Puumalavirus	Hemorrhagic fever with renal syndrome	Intense headache, back and abdominal pain, fever, chills, and blurred vision	Supportive therapy, renal dialysis. Treatment with ribavirin
	Rift Valley fever virus	Rift Valley fever	Transient fever, headache, severe muscle and joint pain, photophobia and anorexia	Drugs like Ibuprofen or Acetaminophen
	Saaremaa virus	Hemorrhagic fever with renal syndrome	Intense headache, back and abdominal pain, fever, chills, and blurred vision	Supportive therapy, renal dialysis. Treatment with ribavirin
	Sin nombre virus	Hantavirus pulmonary syndrome	Fever, muscle pain, and pulmonary edema	Intubation and oxygen therapy, fluid replacement and use of medications to support blood pressure
	Severe fever and thrombocytopenia syndrome virus	Severe fever and thrombocytopenia syndrome	Fever, vomiting, diarrhoea, multiple organ failure, thrombocytopenia, and leucopoenia elevated liver enzyme levels	Intravenous ribavirin
	Tula virus	Hemorrhagic fever with renal syndrome	Intense headache, back and abdominal pain, fever, chills, and blurred vision	Supportive therapy, renal dialysis. Treatment with ribavirin
Filoviridae	Bundibugyo ebola virus	Ebola virus disease	Fever, severe hemorrhage, and organ failure	Supportive care and experimental treatments
	Marburg marburg virus	Marburg haemorrhagic fever	Fever, severe hemorrhage, and organ failure	Supportive care and experimental treatments
	Sudan ebola virus	Ebola virus disease	Sudden onset of fever, fatigue, muscle pain, headaches, sore throat, vomiting, diarrhoea, rash, impaired kidney, and liver functions	Monoclonal antibodies like Inmazeb and Ebanga
	Tai forest ebola virus	Ebola virus disease	Sudden onset of fever, fatigue, muscle pain, headaches, sore throat, vomiting, diarrhoea, rash, impaired kidney, and liver	Monoclonal antibodies like Inmazeb and Ebanga
	Zaire ebola virus	Ebola virus disease	Sudden onset of fever, fatigue, muscle pain, headaches, sore throat, vomiting, diarrhoea, rash, impaired kidney, and liver functions	Monoclonal antibodies like Inmazeb and Ebanga
Flaviviridae	Dengue virus	Dengue fever	Fever, rash, and haemorrhage	Supportive care and fluids
	Kyasanur forest disease virus	Kyasanur forest disease	Sudden onset of chills, fever, and headache	Supportive treatment with maintenance of proper hydration and circulation by transfusion of IV fluids
	Omsk hemorrhagic fever virus	Omsk hemorrhagic fever	Fever, headache, myalgia, cough, petechial rash or bruises	Supportive care
	Yellow fever virus	Yellow fever	Fever, chills, headache, back pain, vomiting, and fatigue	Rest, hydration and seek medical advice

Transmission

Tick bites or coming into touch with infected animal blood or tissues during or just after slaughter are the main routes of transmission for the CCHF virus to humans”. Direct contact with infected blood, saliva, organs, or other bodily fluids is the most typical way infectious illnesses are transmitted from one person to another (Figure 2)[12]. Additional factors that may lead to nosocomial infections include reusing needles, contaminated medical supplies, and insufficient sterilisation of medical equipment[13].

Figure 2 Overview of clinical stages and symptoms in Crimean-Congo hemorrhagic fever patients. Early stage with fever, myalgia, and fatigue. Pre-hemorrhagic stage with signs of conjunctival hemorrhage. Hemorrhagic stage showing extensive petechiae and ecchymosis. Recovery phase after supportive treatment. Post-recovery convalescence with residual symptoms. ELISA: Enzyme-linked immunosorbent assay; RT-LAMP: Reverse transcription loop-mediated isothermal amplification; NGS: Next-generation sequencing.

EPIDEMIOLOGY OF CCHF IN INDIA

On June 29, a male patient suffering from CCHF passed away in a private hospital in Ahmedabad. He was 51 years old and lived in the hamlet of Lakhapar in the Anjar taluka of Kutch. According to health officials, this is the first case of CCHF that has been documented in Gujarat this year. The state of Gujarat recorded five instances of confirmed CCHF in 2022. Since 2011, when the state first recorded a case of CCHF, Gujarat has been the reporting centre for the vast majority of CCHF cases in India[14]. Gujarat reported verified cases of CCHF from 2011 to 2019, with Rajasthan reporting extra cases in 2014, 2015, and 2019. A 39-year-old guy who survived after testing positive for the virus in March 2022 was a cattle rearer. One of them was a 55-year-old housewife who died of CCHF after a tick bit her while she was tending to her cattle. One case of CCHF was recorded in the Sabarkantha district in 2021 by the state[15].

EPIDEMIOLOGY OF CCHF IN AFRICA

There were 494 CCHF cases (115 fatal) recorded in Africa between January 1, 1956, and July 25, 2020. Over the last decade, nine nations Kenya, Mali, Mozambique, Nigeria, Senegal, Sierra Leone, South Sudan, Sudan, and Tunisia have reported the first cases of CCHF[16].

Within the Bunyavirales order, the Nairoviridae family, and the Orthonairo virus genus, there will be enveloped, negative-sense RNA virus known as CCHFV. One crucial component of the virus is the envelope Gn glycoprotein, which, at its C-terminus, possesses a cytoplasmic tail. The genetic code of CCHFV consists of S, M, and L segments of RNA. Segment L encodes an RNA-dependent RNA polymerase, segment M viral glycoproteins, and segment S the nucleocapsid protein (N) (Figure 3)[17].

Figure 3 Structure of Crimean-Congo hemorrhagic fever virus. This includes electron microscopy image of the Crimean-Congo hemorrhagic fever virus virion, schematic of the viral genome, showing S, M, and L RNA segments, envelope structure with Gn and Gc glycoproteins, viral RNA polymerase encoded by the L segment, nucleocapsid protein (N) from the S segment.

STAGES OF CCHF

Incubation stage

The duration of incubation is usually less than a week, falling anywhere from one to nine days (depending on the way the virus was exposed to and the dosage). It lasts the shortest time after a tick bite (about 1-3 days) and the longest time after coming into contact with contaminated human or cattle blood, tissue, or secretions (5-6 days).

Pre-hemorrhagic stage

Begins suddenly with vague symptoms and lasts an average of two to four days (range: One to seven days). Signs and symptoms may manifest as a high temperature (39–41 °C), neck discomfort or stiffness, dizziness, headache, myalgia, backache, eye pain, or photophobia. Nausea, vomiting, diarrhoea, stomach ache, and a sore throat are possible side effects. Jaundice, conjunctivitis, congested sclera, and hyperaemia of the chest, neck, and face are some possible symptoms. Hepatomegaly and splenomegaly, as well as changes in mood and sensory perception (such as somnolence supplanting agitation), may be seen in extreme instances.

Hemorrhagic stage

Usually brief (around two or three days), but may last up to two weeks. One distinctive aspect of CCHF compared to other viral haemorrhagic fevers is the wide variety of hemorrhagic symptoms it may cause, which can vary from little bleeding patches (peteziae) to widespread discolouration of the skin (ecchymosis) on both the skin and mucosal membranes. Some common symptoms may include injection site bleeding, epistaxis, melena, haematuria, haemoptysis, and haematemesis.

Convalescence stage

Within 9–10 days after the beginning of the disease (within a range of 9–20 days), convalescence often occurs in survivors, in the same vein as when laboratory measurements were back to normal. Symptoms such as hypotension, bradycardia or tachycardia, polyneuritis, difficulty breathing, xerostomia, impaired vision or hearing, hair loss, memory loss, and other difficulties might manifest during this protracted period. Although long-term consequences have not been thoroughly investigated, there is no solid proof of recurrence or a biphasic progression of the illness[18-21].

Signs and symptoms

Depending on how the virus is acquired, the incubation time for CCHF might vary in duration. The incubation phase, which begins three to nine days following a tick bite, is when the disease is usually spread. Contact with infected blood or tissues may spread viruses, and the incubation period for these viruses can be anywhere from 5 days to 6 days, up to 13 days[22]. A broad variety of symptoms, including myalgia, vertigo, headache, neck pain, backache, and photophobia, all manifest suddenly. Petechiae, or red patches on the palate, red eyes, heated cheeks, and a red throat are other common early signs (Figure 4). In the beginning, you can have a sore throat, nausea, vomiting, diarrhoea, stomach ache, and confusion[23]. In the two to four days after the start of symptoms, restlessness, melancholy, and lassitude may take the place of agitation. Additionally, the stomach discomfort may shift to the upper right quadrant and be accompanied by noticeable hepatomegaly. About 30% of those with CCHF will pass away throughout the course of their disease, usually during the second week. On the ninth or tenth day after the start of symptoms, individuals who are able to recover often start to feel better. Symptoms such as extensive bruising, nosebleeds, and uncontrolled bleeding at injection sites become apparent on day four of sickness and last for around two weeks. The reported mortality rates of CCHF patients in hospitals range from 9% to 50%[24].

Figure 4 Petechiae on the hand of a Crimean-Congo hemorrhagic fever patient. Petechiae are small red or purple spots resulting from capillary bleeding under the skin, commonly seen in the hemorrhagic phase of Crimean-Congo hemorrhagic fever. These non-blanching spots, distributed unevenly across the skin, indicate the severity of infection and can be accompanied by additional hemorrhagic symptoms like ecchymosis and mucosal bleeding.

Diagnosis in laboratory

A numberof laboratory techniques may be used to diagnose CCHF. By integrating enzyme-linked immunosorbent assay antigen capture for viral antigen detection with RT-PCR in blood or tissues collected from a dead patient and virus isolation, it is feasible to detect CCHF in its acute phase in individuals with a proper medical history. Tissues treated with formalin may also be stained immune-histo-chemically to reveal viral antigens (Figure 5)[25].

Figure 5 Laboratory diagnostic methods for Crimean-Congo hemorrhagic fever detection. PCR amplification of Crimean-Congo hemorrhagic fever virus (CCHFV) RNA in patient blood samples, enzyme-linked immunosorbent assay antigen capture method for viral antigen detection in serum samples, viral isolation technique from infected tick tissues, immunohistochemical staining of CCHFV antigens in formalin-fixed tissue, real-time PCR results showing viral load quantification. CCHF: Crimean-Congo hemorrhagic fever; RT-LAMP: Reverse transcription loop-mediated isothermal amplification.

Treatment

The main strategy is to provide general supportive care with an emphasis on symptom treatment. Both the oral and injectable forms of the antiviral medication ribavirin have shown efficacy in treating CCHF infection. Fluid balance, electrolyte imbalances, oxygenation, haemodynamic support, and secondary infection therapy should all be part of the supportive care plan[26]. At this time, neither humans nor animals have access to any immunizations that have proven successful. Without a vaccine, informing the public about the virus and its dangers and encouraging them to take precautions against exposure is the only method to lessen the likelihood of infection. Everyone who works with animals or in agriculture should wear insect repellent and stay away from potentially infectious blood and other body fluids[27]. Control and prevention The Unnoticed tick-animal-tick cycle poses a significant challenge to tick-borne disease prevention and management. Ticks are abundant, and only properly supervised livestock farms are allowed to use acaricides. There is now no widely accessible, safe, and effective vaccination against CCHF for humans, despite the development and limited use of an inactivated vaccine produced from the mouse brain in Eastern Europe[28]. Public health advice several factors should be at the centre of public health recommendations.

Reducing the risk of tick-to-human transmission: Put on protective clothing, such as long pants and sleeves. To make ticks easier to see, dress in bright colours. Approved acaricides should be applied on garments. To protect one's skin and clothes, use an authorised repellant. Keep an eye out for ticks on a frequent basis, and gently remove them if you discover any. Get out of areas where ticks are common and stay away from areas where ticks are active.

Reducing the risk of animal-to-human transmission: When dealing with animals or their tissues in endemic regions, it is important to use protective clothing, such as gloves, whether you are in an abattoir or at home. This is particularly true while butchering, culling or slaughtering. Either regularly treat animals with pesticides two weeks before slaughter or quarantine them before they reach slaughterhouses.

Reducing the risk of human-to-human transmission in the community: Avoid physical contact with someone who seems to be sick with CCHF. When caring for sick persons, always wear protective clothing, including gloves. After touching or visiting someone who is sick, be sure to wash your hands often.

Controlling infection in health-care workers: All healthcare personnel who come into contact with patients who have CCHF, whether it's suspected or proven, or who handle specimens from these patients, should follow basic procedures for infection control. Basic hand hygiene, personal protective equipment usage, safe injection procedures, and proper burial procedures are all included in this. Samples collected from patients suspected of having CCHF should only be handled by qualified personnel in labs with the proper equipment[29-31].

Health concept: A health concept, emphasizing the interconnectedness of human, animal, and environmental health in the context of CCHF. The zoonotic nature of CCHFV and the role of livestock, wildlife, and tick habitats in the transmission cycle make this approach particularly relevant. By addressing these links, the review highlights the importance of integrated efforts across human, veterinary, and environmental health sectors to effectively manage and control the disease.

CONCLUSION

Conclusion despite the vast number of individuals who could be affected and the virus's extensive circulation, much remains unclear about the viral and host variables that contribute to CCHFV pathogenesis. We will gain greater mechanistic insights into the mechanisms by which CCHFV causes illness when molecular virology techniques and better small-animal models are developed. It is probable that novel viral protein functions will yet be found. Educating the public, limiting tick contact, treating livestock to minimise infestations, quarantining animals, and safeguarding people involved in high-risk activities are all necessary preventative actions for communities at risk in endemic regions. Limiting the impact of CCHF on patients and public health systems requires effective vaccinations and antivirals, as well as prompt and accurate diagnostics. Future perspective research one hope for the future of CCHF therapy is the availability of immunoglobulin products and other alternative medicines. In order to create targeted treatments, researchers need a deeper knowledge of the CCHF pathophysiology. Developing a vaccine against CCHF is an important objective, despite the fact that it is difficult and is not nearing practical application. People in endemic locations are eagerly awaiting the development of a CCHF vaccination since it is the most effective way to decrease the mortality and morbidity caused by CCHF. This review discussed not only the development of new antiviral drugs and vaccines but also basic research aimed at better understanding the mechanisms of the virus, improving tick control strategies, and addressing the human-animal-environment interface. The review aims to serve as a foundation for future studies and interventions in these critical areas.

ACKNOWLEDGEMENTS

I acknowledgement my sincere thanks to Maharajah’s College of Pharmacy, Vizianagaram for continuous support and cooperation for completion of this work.