Crimean-Congo Hemorrhagic Fever Virus (CCHFV): Transmission, Replication, Pathogenesis, Clinical Features, Diagnosis, Treatment, and Prevention

Structure of Crimean-Congo Hemorrhagic Fever Virus

• Crimean-Congo hemorrhagic fever virus (– causative agent of CCHF) falls under the family Bunyaviridae (– family of segmented RNA viruses) and genus Nairovirus (– tick-borne bunyaviruses).
• They are spherical particles (– round virus particles) measuring 90 to 120 nm (– nanometer size range) in diameter with 5–10 nm projections (– surface spikes) visible on the surface.
• They are an enveloped virus (– surrounded by lipid membrane) which comprises two glycoproteins (G1 and G2) (– viral surface proteins involved in attachment and fusion).
• The genome is tripartite (– divided into three segments), negative-sense RNA (– RNA complementary to mRNA), termed the large (L), medium (M), and small (S) segments, which are associated with protein to form nucleocapsids (– RNA–protein complexes).
• The nucleocapsid (– viral genome plus proteins) is surrounded by a lipid-containing envelope (– outer viral membrane).
• The nucleocapsids include the RNA-dependent RNA polymerase (L protein) (– enzyme that synthesizes viral RNA).

Figure: Crimean-Congo hemorrhagic fever virus structure. Source: DOI: 10.3892/br.2015.545

Genome of Crimean-Congo Hemorrhagic Fever Virus

• The genome is linear, tripartite, segmented negative-stranded RNA (– linear RNA genome with three segments of negative polarity).
• It comprises three segments (– genome divisions): large (L), medium (M), and small (S).
• The L segment is 12,164 nucleotides, the M segment is 4,888 nucleotides, and the S segment is 1,712 nucleotides (– segment lengths).
• It encodes four to six proteins (– viral structural and functional proteins).
• Terminal complementary nucleotide sequences (– matching RNA ends) are conserved on the L, M, and S segments (– conserved genomic regions).
• The S segment of nairoviruses encodes only a large N protein (– nucleoprotein that binds RNA) and has no known nonstructural protein coding information (– lacks accessory proteins).
• The M segment of the nairovirus seems to encode only G2 and G1 (– envelope glycoproteins).
• Nucleotide sequencing (– determining RNA sequence) of the L RNA of Crimean-Congo hemorrhagic fever virus revealed that the segment is 12,164 nucleotides in length and encodes 3,944 amino acids (– protein length).
• The viral RNA-dependent RNA polymerase (L) (– viral transcription enzyme) binds to a promoter (– transcription initiation site) on each encapsidated segment (– RNA coated with protein) and transcribes the mRNA (– messenger RNA synthesis).
• These mRNAs are capped (– addition of 5′ cap) by the L protein during synthesis using cap-snatching (– stealing caps from host mRNA).

Figure: Genome of Nairovirus, Source: Viral Zone

Epidemiology of Crimean-Congo Hemorrhagic Fever Virus

• Crimean-Congo hemorrhagic fever (CCHF) virus, of the Nairovirus genus (– tick-borne virus group), was first recognized in the Crimean peninsula (– region in southern Ukraine) during an outbreak of hemorrhagic fever (– bleeding fever) among agricultural workers (– occupational exposure).
• The same virus was isolated in 1956 from a single patient in the present-day Democratic Republic of Congo, leading to the actual naming (– Crimean + Congo).
• Although animals and humans (– multiple hosts) can be infected, only the latter (– humans) develop the disease.
• Crimean-Congo hemorrhagic fever is a tick-transmitted viral disease (– arthropod-borne infection) found in Bulgaria, Yugoslavia, the former Soviet Union, China, Iraq, United Arab Emirates, Pakistan, and sub-Saharan Africa.
• The vector tick (– transmitting arthropod) is usually of the Hyalomma (– hard tick genus).

Source: CDC, 2014

Transmission of Crimean-Congo Hemorrhagic Fever Virus

• Ixodid ticks (– blood-sucking arthropods) especially those of the genus Hyalomma (– tick genus), are both a reservoir (– organism that harbors virus) and a vector (– transmitter of virus) for the CCHF virus (– Crimean-Congo hemorrhagic fever virus).
• Transmission to humans occurs through contact with infected ticks or animal blood (– viremic livestock blood).
• CCHF can be transmitted from one infected human to another by contact with infectious blood or body fluids (– secretions capable of transmission).
• Improper sterilization of medical equipment, reuse of injection needles, and contamination of medical supplies (– hospital-acquired exposure) can result in spread of CCHF in hospital premises.

Figure: Life cycle of the Crimean-Congo hemorrhagic fever virus, Source: CDC

Replication of Crimean-Congo Hemorrhagic Fever Virus

1. Virus attaches to host receptors (– cell surface binding sites) through glycoprotein (– viral attachment protein) and is endocytosed (– internalized) into vesicles in the host cell.
2. Fusion of virus membrane with the vesicle membrane results in the release of the ribonucleocapsid (– RNA–protein complex) into the cytoplasm (– intracellular fluid).
3. The RNA-dependent RNA polymerase (RdRp) (– enzyme synthesizing RNA from RNA) complex initiates transcription (– viral mRNA synthesis) by binding to the leader sequence (– regulatory RNA region) at the 3′ end of the genomic negative-strand RNA, and viral mRNAs (– messenger RNAs) are capped in the cytoplasm.
4. During replication (– genome copying), the RNA-dependent RNA polymerase complex binds to the leader sequence on the encapsidated (-)RNA genome (– protein-coated RNA) and starts replication.
5. The antigenome (– complementary RNA strand) is concomitantly encapsidated (– coated with nucleoproteins) during replication and replicates to give rise to negative-sense genome (– infectious RNA strand).
6. Nucleocapsids (– RNA-protein assemblies) assembled induce formation of membrane curvature (– bending of host membrane) in the host cell membrane and wrap up in the forming bud at the Golgi apparatus (– cellular protein-sorting organelle), releasing the enveloped virion (– lipid-coated virus) by exocytosis (– vesicle-mediated release).

Figure: Replication of Crimean-Congo Hemorrhagic Fever Virus, Source: doi:10.3390/v8040106

Pathogenesis of Crimean-Congo Hemorrhagic Fever

• The gut of the vector (– tick digestive tract) is infected initially, and after a few days or weeks the virus appears in the saliva (– infectious secretions).
• When the vector takes a blood meal (– feeding on host blood), the infective saliva enters the small capillaries (– tiny blood vessels) or lymphatics (– lymph vessels) of the human or other vertebrate host (– animal with backbone).
• An incubation period (– time before symptoms) of a few days ensues, after which the vertebrate host develops viremia (– virus present in blood).
• The host becomes febrile (– develops fever), manifesting the more serious signs and symptoms characteristic of the infecting virus.
• A typical humoral immune response (– antibody-mediated immunity) leads to cessation of viremia and clinical recovery in most cases, with immunoglobulin M (IgM) (– early antibody) predominating initially, followed by immunoglobulin G (IgG) (– long-term antibody), and the host recovers unless a specific target organ (– organ preferentially damaged) is affected.

• The target organ is the liver (– metabolic organ) and vascular endothelium (– inner lining of blood vessels) in Crimean-Congo hemorrhagic fever.
• This further leads to hemostatic failure (– inability to stop bleeding) by stimulating platelet aggregation and degranulation (– platelet activation), with subsequent activation of the intrinsic coagulation cascade (– clotting pathway).
• Proinflammatory cytokines (– immune signaling molecules) are key regulators in the pathogenesis and mortality of patients with CCHF.
• Levels of Interleukin-6 (IL-6) (– inflammatory cytokine) and Tumor Necrosis Factor-α (TNF-α) (– major inflammatory mediator) are significantly higher in patients with fatal CCHF.

Clinical Manifestations of Crimean-Congo Hemorrhagic Fever

• Following an incubation period of 3–21 days, a non-specific febrile illness (– fever with general symptoms) of abrupt onset develops.
• Initial signs and symptoms include headache, high fever, back pain, joint pain, stomach pain, nausea, and non-bloody diarrhea.
• Red eyes, flushed face, red throat, and petechiae (– small red hemorrhagic spots) on the palate are common.
• This is accompanied by hypotension (– low blood pressure), relative bradycardia (– slow heart rate), tachypnea (– rapid breathing), conjunctivitis (– eye inflammation), pharyngitis (– throat inflammation), and cutaneous flushing or rash (– skin redness).
• Symptoms may also include jaundice (– yellowing due to liver damage), and in severe cases, changes in mood and sensory perception (– neurological involvement).
• The hemorrhagic phase (– bleeding stage) is generally short and has a rapid course with signs of progressive hemorrhage and diathesis (– bleeding tendency) including petechiae, conjunctival hemorrhage, epistaxis (– nose bleed), hematemesis (– blood in vomit), hemoptysis (– coughing blood), and melena (– black stools).

• Internal bleeding, including retroperitoneal (– abdominal cavity) and intracranial hemorrhage (– bleeding in brain), may occur.
• Hepatosplenomegaly (– enlarged liver and spleen) may be present, and in severe cases death occurs due to multiorgan failure, disseminated intravascular coagulation (DIC) (– widespread clotting), and circulatory shock (– failure of blood circulation).

Diagnosis of Crimean-Congo Hemorrhagic Fever Virus

• Virus isolation by intracranial inoculation of suckling mice (– sensitive animal model) is thought to be the most sensitive system available; however, several sensitive cell culture systems (– virus-growing cells) such as Vero, LLC-MK2, and BHK-21 cell lines are available.
• Immunohistochemical staining (– antibody-based tissue staining) can show evidence of viral antigen in formalin-fixed tissues (– preserved specimens).
• Detection of antibodies (IgG and IgM) (– immune response markers) by ELISA (– enzyme-linked immunosorbent assay).
• Detection of viral antigen, viral RNA sequence by RT-PCR (– molecular RNA detection), in blood or tissues collected from a fatal case, and virus isolation.

Treatment of Crimean-Congo Hemorrhagic Fever

• Supportive treatment (– symptom-based care) including fluid balance, correction of electrolyte abnormalities, oxygenation, and hemodynamic support (– blood pressure maintenance).
• The virus is sensitive in vitro (– laboratory conditions) to the antiviral drug ribavirin, which is administered in both IV and oral forms (– injection and tablets) with apparent benefit.

Prevention and Control of Crimean-Congo Hemorrhagic Fever Virus

• There is no safe and effective vaccine currently available for human use.
• In case of known direct contact with blood or secretions (– exposure risk) of a probable or confirmed case, such as needlestick injury (– sharp injury) or contact with mucous membranes (– eye or mouth), baseline blood studies should be carried out and oral ribavirin started as post-exposure prophylaxis (– prevention after exposure).
• Use of insect repellent on exposed skin and clothing.
• Wearing gloves and other protective clothing (– barrier protection).
• Avoiding contact with blood and body fluids of livestock or humans showing symptoms of infection.
• Use of proper infection control precautions (– hospital safety measures) to prevent occupational exposure (– workplace infection risk).