Crimean-Congo haemorrhagic fever virus — Questions

Crimean-Congo haemorrhagic fever virus infects mononuclear phagocytes (monocytes and macrophages), dendritic cells, endothelial cells and hepatocytes.

Infection of macrophages and dendritic cells triggers release of pro-inflammatory cytokines which, with direct infection of endothelium, increases vascular permeability and activates coagulation, producing capillary leak and disseminated intravascular coagulation. Infection of hepatocytes causes hepatic necrosis. Together these drive the multi-organ failure of severe disease.

The primary vector is the Hyalomma tick (notably Hyalomma marginatum and H. rufipes).

• Long mouthparts: a long hypostome and palps, longer than in most other hard ticks.
• Banded legs: pale and dark striping along the legs.
• Eyes on the scutum: distinct eyes at the margins of the shield, on a relatively large red-brown body.

• Hyalomma tick exposure: the Hyalomma tick is both reservoir and vector, and farming and outdoor work in the drier interior bring people into contact with infected ticks.
• Livestock contact at slaughter: viraemic cattle, sheep and goats transmit through blood and tissues during slaughter, dehorning and castration, so abattoir and farm workers are at risk.
• Nosocomial and contact spread: a viraemic patient’s blood and body fluids transmit to carers and health workers, extending outbreaks beyond the animal exposure.

CCHFV is the most widely distributed tick-borne virus, endemic across Africa, the Balkans, the Middle East, Central Asia and the Indian subcontinent, following the range of Hyalomma ticks.

It is an Old World, tick-borne virus, not mosquito-borne, rodent-borne or geographically confined.

Ribavirin has been used for decades and may help when started early, but recent meta-analyses question its benefit and several investigators have called for randomised trials.

It is still given in many endemic settings, particularly when CCHF cannot be distinguished from other haemorrhagic fevers, so it is neither proven nor contraindicated.

The CCHFV L and M segments are markedly larger than in other bunyavirals, the oversized L protein carrying a cap-snatching endonuclease and an OTU deubiquitinase domain in addition to the polymerase.

The genome is negative-sense, tripartite RNA; an ambisense S segment is a phlebovirus feature, seen in Rift Valley fever virus, not CCHFV.

The L polymerase cleaves short capped fragments from host messenger RNAs and uses them to prime transcription (cap-snatching), a strategy shared across the bunyavirals and carried out entirely in the cytoplasm.

Protein-primed and self-priming mechanisms belong to other virus groups.

The tick is both vector and reservoir: it passes CCHFV transstadially across its moults and transovarially into its eggs, so the enzootic cycle persists without the vertebrate host being permanently infected.

Humans are dead-end hosts, and mosquitoes play no part in the cycle.

Specific IgM and IgG appear around days five to seven only in those who survive; fatal cases usually die before they seroconvert.

Molecular detection, not serology, is therefore decisive in severe disease, and a negative antibody result never excludes CCHF in a severely ill patient.

Viral loads above roughly 10⁸ genome copies per millilitre predict a fatal course, whereas lower loads accompany milder disease.

Viral load, platelet count and clotting times are combined in severity scores; a high load signals worse, not milder, disease.

The course runs through incubation, a prehaemorrhagic phase, a haemorrhagic phase and convalescence.

The febrile-hypotensive-oliguric-diuretic sequence describes hantavirus haemorrhagic fever with renal syndrome, and a latent-reactivation pattern belongs to the herpesviruses.

Severe CCHF bleeding reflects a dysregulated pro-inflammatory cytokine response, with high tumour necrosis factor alpha, interleukin-6 and interleukin-8, causing endothelial dysfunction and disseminated intravascular coagulation.

Direct lysis of all endothelium, autoantibodies and vitamin K deficiency are not the principal mechanism.

Incubation is shortest after a tick bite, usually about one to three days. After exposure to infected blood or tissue it is longer, around five to seven days and occasionally up to thirteen.

All the blood- and tissue-contact routes give a longer interval than the tick bite.

The OTU domain is a deubiquitinase and deISGylase: it removes regulatory ubiquitin and ISG15 tags from innate-immune signalling proteins, damping the type I interferon response.

Glycoprotein cleavage, capping, integration and translational shut-off are unrelated to this domain.

In 1969 Jordi Casals showed that the agent of Crimean haemorrhagic fever was identical to the Congo virus isolated in the Belgian Congo in 1956, and the two names were joined.

The virus was described in the Crimea in 1944 but not isolated until 1967; it was not co-discovered, and it causes one disease across its range.

GP38 is a secreted glycoprotein cleaved from the M-segment precursor and an important target of protective antibodies.

The same precursor also yields the structural Gn and Gc and the non-structural NSm; the nucleoprotein is an S-segment product, and NSs is a phlebovirus protein not carried by CCHFV.

No CCHF vaccine is widely licensed; an inactivated suckling-mouse-brain preparation used in Bulgaria is the only one in human use, and its efficacy has never been rigorously characterised.

Modern inactivated, virus-like-particle, vectored, DNA and subunit candidates remain in early development.

Like other bunyavirals, CCHFV has no matrix protein. Inside the envelope the three genome segments exist as ribonucleoproteins, each coated by nucleocapsid protein and bound to the L polymerase.

Gn and Gc form the surface spikes, so all four of the other proteins are present.