IN THE NAME OF

GOD

Crimean–Congo Hemorrhagic Fever virus

Producer : Azam Izadi

History of Crimean–Congo hemorrhagic fever

CCHF was described by a physician in the 12th century from the region that is presently Tadzhikistan.

Hemorrhagic disease with the presence of blood in:

o Urineo Vomituso Gumso Sputumo Abdominal cavity

Caused by a tick

CCHF had three names in southern Uzbekistan:

• khungribta (blood taking)• Khunymuny (nose bleeding)• karakhalak (black death)

Discovery of virus: CHF came to the attention of modern

medical science in 1944–1945 when about 200 Soviet military personnel were infected during an epidemic in war-torn Crimea.

Virus isolated from a patient in Congo in 1956

This now gave researchers an actual virus for production of the necessary reagents needed for serological surveys.

In 1967a breakthrough in CHF research came when Chumakov at the Institute of Poliomyelitis in Moscow first used newborn white mice for CHF virus isolation.

Classification of virus:

CCHFV is a member of the Nairovirus genus of the family Bunyaviridae.

There are seven recognized species in the genus Nairovirus containing 34 viral strains

Structure of virus:

Virions are spherical

Helical nucleocapsid

Approximately 100 nm in diameter

Lipid bilayered envelope approximately 5–7 nm thickGlycoprotein spikes 8–10 nm in length

Contain three structural proteins:

Two envelope glycoproteins G2 and G1

Nucleocapsid protein (N)

Genome of virus

The genome is composed of three negative-strand RNA segments:S, M, and L.(11-19 kb)

S encoding N nucleocapsid M encoding G2 and G1 glycoproteins L encoding L polymerase

The three RNA genome segments (S, M, and L) are complexed with nucleocapsid protein to form ribonucleocapsid structures.

The nucleocapsids and RNA dependent RNA polymerase are packaged within a lipid envelope that contains the viral glycoproteins G1 and G2.

1. attachment of virions to cell-surface receptors

2. entry via endocytosis followed by membrane fusion

3. primary transcription ( Transcription of negative sense vRNA to mRNA)

4. translation of viral proteins

Replication of virus:

Translation :

L and S segments of mRNA are translated on free ribosomes in cytoplasm

M segment mRNA is translated on ER-bound ribosomes

5. replication of vRNA via a cRNA intermediate

vRNA is used as a template by viral polymerase to make cRNA

cRNA is used as a template to make more negative sense strands of vRNA

6. assembly of virions at the Golgi or plasma membrane

7. egress by budding into the

Golgi followed by exocytosis, or budding through the plasma membrane.

Replication cycle

Tick vectors:

CCHFV has been isolated from at least 31 species of ticks.

The biological role of ticks is also important, not only as virus vectors, but also as reservoirs of the virus in nature.

Hyalomma anatolicum ticks a common CCHFV vector .

Vertebrate reservoir hosts:

Isolated from numerous domestic and wild vertebrates, including:

-Goats-Sheep-Hares-Mouse-Domestic dogs-Horses-Donkeys

After experimental inoculation of birds with CCHFV, they remained healthy.

Birds appear to be refractory to CCHF viremia.

In 1984, a case of CCHF occurred in a worker who became ill after slaughtering ostriches on a farm in South Africa.

tick–vertebrate–tick cycle

How is the disease transmitted to humans?

- Congo fever is transmissible to humans through contact with infected blood, other tissue or a tick bite.

-People handling livestock or ostriches

during routine procedures, such as vaccinations or

slaughtering of animals, are at risk.

-People can also get infected through the handling of ticks.

Four distinct phases: 1- Incubation:the incubation period after a tick

bite can be as short as 1–3 days, but can much longer.

2- Prehemorrhagic:

Sudden fever(39-41 ◦C) , 5-12 days

Chills

Headache

Dizziness

Photophobia

Abdominal pains, vomiting, diarrhea

Brady cardia, low blood pressure

.

3-Hemorrhagic: In severe cases, 3–6 days after onset of disease:

The virus attacks and destroys blood vessels.

The red rash, first appears on the whites of the eyes, roof of the mouth, throat and skin. this rash spreads and bleeding from the bowel.

Petechiae and ecchymosis

Bleeding from: Nose Gums Vagina Blood in the urine

Vomitus and tar-like stools resulting from intestinal hemorrhages.

In severe cases, the haemorrhaging causes major organs - such as the liver, kidneys and lungs - to fail.

4-Convalescence: it begins about 15–20 days after onset of illness

Weak pulse

Sometimes complete loss of hair

Headache, dizziness, nausea

Poor appetite, poor vision

Loss of hearing, and loss of memory

These problems are rarely permanent,

but may persist for a year or more.

Fever

Headache

Sore throat

General malaise

Muscle aches

Sore eyes, including light sensitivity. Red rash on the eyes, roof of the mouth and skin, caused by haemorrhaging of tiny blood vessels.

Symptoms:

Nosebleeding

Bleeding gums

Nausea

Loss of appetite

Vomiting

Diarrhoea

Chest painDizzinessSeizuresDeath

Antibody Response in CCHF:

IgG and IgM antibodies became demonstrable by indirect immunofluorescence on days 7 to 9 of illness

Maximum titers of antibody were usually attained in the second to third week of illness.

Titers of IgM declined gradually and were low or negative by the fourth month. .

In some patients titers of IgG increased markedly between 2 and 4 months after onset of illness and remained demonstrable by indirect immunofluorescence 3 years after infection.

Techniques for demonstrating antibody were: indirect immunofluorescencecomplement-fixation immunodiffusion

Viral detection : (blood specimen)

-RT-PCR

- Cell culture

Antibody detection : (serum sample)- IFA - ELISA

CCHF : laboratory diagnosisCCHF : laboratory diagnosis

VACCINE:An inactivated suckling mouse brain vaccine was developed in the Soviet Union in 1960.

Brain tissue suspensions were inactivated by formaldehyde and heat treatment to obtain safe.

The efficacy of the vaccine was tested using the complement fixation (CF) technique.

.

Modern vaccines are DNA vaccines, recombinant viral protein-based vaccines.

American scientists have developed a DNA vaccine containing the CCHFV genome M segment.

The vaccine has been used for high risk groups in Bulgaria since 1974. There are concerns about using mouse brain vaccine because of possible autoimmune responses.

How can people at risk be protected against CCHF?Many human infections result by tick bites:

- Animals should be treated with acaricides to reduce the number of ticks.

- Clothing can be treated with acaricides.

People coming into contact with fresh blood are at risk:

- Protective clothing should be worn

Prevention strategiesAvoid travelling to regions where CCHF is endemic.

Wear long trousers, long socks and boots when outdoors.Use insect repellent on all areas of exposed skin.

Avoid touching animals or, if you must, wear gloves and other protective clothing.

If you find a tick on your skin, Use tweezers to grasp the tick’s head, then pull the tick out of your skin, don’t squeeze the tick’s body.

TREATMENT: Ribavirin: The efficacy of ribavirin against

CCHFV was first described in vitro in 1989.

Ribavirin is a purine nucleoside analogue with broad-spectrum antiviral activity.

A recent study confirmed that ribavirin inhibited CCHFV replication .

In a study in suckling mice using the ribavirin significantly reduced viral replication in the liver and prevented infection of brain and heart tissues.

WITH RIBAVIRIN:

Higher survival rates

Shorter recovery time

Earlier return to normal levels of laboratory parameters

CCHFV possesses mechanisms to defeat the interferon-induced defense mechanisms by delaying IFN secretion for 48 hours post-infection.

Recombinant interferons exhibit activity against CCHFV in vitro

Mortality rate:

-The average mortality rate is 30–50%

-However, rates as high as 72.7% and 80% have been reported from the United Arab Emirates and China.

CCHFV might be used as an agent of bioterrorism or biowarfare.

CCHFV can be transmitted from person to person, has a high case-fatality rate.

BIOTERORISM:

Geographical distributionThere are reports of viral isolation and disease from more than 30 countries in Africa, Asia, southeast Europe.

Turkey has experienced the largest ever recorded CCHF outbreak with more than 4,400 confirmed cases mainly from rural areas.

CCHF in IRAN:610 cases have been reported in Zahedan 100 cases have been reported in Khorasan

References1-Whitehouse ,C.,(2004), Crimean–Congo hemorrhagic fever,Crimean–Congo fever, Antiviral Research,64:145-160

2- Paragas,J. Whitehouse,C. Endy,T. Bray,M.,(2004),A simple assay for determining antiviral activity against Crimean-Congo hemorrhagic fever virus, Antiviral Research,62:21-25

3-Samudzia,R. Lemanb, P. Paweskab,J. Swanepoelb,R. Burta,F.,(2012), Bacterial expression of Crimean-Congo hemorrhagic fever virus nucleoprotein, Journal of Virological Methods ,179:70-76

4-Shepherd,J.Swanepoel,R.Leman,A., (1989), Antibody Response in Crimean-Congo Hemorrhagic Fever, Clin Infect Dis,11:801-806

5- Keshtkar,M. ,Kuhnb,J. Christovac,I. Bradfuted,B.,(2011), Crimean-Congo hemorrhagic fever: Current and future prospects of vaccines and therapies, Antiviral Research ,90:85-92