Crimean–Congo hemorrhagic fever

Crimean–Congo hemorrhagic fever (CCHF) is a widespread tick-borne viral disease that is endemic in Africa, the Balkans, the Middle East and Asia. The virus is a member of the Bunyaviridae family of RNA viruses. It is a zoonotic disease carried by several domestic and wild animals. While clinical disease is rare in infected animals, it is severe in infected humans, with a mortality rate of 10-40%. Outbreaks of illness are usually attributable to Hyalomma tick bites or contact with infected animals or people.^[1]

Signs and symptoms

Typically, after a 1–3 day incubation period following a tick bite (5–6 days after exposure to infected blood or tissues), flu-like symptoms appear, which may resolve after one week. In up to 75% of cases, however, signs of hemorrhage appear within 3–5 days of the onset of illness in case of bad containment of the first symptoms: mood instability, agitation, mental confusion and throat petechiae; and soon after nosebleeds, vomiting, and black stools. The liver becomes swollen and painful. Disseminated intravascular coagulation may occur, as well as acute kidney failure, shock, and sometimes acute respiratory distress syndrome. Patients usually begin to show signs of recovery after 9–10 days from when symptoms presented. However 30% of the cases result in death by the end of the second week of illness.

Virology

The virus is a member of the genus Nairovirus, family Bunyaviridae.

Molecular biology

The genome is circular, ambisense RNA in three parts - Small (S), Middle (M) and Large (L). The L segment is 11–14.4 kilobases in length while the M and S segments are 4.4–6.3 and 1.7–2.1 kilobases long respectively. The L segment encodes the RNA polymerase, the M segment encodes the envelope proteins (Gc and Gn), and the S segment encodes the nucleocapsid protein. The envelope protein is initially translated as a glycoprotein precursor, which is then cloven into two smaller proteins.

Population genetics

CCHFV is the most genetically diverse of the arboviruses: Its nucleotide sequences frequently differ between isolates with a range of 20% of the based being different (viral S segment) to 31% (viral segment M).^[2] Viruses with diverse sequences can be found within the same geographic area; closely related viruses have been isolated widely separated regions. This suggests that viral dispersion has occurred possibly by ticks carried on migratory birds or through the international livestock trade. Reassortment among genome segments during coinfection of ticks or vertebrates seems likely to have played a role in generating diversity in this virus.

Based on the sequence data seven genotypes have been recognised: Africa 1 (Senegal), Africa 2 (Democratic Republic of the Congo and South Africa), Africa 3 (southern and western Africa), Europe 1 (Albania, Bulgaria, Kosovo, Russia and Turkey), Europe 2 (Greece), Asia 1 (the Middle East, Iran and Pakistan) and Asia 2 (China, Kazakhstan, Tajikistan and Uzbekistan).

Morphology

The virons are 80–120 nanometers (nm) in diameter and are pleomorphic. There are no host ribosomes within the viron. Each viron contains three copies of the genome. The envelope is single layered and is formed from a lipid bilayer 5 nm thick. It has no protrusions. The envelope proteins form small projections ~5–10 nm long. The nucleocapsids are filamentous and circular with a length of 200–3000 nm.

Evolution

This virus appears to have evolved 3100–3500 years ago.^[3] The mutation rates for the three parts of the genome were estimated to be: 1.09×10⁻⁴, 1.52×10⁻⁴ and 0.58×10⁻⁴ substitutions/site/year for the S, M, and L segments respectively.

Vectors

Hyalomma tick

The virus has been isolated from at least 31 different species of ticks from the genera Haemaphysalis and Hyalomma.^[4] Sporadic infection of people is usually caused by Hyalomma tick bite. Clusters of illness typically appear after people treat, butcher or eat infected livestock, particularly ruminants and ostriches. Outbreaks have occurred in clinical facilities or in abattoirs where health workers have been exposed to infected human or animal blood and fomites. Humans and animals can transmit the virus to other humans.

The causative organism is found in Asia, Eastern Europe, the Middle East, a belt across central Africa and South Africa and Madagascar (see map ^[5]) The main environmental reservoir for the virus is small mammals (particularly European hare, Middle-African hedgehogs and multimammate rats). Ticks carry the virus to domestic animal stock. Sheep, goats and cattle develop high titers of virus in blood, but tend not to fall ill. Birds are generally resistant with the exception of ostriches.

Tick species that have been identified as infected with this virus include Argas reflexus, Hyalomma anatolicum, Hyalomma detritum, Hyalomma marginatum marginatum and Rhipicephalus sanguineus.

Receptors

The cell surface protein nucleolin has been identified as a putative receptor for this virus.^[6]

Prevention

Where mammalian tick infection is common, agricultural regulations require de-ticking farm animals before transportation or delivery for slaughter. Personal tick avoidance measures are recommended, such as use of insect repellents, adequate clothing and body inspection for adherent ticks.

When feverish patients with evidence of bleeding require resuscitation or intensive care, body substance isolation precautions should be taken.

The United States armed forces maintain special stocks of ribavirin to protect personnel deployed to Afghanistan and Iraq from CCHF.

Vaccine

Since the 1970s, several vaccine trials around the world against CCHF have been scrapped due to high toxicity. The only available and probably somewhat efficacious CCHF vaccine is an inactivated antigen preparation currently used in Bulgaria. More modern vaccines are under development, but the sporadic nature of the disease even in endemic countries suggests that large trials of vaccine efficacy will be difficult to perform. Finding volunteers may prove challenging, given the growing resistance of populations to vaccination against contagious diseases such as measles or poliomyelitis. The number of people to be vaccinated and the length of time they would have to be followed to confirm protection would have to be carefully defined. Alternatively, many scientists appear to believe that treatment of CCHF with ribavirin is more practical than prevention, but some recently conducted clinical trials appear to counter assumptions of drug efficacy. Immunoglobulin preparations have been used for more than 30 years to prevent and treat CCHF in Bulgaria, but few data have been published, and their efficacy remains unproven. Although recent developments in antibody engineering have raised hopes for novel mAb therapies, this approach remains in its infancy.^[7]

In 2011, a Turkish research team led by Erciyes University has successfully developed the first non-toxic preventive vaccine, which passed clinical trials. The vaccine is pending approval by the FDA.^[8]

Treatment

Treatment is primarily symptomatic and supportive, as there is no established specific treatment. Ribavirin is effective in vitro^[9] and has been used during outbreaks,^[10] but there is no trial evidence to support its use.

A Turkish research team led by Refik Saydam Health Institute has developed treatment-serum derived from blood of several CCHF-patients, which have been proven to be 90% effective in CCHF-patients.^[11]

Epidemiology

Crimean–Congo hemorrhagic fever occurs most frequently among agricultural workers following the bite of an infected tick, and to a lesser extent among slaughterhouse workers exposed to the blood and tissues of infected livestock, and medical personnel through contact with the body fluids of infected people.^[2]

On July 28, 2005 authorities reported 41 cases of CCHF in Turkey's Yozgat Province, with one death. As of August 2008, a total of 50 people were reported to have lost their lives in various cities in Turkey due to CCHF. 3128 Crimean–Congo hemorrhagic fever cases with 5% of case-fatality rate have been reported by the Ministry of Health of Turkey between 2002–2008.

CCHF is also endemic in Kosovo. Institute of Public Health of Kosovo reported 228 cases of CCHF in the Republic of Kosovo from the year 1995 to 2013, with the mortality rate of disease being 25.5%.^[12]

In September 2010 an outbreak has been reported in Pakistan's Khyber Pakhtunkhwa province. Poor diagnosis and record keeping has caused the extent of the outbreak to be uncertain, though some reports indicate over 100 cases, with a case-fatality rate above 10%.

In January 2011, the disease was reported in Sanand, Gujarat, India, with 4 reported deaths, which consisted of the patient along with the doctor and the nurse who treated the patient.^[13]

As of May 2012, 71 people are reported to have contracted the disease in Iran, resulting in 8 fatalities.^[14]

In October 2012, a British man died from the disease at the Royal Free Hospital in London. He had earlier been admitted to Gartnavel General Hospital in Glasgow after returning on a flight from Kabul in Afghanistan.^[15]

In July 2013, the seven persons died due to CCHF in Kariyana village in Babra Taluka, Amreli district, Gujarat, India.^[16][17]

On August 16, 2013, a farmer from Agago, Uganda was treated at Kalongo Hospital for a confirmed CCHF infection. Additionally, the deaths of three other people in the northern region were suspected to have been caused by the virus.^[18] Six people who had come in contact with the Agago man were placed under observation, and released after showing no symptoms in two weeks. Another unrelated suspected CCHF patient as admitted to Mulago Hospital on the same day. The Ministry of Health announced on the 19th that the outbreak was under control, but the second patient, a 27-year-old woman from Nansana, died on the 21st. She is believed to have contracted the virus from her husband, who returned to Kampala after being treated for CCHF in Juba, South Sudan.^[19] In the recent years cases have been diagnosed in Kazakhstan. Ten people, including an ambulance crew, were admitted on Jun 23rd 2014 to Hospital in Southern Kazakhstan on suspicions of carrying the virus. In Pakistan, at Hayatabad Medical Complex (HMC) an 8th person was infected from [Crimean-]Congo hemorrhagic fever [CCHF] on July 11, 2014. The eight patients, including a nurse and 6 Afghan nationals, died in the period April–July 2014.^[20]

The sporadic confirmed cases have been reported from Bhuj, Amreli, Sanand, Idar and Vadnagar in Gujarat since first case in 2011. In November 2014, a doctor and a labourer belonged Bayad taluka of north Gujarat tested positive for the disease.^[21] In December 2014, one person died due to disease who belonged to belong to Madhapar village near Bhuj, Kutch district of Gujarat, India.^[22] In following weeks, three people including one patient who belonged to Jaisalmer and two male nurses who belonged Jodhpur, Rajasthan died and one person from Himachal Pradesh.^[23] In January 2015, one woman died who belonged to from Pattiwala village in Kanth tehsil of Moradabad district.^[24] In March 2015, one more person died following CCHF who hailed from Ratadiya village of Mundra taluka of Kutch.^[25]

Among livestock CCHF has become widespread in India, which the first human case was found only 4 years prior.^[26]

A man died of CCHF in Spain August 25, 2016 and infected a nurse.^[27] In August 2016 a number of news ources raised concerns regarding the disease.^[28][29]

History

A case reported in the 12th century of a hemorrhagic disease from what is now Tajikistan may have been the first known case of Crimean–Congo hemorrhagic fever. The disease was known as "Crimean fever" during the Crimean War, and was contracted by many, including Florence Nightingale.^[30] Soviet scientists first identified the disease they called Crimean hemorrhagic fever in 1944 in Crimea^[31] and established its viral etiology by passage of the virus through human "volunteers" (fatality rate unreported), but were unable to isolate the agent at that time.^[32] In June 1967, Soviet virologist Mikhail Chumakov registered an isolate from a fatal case that occurred in Samarkand (on the ancient Silk Road in Central Asia) in the Catalogue of Arthropod-borne Viruses.^[33]

Four months earlier, virologists Jack Woodall, D Simpson and others had published initial reports^[34][35] on a virus they called the Congo virus, first isolated in 1956 by physician Ghislaine Courtois, head of the Provincial Medical Laboratory, Stanleyville, Belgian Congo. Strain V3010, isolated by Courtois, was sent to the Rockefeller Foundation Virus Laboratory (RFVL) in New York City and found to be identical to another strain from Uganda, but to no other named virus at that time. Chumakov later sent his strain to the RFVL, where it was found to be identical to the Congo virus.^[36]

The International Committee on Taxonomy of Viruses proposed the name Congo–Crimean hemorrhagic fever virus, but the Soviets insisted on Crimean–Congo hemorrhagic fever virus. Against all principles of scientific nomenclature based on priority of publication, it was adopted as the official name in 1973 in possibly the first instance of a virus losing its name to politics and the Cold War.^[37] However, since then Congo–Crimean or just Congo virus has been used in many reports, which would be missed in searches of medical databases using the official name. These reports include records of the occurrence of the virus or antibodies to the virus from Greece, Portugal, South Africa, Madagascar (the first isolation from there), the Maghreb, Dubai, Saudi Arabia, Kuwait and Iraq.^[38][39][40]

References

External links

• Ergönül O. (2006). "Crimean–Congo haemorrhagic fever". Lancet Infect Dis. 6 (4): 203–214. doi:10.1016/S1473-3099(06)70435-2. PMID 16554245. 
• World Health Organization Fact Sheet