Thursday, October 11, 2012

Crimean–Congo Hemorrhagic Fever


This week we cover another virus in the Bunyaviridae family that causes hemorrhagic fever in humans: Crimean–Congo hemorrhagic fever virus. This is a zoonotic arbovirus vectored by ticks and demonstrates a wide geographic range from southern and eastern Europe, across the Middle East and western and central Asia, and down through sub-Saharan Africa. Human infection can be quite severe with high mortality.

The Pathogen. Crimean–Congo hemorrhagic fever (CCHF) is caused by Crimean–Congo hemorrhagic fever virus (CCHFV), which is a Nairovirus in the Bunyaviridae family. These viruses are approximately 80 to 120 nanometers in diameter. They are enveloped viruses with ambisense, single-stranded RNA genomes in three segments. The three genome segments are circular and are classified as large (L), medium (M), and small (S).

Crimean–Congo hemorrhagic fever virus (Published in Antiviral Research, Volume 64, Issue 3, December 2004, Pages 145-160)

Macrophages, hepatocytes and endothelial cells are the target cells in the human host and, like hantaviruses, CCHFV invades host cells by endocytosis and replicates via the ER-Golgi intermediate compartment.

Bunyaviridae infection cycle (Published in: Antiviral Research, Volume 64, Issue 3, December 2004, Pages 145-160)

The Vector. CCHFV is vectored by ticks between reservoir hosts, which maintains the natural sylvan infection cycle. However this vector is also very important in introducing the infection to domestic livestock. While tick-borne transmission is a relevant pathway to infection in humans, this mode of transmission generally accounts for sporadic human cases only. On the other hand, outbreaks in humans typically result from contact with infected livestock, which in turn are infected by ticks.

The most important tick vectors for CCHFV transmission are those of the genus Hyalomma.

 Hyalomma marginatum

These are hard-bodied ticks in the family Ixodidae. Unlike other hard-bodied ticks, the Hyalomma leave a moderately serious bite wound after detaching, which can often necrotize the surrounding tissue. These ticks are widely distributed throughout Europe, Africa, and Asia. The graphic below developed by the Centers for Disease Control and Prevention (CDC) nicely depicts the two year life cycle of the Hyalomma ticks. 


The Reservoir. Small mammals comprise the natural reservoir hosts of CCHFV, with rodents in the genus Mastomys:


the hedgehogs (Erinaceinae subfamily):


 and the European Hare (Lepus europaeus):


acting as the primary reservoirs throughout most of the range of this virus.

The Disease. Symptoms typically present with an abrupt onset and include fever, malaise, muscle pain, and headache early in the clinical course. Abdominal pain and nausea, with associated diarrhea and vomiting, respectively, can also present early on in the disease. Hepatomegaly is also a common clinical feature. As the disease progresses in subsequent days confusion and aggression commonly occur in concert with mood swings. Several bleeding symptoms often present with this disease. Petechiae commonly occur on the skin and in the mouth and throat. Intestinal bleeding can produce black stools or frank blood, and hematuria can present with or without visible discoloration. Bleeding from the nose and gums is quite common. By or before the end of the first week of illness, hepatitis is common and liver, renal, and/or pulmonary failure may ensue in those with a severe clinical course. By 10 to 14 days affected individuals begin to recover, but approximately 30% succumb to the infection.

Patient with severe petechial rashes (ecchymoses)

The Epidemiology and the Landscape. CCHFV is transmitted to humans by the Hyalomma tick vector, as described above, from infected domestic livestock animals, or directly from person to person by way of contaminated blood or body fluid exposure. Vector-borne transmission is typically responsible for sporadic cases, whereas outbreaks typically follow from exposure to contaminated livestock during processing or consumption, or from exposure to contaminated body fluids during the care of infected patients in a clinical setting.

The map below produced by the World Health Organization (WHO) shows the global distribution of Hyalomma ticks (white and colors), viral- and seroprevalence (yellow), and incident cases (orange and red).

High concentrations of disease activity are apparent in parts of South, Central, and West Asia, and southeastern Europe. While the virus is present in much of Africa, significant numbers of human cases are only seen in South Africa, although this apparent anomaly could be due to under-reporting in several African countries.

The graphic below nicely depicts the key features of the landscape of CCHFV transmission and disease ecology.

Sylvan and Human Infection Cycles (Published in Perspectives in Medical Virology, Elsevier, 2006, Volume 16, Pages 299-324)

The cycle above highlights different aspects of the complex landscape epidemiology of CCHF. The sylvan infection cycle is maintained by the tick vector and extraordinarily diverse small mammal populations in varied terrain, though many of these species prefer open field and fringe forest and scrub habitats. The same ticks that maintain the sylvan cycle also act as bridge vectors for transmission of CCHFV to livestock, or less commonly, directly to humans. Transmission to humans occurs most frequently following 1) exposure to their livestock or 2) exposure to each other in a health care setting following initial infection and presentation of index cases. Thus, animal husbandry and nosocomial transmission are the most significant conduits to human infection in the landscape even though direct transmission from ticks to humans remains a distinctly viable route of infection.

Control and Prevention. While most human infections in the outbreak setting are not attributable to tick bites, vector control is still a primary locus of prevention and control of human disease. It is generally comprised of two strategies.

The first vector control strategy is to take the usual precautions to prevent tick bites in humans and, thus, prevent sporadic cases. Use of long-sleeved shirts and long pants are very effective control measures as these reduce tick access to human skin. However, this approach may not be realistic for those that live or work outdoors in endemic areas during hotter months. As such, individuals who do spend time outside, and are at risk of exposure to ticks, should practice regular body tick checks.

Here is a nice video on the proper way to remove ticks from the skin:


The second vector control strategy is to prevent or minimize tick bites in domesticated livestock. This usually includes government regulated tick removal prior to the transport and processing of livestock animals. Acaricides are also frequently used and probably constitute the largest agricultural prevention strategy in many areas. However, both the above livestock vector control methods require significant resources and good livestock production infrastructure, neither of which are often available for poor subsistence farmers and herders in many areas where CCHFV is endemic.

Another important non-vector control strategy employs good barrier protection and patient isolation to prevent nosocomial spread from infected patients to health care personnel and/or other non-infected patients in a hospital or health care setting. This is a critical component to CCHFV control and prevention as outbreaks often generate many secondary cases by human to human transmission during the care of infected individuals.

18 comments:

  1. First: the video indicates that the tick is not able to transmit infectious agent unless it has penetrated the skin for at least 24 hours. Is this true only for tick-borne bacterial infections, or does the same apply to tick-borne viral infections, such as CCHF? Second: how do livestock transfer the virus to humans, through body fluids, aerosols, etc.? Also, I find it very interesting that this virus contains ambisense RNA (meaning that part of the strand is positive sense, part is negative sense, correct?). Ambisense viral RNA is another exmaple of the peculiarity of viral genomes.

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    1. I believe the transmission from livestock to humans is mediated by the tick. Thus it is vectored, and transferred through body fluids.
      The University of Texas Medical Branch, in Galveston, TX is one site that is working on a vaccine for CCHFV, continuing on from their determination of an appropriate animal model to study the virus and its vaccine.

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  2. I did a little bit of research on the usefulness of an ambisense RNA genome:

    http://www.microbiologybytes.com/blog/2010/02/08/expression-strategies-of-ambisense-viruses/

    It seems that viruss with ambisense RNA genomes, such as CCHFV, have an easier time controlling expression of viral proteins (because of the alternate sense patterns). This control leads to the ability to have one effect in one host, and a completely different (potentially lethal) effect in another host (hence, a reason for differential effects in the livestock vs. human host in the case of CCHFV, etc.). Just a thought.

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  3. I was not familiar with ambisense RNA, so I had to look it up. Using the most advanced methods of our time (Wikipedia) I was able to learn what it is: ambisense RNA is an RNA that characterized by partial positive and partial negative polarity. Ambisense viruses actually possess more features with negative sense RNA viruses, and Nairoviruses are treated as a negative sense RNA virus.

    From: Nguyen M and Haenni AL. Expression strategies of ambisense viruses. Virus Research. 2003; 93: 141-150.

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    1. I shouldn't have taken so long to write my post.

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  4. I find it interesting that South Africa (and possibly other African countries) has the most significant number of human cases than South, Central, and West Asia, and southeastern European counties...but why is it so? Is it because of poor tick prevention practices? Also, I am curious of the incubation period of CCHFV.

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  5. @Flynn: Transmission from livestock to humans is primarily a function of contact with blood/body fluids of the subsistence animals during processing, NOT from contact with the tick. Although, of course, CCHFV can be transmitted to humans by way of the tick as well. See post above.

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  6. How many people actually contract the Crimean–Congo hemorrhagic fever virus (CCHFV) through the consumption of meat from infected livestock? And of these cases how many result in death? I am asking because the mode of transmission (that being the consumption of meat from infected livestock) sounds similar to how humans contract BSE (bovine spongiform encephalopathy) more commonly known as “Mad Cow Disease.” However, there is not too much public awareness about Crimean–Congo hemorrhagic fever virus (CCHFV), but if a case of Mad Cow Disease is discovered in some region it will get world-wide attention. Why is this? Could, the difference be that there are treatments available for CCHFV none for BSE or maybe a lower fatality rate is associated with CCHFV? Or could it be that this disease has yet to appear in the US or Western parts of Europe?

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    1. @Bianca,
      I have been reading news reports from Turkey and Iran regarding recent cases and outbreaks of CCHFV. Apparently, public awareness is growing in those countries; we may just not hear about it here. Mad cow disease may get more widespread attention potentially, because of its occurrence in a core country vs a peripheral country (according to world systems theory designations). People in other nations know who our president is, yet Americans and the British may not know the heads of state or current issues that are occurring in other nations.
      As far as I know, there is significant migration of Turkish peoples to the US and European countries, especially Germany, so it may not be simply about the movement of peoples.

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    2. @Bianca: It could be a combination of all the reasons you have listed. I believe one of the main reasons why BSE may have gotten more attention than CCHF in some industrialized nations was due to the fact that BSE was more prevalent than CCHF in those areas and far more "mysterious". The UK was largely affected by BSE and was a large exporter of cattle which would greatly increase the risk transmission and cause the disease to spread globally -- it had gotten so bad that there was a widespread ban on British beef. All of this likely added to the hysteria and the heightened public awareness throughout the US and Europe.

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    3. Russel Sharif (MPH)November 30, 2012 at 9:41 PM

      Hi Bianca, I found the following about the number of mortality of this disease-

      * On July 28 2005 authorities reported 41 cases of CCHF in Turkey's Yozgat Province, with one death.
      * On May 27 2010 Hospitals reported 70 cases of CCHF in Kosovo's Kosovo Polje, with 4 deaths reported so far.
      * In January 2011, the disease has been reported in Gujarat, India, with 4 reported deaths.
      * As of May 2012, 71 people are reported to have contracted the disease in Iran, resulting in 8 fatalities.

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  7. How was the disease discovered?

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    1. I love these narratives. It appears that this hemorrhagic fever was known in Central Asia/Crimea for centuries, although the cause was, of course, unknown. Many people in that region probably had regular contact with animals before the 20th century.

      In the 1940s, Soviet scientists identified "Crimean hemorrhagic fever", and in 1967 Chumakov isolated and identified the virus (from a fatal case in Samarkand). Meanwhile, on another continent, the "Congo virus" was isolated in 1956 by Courtois, and the same year Chumakov isolated his virus, identification studies and clinical reports were being published about the Congo virus (by Woodall and Simpson).

      Many newly discovered viruses are sent to the Rockefeller Foundation Virus Laboratory for formal classification and analysis. There, the Crimean hemorrhagic virus and the Congo virus were found to be identical. The official name, Crimean-Congo hemorrhagic fever, was not formalized until 1973.

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  8. This is the second week of reading disease posts, and I tried to pick a disease that wasn't related to ticks. I was surprised once the first pararaph read this disease was transmitted by ticks. What I found interesting is that most human cases are caused by nosocomial transmission. I feel as though if there was better reporting in Africa, there would be more numbers in persons who are exposed by animals.

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  9. I can see why it would be difficult to lower infection rates of CCHF in resource-stricken areas. While most of the cases are by HAI and poor screening on blood transfusions, the smaller portion of cases from livestock interaction shouldn't be ignored. Besides the difficulty to finding these ticks on large ungulates, I think that's part of a larger problem. That larger problem would be how would you identify livestock that have been previously bitten? And better yet, is the bite wound on the livestock enough to stand out from other possible ailments that may affect livestock? I guess I want to know how sensitive and specific are the tests for livestock infection so that this pathway of infection can be minimized to farmers.

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  10. Effective control measures are needed against vectors of CCHFV. Regions affected with this disease need to utilize surveillance approaches for monitoring and controlling of CCHF. Approaches for surveillance should consider the endemicity of the infection and the level of risk of introduction of the infection. Also, vector surveillance and reliable identification methods should be strengthened especially where CCHFV occur or can potentially occur in the future. Lastly, geographical information systems will be necessary in order to increased surveillance and appropriate control of CCHRP.

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  11. The Crimean-Congo hemorrhagic fever virus, unlike other tick-borne viruses, has many and various small mammal reservoir hosts. This is what makes CCHF re-occur throughout human history, and thus, makes it a poor candidate for eradication. However, it is important to note, as mentioned in the article, the majority of cases are due to contact with infected domestic livestock. There are other infectious diseases transmitted by infected livestock, such as anthrax. Some solutions to diseases transmitted via contact with domestic livestock are to vaccinate the livestock, community education on reading signs of infection in both animals and human (if symptoms are readable), and appropriate disposal of infected carcasses. According to the WHO, there is currently no approved vaccine for both animals and humans for CCHF. However, an article published in 2014 shows promising results in a break-through experimental vaccine in animals.
    http://www.who.int/mediacentre/factsheets/fs208/en/
    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091516

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  12. In regions where the primary source of livelihood and income is farming and livestock, vector control is incredibly important for humans and the animals. By being outdoors, humans need to make sure they are protecting themselves appropriately from ticks. This relies on teams teaching farmers and other people in the community to properly do this in a feasible and culturally acceptable way.

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