Habip Gedik MD
Republic of Turkey Ministry of Health, Çan Hospital, Dept. of Infectious Diseases and Clinical Microbiology, Çan, Çanakkale, TURKEY
Crýmean-Congo
Hemorrhagýc Fever Výrus,
Týcks and Base Measures
ABSTRACT
Crimean-Congo haemorrhagic fever (CCHF) is a viral
haemorrhagic fever of the Nairovirus, of the Bunyaviridae
family of viruses. CCHF virus possesses a negative-sense
RNA genome consisting of three RNA segments: the large
(L), medium (M), and small (S) segments. For an arthropod-
borne virus, the genomic plasticity of CCHF virus is
surprisingly high. It seems likely that genetic reassortment
may primarily occur during coinfection of ticks due to the
transient nature of vertebrate infections relative to the
long-term persistent virus infections seen in ticks and their
obligation to obtain blood meals at metamorphic junctures.
Substantially, movement of genetic lineages of CCHF virus,
particularly over greater distances and between regions
not linked by livestock trade, likely also involves migratory
animals or birds that are either infected or are carrying
virus-infected ticks. Consequently, however migratory birds
those mediate genetic lineages of CCHF exist critical point
for CCHF struggle such as avian influenza, ticks should
be targeted at first. Especially, fields with high risk should
be out of order for pasturing and disinfected with repellent
medicines. Acaricide treatment of livestock in CCHFV
endemic areas is effective in reducing the population of
infected ticks.
Key Words:
Crimean-Congo haemorrhagic fever virus,
tick, measures. Nobel Med 2009; 5(2): 10-14
ÖZET
KIRIM-KONGO KANAMALI ATEÞÝ VÝRÜSÜ,
KENELER VE TEMEL ÖNLEMLER
Kýrým-Kongo Kanamalý Ateþi (KKKA), Bunyaviridae
ailesi virüslerinden Nairovirüs'ün yapmýþ olduðu viral
kanamalý ateþi hastalýktýr.
KKKA virüsü büyük (L), orta (M) ve küçük (S) olmak
üzere üç adet RNA segmentinden oluþmuþ negatif
RNA sarmalýndan oluþmaktadýr. Artropod aracýlý bir
virüs olmasýna raðmen KKKA virüsünün genetik
deðiþkenliði dikkat çekici bir þekilde yüksektir. Görünen
o ki, kenelerin yaþamsal döngüsünü devam ettirmek
için kanla sürekli beslenmesi gerektiðinden ve infeksiyon
sürecinin vertebralýlardaki kadar kýsa süreli olmamasý
nedeniyle, virüsün genetik yapýdaki deðiþikliklerini
kenelerde gerçekleþtirdiði ko-infeksiyonlarla saðlamaktadýr.
KKKA virüsünün genetik deðiþkenliðinde büyükbaþ
hayvan ticaretinden çok kuþlar ya da bunlarýn taþýdýðý
keneler aracýlýk etmektedir. Sonuç olarak, her ne kadar
göçmen kuþlar genetik deðiþkenlikte önemli rol alsalar
da; KKKA hastalýðý ile mücadelede keneler birincil
hedef olmalýdýrlar. Özellikle hayvanlarýn otladýðý yüksek
riskli alanlar repellentlerle dezenfekte edilmelidir. Zira,
akarasid adý verilen maddelerle yapýlan dezenfeksiyon,
KKKA' nin endemik olduðu yerlerde infekte kene
sayýsýný azaltmakta önemli derecede etkin olmuþtur.
Anahtar Kelimeler:
Kýrým-Kongo kanamalý ateþi
virüsü, kene, önlemler. Nobel Med2009; 5(2):10-14
DERLEME
REVIEW
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NOBEL MEDICUS 14 | CÝLT: 5, SAYI: 2
INTRODUCTION
Crimean-Congo hemorrhagic fever (CCHF) is a viral
haemorrhagic fever of the Nairovirus, a group of
related viruses forming one of the five genera in the
Bunyaviridae family of viruses. All of the 32 members
of the Nairovirus genus are transmitted by argasid
or ixodid ticks, but only three have been implicated
as causes of human disease: the Dugbe and Nairobi
sheep viruses and CCHF, which is the most important
human pathogen amongst them. Tree topology supports
previous evidence for the existence of three groups
of genetically related isolates, A, B and C (Figure 1).
1
Within group A there are two clades: an African clade
and a predominantly Asian clade comprising isolates
from Pakistan, China, Iran, Russia and Madagascar.
Group B includes isolates from southern and West
Africa and Iran, and group C includes a single isolate
from Greece (Figure 2). Despite the potential which
exists for dispersal of the virus between Africa and
Eurasia, it appears that circulation of the virus is
largely compartmentalized within the two land masses
and the inference is that the geographic distribution
of phylogenetic groups is related to the distribution
and dispersal of tick vectors of the virus.
1, 2
CCHF virus possesses a negative-sense RNA genome
consisting of three RNA segments: the large (L),
medium (M), and small (S) segments. The S segment
encodes a nucleoprotein (NP), the M segment encodes
a glycoprotein precursor, which is cleaved into mature
glycoproteins, G1 and G2, and the L segment encodes
RNA polymerase (Figure 3). Discrepancies among the
virus S, M, and L phylogenetic tree topologies
document multiple RNA segment reassortment events.
An analysis of individual segment datasets suggests
genetic recombination also occurs. For an arthropod-
borne virus, the genomic plasticity of CCHF virus
is surprisingly high.
1-4
As expected, the greatest
accumulation of mutations was seen in the surface
glycoprotein encoding M RNA segment (31% nucleotide
and 27% amino acid divergence). This may reflect
varying positive selection operating in the form of
immune selection or selection for efficient attachment
to different combinations of arthropod and vertebrate
host cells in different natural cycles throughout the
virus geographic range. The virus exists across numerous
ecologic zones, with different Hyalomma species tick
vectors important in different regions.
3-6
CCHF virus
M segment reassortment events are more frequent
than for S and L segments or more frequently result
in high fitness viable virus. Reassortment between
viruses from different geographic groups and its
dependence on coinfection reinforces the point, that
movement and mixing of viruses over large geographic
distances is occurring with some frequency. It seems
likely that genetic reassortment may primarily occur
during coinfection of ticks due to the transient nature
of vertebrate infections relative to the long-term
persistent virus infections seen in ticks and their
obligate need to obtain blood meals at metamorphic
junctures.
7
Virus was isolated from 30 kinds of tick which include
28 Ixodidae, 2 Argasidae. Hyalomma marginatum
marginatum, H.m.rufipes ve H.anatolicum anatolicum
are the most common porter-ticks but Ixodes ricinus,
Dermacentor spp., Rhipicephalus spp. and Boophilus
annulatus could have be porters in some countries.
8
Once infected, the tick remains infected through its
developmental stages and the mature tick may transmit
the infection to large vertebrates, such as livestock.
Figure 1. Phylogenetic analysis of Crimean-Congo hemorrhagic fever virus (CCHFV)
1
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NOBEL MEDICUS 14 | CÝLT: 5, SAYI: 2
Crýmean-Congo
Hemorrhagýc Fever
Výrus, Týcks and Base
Measures
SPU70/01, South Africa (AY905650)
SPU51/01, South Africa (AY905849)
Ard39554, Mauritania (U15089)
SPU128/81/7, South Africa (DQ076415)
IbAr10200, Nigeria (U88419)
Arb604, Congo (U15092)
7803 XinJiang, China (AF354296)
SPU190/00/18, Ýran (AY905654)
Uzbek/TI10145, Uzbekistan (AF481799)*
0.1
BT958, Central African Rep (EF123122)
Babhdad-12, Irag(AJ538196)
SPU280/02/10, Pakistan (AY905663)
ArMg951, Madagascar (U15024)
Ug3010, Dem Rep Congo (U88416)
Drosdov, Russia (DQ211643)**
Hoti, Kosovo (DQ133507)
SPU9/00/5, Ýran (AY905553)
4348/02, Turkey (DQ211649)
SPU80/89, South Africa (AY905836)
ArD8194, Senegal (DQ211639)*
AP92, Greece(DQ211638)***
II. DRC
III, South Africa/ West Africa 2
IV, Asia
IV. Middle East
V. Europe/Turkey
I. West Africa 1
VI. Greece
Domestic ruminant animals, such as cattle, sheep and
goats are viraemic (virus circulating in the bloodstream)
for around one week after becoming infected (Figu-
re 4).
8
However, CCHFV or antibodies to it have been found
in numerous smaller wild mammalian species, including
hedgehogs, bats, hares, mice, rats, squirrels, eland
antelopes, gerbils, genets.
9-15
These animals rarely
have large numbers of ticks, but the large populations
of these animals may indirectly create a strong density
of ticks. Infection in these animals generally results
in inapparent or subclinical disease but generates
viremia levels capable of supporting virus transmission
to uninfected ticks. Antibodies against CCHF virus
have been detected in the sera of horses, donkeys,
goats, cattle, sheep, and pigs in various regions of
Europe, Asia, and Africa.
16
Although CCHFV has
never been definitively isolated from large mammals
in the wild, antibodies to CCHFV have been found
in foxes in Central Europe and in baboons and gazelles
in Africa.
11, 17
Natural infection of large domestic
mammals does occur, such as in camels, horses, and
donkeys; in fact, cattle in Central Europe and goats
and sheep in western Africa are the primary reservoirs
for CCHFV infection in those areas.
18, 19
High
prevalences of antibody occur in domestic ruminants
in areas infested by Hyalomma ticks and the virus
causes inapparent infection or mild fever in cattle,
sheep and goats, with viraemia of sufficient intensity
to infect ticks.
9, 20
Movement of CCHF virus-infected
livestock (or uninfected livestock carrying infected
ticks) via trade may explain some of the movement
of virus genetic lineages within regions. For instance,
there is considerable movement of sheep and goats
into the Arabian Peninsula from countries in the horn
of Africa or Iran and Pakistan, particularly in association
with major religious festivals. The genetic links seen
between virus strains and detailed epidemiologic and
genetic analysis of past CCHF virus outbreaks in
United Arab Emirates and Oman are consistent with
this view.
21
Furthermore these researchers also
showed that even sheep that were infected previously
and had anti-CCHF virus IgG can be reinfected and
transmit the virus.
22
CCHFV is transmitted to humans through one of the
following modes: 1-the bite of a tick, 2-contact with
the tissues or blood of a recently slaughtered infected
animal in the viremic phase of infection (butchers
are particularly at risk), 3-contact with the blood of
viremic-phase patients, most frequently in a hospital
setting.
23-27
Human epidemics of CCHF rarely affect
more than a few individuals. Human-to-human
transmission of CCHFV is rare, except in the presence
of hemorrhage, unsafe injections, unprotected
venipuncture, or other types of hospital exposures.
It is believed that infected blood plays an important
role; in Pakistan in 1976, 10 hospital staff members
who had contact with a patient with CCHF became
ill and all those infected had been heavily exposed
to blood from the infected patient.
28
The role of birds in the ecology and epidemiology
remains unclear. Antibodies to CCHFV have been
detected in many species of wild birds (hornbills,
guinea fowl, and blackbirds) and in one domestic
bird (ostriches).
15, 29
Their role in virus transmission
has been demonstrated experimentally.
30
For example,
birds experimentally infected with CCHFV remained
healthy, with no evidence of viremia or antibody
response. This also seems to mimic the natural
Figure 2. Geographic distribution of CCHF virus. Context: World Health Organization (WHO)
Figure 3. Viral structure of CCHF virus
33
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North limit for the geographic distribution
of genus Hyalomma ticks
CCHF viral leolation
Country at risk
(serological evidence+vector)
Country with lowrisk
(presence of vector only)
Ribonucleocapsids
Lipid envelope
N-linked
carbohydrates
G1&G2
Polymerase (L)
80-120 nm
reducing the population of infected ticks.
27
The
migratory birds should be pursued all season and
their residence should be researched for infected ticks
and virologic sampling.
This problem could not be resolved just local measures
so endemic countries should collaborate about
measures, instructions about bird, livestock and their
carrying infected tick existence and virologic studies.
21
CCHF cases are related with person that encounter
tick-born and work about breeding, so that people
that live in rural areas and breeds, should be educated
situation because work by the same group showed
that even though CCHFV could be isolated from
nymphal ticks collected from over 600 birds, the
birds remained ser-negative and no virus could be
isolated from their blood or organs. Thus, it appears
that birds are refractory to CCHF infection, even
though they can support large numbers of CCHF-
infected ticks.
31
One interesting exception is ostriches,
which become infected with CCHFV and have been
the source of several cases of CCHF associated with
the slaughtering ostriches in South Africa. Although
some studies have suggested birds are not readily
infected with CCHF virus, ostriches and several West
African ground-feeding birds have been shown to be
susceptible to infection, and even refractory species
could move attached infected ticks without themselves
becoming infected.
30, 31
Examination of major migratory
bird flyways suggests this type of movement could
provide a plausible explanation for virus lineage
linkages between such areas as West and South Africa,
for instance. Substantially, movement of genetic
lineages of CCHF virus, particularly over greater
distances and between regions not linked by livestock
trade, likely also involves migratory animals or birds
that are either infected or are carrying virus-infected
ticks.
7
CCHF has been emerged in Turkey since 2002, in
which suspicious deaths became an outbreak in
middle region of Anatolia and were confirmed by
ELISA and PCR methods. Between 2000 and 2003
years six exitus in 150 cases, in 2004 13 exitus in
249, in 2005 13 exitus in 266, in 2006 27 exitus
in 438, in 2007 33 exitus in 717 and in 2008 63
exitus in 1315 cases reveal that CCHF is a infectious
disease problem for Turkey at that and should be
examined not only about treatment which had been
issued but also about ticks, rural areas, preventive
measures which had not been taken up comprehensively
yet (Figure 5).
32
Moreover, Turkey should collaborate
with endemic countries such as Iran, Russian, Greece,
Bulgaria etc. which have neighborhood, since CCHF
is not a local infectious disease problem.
Consequently, however migratory birds those mediate
genetic lineages of CCHF exist critical point for CCHF
struggle such as avian influenza, ticks should be
targeted at first. Since increasing infected ticks rates
lead to reassortment of virus due to viruse has not
proofreading mechanism and tends to mutation.
2
So
livestock and their pasturing rural ares should be
researched about carrying infected ticks and virus
mutation by tick and virologic sampling. Fields with
high risk should be out of order for pasturing and
disinfected with repellent medicines. Acaricide treatment
of livestock in CCHFV endemic areas is effective in
Figure 4. Example of CCHF virus circulation: transmission by the Hyalomma marginatum rufipes ticks.
Context: Pierre Nabeth. Crimean-Congo Haemorrhagic Fever Viruse In Emerging Viruses in Human
Populations ( Edward Tabor, editor) Elsevier Science, 2007, England). Figure-3, p 307.
2002
2003
2004
2005
2006
2007
2008
Case
Death
800
700
600
500
400
300
200
100
0
17
133
249
6
13
266
13
438
27
717
33
1315
63
Figure 5. Number of Crieman-Congo hemorrhagic fever cases and deaths in Turkey between 2002-2008.
32
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Crýmean-Congo
Hemorrhagýc Fever
Výrus, Týcks and Base
Measures
Year
Number
of
cases
and
death
Hospital
Man
Ungulates
Imago (Adult)
Nymph
Eggs
Larvae
TICK CYCLE
Small mammals, birds
about ticks and CCHA. Control and disinfection
programs should be put into practice for domestic
ruminant animals which contact the rustic unsure
areas and probable infected ticks carrying by
veterinarians.
21
Suppression of rodent populations
apparently reduced the numbers of D. marginatus
in Europe and H. a. asiaticum in the Asian deserts
and semideserts. Hyalomma ticks were reduced in
Europe by controlling hares and hedgehogs. Control
of birds could also limit the dispersion of tick vectors.
33
DELIVERING DATE:
15 / 06 / 2008 ACCEPTED DATE: 14 / 10 / 2008
CORRESPONDING AUTHOR:
Habip Gedik MD, Republic of Turkey Ministry of Health, Çan Hospital, Dept. of Infectious Diseases and Clinical Microbiology, Çan, Çanakkale,TURKEY habipgedik@yahoo.com
C
REFERENCES:
1 Burt FJ, Swanepoel R. Molecular epidemiology of African and Asian
Crimean-Congo haemorrhagic fever isolates. Epidemiol Infect 2005;
133: 659 - 666.
2 Varough M D, Marina L K, Pierre E R. Crimean-Congo hemorrhagic
fever virus genomics and global diversity. J Virol 2006; 80: 8834-
8842.
3 Honig J E, Osborne J C, and Nichol S T. Crimean-Congo hemorrhagic
fever virus genome L RNA segment and encoded protein. Virology
2004; 321: 29-35.
4 Kinsella E, Martin SG, Grolla MA, et al. Sequence determination of
the Crimean-Congo hemorrhagic fever virus L segment. Virology
2004; 321: 23-28.
5 Marriott, A C, Nuttall P A. Large RNA segment of Dugbe nairovirus
encodes the putative RNA polymerase. J Gen Virol 1996; 77: 1775-
1780.
6 Chamberlain J, Cook N, Lloyd G, et al. Co-evolutionary patterns of
variation in small and large RNA segments of Crimean-Congo
hemorrhagic fever virus J Gen Virol 2005; 86: 3337-3341.
7 Zeller HG, Cornet JP, Camicas JL. Crimean-Congo haemorrhagic
fever virus infection in birds: field investigations in Senegal. Res
Virol 1994; 145: 105-109.
8 Zeller HG, Cornet JP, Camicas JL. Experimental transmission
of Crimean-Congo hemorrhagic fever virus by West African wild
ground-feeding birds to Hyalomma marginatum rufipes ticks. Am
J Trop Med Hyg 1994; 50: 676-681.
9 Causey OR, Kemp GE, Madbouly MH, et al. Congo virus from domestic
livestock, African hedgehog, and arthropods in Nigeria. Am J Trcp
Med Hyg 1970; 19: 846-850.
10 Tkachenko EA, Khanun K, Berezin VV. Serological investigation of
human and animal sera in agar gel diffusion and precipitation (AGDP)
test for the presence of antibodies of Crimean hemorrhagic fever
and Grand Arbaud viruses. Mater 16 Nauchn Sess Inst Polio Virus
Entsefalitov Moscow October 1969 [2] 1969; 2: 265. (In English,
NAMRU3-T620).
11 Chumakov MP. On 30 years of investigation of Crimean hemorrhagic
fever (in Russian). Tr Inst Polio Virusn Entsefalitov Akad Med Nauk
SSSR 1974; 22: 5-18 (In English, NAMRU3-T950).
12 Saluzzo JF, Digoutte JP, Camicas JL, et al. Crimean-Congo
haemorrhagic fever and Rift Valley fever in south-eastern Mauritania.
Lancet 1985b; 1: 116.
13 Swanepoel R, Struthers JK, Shepherd AJ, et al. Crimean Congo
hemorrhagic fever in South Africa. Am J Trop Med Hyg 1983; 32:
1407-1415.
14 Darwish MA, Hoogstraal H, Roberts TJ, Ghazi R, Amer T. A sero-
epidemiological survey for Bunyaviridae and certain other arboviruses
in Pakistan. Trans R Soc Trop Med Hyg 1983; 77: 446-450.
15 Hoogstraal H. The epidemiology of tick-borne Crimean Congo
hemorrhagic fever in Asia Europe and Africa. J Med Entomol 1979;
15: 307-417.
16 Watts DM, Ksiazek TG, Linthicum KJ, et al. Crimean-Congo Hemorrhagic
Fever. 177 - 222. In: Monath Thomas P. The Arboviruses: Epidemiology
and Ecology Volume II 1988. CRC Press, Boca Raton, Florida.
17 Zarubinski VI, Klisenko GA, Kuchin VV, et al. Application of the indirect
hemagglutination inhibition test for serological investigation of Crimean
hemorrhagic fever focus in Rostov Oblast (in Russian). Sb Tr Inst
Virus imen D.I. Ivanovsky, Akad Med Nauk SSSR 1975; 2: 73-77. (In
English, NAMRU3-T1145).
18 Pak TP. Structure of the distribution area of Crimean hemorrhagic
fever in Tadzhikistan. Mater 9 Simp Ekol Virus (Dushanbe, October
1975) 1975; 39-43. (In English, NAMRU3- T1131).
19 Gonzalez JP, Camicas JL, Cornet JP, et al. Biological and clinical
responses of West African sheep to Crimean-Congo haemorrhagic
fever virus experimental infection. Res Virol 1998; 149: 445-455.
20 Woodall JP, Williams MC, Simpson DIH, et al. The Congo group
of agents. Rep E Afr Virus Res Inst (1963-1964) 1965; 14: 34-36.
21 Rodriguez LL, Maupin GO, Ksiazek TG, et al. Molecular investigation
of a multisource outbreak of Crimean-Congo hemorrhagic fever
in the United Arab Emirates. Am J Trop Med Hyg 1997; 57: 512-518.
22 Gozalan A, Esen B, Fitzner, et al. Crimean-Congo haemorrhagic
fever cases in Turkey. Scand J Infect Dis 2007; 39: 332-336.
23 Chapman LE, Wilson ML, Hall DB, et al. Risk factors for Crimean-
Congo hemorrhagic fever in rural northern Senegal. J Infect Dis
1991; 164: 686-692.
24 Williams RJ, Al-Busaidy S, Mehta FR, et al. Crimean-Congo
haemorrhagic fever: a seroepidemiological and tick survey in the
Sultanate of Oman. Trop Med Int Health 2000; 5: 99-106.
25 Papa A, Bozovi B, Pavlidou V, et al. Genetic detection and isolation
of Crimean-Congo hemorrhagic fever virus, Kosovo, Yugoslavia.
Emerg Infect Dis 2002b; 8: 852-854.
26 Athar MN, Baqai HZ, Ahmad M, et al. Short report: Crimean-Congo
hemorrhagic fever outbreak in Rawalpindi, Pakistan, February 2002.
Am J Trop Med Hyg 2003; 69: 284-287.
27 Nabeth P, Cheikh DO, Lo B, et al. Crimean-Congo hemorrhagic
fever, Mauritania. Emerg Infect Dis 2004a; 10: 2143-2149.
28 Burney MI, Ghafoor A, Saleen M, Webb PA, Casals J. Nosocomial
outbreak of viral hemorrhagic fever caused by Crimean hemorrhagic
fever-Congo virus in Pakistan, January 1976. Am J Trop Med Hyg
1980; 29: 941-947.
29 Shepherd AJ, Swanepoel R, Leman PA, et al. Field and laboratory
investigation of Crimean-Congo haemorrhagic fever virus (Nairovirus,
family Bunyaviridae) infection in birds. Trans R Soc Trop Med Hyg
1987; 81: 1004-1007.
30 Swanepoel R, Leman P A, Burt F, J et al. Experimental infection
of ostriches with Crimean-Congo haemorrhagic fever virus. Epidemiol
Infect 1998; 121: 427-432.
31 Hoogstraal, H. Migrating birds and their ectoparasites in relation
to disease. East Afr Med J 1961: 38: 221-226.
32 Crieman-Congo Haemorrhagic Fever Cases in Turkey, up to years.
Extracted from Ministery of Health Formal Web Page: http://www.kirim-
kongo.saglik.gov.tr
33 Whitehouse CA. Crimean-Congo hemorrhagic fever. Antiviral Res
2004; 64: 145-160.
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