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Volume 1 Number 1 (Spring 2009) 7 - 12

An overview of Crimean- Congo Hemorrhagic Fever in Iran
Chinikar S *1, Ghiasi SM 1, Ghalyanchi- Langeroudi A1, Goya MM 2 , Shirzadi MR2,
Zeinali M 2 and Haeri A3
1
Laboratory of Arboviruses and Viral Haemorrhagic Fevers (National Reference Laboratory), Pasteur Institute of Iran,
Tehran, Iran.
2
Center for Disease Control (CDC), Ministry of Health, Tehran, Iran.
3
School of Medicine , Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Received: November 2008 , Accepted: January 2009.

ABSTRACT
Crimean- Congo Hemorrhagic Fever (CCHF) is a viral zoonotic tick-born disease with a mortality rate of up to 50% in
humans. After a short incubation period, the disease is characterized by sudden fever, chills, severe headache, dizziness, back,
and abdominal pain. Additional symptoms can include nausea, vomiting, diarrhea, neuropsychiatric, and cardiovascular
changes. In severe cases, hemorrhagic manifestations, ranging from petechiae to large areas of ecchymosis develop. The
CCHF Virus (CCHFV) is from the genus Nairovirus and family Bunyaviridae. CCHFV is transmitted to humans by the
bite of infected tick and by direct contact with blood or tissue from infected humans and livestock. In addition to zoonotic
transmission, CCHFV can be spread from person to person and is one of the rare hemorrhagic fever viruses able to cause
nosocomial outbreaks in hospitals. CCHF is a public health problem in many regions of the world e.g Eastern Europe, Asia,
Middle East, and Africa. The history of CCHF in Iran shows that the disease has been detected in Iran since 1970. From 1970
to 1978 some scientists worked on serology and epidemiology of this disease in humans and livestock in Iran. Since 1999 ,
establishment of a surveillance and laboratory detection system on viral hemorrhagic fevers particularly on CCHF has had
benefits. One of which is the fact that a mortality rate approaching 20% in the year 2000 remarkably dropped to 6% in the
year 2007.

Keywords: CCHF, Arboviruses, Iran.

INTRODUCTION Crimean- Congo haemorrhagic fever in Iran was
first reported in 1970, where 45 of 100 sheep sera
Crimean-Congo hemorrhagic fever (CCHF)
that were sent from the Tehran abattoir to Moscow
may have been reported as early as 1110 AD. In
(Institute of Polio-myelitis and Viral Encephalitides)
the thesaurus of the Khwarazm, compiled by the
reacted positively for CCHF virus infection (1). In
Dzhurzhoni, a disease in Tajikistan similar to CCHF,
1974, a type of typhoid in 60 suspected cases with
transmitted by an arthropod was described (1) . The
haemorrhagic syndromes in eastern Azerbaijan was
disease was first characterized in the West Crimean
described, and it was suggested the disease had been
region of the former USSR in 1944 (2). In 1956,
CCHF (6). In 1974 – 1975 , more clinical cases in
a virus was isolated from the blood of a patient in
this area were reported (7). In 1975 , a large scale
the Belgian Congo and became the prototype of the
serological study was performed in cooperation of
Congo virus (3- 4). In 1969, Casals antigenically
Tehran university with Yale University, mostly in the
demonstrated similarity between the Crimean and the
northern half of Iran. In this study, where agar gel
Congo prototypes (5) , and then the name Crimean-
diffusion precipitation tests were used, 13% of human
Congo Hemorrhagic Fever virus gradually took
sera, 38% of cattle sera and 18% of sheep sera were
acceptance.
seropositive for CCHF (8). In 1978, CCHFV was
isolated for the first time from the tick Alveonasus
* Corresponding Author: Dr. Sadegh Chinikar lahorensis in the north eastern region of Iran (9).
Laboratory of Arboviruses and Viral Hemorrhagic Fevers (National
Subsequently, there was no report of the disease until
Reference Laboratory),Pasteur Institute of Iran, No.69, Pasteur
Ave, 1316943551, Tehran, Iran.
1999 , when several cases were seen in different
Tel- Fax: + 982166480778 provinces, mainly Chaharmahal-va-Bakhtiari province
E-mail: chinikar@pasteur.ac.ir south-west of Iran (10 - 11).

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different aspects of CCHF are progressively being Europe. vertebrates are needed to provide blood relationship of the virus strains circulating in Iran meals for the ticks (27 . recombinant antigen of CCHF virus was produced by Semliki Forest Virus expression EPIDEMIOLOGY OF CCHF IN IRAN AND system. although Sistan-va-Balouchistan. although there have been some studies Iranian strains are very similar to the Matin strain of on the development of a subunit vaccine (31) . It was also demonstrated that virus till now. livestock and ticks suspected of having CCHF encodes a nucleocapsid protein (NP) . 1 (7 .26). CCHF virus routes in Iran related to people indicate close contact genome was detected in 22.. CCHFV after feeding on a viremic host. 77. efficient in the cycle of CCHFV. It has also been reported in parts performed in the National Reference Laboratory of Europe including southern parts of the former (10-16). hemorrhagic fever viruses able to cause nosocomial demonstrated CCHF virus infection in 11. Fars. suggesting volunteers. and charge detection. In 2004. the geographical With respect to the 2003 . MICROBIOL. from infected livestock (23). phylogenetic in ticks. In 2006.. Transovarial northeast of Iran. the large (L) segment encodes an RNA.2005 demonstrated 56% shown to be capable of transstadial transmission (i. of the passing the virus from larva to nymph to adult) of 448 livestock sera collected from Khorasan province. In recent years. The virus is Committee on Viral Hemorrhagic Fevers) and enveloped and possesses a tripartite. of CCHF infection in Iran and also showed that 24 The virus is transmitted to humans through the provinces out of 30 provinces of Iran are infected bite of Ixodid ticks or by contact with blood or tissues with CCHF virus. From 2000 till now (October 2008). among 285 human with the distribution of Hyaloma ticks. Pakistan.Congo Hemorrhagic Fever (CCHF) .3% appeared seropositive for the their role as the principal vector. Although virus can persist and analyzing the CCHF virus genome. among the livestock population of Isfahan province Dermacentor. Moreover. 21. As ticks are and nearly 30% of the livestock were seropositive. Turkmenistan. It is worth mentioning were determined on the basis of the (S) segment of that there was no efficient vaccine against the CCHF the genome in 2004. some species of the Hyaloma. 6. J.12) In 2000 . The disease is caused by CCHF virus Fevers as a National Reference Laboratory in (CCHFV) which is a member of the genus Nairovirus Pasteur Institute of Iran (member of National Expert and family of Bunyaviridae (17 . some research projects on reported in many regions of Africa.30). can develop into a severe health problem and with establishment of the hemorrhagic fever in humans resulting in death rates laboratory of Arboviruses and Viral Hemorrhagic of 13-50 %. CCHFV can be of Iran. USSR (Moldova. . CCHF was recognized as a major public a viral zoonotic disease. resulting Iran were monitored for CCHF with rapid and free of in the two envelope glycoproteins. and all provinces of segment encodes a glycoprotein precursor. passage of virus to offspring) of of 150 goat samples were sero positive which suggested CCHFV has also been shown to occur with some of to be a hyper enzootic region for CCHF.22).3% of ticks collected to tissue and blood of affected livestock (13). it has been Isfahan. western region of Iran. and Rhipicephalus genera have been between the years 2004 .3% of ticks outbreaks in hospitals (14. The advantage of Since CCHF was first discovered in the Crimean which is that its production does not need biosafety region of Russia in the 1940s. and Crimean. southwest addition to zoonotic transmission. the disease has been level 4. G1 and G2. negative-sense. In the years 2003 to 2005 . By isolating the species in these genera. the medium (M) have been sent to the laboratory. In from Chaharmahal-va-Bakhtiari province. The small (S) segment human.e. The recombinant antigen is used for ELISA ELSEWHERE serological diagnosis of CCHF.e.Balouchistan province. as in central Asian countries (Tajikistan. all single. Ukraine and Transcancasus).8 CHINIKAR ET AL . after a report of a confirmed human spread from person to person and is one of the rare case in Hamadan province. Although other Ixodid CCHF virus infection. Khozestan are the most infected demonstrated that most statistics about transmission provinces of Iran in that order. and Asia.stranded RNA genome.dependent Chinikar and colleagues demonstrated the prevalence RNA polymerase (13. seropositivity. according to the protocols from the committee.2004 study done in Sistan- distribution of CCHF cases corresponds most closely va. IRAN. A seroepidemiology survey ticks can be infected. 24 .5% of 298 sheep samples and 46% transmission (i. In 2002. the Middle East.20).

diagnosis. Universities CLINICAL FEATURE AND PATHOGENESIS and public health centers located in different cities. Kyrgyzstan. at the National Level. Also.35). After the incubation period. and Fars provinces ranked the highest rate of instituted a National Expert Committee on Viral infection. and convalescence (1). It is necessary to mention that Hemorrhagic Fevers (NECVHFs). above) including production of recombinant antigen Mauritania. The incubation During the course of the disease. 24 of 30 provinces of Fevers Laboratory known as a National Reference Iran have been shown to be affected by CCHF. and onset. the complete distribution map of CCHF in Disease Control (CDC) at the Ministry of Health Iran has been extensively identified by the laboratory (MOH). According to the findings. The main course of CCHF has of health care and administrative activities. and Kazakhstan) Turkey. ELISA IgM and IgG detection (14). 31. the CDC of Iran in order for them to treat the CCHF prehemorrhagic period is characterized by a sudden Fig. the National Reference Laboratory of the former Yugoslavia. outbreak in Larestan region of Fars province. According to the protocol. treatment. patient with Ribavirin and supportive medication free Bulgaria. This committee some outbreaks are seen in the country like the recent has been dedicated to all activities related to control. awareness. respectively. hemorrhagic. etc. prehemorrhagic. the sera are sent to the from 5 to 6 days with a maximum of 13 days when Arboviruses and Viral Hemorrhagic Fevers ( National the infection is due to contact with infected tissue Reference Laboratory) .Va. Massive hemorrhages on the upper body of an Iranian patient. These three organizations Isfahan. and development of a subunit vaccine against CCHF virus. A surveillance and control program of CCHF in Iran was established by three collaborating Since the outbreak in Chaharmahal. Lab) and the Veterinary Organization.Bakhtiari organizations in 1999 including the Center for in 1999.va. and Senegal through a mammalian cell expression system used for (25. Albania and Kosovo. establishment of Arboviruses and viral Hemorrhagic. Pasteur Institute of Iran (PII) (with the of Arboviruses and Viral Hemorrhagic Fevers. province of charge.35). have also been dictated lots Human infection with CCHF virus results in severe hemorrhagic disease. all organized Among infected provinces. the sera samples period is variable and influenced by the route of are taken three times respectively at the onset of the exposure from 1 to 3 days with a maximum of 9 days disease. The initial recognition has been conducting several research projects such as of hemorrhagic cases in Africa occurred in 1960s. (2008). . been noted by authors as progressing through four Patients screened as probable cases through the distinct phases including incubation. categorized as Level II. .Balouchistan. NECVHFs protocol issued by Chinikar et al. Burkina Faso. Tanzania.1. Sistan. 5 days after the onset and 10 days after the when infection is caused by the bite of a tick. serological and molecular epidemiology of the CCHF resulting in a series of in-depth studies in South Africa virus in the country (some of which has been mentioned and reports of additional outbreaks from Congo. Greece. CCHF IN IRAN 9 Uzbekistan. the laboratory informs the or blood (34 .

IRAN. The plates various outbreaks. 14 ) . A common pathogenic feature of hemorrhagic reader at 450 nm. Symptoms may last from 1 to 7 days after incubation Serological Assay. 20 ) but labled anti-mouse immunoglobulin is added and the mortality rates of 10% to 80% have been reported in plates are incubated for 1 hour at 37˚C. Viral RNA is extracted from 140 μl of serum or from phenol extracted tick suspensions LABORATORY DIAGNOSIS using QIAamp RNA Easy Mini kit according to The laboratory of Arboviruses and Viral manufacturers instructions (QIAgen. 1hour at 37˚C. Then the and skin. and some research is being done on this aspect of The plates then are washed 3 times with phosphate- CCHF.6 days after onset of disease. In IgG detection. Ross River Fever. the plates are incubated for 1 hour at 37˚C. fragment of the S-segment of the CCHFV genome. Diluted serum vascular system and lymphoid organs (41). Molecular Assay. The virus mainly infects endothelial cells buffered saline (PBST) containing 0. The extracted viral RNA is analyzed molecular and serological techniques for diagnosis subsequently by Real-time RT-PCR using the one- and research on the CCHF virus and other arboviruses step RT-PCR kit (QIAgen. 27. a fulminant shock-like syndrome occurs. In IgM hemorrhagic symptoms rapidly manifest. The enzymatic reaction is stopped by the addition Pathogenesis of CCHF is not well understood of 4 N sulfuric acid. After dilution of the by some documents (37). 38 . Organ lesions cause the release read by ELISA reader (Anathos 2020) at 450 nm of procoagulants and disruption of the capacity to ( 11. Diluted immuno ascites then is added and the begins about 15. The plates are coagulation cascade. Onyog Nyoung.50% (1 . Germany) and viral hemorrhagic fevers like the West Nile. 36). 5' Tetra Methyl Benzedrine) is added and the plates higher than those acquired naturally through tick bite are incubated for 15 minutes at room temperature. 40) PBSTM. regenerate the consumed clotting factors (42). the ELISA plates fever viruses is their ability to disable the host are coated with the mouse hyper immune ascetic immune response by attacking and manipulating fluid diluted in PBS 1X and incubated overnight at the cells that initiate the antiviral response (40). J.20 days after onset of illness.12) onset of fever. Convalescence period at 37˚C . 12 . Hanta. especially on the upper body and/or serum sample is diluted in PBS containing Tween extremities (36). Serum samples are analyzed (32) . Sindbis. Mortality rates for various antigen in PBSTM. The plates are read by ELISA yet. Yellow Fever. Dengue. Peroxidase- average fatality rate is often 30 . After adding the diluted Peroxidase- It is suggested that inflammatory mediators may labled anti-human or animal immunoglobulin in play an important role in the pathogenesis (32. the ELISA plates are coated with the goat range from petechiae to large areas of ecchymosis IgG fraction to human IgM (anti μ chain) diluted in (Fig. the plates are incubated for 3 hours CCHF outbreaks varied greatly. dizziness. Tween. Hilden. evidenced is added and the plates are incubated for 15 minutes at in the skin by a rash. respectively. Tick Born The PCR reaction is done in 50 μl of total volume in . Finally.10 CHINIKAR ET AL . The native or recombinant antigen (which is This damage is characterized by marked replication produced in this lab) diluted in PBSTM is added and of the virus together with dysregulation of the the plates incubated for 3 hours at 37˚C. 3 . and this may be due to viral load (36). 5 Mortality rates of nosocomial infections are often much . 1) and often appear on the mucus membranes PBS 1 X and incubated overnight at 4˚C. Rift and using specific primers which amplify a 536 bp Valley Fever. Hemorrhagic Fevers has been equipped with advanced Germany).5% United Arab Emirates and China. The enzymatic reaction is stopped platelet aggregation and activation of the intrinsic by the addition of 4 N sulfuric acid. Mayaro and photophobia. by specific ELISA for IgM and IgG detection. back and abdominal pain (34. Lassa Fever. chills. severe headache. 3'. 1 (7 . MICROBIOL. contributes to stimulating room temperature. (e.5% Tween after and monocytes which cause the viremic phase each incubation. Finally.7 % and 80% from the are then washed 3 times with PBST containing 0.g. hydrogen peroxide and TMB (3 .39). In fatal in PBSTM is added and the plates are incubated for cases. In severe cases. Pumala. GmbH. Endothelial damage. The primary cause of bleeding may (PBST) and 3% skim milk (PBSTM) and the plates be due to a cytokine storm that has been demonstrated are incubated for 1 hour at 37˚C. Encephalities. hydrogen peroxide and TMB of the disease. Chikungunia. Hilden. The plates are incubated for 1 hour at 37˚C. 4˚C. Alkhorma. These can detection. GmbH.

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