Imported Crimean-Congo hemorrhagic fever cases in Istanbul

Crimean-Congo hemorrhagic fever (CCHF) is a fatal viral infection described in about 30 countries over the world. It has the most extensive geographic range among the medically significant tick-borne viruses [1]. The occurrence of CCHF closely approximates the known world distribution of Hyalomma spp. ticks. The virus belongs to the genus Nairovirus in the Bunyaviridae family and causes severe diseases in humans, with a reported case fatality rate of 3–30% [1]. CCHF outbreak in Turkey was reported in 2003 [2‐4]. By the year 2006, 1103 CCHF confirmed patients were recorded at the Ministry of Health (MOH) of Turkey [5]. The diagnoses of these cases were performed by detection of the virus by PCR or IgM and/or IgG positivity by ELISA. All these patients were hospitalized, 59 of them died, and the case fatality rate was calculated as 5.3%. A great majority of the cases were seen in the eastern Anatolia. No local case was reported from Istanbul yet. However, cases were recently observed in other regions of the country, and the rate of the domestic travel and mobility is high in the country.

Humans become infected through the bites of ticks, by contact with a patient with CCHF during the acute phase of infection, or by contact with blood or tissues from viremic livestock [6]. In 1969, the antigenic structures of the viruses from various geographic regions were reported to be indistinguishable [7]. However, the development of nucleic acid sequence analysis revealed extensive genetic diversity. Furthermore, more data on the genetic sub-types of the viral strains could shed light on the transmission dynamics of the virus. In this study we describe the genetic variation and clinical characteristics of the CCHF cases observed in Istanbul, in the western part of the country.

Since CCHF was endemic for the last four years in Eastern Anatolia, the ad hoc committee for CCHF in Istanbul initiated series of activities including the management of the suspected cases, in a city with the population of over 10 millions. A public awareness campaign was launched which included brochures, TV programs, and public health worker education programs about early diagnosis and preventive measures concerning tick bites and CCHF infections. As a result, there is improved surveillance and diagnosis of suspected cases (Figure 1). It is possible that previous introductions have gone unnoticed, especially since the majority of the cases appear to be relatively mild.

Suspected CCHF infections in people traveling from endemic regions to disease-free areas, such as Istanbul, were confirmed in 10 out of 91 cases. Nine out of 10 cases were from Eastern Anatolian provinces, where cases were reported previously [2, 3, 13]. However, one case originated from Kirklareli near the border with Bulgaria, which is the first report from this area (Figure 2). Imported cases of CCHF were reported previously, as cases from people traveling from one country to another [14, 15].

Sixty percent of our patients reported the tick bite, and all the patiens had been bitten out of Istanbul (Table 2). The HCWs facing with the suspected cases should be aware that, a significant proportion of the suspected cases did not report tick bite, as it was previously published [1]. In South Africa, the time to onset of disease after exposure to tick bite was 3.2 days, to blood or tissue of livestock was 5 days, and to blood of human cases was 5.6 days [16]. The mean duration of the disease course before the hospital was reported to be 5.5 days in a previous study from Turkey [2]. However in our study, the average time from onset of disease to admission to hospital was 7 days (Table 2). None of the cases was fatal. The patients were given erythrocyte, fresh frozen plasma, and total blood preparations depending on their hemostasis. All the patients were given ribavirin therapy before the virologic evidence of CCHF infection.

Although the genetic heterogeneity of tick-borne RNA viruses is generally low, CCHFv shows a high level of genetic heterogeneity up to 22% nucleotide variations and 27% amino acid variations based on the S fragment, which is reflected into six genetically distinct clades [12]. Although confirmed patients came from 8 different localities in Turkey, all CCHFv sequences were closely related. The nucleotide variation ranged between 0.66% and 3%, and this variation did not result in any amino acid substitution. In comparison with representative strains from different geographic regions, those strains found in this study displayed the highest homology with the Eastern European and some Russian isolates (clade V)(Fig. 3). Also, CCHF is endemic in neighboring countries and genetically distant strains circulate in Bulgaria, Iran and Greece [17‐19]. Moreover, in Iran, two different lineages of the virus have been reported; one belonging to the Asian-Middle Eastern clade and the other to the African clades [18]. Strains reported from Iraq and Arabian countries were closely related to those reported from Iran. Nevertheless, strains from the Eastern European countries and South-western Russia form a distinct group with relatively low heterogeneity (Figure 3).

Although relatively few sequences are available since the disease outbreaks were recorded in Turkey for the first time in 2003, those which are available are related to viral lineages found in Kosovo and South-western Russia [3]. Furthermore, viral strains in ticks collected from the endemic region where the first outbreaks occurred, were also found to be closely related with the Europe/Turkey strains [20, 21]. In our study, all strains clustered within the same group with the Europe/Turkey isolates, despite they originated from eight different geographic areas, 7 previously known and one focus on the European part of the Turkey, which was identified in this study (Figure 3). Interestingly one strain (SPU 9/00/5) from Iran reported by Burt and Swaenopel [22] clustered also with Europe/Turkey clade.

Despite more viral strains are needed to draw any definite conclusion, it appears the emergence of CCHF in Turkey may be the result of an amplification of local viral isolates by wildlife populations rather than resulting from novel introductions from neighbouring countries. Continued surveillance to monitor suspected CCHF cases, not only within known foci, but also outside endemic areas as reported herein, is required.