Crimean-Congo hemorrhagic fever (CCHF) seroprevalence: A systematic review and meta-analysis

Acta Tropica 196 (2019) 102–120

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Crimean-Congo hemorrhagic fever (CCHF) seroprevalence: A systematic review and meta-analysis

T

Hassan Nasirian Department of Medical Entomology and Vector Control, School of Public Health, Tehran University of Medical Sciences, Enqelab Square, Zip code 1346689151, Tehran, Iran

ARTICLE INFO

ABSTRACT

Keywords: Crimean-Congo hemorrhagic fever CCHF CCHF seroprevalence Epidemiological aspects of CCHF Seroprevalence features

Crimean-Congo haemorrhagic fever (CCHF) is the most widespread, tick-borne viral disease affecting humans and therefore this paper performed a meta-analysis to highlight seroprevalence features of CCHF in a global context. After a preliminary review of the 396 papers representing areas throughout the world, 206 were selected for detailed meta-analysis. In general the total means of CCHF seroprevalence were, respectively 4.7 and 24.6% for humans and animals; and 17.1, 18.9, 24.3, 29.3 and 27.1% for camels, cattle, goats, sheep and livestock. Statistical analysis revealed a significant difference in seroprevalence between humans and camels (P = 0.043), cattle (P = 0.010), goats (P = 0.015), sheep (P = 0.005) and livestock (P = 0.017). Regionally, there also was a difference between humans, and goats (P = 0.0001), sheep (P = 0.007) and livestock (P = 0.002). Globally, CCHF seroprevalence in at-risk professionals was 7.5 fold greater than in normal humans, while CCHF seroprevalence was 5 fold greater in animals, camels, cattle, goats, sheep and livestock than normal humans. Animal contact, animal husbandry, farming, tick bite history and secretion exposure were the most frequently reported CCHF seropositivity risk factors. This study serves as an important resource for epidemiological discussions related to CCHF and CCHF seroprevalence features, providing specific information in understanding human and animal mean and trend CCHF seroprevalence for different regions of the world and on an aggregate global scale; seroprevalence in at-risk professionals; and total mean and trend CCHF seropositivity involving risk factors.

1. Introduction Crimean-Congo hemorrhagic fever (CCHF) is a virulent tick-borne viral zoonotic disease that is endemic in a wide areas of the world and represents a health threat due to an acute and potentially fatal human infection. Currently CCHF has been recognized as being endemic or potentially endemic in about 50 countries throughout Europe, Africa, and Asia, and has led to a severe hemorrhagic syndrome in humans and sporadic infection in travelers visiting these areas. In addition, CCHF can occur in domestic and wild animals without any specific accompanying clinical symptoms (Abbas et al., 2015; Aslani et al., 2017; Atkinson et al., 2013; Bannazadeh Baghi and Aghazadeh, 2016; Davari et al., 2017a; Ertugrul et al., 2009; Fakoorziba et al., 2012; Fatemian et al., 2018; Mostafavi et al., 2013a; Rahpeyma et al., 2017; Shayeghi et al., 2016; Telmadarraiy et al., 2007; Vincent et al., 2003). CCHF is caused by Crimean-Congo hemorrhagic fever virus (CCHFV) belonging to the genus Orthonairovirus of the family Nairoviridae and order Bunyavirales (Adams et al., 2017; King et al., 2018). CCHFV generally circulates in nature in an enzootic tick-vertebrate-

tick cycle. A variety of domestic and wild animals may provide asymptomatic hosts of CCHFV in an endemic CCHF cycle of transmission, critical to feeding ticks that are aiding in the transmission cycle to a new populations of ticks. To detect endemic foci of viral transmission, seroepidemiological, serosurveillance or serosurvey studies have been instrumental in elucidating CCHFV hosts (Spengler et al., 2016a). As the antibody prevalence in animals is a good indicator for the presence or absence of the virus in a region, seroepidemiological studies can be used to define risk areas of CCHF (Schuster et al., 2016). Serological surveys are also the principal source of information to monitor areas with natural virus transmission and to identify species exposed to the virus (Spengler et al., 2016b). The absence of the CCHFV and the lack of antibodies against the virus in human and animal populations would also seem to suggest a low risk of acquisition of human infection by CCHFV (Palomar et al., 2017). Fairly extensive research has been conducted on CCHFV hosts and their respective roles in virus maintenance and transmission (Spengler et al., 2016a) and recently, several groups have published reports of detailed serosurveys. However, the studies generally have a local focus and do not provide a comprehensive

E-mail address: [email protected]. https://doi.org/10.1016/j.actatropica.2019.05.019 Received 4 December 2018; Received in revised form 7 April 2019; Accepted 15 May 2019 Available online 18 May 2019 0001-706X/ © 2019 Elsevier B.V. All rights reserved.

Acta Tropica 196 (2019) 102–120

H. Nasirian

assessment across large areas, or globally (Keshtkar-Jahromi et al., 2013). Localized studies have also shown variable results (Lotfollahzadeh et al., 2011) and therefore there is a need for a systematic meta-analysis review that summarizes large scale spatial trends. Many valuable reviews that focus on CCHF are available to develop this meta-analysis (Abbas et al., 2015; Al-Abri et al., 2017; Ansari et al., 2015, 2014; Atif et al., 2017; Bente et al., 2013; Brackney and Armstrong, 2016; Gargili et al., 2017; Keshtkar-Jahromi et al., 2013; Leblebicioglu, 2010; Spengler et al., 2016a, b). Dantas-Torres et al. (2012) provided a contemporary review of representative tick-borne diseases of humans and discussed aspects linked to their medical relevance. They emphasized the importance of a One Health approach to tick-borne diseases, calling on physicians and veterinarians to unify their efforts in the management of these diseases, several of which are zoonoses (Dantas-Torres et al., 2012). Dereli and Kayser (2017) provided a brief summary of the patterns in scientific research output, trends and academic collaboration in CCHF, which provided insights to new research strategies for the control of CCHF (Dereli and Kayser, 2017). Leblebicioglu et al. (2016a) conducted a systematic review about CCHF in travelers (Leblebicioglu et al., 2016a). Reviews of serosurvey also have been conducted (Bente et al., 2013; Hoogstraal, 1979; Spengler et al., 2016a, b). However, there is no a systematic meta-analysis review about epidemiological aspects of CCHF and CCHF comprehensive seroprevalence features including mean and trend of CCHF seroprevalence in human and animals such as cattle, goats and sheep; seroprevalence in at-risk professionals; mean and trend of CCHF seropositivity involving risk factors. Therefore this systematic metaanalysis review looks to summarize global characteristics and trends related to all above mentioned CCHF comprehensive features.

Fig. 1. Flow chart of the meta-analysis process.

summarized in Tables 1 and 2. The risk factors involved in CCHF seropositivity summarized in Table 3. Tables 4–6 show the CCHF seroprevalence results for cattle, sheep, goats and miscellaneous animals, respectively. All data presented in Tables 1–6 subsequently were entered into statistical analysis and Table 7 shows the mean CCHF seroprevalence in humans and animals based on literature resources in Table 1 and 4–6.

2. Materials and methods 2.1. Paper collection and selection of papers for review

2.3. Statistical analysis

As a first step, preliminary key words or phrases including epidemiology of Crimean-Congo hemorrhagic fever or CCHF disease, Crimean-Congo hemorrhagic fever or CCHF disease, Crimean-Congo hemorrhagic fever or CCHF seroepidemiological, serosurveillance, seroprevalence or serosurvey in humans and animals including cattle, goats and sheep; seroprevalence in at-risk professionals; and CCHF seropositivity involving risk factors were considered as the search terms within leading scientific websites including Web of Science, PubMed, Scopus, Google Scholar, Elsevier, Springer, and ScienceDirect, and covers the publication period November 2017–November 2018. For the second step, special key words or phrases including CCHF seroprevalence in at-risk professionals, humans and animals, and risk factors involved in CCHF seropositivity were selected, based on a detailed reading of the initially searched papers. These new key words and phrases were included in an additional search that expanded beyond the initially defined publication period of November 2017–November 2018. The meta-analysis process is summarized in Fig. 1. After a preliminary review of the 396 papers from the above mentioned addresses, 206 were selected to become part of the comprehensive systematic meta-analysis study, based on relevance to the study objectives, geographical representation, clarity, and quality assurance of reported results. Apparent outlying results were excluded from further consideration.

SPSS and Microsoft Excel were used to analyze the data presented in Tables 1–6. Specifically, Wilcoxon signed-ranks-tests and Pearson correlation were used to compare CCHF seroprevalence between humans and animals, and between seroprevalence of humans and animals, by region (Table 8). The methods following Nasirian, 2017a; b; 2019) were used to calculate and estimate the mean and trend mean of CCHF seroprevalence in human and animals, in at-risk professionals and the mean and trend mean of CCHF seropositivity involving risk factors, again based on the data summarized in Tables 1–6 (see also, Nasirian, 2017a, b; Nasirian, 2019). Fig. 2 shows the trend means of CCHF seroprevalence in humans and animals. Fig. 3 shows the mean and trend means of CCHF seroprevalence in humans and animals, and mean for at-risk professionals. Fig. 4 shows the trend mean of CCHF seropositivity involving risk factors and their correlation with seropositivity. Fig. 5 shows the mean and trend mean of CCHF seropositivity involving risk factors and correlation between seropositivity and risk factors. 3. Results 3.1. CCHF seroprevalence for at-risk professionals, humans and patient related populations Many studies have been done on CCHF seroprevalence in humans and at-risk professionals among different regions of the world, as summarized in Tables 1 and 2. Based on literature research in Table 1, CCHF seroprevalence in human populations ranged between 0.1–14.4%. While CCHF seroprevalence for at-risk professionals and patient related populations ranged between 16.5–30.3 and 18.5–85.0 %, respectively (Table 2).

2.2. Summary of the meta-analysis approach The 206 scientific papers were read carefully and the extracted data analyzed. Crimean-Congo hemorrhagic fever (CCHF) seroprevalence primarily was categorized according to the subjects including humans, cattle, sheep, goats and miscellaneous animals. The CCHF seroprevalence results for humans and at-risk professionals are 103

Acta Tropica 196 (2019) 102–120

H. Nasirian

Table 1 Crimean-Congo hemorrhagic fever seroprevalence in humans. Country

S (%)

Sampling

Iran Kuwait Saudi Arabia United Arab Emirates Oman Iran Turkey China Iran Afganistan Saudi Arabia China Madagascar Iran Greece Turkey Greece Greece Turkey Nigeria Kosovo Bulgaria Turkey Malaysia Tunisia Tunisia Turkey Greece Nigeria Turkey Georgia Ghana Bulgaria Mozambique Turkey Cameroon

4.0 4.0 0.8 4.0 2.4 2.4 12.8 1.7 6.3 11.2 0.6 3.4 0.5 12.0 4.2 10.0 3.4 2.2 13.6 2.4 4.0 2.8 2.3 0.1 2.7 5.2 14.0 3.8 10.6 3.7 3.0 5.7 3.7 2.7 14.4 4.4

Location Across Across Local Across Across Local Across Across Local Local Local Local Across Local Across Across Across Across Across Local Across Across Across Across Across Across Local Across Local Local Local Local Across Local Local Local

Reference n 100 502 354 291 41 297 782 2454 285 320 1024 1657 1995 100 1611 3557 207 277 625 297 1105 751 1066 682 181 38 322 3152 1189 324 905 109 1500 300 368 137

Date May 1970-Sep 1971 Dec 1979-Oct 1982 1997 Jan 1994-Mar 1995 1995-1996 Jan 2002-Mar 2002 Jun 2006-Sep 2006 2004-2005 2003-2004 2009 2010 Apr 2008-Jun 2008 Sep 2008-May 2009 2008 Jun 2009-Dec 2010 Jan 2009-Apr 2009 Mar 2012-Jul 2012 2010-2011 2012 Sep 2011-Feb 2012 May 2012-Dec 2012 2011-2012 2013 Sep 2012- Feb 2013 2014 2014 2015 2010-2012 2010-2014 2012 Jan 2014-Sep 2014 May to November 2011 2015 Mar 2015-Mar 2016 Jan 2012-Jul 2012 2005-2012

(Keshtkar-Jahromi et al., 2013; Saidi, 1974) (Al-Nakib et al., 1984) (Hassanein et al., 1997) (Khan et al., 1997) (Williams et al., 2000) (Izadi et al., 2006) (Gunes et al., 2009) (Sun et al., 2009) (Chinikar et al., 2010) (Mofleh and Ahmad, 2012; Mustafa et al., 2011) (Memish et al., 2011) (Xia et al., 2011) (Andriamandimby et al., 2011) (Chinikar et al., 2012a) (Sidira et al., 2012) (Bodur et al., 2012) (Sargianou et al., 2013) (Sidira et al., 2013) (Koksal et al., 2014) (Bukbuk et al., 2014) (Fajs et al., 2014) (Gergova and Kamarinchev, 2014) (Yagci-Caglayik et al., 2014) (Lani et al., 2015) (Wasfi et al., 2016) (Wasfi et al., 2016) (Cikman et al., 2016) (Papa et al., 2016) (Bukbuk et al., 2016) (Gazi et al., 2016) (Greiner et al., 2016) (Akuffo et al., 2016) (Christova et al., 2017) (Muianga et al., 2017) (Bayram et al., 2017) (Sadeuh-Mba et al., 2018)

Abbreviations: n=Sample size and S=Seroprevalence. Table 2 CCHF seroprevalence for at-risk professionals and patient related populations. Country

S (%)

Population at risk

Oman Turkey Iran Iran Total (Mean) Std. Deviation

30.3 19.6 16.5 29.0 23.8 6.8

Turkey Kenya Pakistan Iran Kenya Total (Mean) Std. Deviation

85.0 18.5 49.0 42.5 25.6 44.1 26.0

Animal workers Endemic regions Butchers and slaughterhouse workers Slaughterhouse workers – – Patient or patient related populations CCHF patients Patients attending health centers CCHF suspected patients Endemic retrospective survey Febrile patients – –

Sampling

Reference

Location Across Local Local Local – –

n 282 429 190 136 – –

Date 1995-1996 2011 2011 2014 – –

(Williams et al., 2000) (Ertugrul et al., 2012) (Mostafavi et al., 2017) (Shahhosseini et al., 2018) – –

Across Local Across Local Local – –

99 517 100 42 379 – –

2003 Oct 2010-Mar 2011 Jan 2011-Dec 2011 1999-2015 Sep 2009-Dec 2012 – –

(Bakir et al., 2005) (Lwande et al., 2012) (Khurshid et al., 2015) (Sharififard et al., 2016) (Tigoi et al., 2015) – –

Abbreviations: n=Sample size and S=Seroprevalence.

3.2. Risk factors involved in CCHF seropositivity

housewife, hunting, secretion exposure and slaughtering activities were observed as the most frequent risk factors involved in CCHF seropositivity based on literature resources in Table 3.

Some of the miscellaneous risk factors involved in CCHF seropositive serosurveys are animal tick adhesion, CCHF high-risk activity, endemic area traveling, hand or body contusion, those with knowledge about CCHF, and literacy level. Other risk factors included livestock transportation, milking, improper (non) use of personal protective equipment, time spent in rural areas and activity in forested areas. Animal contact, animal husbandry, farming, history of tick bite,

3.3. CCHF seroprevalence in animals Many studies have been done on CCHF seroprevalence in cattle, sheep, goats and camels among different regions of the world and the results are summarized in Tables 4–6, respectively. CCHF 104

Population at-risk Human High-risk human Human Rural endemic area Volunteer Human Endemic and nonendemic area Human (endemic) Human (endemic) Rural endemic area High-risk human High-risk human Outbreak household Volunteer Rural household Butchers and slaughterhouse worker High-risk human Butchers and slaughterhouse worker Health center patient Outbreak household Volunteer Butchers and slaughterhouse worker Health center patient Health center patient Human Butcher and slaughterhouse worker Human Butcher and slaughterhouse worker CCHF patient High-risk human Human Rural endemic area Health center patient Volunteer Human Endemic retrospective survey Rural resident Human (endemic) Human (endemic) CCHF patients High-risk human Volunteer Rural endemic area Human Human Endemic and non-endemic areas Rural household Human (endemic) Rural endemic area Butchers and slaughterhouse worker Slaughterhouse worker Health center patient Volunteer

Risk factor

Animal husbandry Animal husbandry Animal husbandry Animal husbandry Animal husbandry Animal husbandry Animal husbandry Animal husbandry Animal husbandry Animal husbandry Secretion exposure Secretion exposure Secretion exposure Secretion exposure Secretion exposure Secretion exposure Animal contact Camel contact Camel contact Cattle contact Cattle contact Cattle contact Donkey contact Goat contact Goat contact Goat contact Sheep contact Sheep contact Farming Farming Farming Farming Farming Farming Farming Farming Farming Farming Farming History of tick bite History of tick bite History of tick-bite History of tick bite History of tick bite History of tick bite History of tick bite History of tick bite History of tick bite History of tick bite History of tick bite History of tick bite Housewife Housewife

Table 3 Risk factors involved in CCHF seropositivity.

Iran Turkey China Turkey Turkey Greece Bulgaria Turkey Turkey Turkey Turkey Turkey Afghanistan Turkey Georgia Iran Turkey Iran Kenya Afghanistan Turkey Iran Kenya Kenya Greece Iran Greece Iran Turkey Turkey China Turkey Kenya Turkey Greece Iran Turkey Turkey Turkey Turkey Turkey Turkey Turkey Greece Greece Bulgaria Georgia Turkey Turkey Iran Iran Kenya Turkey

Place 100 14.2 56.1 16.6 24.8 57.1 66.7 39.0 7.9 4.3 14.1 15.7 16.7 29.4 57.9 12.8 16.6 17.5 20.0 12.5 79.0 14.9 20.2 18.8 57.1 15.0 100 15.0 90.0 14.2 22.8 49.9 29.0 19.8 2.5 28.6 3.9 7.9 11.5 60.0 11.5 41.1 29.7 71.4 8.3 95.8 66.7 46.8 7.7 11.1 23.0 18.0 24.1

S (%)

105

(continued on next page)

(Izadi et al., 2006) (Gunes et al., 2009) (Xia et al., 2011) (Bodur et al., 2012) (Ertugrul et al., 2012) (Sargianou et al., 2013) (Gergova and Kamarinchev, 2014) (Cikman et al., 2016) (Cikman et al., 2016) (Gazi et al., 2016) (Gunes et al., 2009) (Gunes et al., 2009) (Mustafa et al., 2011) (Ertugrul et al., 2012) (Greiner et al., 2016) (Mostafavi et al., 2017) (Gunes et al., 2009) (Mostafavi et al., 2017) (Lwande et al., 2012) (Mustafa et al., 2011) (Ertugrul et al., 2012) (Mostafavi et al., 2017) (Lwande et al., 2012) (Lwande et al., 2012) (Sargianou et al., 2013) (Mostafavi et al., 2017) (Sargianou et al., 2013) (Mostafavi et al., 2017) (Bakir et al., 2005) (Gunes et al., 2009) (Xia et al., 2011) (Bodur et al., 2012) (Lwande et al., 2012) (Ertugrul et al., 2012) (Sidira et al., 2013) (Sharififard et al., 2016) (Gazi et al., 2016) (Cikman et al., 2016) (Cikman et al., 2016) (Bakir et al., 2005) (Gunes et al., 2009) (Ertugrul et al., 2012) (Bodur et al., 2012) (Sargianou et al., 2013) (Sidira et al., 2013) (Gergova and Kamarinchev, 2014) (Greiner et al., 2016) (Cikman et al., 2016) (Gazi et al., 2016) (Mostafavi et al., 2017) (Shahhosseini et al., 2018) (Lwande et al., 2012) (Ertugrul et al., 2012)

Date Jan 2002-Mar 2002 Jun 2006-Sep 2006 Apr 2008-Jun 2008 Jan 2009-Apr 2009 2011 Mar 2012-Jul 2012 2011-2012 2015 2015 2012 Jun 2006-Sep 2006 Jun 2006-Sep 2006 2009 2011 Jan 2014-Sep 2014 2011 Jun 2006-Sep 2006 2011 Oct 2010-Mar 2011 2009 2011 2011 Oct 2010-Mar 2011 Oct 2010-Mar 2011 Mar 2012-Jul 2012 2011 Mar 2012-Jul 2012 2011 2003 Jun 2006-Sep 2006 Apr 2008-Jun 2008 Jan 2009-Apr 2009 Oct 2010-Mar 2011 2011 2010-2011 1999-2015 2012 2015 2015 2003 Jun 2006-Sep 2006 2011 Jan 2009-Apr 2009 Mar 2012-Jul 2012 2010-2011 2011-2012 Jan 2014-Sep 2014 2015 2012 2011 2014 Oct 2010-Mar 2011 2011

Location Local Across Local Across Local Across Across Local Local Local Across Across Local Local Local Local Across Local Local Local Local Local Local Local Across Local Across Local Across Across Local Across Local Local Across Local Local Local Local Across Across Local Across Across Across Across Local Local Local Local Local Local Local

n 297 664 1657 3557 429 207 751 322 322 324 135 89 144 429 905 190 734 190 517 264 429 190 517 517 207 190 207 190 99 656 1657 3557 517 429 277 42 324 322 322 99 483 429 3557 207 277 751 905 322 324 190 136 517 429

Reference

Sampling

H. Nasirian

Acta Tropica 196 (2019) 102–120

Acta Tropica 196 (2019) 102–120 (Sharififard et al., 2016) (Ertugrul et al., 2012) (Bodur et al., 2012) (Sargianou et al., 2013) (Gunes et al., 2009) (Sargianou et al., 2013) (Mostafavi et al., 2017) (Gunes et al., 2009) (Ertugrul et al., 2012) (Bodur et al., 2012) (Ertugrul et al., 2012) (Ertugrul et al., 2012) (Sargianou et al., 2013) (Gergova and Kamarinchev, 2014) (Greiner et al., 2016) (Mostafavi et al., 2017) (Mostafavi et al., 2017) (Mostafavi et al., 2017) (Mostafavi et al., 2017)

seroprevalence ranged between 0.6–79.1, 0.3–85.7, 0.4–68.8 and 1.4–40.0 % for cattle, sheep, goats and camels, respectively. Several studies have been done on CCHF seroprevalence in livestock and ruminant among different regions of the world and results are summarized in Table 6. CCHF seroprevalence ranged between 2.5–75.0 and 1.6–57.0 % for livestock and ruminant, respectively. 3.4. Mean of CCHF seroprevalence in humans and animals The means of human and animal CCHF seroprevalence are provided in Table 7 and were calculated based on literature resources in Tables 1 and 4–6. In general, the mean of CCHF seroprevalence in human and animals were 4.7 and 24.6%, respectively, while the means of CCHF seroprevalence in camels, cattle, goats, sheep and livestock were 17.1, 18.9, 24.3, 29.3 and 27.1%, respectively (Table 7). Wilcoxon signedranks-tests revealed a significant difference between seroprevalence of humans, and camels (P = 0.043), cattle (P = 0.010), goats (P = 0.015), sheep (P = 0.005) and livestock (P = 0.017). Wilcoxon signed-rankstests also revealed a significant difference between seroprevalence of humans, and goats (P = 0.0001), sheep (P = 0.007) and livestock (P = 0.002) for different regions. Wilcoxon signed-ranks-tests did not reveal a significant difference between seroprevalence of humans, and camels (P = 0.077) and cattle (P = 0.536) for different regions (Table 8).

Local Local Across Across Across Across Local Across Local Across Local Local Across Across Local Local Local Local Local

3.5. Trend mean of CCHF seroprevalence in humans and animals The trend means of human and animal CCHF seroprevalence which were provided in Fig. 2 were estimated based on literature resources in Tables 1 and 4–6. The trend mean of CCHF seroprevalence in humans during the decades reported in the studies exhibited a slightly increasing trend, with the increasing trend mean ranging from 3.5 to 5.5%. The trend means of CCHF seroprevalence in camels, sheep and livestock during the decades reported in the studies also generally exhibited an increasing trend, with the trend means increase trends ranging from 10.0 to 25.0, 17.0–41.0 and 18.0–36.0 % for camels, sheep and livestock, respectively. The trend means of CCHF seroprevalence in cattle and goats during the decades reported in the studies exhibited a slightly increasing trend, with the increase in trend means ranging from 16.5 to 21.0 and 22.0–24.5 % for cattle and goats, respectively (Fig. 2). The Pearson correlation coefficient (r) was not significant between seroprevalence of humans and animals; and humans, and cattle, sheep and livestock for different regions (P > 0.05) while it was significant between seroprevalence of humans, and camels (P = 0.003) and goats (P = 0.001) for different regions (Table 8). 3.6. Mean and trend mean of CCHF seroprevalence for at-risk professionals The total mean of CCHF seroprevalence (%) for at-risk professionals were provided in Fig. 3 based on literature resources in Table 2. The total mean of CCHF seroprevalence for at-risk professionals were: animal workers (30.3%), butchers and slaughterhouse workers (16.5%), endemic region (19.6%) and farm workers (36.5%). The total mean of CCHF seroprevalence for patients or patient related populations were: CCHF patients (85.0%), CCHF suspected patients (49.0%), endemic retrospective survey (42.5%), febrile patients (25.6%) and patients attending health centers (18.5%) (Fig. 3).

Abbreviations: n=Sample size and S=Seroprevalence.

Iran Turkey Turkey Greece Turkey Greece Iran Turkey Turkey Turkey Turkey Turkey Greece Bulgaria Georgia Iran Iran Iran Iran Endemic retrospective survey Volunteer Rural endemic area Human High-risk human Human Butchers and slaughterhouse worker High-risk human Volunteer Endemic CCHF rural areas Volunteer Volunteer Humans Endemic and nonendemic areas Rural household Butchers and slaughterhouse worker Butchers and slaughterhouse worker Butchers and slaughterhouse worker Butchers and slaughterhouse worker Housewife Hunting Hunting Hunting Slaughtering Slaughtering Slaughtering Milking Lack of reading and writing skills Informed about CCHFV Animal tick adhesion Endemic area traveling Wood visiting Staying in rural areas CCHF high-risk activity Livestock transportation Considering self at risk of zoonosis diseases Not use any personal protective equipment Hand or body cutting

26.0 18 15.5 16.7 16.6 28.6 18.0 13.3 22.2 73.7 29.1 15.9 33.3 87.5 91.5 20.0 18.1 39.7 22.5

Place Population at-risk Risk factor

Table 3 (continued)

S (%)

Sampling

42 429 3557 207 151 207 190 263 429 3557 429 429 207 751 905 190 190 190 190

1999-2015 2011 Jan 2009-Apr 2009 Mar 2012-Jul 2012 Jun 2006-Sep 2006 Mar 2012-Jul 2012 2011 Jun 2006-Sep 2006 2011 Jan 2009-Apr 2009 2011 2011 Mar 2012-Jul 2012 2011-2012 Jan 2014-Sep 2014 2011 2011 2011 2011

Reference

H. Nasirian

3.7. Total trend mean of CCHF seroprevalence in humans and animals The total trend means of human and animal CCHF seroprevalence were provided in Fig. 3, based on literature resources in Tables 1 and 4–6. The total trend mean of CCHF seroprevalence in humans exhibit a slightly increasing trend over time, with the increases ranging between 2.5 and 5.5%. The total trend mean of CCHF seroprevalence in animals generally exhibited an increasing trend over time, with the increases 106

107

5.1 23.0 16.2 11.9 10.1 11.0 3.1 3.8 4.2 4.7 1.1 3.5 31.0 19.0 76.3 33.2 4.2 18.0 0.9 0.7 0.9 5.6 0.6 29.3 25.7 2.2 26.5 28.0 46.0 6.3 1.9 4.0 37.0

Russia Russia Azerbaijan Azerbaijan Azerbaijan Azerbaijan Azerbaijan Azerbaijan Azerbaijan Azerbaijan Tajikistan Turkmenistan Turkmenistan Iran Kenya/Uganda Bulgaria Armenia Iran Hungary Kazakhstan Hungary Afghanistan

(Berezin et al., 1969; Spengler et al., 2016a) (Badalov, 1969;Spengler and Rollin, 2016a) (Chumakov et al., 1970; Spengler et al., 2016a) (Chumakov et al., 1970; Spengler et al., 2016a) (Chumakov et al., 1970; Spengler et al., 2016a) (Chumakov et al., 1970; Spengler et al., 2016a) (Chumakov et al., 1970; Spengler et al., 2016a) (Chumakov et al., 1970; Spengler et al., 2016a) (Chumakov et al., 1970; Spengler et al., 2016a) (Chumakov et al., 1970; Spengler et al., 2016a) (Smienova, 1971; Spengler et al., 2016a) (Smienova, 1971; Spengler et al., 2016a) (Smienova, 1971; Spengler et al., 2016a) (Chumakov, 1972; Spengler et al., 2016a) (Chumakov, 1972; Spengler et al., 2016a) (Spengler et al., 2016a; Vasilenko, 1973) (Matevosyan et al., 1974; Spengler et al., 2016a) (Saidi et al., 1975; Spengler et al., 2016a) (Horvath, 1975; Spengler et al., 2016a) (Semashko, 1975; Spengler et al., 2016a) (Horvath, 1975; Spengler et al., 2016a) (Chumakov, 1974; Spengler et al., 2016a) (Hoogstraal, 1979; Spengler et al., 2016a) (Spengler et al., 2016a; Tantawi et al., 1981) (Spengler et al., 2016a; Umoh et al., 1983) (Darwish et al., 1983; Spengler et al., 2016a) (Spengler et al., 2016a; Swanepoel et al., 1985) (Spengler et al., 2016a; Swanepoel et al., 1987) (Mariner et al., 1995; Spengler et al., 2016a) (Khan et al., 1997; Spengler et al., 2016a) (Hassanein et al., 1997; Spengler et al., 2016a) (Spengler et al., 2016a; Williams et al., 2000) (Al-Yabis et al., 2005)

Date 1969 1969 1970 1970 1970 1970 1970 1970 1970 1970 1971 1971 1971 1972 1972 1973 1974 1975 1975 1975 1975 1974 1979 1981 1983 1983 1985 1987 1984-1988 Jan 1994-Mar 1995 1997 Mar 1996 Nov 1996- Jun 1997

Location Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Across Local

n – 430 651 142 38 102 161 238 454 424 775 199 29 100 93 1756 1373 130 687 842 687 230 166 411 1164 45 6128 8667 2263 16 54 282 48

Reference

Sampling

Abbreviations: n=Sample size and S=Seroprevalence.

Iraq Nigeria Pakistan South Africa South Africa Niger Somalia Ireland Oman Iraq

S (%)

Country

Table 4 Crimean-Congo hemorrhagic fever seroprevalence in cattle.

Iran Iran Iran Iran Iran Afghanistan Iran India Iran Bulgaria Sudan India Albania Albania Albania Albania Kosovo Bulgaria India India India India Egypt Albania Republic of Macedonia Sudan Tajikistan Russia Senegal Kosova West Africa Mauritania Greece

Region 9.6 3.7 30.0 9.0 5.9 79.1 20.0 4.1 25.0 7.9 7.0 44.6 4.7 4.0 2.1 7.4 18.4 71.0 12.1 43.8 12.1 43.8 0.6 2.6 14.6 19.1 1.1 2.8 6.1 4.1 66.0 67.0 12.0

% Location Local Local Local Local Across Local Local Local Across Across Local Local Across Local Local Local Across Local Local Local Local Local Local Local Local Local Local Local Local Local Across Across Across

Sampling n 248 56 56 56 876 92 322 239 1091 1775 299 82 337 104 104 104 401 127 1226 82 1226 82 161 104 102 282 1585 355 1269 172 1075 495 330

Time 2009 2004-2005 2004-2005 2004-2005 2006-2008 2009 2008 Nov 2010-Dec 2010 1999-2011 1006-2012 2012 2013 2013 2013 2013 2013 Jun 2012-Nov 2012 2011 2013 2013 2013 2013 2009 2013 2011 2014 1970 1974 1969 2016 2005-2014 2013 2009-2011

(Lotfollahzade et al., 2009) (Telmadarraiy et al., 2010) (Telmadarraiy et al., 2010) (Telmadarraiy et al., 2010) (Lotfollahzadeh et al., 2011) (Mustafa et al., 2011) (Chinikar et al., 2012a) (Mourya et al., 2012) (Mostafavi et al., 2013c) (Gergova and Kamarinchev, 2013) (Adam et al., 2013) (Yadav et al., 2014) (Lugaj and Bërxhol, 2014) (Lugaj et al., 2014) (Lugaj et al., 2014) (Lugaj et al., 2014) (Fajs et al., 2014) (Barthel et al., 2014) (Mourya et al., 2014) (Yadav et al., 2014) (Mourya et al., 2014) (Yadav et al., 2014) (Horton et al., 2014) (Lugaj et al., 2014) (Mertens et al., 2015) (Ibrahim et al., 2015) (Spengler et al., 2016a) (Spengler et al., 2016a) (Spengler et al., 2016a) (Sherifi et al., 2016) (Maiga et al., 2017) (Sas et al., 2017) (Schuster et al., 2017)

Reference

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0.3 16.2 6.7 1.5 11.3 45.0 7.7 32.9 49.0 31.3 38.0 0.4 0.7 23.1 57.6 10.4 3.0 50.0 4.3 3.2 3.0 20.0 54.2 20.0 76.6 77.5 12.6 32.6 41.9 77.5 75.0 75.0 85.7 3.7 27.8 35.3 50.0 77.5 12.6 15.6 58.7 53.3 74.0 25.0 32.6 47.4 31.8

Sheep Russia Azerbaijan Azerbaijan Tajikistan Turkmenistan Iran India Bulgaria Iran Hungary Iran Kazakhstan India Egypt Iraq Senegal Niger Somalia Sudan Turkey Oman Mauritania Iran Iraq Iran Iran China Kosovo Iran Iran Afghanistan Afghanistan Turkey Iran Romania India India Iran Iran Iran Iran India Bulgaria Greece India India Turkey

Local Local Local Local Local Local Local Local Across Local Local Local Local Local Local Across Local Local Local Local Across Local Local Local Local Local Across Across Local Across Local Local Across Local Local Local Local Local Local Local Across Local Local Local Local Local Local

Location

Sampling

– 651 89 326 663 201 13 1190 580 48 728 832 149 52 769 942 271 12 1972 95 282 97 170 74 286 286 5629 – 56 298 40 40 105 270 471 239 305 298 322 167 1091 82 242 40 1226 82 508

n

1969 1970 1970 1970 1970 1972 1973 1973 1974 1975 1975 1975 1976 1978 1981 1990 1995 1997 1997 1997 Mar 1996 Feb 2003-Aug 2003 2004 Nov 1996- Jun 1997 2008 2008 2004-2005 2010 2004-2005 2003-2005 2009 2009 2012 2010-2011 2012 Nov 2010-Dec 2010 Nov 2010-Dec 2010 2012 2008 2012 1999-2011 2013 2011 2014 2013 2013 2008-2009

Date

Abbreviations: n=Sample size and S=Seroprevalence.

S (%)

Country

(Berezin et al., 1969; Spengler et al., 2016a) (Chumakov et al., 1970; Spengler et al., 2016a) (Chumakov et al., 1970; Spengler et al., 2016a) (Smienova, 1971; Spengler et al., 2016a) (Smienova, 1971; Spengler et al., 2016a) (Chumakov, 1972; Spengler et al., 2016a) (Shanmugam, 1973) (Spengler et al., 2016a; Vasilenko, 1973) (Keshtkar-Jahromi et al., 2013; Saidi, 1974) (Horvath, 1975; Spengler et al., 2016a) (Saidi et al., 1975; Spengler et al., 2016a) (Semashko, 1975; Spengler et al., 2016a) (Shanmugam et al., 1976) (Darwish et al., 1978) (Spengler et al., 2016a; Tantawi et al., 1981) (Wilson et al., 1990) (Mariner et al., 1995; Spengler et al., 2016a) (Khan et al., 1997; Spengler et al., 2016a) (Hassanein et al., 1997; Spengler et al., 2016a) (Hassanein et al., 1997; Spengler et al., 2016a) (Spengler et al., 2016a; Williams et al., 2000) (Nabeth et al., 2004) (Izadi et al., 2004; Mostafavi et al., 2012) (Al-Yabis et al., 2005) (Ataei et al., 2006; Mostafavi et al., 2012) (Bokaie et al., 2008) (Spengler et al., 2016a; Sun et al., 2009) (Humolli et al., 2010) (Telmadarraiy et al., 2010) (Chinikar et al., 2010) (Mustafa et al., 2011; Spengler et al., 2016a) (Mustafa et al., 2011) (Albayrak et al., 2012) (Mostafavi et al., 2012) (Ceianu et al., 2012) (Mourya et al., 2012) (Mourya et al., 2012) (Chinikar et al., 2012b; Spengler et al., 2016a) (Chinikar et al., 2012a) (Rezazadeh et al., 2012, 2013) (Mostafavi et al., 2013c) (Yadav et al., 2014) (Barthel et al., 2014) (Papa et al., 2014) (Mourya et al., 2014) (Yadav et al., 2014) (Tuncer et al., 2014)

Reference

Table 5 Crimean-Congo hemorrhagic fever seroprevalence in sheep and goats.

Kosovo Yugoslavia Iran Kosova Tajikistan Tajikistan Tajikistan Greece Goats Tajikistan Turkmenistan Iran Uganda Bulgaria India India Afghanistan Iran Kazakhstan India Tanzania Tanzania Tanzania Iraq Zimbabwe Niger Somalia Sudan Iran Oman Mauritania Iran Albania Iran Iran Iran Turkey India India Iran India Turkey Bulgaria India India Kosovo Turkey Tajikistan

Country Location Across Across Local Local Local Local Local Across Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Local Across Local Local Local Local Across Local Across Local Local Across Local Local Local Local Local Across Local Local

1.5 11.3 45.0 36.5 62.3 9.4 40.0 9.0 36.0 0.4 16.1 7.4 4.8 6.3 49.6 45.0 4.9 21.4 3.9 40.0 14.0 11.1 46.0 20.0 33.3 46.0 9.5 66.7 2.1 30.3 24.8 68.8 13.0 60.0 41.2 46.4 10.0 66.0 0.9

Sampling

10.0 49.0 4.8 3.2 0.9 2.6 4.9 2.0

S (%)

326 663 201 104 411 117 45 233 135 832 186 256 209 417 562 763 2263 14 356 5 282 97 150 10 56 150 322 105 305 239 1091 82 508 15 1226 82 401 508 107

n 401 330 84 95 107 614 82 330 1971 1971 1972 1972 1973 1973 1973 1974 1975 1975 1976 1979 1979 1979 1981 1987 1984-1988 1997 1997 1997 Mar 1996 Feb 2003-Aug 2003 2008 2009 2004-2005 2003-2005 2008 2012 Nov 2010-Dec 2010 Nov 2010-Dec 2010 1999-2011 2013 2008-2009 2011 2013 2013 Jun 2012-Nov 2012 2008-2009 1970

Date Jun 2012-Nov 2012 2009-2011 2016 2016 1970 1970 1970 2009-2011

(Smienova, 1971; Spengler et al., 2016a) (Smienova, 1971; Spengler et al., 2016a) (Chumakov, 1972; Spengler et al., 2016a) (Kirya et al., 1972) (Spengler et al., 2016a; Vasilenko, 1973) (Shanmugam, 1973) (Shanmugam, 1973) (Chumakov, 1974; Spengler et al., 2016a) (Saidi et al., 1975; Spengler et al., 2016a) (Semashko, 1975; Spengler et al., 2016a) (Shanmugam et al., 1976) (Hoogstraal, 1979; Spengler et al., 2016a) (Hoogstraal, 1979; Spengler et al., 2016a) (Hoogstraal, 1979; Spengler et al., 2016a) (Spengler et al., 2016a; Tantawi et al., 1981) (Spengler et al., 2016a; Swanepoel et al., 1987) (Mariner et al., 1995; Spengler et al., 2016a) (Khan et al., 1997; Spengler et al., 2016a) (Hassanein et al., 1997; Spengler et al., 2016a) (Khan et al., 1997; Spengler et al., 2016a) (Spengler et al., 2016a; Williams et al., 2000) (Nabeth et al., 2004) (Bokaie et al., 2008) (Papa et al., 2009) (Telmadarraiy et al., 2010) (Chinikar et al., 2010) (Chinikar et al., 2012a) (Albayrak et al., 2012) (Mourya et al., 2012) (Mourya et al., 2012) (Mostafavi et al., 2013c) (Yadav et al., 2014) (Tuncer et al., 2014) (Barthel et al., 2014) (Mourya et al., 2014) (Yadav et al., 2014) (Fajs et al., 2014) (Tuncer et al., 2014) (Spengler et al., 2016a)

(Fajs et al., 2014) (Schuster et al., 2016) (Hosseini-Vasoukolaei et al., 2016) (Sherifi et al., 2016) (Spengler et al., 2016a) (Spengler et al., 2016a) (Spengler et al., 2016a) (Schuster et al., 2017)

Reference

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Local Local Across Local Local Local Local Local Local Local Across Across Across

Local Local Across Local Local Across Local Local Across Across Local Local Local Local Local

2.5 7.9 10.3 18.1 27.8 12.7 39.0 56.0 61.8 14.0 75.0 17.0 12.7 56.0 43.9

Location

Sampling

1.4 19.1 19.0 8.8 23.2 12.0 26.0 13.6 7.7 6.3 16.0 40.0 21.3

S (%)

40 139 2,263 97 – 3175 56 – 448 – 132 239 322 – 82

– 99 580 34 99 3802 499 2263 13 80 109 3175 361

n

1976 1976 1995 Feb 2003-Aug 2003 2008 2004-2005 2004-2005 2003-2004 2003-2005 2010 2009 Nov 2010-Dec 2010 2008 2004-2005 2013

1971 1972 1974 1978 1981 1990 1990 1984-1988 1997 Jan 1994-Mar 1995 1995-1996 2004-2005 Oct 2014-Mar 2015

Date

Abbreviations: n=Sample size and S=Seroprevalence.

Camels Russia Iran Iran Egypt Iraq Sudan Kenya Niger Sudan United Arab Emirates Oman China Sudan Livestock India India Niger Mauritania Iran China Iran Iran Iran Kosovo Afghanistan India Iran Iran India

Country

(Shanmugam et al., 1976) (Shanmugam et al., 1976) (Mariner et al., 1995) (Nabeth et al., 2004) (Telmadarraiy et al., 2008) (Sun et al., 2009) (Telmadarraiy et al., 2010) (Chinikar et al., 2010) (Chinikar et al., 2010) (Humolli et al., 2010) (Mustafa et al., 2011) (Mourya et al., 2012) (Chinikar et al., 2012a) (Chinikar et al., 2012a) (Yadav et al., 2014)

(Berezin et al., 1971) (Chumakov, 1972; Spengler et al., 2016a) (Keshtkar-Jahromi et al., 2013; Saidi, 1974) (Darwish et al., 1978) (Spengler et al., 2016a; Tantawi et al., 1981) (Morrill et al., 1990) (Morrill et al., 1990; Spengler et al., 2016a) (Mariner et al., 1995; Spengler et al., 2016a) (Khan et al., 1997; Spengler et al., 2016a) (Khan et al., 1997; Spengler et al., 2016a) (Williams et al., 2000) (Sun et al., 2009) (Suliman et al., 2017)

Reference

Table 6 Crimean-Congo hemorrhagic fever seroprevalence in miscellaneous animals.

Sudan Senegal Iran Buffalo Pakistan India India Ruminant Niger Kosovo Iran Iran Bulgaria Turkey Albania Senegal Donkey Azerbaijan Bulgaria Bulgaria Tajikistan Horses Tajikistan Bulgaria India Iraq Russia Ostrich South Africa Iran

Country Location Local Local Across Local Local Local Local Across Local Local Across Across Across Local Local Local Local Local Local Local Local Local Local Local Local

4.5 2.2 19.5 10.3 14.0 56.0 56.0 26.0 57.0 23.0 6.1 18.8 17.4 50.0 39.5 2.8 39.0 1.1 58.8 3.1 23.9 20.0

Sampling

19.1 6.1 35.8

S (%)

92 5

71 536 282 252 –

69 103 8 38

2263 – – – 1165 1165 534 1269

22 239 305

n 282 1269 5842

1987 1007

1971 1973 1976 1981 1969

1970 1973 2011 1970

1984-1988 2010 2004-2005 2004-2005 2016 2016 2011-2013 1969

1983 Nov 2010-Dec 2010 Nov 2010-Dec 2010

Date 2014 1969 2000-2015

(Shepherd et al., 1987) (Mostafavi et al., 2013b)

(Smienova, 1971; Spengler et al., 2016a) (Spengler et al., 2016a; Vasilenko, 1973) (Shanmugam et al., 1976) (Spengler et al., 2016a; Tantawi et al., 1981) (Berezin et al., 1969; Spengler et al., 2016a)

(Chumakov et al., 1970; Spengler et al., 2016a) (Spengler et al., 2016a; Vasilenko, 1973) (Barthel et al., 2014) (Spengler et al., 2016a)

(Mariner et al., 1995; Spengler et al., 2016a) (Humolli et al., 2010) (Chinikar et al., 2012a) (Chinikar et al., 2012a) (Mertens et al., 2016) (Mertens et al., 2016) (Schuster et al., 2016) (Spengler et al., 2016a)

(Darwish et al., 1983; Spengler et al., 2016a) (Mourya et al., 2012) (Mourya et al., 2012)

(Ibrahim et al., 2015) (Spengler et al., 2016a) (Al-Abri et al., 2017)

Reference

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The trend mean of seropositivity among animal husbandry groups ranged from 6.5 to 7.7% and exhibited a very slight increasing trend between 2006 and 2016. The data suggest that with a slight increase in the seropositivity, the involvement of the animal husbandry risk factor has decreased over the years (Fig. 4). The trend mean of the animal contact risk factor ranged from 19.5 to 46.5% and generally exhibited an increasing trend between 2009 and 2017, while the trend mean of seropositivity among animal contact groups ranged from 12.6 to 12.5% and remained approximately constant between 2009 and 2017. The data suggest with consistency of the seropositivity, the involvement of the animal contact risk factor has increased over the years (Fig. 4). The trend mean of history of the tick bite risk factor ranged from 44.0 to 46.5% and exhibited a very slight increase between 2005 and 2018, while the trend mean of seropositivity among the history of tick bite group ranged from 38.0 to 4.5% and generally exhibited a decreasing trend between 2005 and 2018. The data indicate that with decreasing seropositivity, the involvement of the history of tick bite risk factor remains constant or has slightly increased over the years and suggests that the history of tick bite has an essential role as a risk factor of CCHF seropositivity (Fig. 4). The trend of the secretion exposure risk factor ranged from 18.5 to 34.0% exhibiting an increasing trend between 2009 and 2017, while the trend mean of seropositivity among secretion exposure groups ranged from 12.8 to 12.5% and remained approximately constant between 2009 and 2017. With consistency of the seropositivity, the importance of the secretion exposure risk factor of CCHF seropositivity has increased over the years (Fig. 4). The trend mean of the farming risk factor and seropositivity ranged between 58.5–0.1 and 48.0-0.1% and generally exhibited a decreasing trend between 2005 and 2016. With decreasd seropositivity among farming groups, the importance of the farming risk factor of CCHF seropositivity also has decreased over the years (Fig. 4). Some reported risk factors involved in CCHF seropositivity were categorized as a “miscellaneous group”. Some of the miscellaneous risk included animal tick adhesion, CCHF high-risk activity, traveling in endemic areas, hand or body contusions, those with knowledge about CCHF, and literacy level. Other factors in the miscellaneous group included livestock transportation, milking, improper (or non) use of personal protective equipment, time spent in rural areas and activity in forested areas. The trend of the miscellaneous risk factor ranged from 26.5 to 73.0% and generally exhibited an increasing trend between 2009 and 2017, while the trend mean of seropositivity among the miscellaneous group ranged from 11.0 to 7.5% and exhibited a slightly decreasing trend between 2009 and 2017. This result suggests with a slightly decreasing trend in the seropositivity among the miscellaneous group, the importance of miscellaneous risk factor for CCHF seropositivity increased over the years (Fig. 4).

Table 7 Mean CCHF seroprevalence (%) in humans and animals (calculated based on literature research in tables 1 and 4–6). Year

1969 1970 1971 1972 1973 1974 1975 1976 1978 1979 1981 1983 1984 1985 1987 1990 1995 1997 2000 2004 2005 2006 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 Total (Mean) Std. Deviation A/Ha a

Human

– – – – – 4.0 – – – – – – 4.0 – – – – 2.4 2.4 – – 2.4 – 7.3 6.3 5.6 8.7 2.8 5.0 0.1 7.5 6.9 4.4 4.7 2.4 –

Animal Camels

Cattle

Goats

Sheep

Livestock

Total (Mean)

– – 1.4 19.1 – 19.0 – – 8.8 – 23.2 – – – – 19.0 13.6 7.0 16.0 – – – – 40.0 – – – – – – – 21.3 – 17.1 10.1 3.6

14.1 8.1 11.9 47.7 33.2 4.2 5.1 5.6 – 0.6 29.3 14.0 – 26.5 28.0 – 46.0 4.1 4.0 – 37.0 – – 9.6 14.2 42.5 9.4 16.2 20.6 18.4 4.6 37.2 – 18.9 14.5 4.0

– – 6.4 40.8 37.2 9.0 18.2 16.1 – 6.2 49.6 – – – 45.0 – 4.9 21.8 14.0 11.1 – – 46.0 20.0 39.7

0.3 11.5 6.4 45.0 20.3 49.0 23.2 0.7 23.1 – 57.6 – – – – 10.4 3.0 19.2 3.0 37.1 20.0 76.6 77.5 12.6 50.7 75.0 34.7 58.7 34.3 – 10.9 2.0 – 29.3 24.9 6.2

– – – – – – – 5.2 – – – – – – – – 10.3 – – 18.1 – – 27.8 12.7 42.7 75.0 28.6 – 43.9 19.1 6.1 35.8 – 27.1 20.1 5.8

7.2 9.8 6.5 38.2 30.2 20.3 15.5 6.9 16.0 3.4 39.9 14.0 – 26.5 36.5 14.7 15.6 13.0 9.3 22.1 28.5 76.6 50.4 19.0 36.8 64.2 25.9 33.2 35.6 18.8 5.6 24.1 – 24.6 17.1 5.0

30.9 24.8 43.6 – 0.9 – 24.3 16.0 5.2

Total mean of animal CCHF seroprevalence divided by humans.

ranging between 15.0 and 35.0% (Fig. 3). The total trend mean of CCHF seroprevalence in camels, sheep and livestock generally exhibited an increasing trend over time, with the increases ranging between 10.0–27.0, 19.0–41.0 and 0.5–37.0 % for camels, sheep and livestock, respectively. The total trends of CCHF seroprevalence in cattle and goats exhibited a slightly increasing trend over time, with the increases ranging between 16.5–21.0 and 22.0–27.0 % for cattle and goats, respectively (Fig. 3). 3.8. Mean and trend of CCHF seropositivity involving risk factors

3.9. Correlation of seropositivity with CCHF seropositivity involving risk factors

The mean and trend of CCHF seropositivity involving risk factors were provided in Figs. 4 and 5 based on literature research in Table 3. The mean seropositivity among the most important risk factors involved in CCHF seropositivity were: animal contact (12.5%), animal husbandry (7.2%), farming (23.0%), history of tick bite (21.2%), housewife (30.8%), hunting (9.1%), miscellaneous (9.8%), secretion exposure (12.6%) and slaughtering (10.9%). The mean of the risk factors values involved in CCHF seropositivity were animal contact (32.5%), animal husbandry (47.4%), farming (29.2%), history of tick bite (45.2%), housewife (23.6%), hunting (16.8%), miscellaneous (44.6%), secretion exposure (29.6%) and slaughtering activities (21.1%) (Fig. 5A). The trend mean of the animal husbandry risk factor ranged from 62.5 to 32.0% and generally exhibited a decreasing trend over time.

The mean seropositivity among the most frequent risk factors involved in CCHF seropositivity including animal contact, animal husbandry, farming, history of tick bite, housewife, hunting, miscellaneous, secretion exposure and slaughtering activities had values ranging between 7.2 and 30.8% (Fig. 5A). The trends of animal contact, secretion exposure and miscellaneous risk factors of CCHF seropositivity generally exhibited an increasing trend which ranged between 20.0–45.0, 18.5–34.0 and 15.5–83.5 %, respectively, while the trends of history of tick bite, animal husbandry and farming risk factors of CCHF seropositivity exhibited a very slight increasing and decreasing trend ranged from 44.0 to 46.5, 62.75 to 32.0 and 58.0 to 0.5%, respectively (Fig. 5B). 110

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Table 8 Wilcoxon signed-ranks and Pearson correlation analyses on CCHF seroprevalence. Between seroprevalence of humans and animals Mean rank Negative Positive Z Asymp. Sig. (2-tailed)

Camels 0.001 3.0 −2.023a 0.043

Cattle 6.0 6.6 −2.589a 0.010

Goats 2.0 5.4 −2.429a 0.015

Sheep 3.0 6.8 −2.824a 0.005

Livestock 1.0 5.0 −2.380a 0.017

Between seroprevalence of human and animal regions Mean rank Camels Negative 8.8 Positive 3.3 Z −1.767b Asymp. Sig. (2-tailed) 0.077

Cattle 13.5 17.5 −0.619a 0.536

Goats 20.1 7.6 −4.176b 0.0001

Sheep 19.2 15.0 −2.710b 0.007

Livestock 11.1 4.0 −3.030b 0.002

Pearson correlation between seroprevalence of human and animals Humans Camels Mean 5.6 16.5 Std. Deviation 4.5 10.1 Pearson – −0.209 Sig. (2-tailed) – 0.493

Cattle 16.4 17.1 −0.176 0.343

Goats 25.2 23.7 0.091 0.602

Sheep 33.1 27.3 −0.053 0.747

Livestock 31.1 23.8 −0.302 0.208

Goats 3.5 2.1 −0.554** 0.001

Sheep 7.5 3.4 −0.128 0.439

Livestock 4.2 2.1 0.108 0.659

Pearson correlation between seroprevalence of human and animal regions Humans Camels Cattle Mean 10.6 5.8 12.6 Std. Deviation 6.1 3.1 9.2 ** Pearson – −0.748 0.072 Sig. (2-tailed) – 0.003 0.699

**Correlation is significant at the 0.01 level (2-tailed). a Based on negative ranks. b Based on positive ranks.

3.10. CCHF epidemiology, control and prevention aspects

vertebrates such as hedgehogs, rats, and hares may be particularly important as amplifying hosts after their infection by immature ticks. Birds and reptiles seem to be refractory to CCHFV infection with the exception of ostriches. The infection may emerge to novel areas or reemerge to endemic areas having mild winters that result in an increased tick population, and particularly in those areas experiencing disruption due to agricultural activities or transportation by tick-infested birds or animals. The CCHF virus can be spread to previously unaffected areas or from endemic to non-endemic areas by the legal or illegal animal trade (Gargili et al., 2017; Maltezou and Papa, 2011; Metanat et al., 2014; Papa et al., 2015a; Vorou, 2009; Whitehouse, 2004). There are several route of CCHFV transmission to humans. Various factors including behavioral, cultural and education are implicated in

The epidemiology of CCHF is very complicated. Various invertebrate ticks and several vertebrate animals are involved in the CCHF viral life cycle. The natural clades of CCHFV with diverse sequences circulate naturally in an enzootic tick-vertebrate-tick cycle, livestock and migrating birds. The clades maintain and transmit in vertical and horizontal transmission cycles involving a variety of domestic and wild vertebrates acting as amplification subclinical infected hosts. These subclinical infected vertebrates have traditionally been considered CCHFV reservoirs, but in fact they experience only a transient viremia for a few days. Many mammal species may transmit CCHFV to ticks after their infection with the viral agent. Small

Fig. 2. Trend means of CCHF seroprevalence in humans and animals (estimated based on literature research in Tables 1 and 4–6). 111

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Fig. 3. Total mean and trend mean of CCHF seroprevalence in humans and animals, and total mean for at-risk professionals and patients or patient related populations (estimated based on literature research in Tables 1–6).

CCHF disease acquisition (Papa et al., 2015a). Humans can be contaminated incidentally by infected tick bites, direct contact with blood or body fluids of an infected human or viremic animals, or via aerosol generated from infected human or rodents. Adult and immature ticks actively seeking hosts for blood meals required at each stage of maturation will be an important infection mechanism (Maltezou and Papa, 2011). Nosocomial transmission has been reported from various areas such as Iran, Iraq, Pakistan, South Africa and UAE. Appropriate infection-control measures, careful management of infected patients, and providing prophylactic treatments for health-care workers after exposure to infection can diminish risk of nosocomial transmission. CCHFV horizontal transmission from a mother to her offspring has also been reported. One of the most important risk factors for CCHF is history of tick bite. The jobs requiring some contact with animals and animal products including farming, livestock handling, livestock market employees, skin processors and veterinary staff are also at high risk for infecting CCHF (Alavi-Naini et al., 2006; Mardani and Pourkaveh, 2012; Metanat et al., 2014; Sharifi-Mood et al., 2008). The majority of human infections have occurred among people involved in the livestock industry including animal herders, butchers and slaughterhouse workers (Fazlalipour et al., 2016).

The clades of CCHFV circulate naturally in a wide range of tick species, but only a few have been proven to be vectors and reservoirs because species identification under a broad variety of conditions has been limited. The CCHFV can persist in the entire lifespan of the ticks transmitting vertically to the next generation. As a result, ticks are being considered the vector and the reservoir for the CCHFV (Champour et al., 2016; Gargili et al., 2017; Maltezou and Papa, 2011; Mehravaran et al., 2013; Tahmasebi et al., 2010). A variety of environmental factors play a role in tick abundance and survival (Papa et al., 2015b). It is well known that the species of Hyalomma genus ticks are the main vector of human CCHFV infection preferring arid-type vegetation and dry climates (Champour et al., 2016; Gargili et al., 2017; Maltezou and Papa, 2011; Mehravaran et al., 2013; Sedaghat et al., 2017; Široký et al., 2014; Tahmasebi et al., 2010). An increase in temperature and decrease in rainfall in the Mediterranean region probably have resulted in an expansion of suitable habitat for Hyalomma ticks northwards, with the greatest impact at the boundaries of their current range. CCHFV introduction to a non-endemic area may occur either through legal or illegal trade of infected animals or animals infested with infected ticks or through geographic expansion of CCHFV infected Hyalomma ticks from endemic to areas free of CCHF (Aradaib 112

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Fig. 4. Trend mean of CCHF seropositivity involving risk factors and their correlation with seropositivity.

CCHFV infection by other genera of ticks suggesting a potentially supportive role in CCHFV transmission (Fakoorziba et al., 2015). Isolation of CCHFV from infected ticks that have not previously been identified as vectors needs to be investigated through additional laboratory and epidemiological studies (Ergönül, 2006). It should be noted that several other criteria having to be met in order to be recognized an arthropod species as a vector, including natural bloodsucking of the suspected tick on humans or other hosts, survival of the CCHFV in the entire lifespan of the ticks, CCHFV detection in the vector and amplifying vertebrate host, the ability of the vector to transmit the virus by bite, and the vector abundance and survival (Fakoorziba et al., 2015). Travel to migratory bird habitats or tourism sites like wetlands that are natural tourism attractions with their unique biodiversity have been identified as risky places for transmission. Migratory birds can import and carry CCHFV infected ticks that may create a CCHF outbreak. Phylogenetical RNAs of Russian and European CCHFV strains are close to each other (Jameson et al., 2012; Leblebicioglu et al., 2014, 2015; Leblebicioglu et al., 2016b; Nasirian, 2013, 2014; Nasirian et al., 2015a; Nasirian and Irvine, 2017; Nasirian et al., 2016, 2013; Nasirian et al., 2015b, a; Nasirian et al., 2014b). Although the risk of CCHFVinfected ticks attached to migratory birds to reach the north of Spain seems to be low (Palomar et al., 2016), while substantial importation of CCHFV infected ticks into the United Kingdom by migratory birds seems to occur (Jameson et al., 2012). Among the arboviruses, the CCHF agent has the most genetically diverse structure with nucleotide sequence differences among isolates of the viral S and the M segments ranging from 20 to 31%, respectively. Interestingly, while CCHF viruses with diverse sequences have been observed within the same geographic territory, closely related CCHF viruses can be isolated in far distant regions. It can be concluded that the widespread dispersion of the CCHF virus has occurred over decades, possibly by the migratory birds carrying infected ticks or the trade of livestock internationally. Novel viruses are created by redistribution of CCHFV genome segments during co-infection of ticks or vertebrates. This redistribution plays an important role in generating CCHFV diversity and appears as a potential future source of CCHF (Maltezou and Papa, 2011). In comprehensive reviews Bente et al. (2013) and Metanat et al. (2014) described the detailed CCHF history, pathogenesis, clinical signs and syndrome, diagnosis, and treatment. Avoiding or minimizing exposure to the virus is the best preventative measure against the spread of CCHF disease. In particular,

Fig. 5. Mean and trend mean of CCHF seropositivity involving risk factors (estimated based on literature resources in Tables 3). A. Mean of risk factors. B. Trend mean of risk factors.

et al., 2011; Estrada-Pena and Venzal, 2007; Maltezou and Papa, 2011; Papa et al., 2010). In addition to the Hyalomma ticks, there are increasing reports of 113

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body protection is the best human precaution against CCHFV. Personal protective measures for people living in or traveling to endemic areas include the avoidance of areas where tick vectors are abundant particularly during their active period, regular examination of clothing, and skin to remove sticky ticks, and the use of repellents. Another way to prevent skin tick attachment is wearing long pants tucked into boots and long-sleeved shirts. CCHFV is usually killed or inactivated in meat after cooking at 56 °C for 30 min or acidifying post-slaughtering. Unpasteurized milk should not be drunk. Individuals in high-risk occupations such as animal husbandry and slaughterhouse workers, butchery staff, and veterinarians should take every precaution measure including use of gloves, gowns and faceshields, and limiting traditional slaughtering to avoid exposure to CCHFV infected ticks or fresh infected tissues or fluids of animals. Health-care workers have a serious risk of infection, particularly during care of patients with bleeding gums, injection sites, mouth, nose and vagina. Safety measures including standard barrier-nursing techniques and isolation, and the use of gowns, gloves, goggles and face-shields with side shields when in contact with patients or soiled environmental surfaces are recommended for protection of health-care workers. Laboratory staff must follow strict biosafety precautions. Negativepressure respiratory isolation should be instituted, particularly after the generation of large-droplet aerosols followed by the occurrence of coughing, vomiting or other activities. To prevent nosocomial infections, strict universal precautions are necessary (Bannazadeh Baghi and Aghazadeh, 2016; Ergönül, 2006; Fazlalipour et al., 2016; Metanat et al., 2014; Öncü, 2013; Whitehouse, 2004). As numerous human tick bite cases are commonly reported annually in CCHFV endemic regions during tick activity seasons, application of tick repellents on exposed skin or cloths and impregnating the cloths with permethrin are measures to avoid tick bites. In CCHF endemic areas, acaricides should be used on livestock and the other domestic animals to control ticks, particularly before slaughtering or export to another region (Chinikar et al., 2010; Metanat et al., 2014; Whitehouse, 2004). Climate factors can contribute to the expansion of tick infected areas and spread of CCHF from an endemic geographic range. Climate change, including increasingly frequent drought and warming in some countries have also caused increases in tick populations and consequently in CCHF cases (Chinikar et al., 2010; Dreshaj et al., 2016). Strategies like surveillance using standardized case definitions, and increasing laboratory capacity within already endemic areas and areas at risk for CCHF expansion should be enhanced. Human, vector, and veterinary surveillance of CCHF which are important aspects of the work of the laboratory of Arboviruses and Viral Hemorrhagic Fevers and country wide tick recording schemes should also be enhanced. The general and at-risk populations like high-risk occupations and healthcare workers should be aware of prophylactic measures and to reduce their risk for CCHFV infection. People in endemic regions must be informed about the CCHF transmission routes including raw fresh or under-cooked meat immediately after slaughtering (Chinikar et al., 2010; Dreshaj et al., 2016; Fazlalipour et al., 2016; Keshtkar-Jahromi et al., 2011; Maltezou et al., 2010; Maltezou and Papa, 2011; Maltezou et al., 2009). The above mentioned control and preventative measures are recommended to be undertaken as part of a multidisciplinary cooperation at national, regional and international levels especially in areas where CCHF is expected to occur. Guidelines for early prompt response interventions at patient, community, and hospital levels should be established and implemented. Laboratory capacities for CCHF rapid confirmation of suspected clinical cases should be increased (Dreshaj et al., 2016). To prevent CCHF among at risk populations, a focus on education to increase awareness levels has been effective (Chinikar et al., 2012b; Çİlİngİroğlu et al., 2010). Well trained and informed healthcare workers are essential to prevent, detect and take adequate measures for specific infectious diseases that present a threat to the general

population (Dreshaj et al., 2016). Healthcare workers must undergo regular refresher training to reinforce sound public health practices and understand new developments in the field (Leblebicioglu et al., 2016b). Early diagnosis of CCHF is critical both for patient survival and for the prevention of potential nosocomial infections and transmission in the community. Supportive therapy is also an essential part of case management (Ergönül, 2006; Spengler et al., 2016a). Currently, ribavirin is used in most endemic countries to treat CCHF and recent studies suggest that ribavirin can be effective (Ergönül, 2006). Although promising results were also reported by others, and were mainly associated with early treatment, the use of ribavirin for CCHF treatment remains an issue of controversy since no difference in case fatality rates was found in other studies. Almost all data about ribavirin efficacy are limited to small observational studies and case series, and questions about methodological issues have been raised. It can be concluded that current evidence is insufficient to provide a clear answer with respect to the efficacy of ribavirin (Soares-Weiser et al., 2010). Given the high fatality rates associated with CCHF, a well-designed multi-center, randomized controlled trial taking into account severity criteria, is urgently needed in order to provide evidence-based data about ribavirin efficacy (Maltezou and Papa, 2011). Overall, there are concerns about using inactivated suckling mouse brain vaccines because of possible autoimmune responses. CCHF is mainly confined to poor resource countries, and research has been extremely slow. Recently, the CCHFV strain which is used for vaccine preparation was genetically characterized, providing the basis for further studies. A humanized vaccine against CCHF is needed, however long-term field studies will be required to show efficacy (KeshtkarJahromi et al., 2011; Maltezou and Papa, 2011; Papa et al., 2011; Whitehouse, 2004). To design the best immunogenic vaccine against CCHFV, wide scale phylogenetic studies and worldwide close collaboration among researchers working on CCHF is also essential and will assist in achieving the goals of more effective treatment (Chinikar et al., 2010). 4. Discussion 4.1. Comparing the human CCHF seroprevalence with at-risk professionals and animals CCHF is the most widespread, tick-borne viral international disease affecting humans (Al-Abri et al., 2017). Globally CCHF seroprevalence values in at-risk professional populations are about 7.5 fold more than normal human populations (Tables 2 and 8), which explains why people in high-risk occupations are prone to CCHFV infection (Fakoorziba et al., 2012; Garcia et al., 2006; Gargili et al., 2011; Gunes et al., 2011). Some factors that increase the chance of CCHFV infection were found as follows: occupation in the agro-pastoral or animal husbandry fields; participation in animal breeding; contact with animal fresh flesh and blood; and removing ticks from animals. Geographic characteristics that affect risk include altitude, distance to rivers and slope angle of land, living in rural or hilly and highland areas (Cikman et al., 2016; Gergova and Kamarinchev, 2014; Koksal et al., 2014; Sargianou et al., 2013; Sidira et al., 2013; Tigoi et al., 2015; Xia et al., 2011; Ziapour et al., 2016). Numerous cases of human CCHF were associated with the above mentioned factors. Several significant results were obtained from statistical analysis by researchers including history of tick bite or contact [odds ratio (OR) 16.6, 95% confidence interval (CI) 7.5–37.0) and age > 30 years (OR 6.8, 95% CI 1.6–28.2)] (Xia et al., 2011); agro-pastoral occupation (P = 0.015), contact with sheep (P = < 0.001) and goats (P = 0.008); former tick bite (P = 0.001) ; increasing age (P = 0.018); and living at an altitude of ≥ 400 m (P = 0.001) (Sargianou et al., 2013). Others also have found history of tick bite (P = 0.040); residence in a hilly territory (P = 0.025); and increased age (P = 0.043) were significant (Sidira et al., 2013); as were animal husbandry [OR 1.8, 95% CI 1.1–3.1], 114

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contact with animals (OR 2.3, 95% CI 1.1–5.1), contact with ticks (OR 3.4, 95% CI 1.9–6.5), removing ticks from animals by hand (OR 2.5, 95% CI 1.5–4.2) and living in a rural area (OR 4.1, 95% CI 1.6–10.6) (Koksal et al., 2014). Livestock breeding (P = 0.026) and age of > 50 years (P < 0.001) were reported by Gergova and Kamarinchev (2014) as significant (Gergova and Kamarinchev, 2014), while contact with goats (OR = 3.4, 95% CI 1.7–6.8) (Tigoi et al., 2015); geographic characteristics (P < 0.05) (Cikman et al., 2016); slaughtering activities, contact with fresh flesh and blood of livestock (OR = 3.4, 95% CI 1.7–6.5) and lack of protective clothing in highland areas (OR = 9.2, CI 95%: 2.7–32.1) were found significant by Ziapour et al. (2016). Although several cases of contact transmission associated with caring for sick patients have been documented (Nurmakhanov et al., 2015) the typical route of infection was via tick-bite. Enzootic infections, outbreaks and sporadic small clusters of CCHF cases occur in humans following direct bites of infected ticks, which are competent reservoirs, or via dermal contact with virus-contaminated tissues, blood, or other body fluids of patients or infected domestic ruminants such as cattle, sheep, and goats (Fakoorziba et al., 2012). Wild and domestic animals infected with CCHFV develop a brief viremia, but do not become clinically ill and also do not present symptoms (Papa et al., 2009). These animals provide blood meals for large numbers of ticks and serve as amplifying hosts (Spengler et al., 2016b) and this association may be revealed by the absence of a significant correlation between seroprevalence in humans and animals (P > 0.05) (Table 8). Viremia is rarely detected in birds, but they may transport CCHFV-infected ticks across wide areas (Spengler et al., 2016b). Among risk factors involved in CCHF seropositivity, animal contact, animal husbandry, farming, history of tick bite, housewife, hunting, secretion exposure and slaughtering were the most frequent risk factors (Table 3). It seems that the history of tick bite, animal contact and animal husbandry with respective values of 45.2, 35.2 and 47.7% have the greatest impact on CCHF seropositivity (Fig. 5A). Age, breed, locality and tick control are considered as risk factors for influencing CCHF seroprevalence in animals (Lotfollahzadeh et al., 2011; Mostafavi et al., 2012; Suliman et al., 2017). Logistic regression analysis showed that a 1-year increase in the age of a sheep increased the risk of infection by 2.7 times (OR 2.7; 95% CI 1.5, 4.9; P < 0.001). Others have found the probability of infection significantly increases with increasing age (Mohamed et al., 2008; Mostafavi et al., 2012; Wilson et al., 1990). Regional seroprevalence rates seemed to correlate with cattle density (Maiga et al., 2017). Globally, the CCHF seroprevalence means and trends in animal populations especially camel, cattle, goat, sheep and livestock are about 5.0 fold more than normal human populations (Table 7 and Fig. 2). A difference was revealed between the seroprevalence of humans, and camels (P = 0.043), cattle (P = 0.010), goats (P = 0.015), sheep (P = 0.005) and livestock (P = 0.017), and between the seroprevalence of humans, and goats (P = 0.0001), sheep (P = 0.007) and livestock (P = 0.002), by region through the statistical analysis of the Wilcoxon signed-ranks test (Table 8). These findings are in accordance with the results of previous studies such as Mustafa et al. (2011); Ertugrul et al. (2012) and Bodur et al. (2012). They were concluded daily contact with cattle (12.5% vs. 1.8%, χ2 = 5.1, P = 0.02) and exposure to raw animal skins (16.7% vs. 6.8%, χ2 = 7.7, P = 0.006) were the factors which were associated with an elevated risk of IgG positivity (Mustafa et al., 2011). A significant relationship between IgG seropositivity and tickbite (P < 0.001) was also found (Ertugrul et al., 2012). Seropositivity increased with age (P < 0.001), insufficient education (P < 0.001), farming (P < 0.001) and higher tick bite frequency (P < 0.001) (Bodur et al., 2012). However, standard hand disinfectants had a significant role in decreasing CCHF IgG seropositivity (OR = 0.2, P = 0.004) (Shahhosseini et al., 2018).

4.2. Comparing the trend of human CCHF seroprevalence with animals CCHF is maintained in nature through a tick-vertebrate-tick enzootic cycle (Spengler et al., 2016b). Similar to the trend in animals including camels, cattle, goats, sheep and livestock, the trend of CCHF seroprevalence of humans exhibits an increasing trend during recent decades (Figs. 2 and 3). These results are in accordance with the increasing the incidence of CCHF reported globally (Al-Abri et al., 2017). 4.3. Correlation of CCHF seropositivity involving risk factors with seropositivity The trend mean for animal contact, history of tick bite, secretion exposure and miscellaneous risk factors generally is positive while the trend mean of animal husbandry and farming risk factors generally exhibit a negative (or decreasing) trend. The trend mean of seropositivity exhibits an increasing trend among animal husbandry group, remain approximately constant among animal contact and secretion exposure groups, and a decrease among history of tick bite, miscellaneous and farming groups (Fig. 4). These results suggest that with increasing the seropositivity among animal husbandry group, the importance of the animal husbandry risk factor of CCHF seropositivity has decreased. Also with consistency of the seropositivity among animal contact and secretion exposure groups, the involvement of animal contact and secretion exposure risk factors of CCHF seropositivity increases. Again with decreasing the seropositivity among history of tick bite and miscellaneous groups, the involvement of history of tick bite and miscellaneous risk factors of CCHF seropositivity increases or remains constant for history of tick bite. Finally with decreasing the seropositivity among the farming groups, the involvement of farming risk factor of CCHF seropositivity also decreases over the years (Fig. 4). These valuable results suggest that human preventive measures in animal husbandry and farming have been successful, which reduces the importance of animal husbandry and farming as risk factors over the years. By training, forecasting and planning, we will also increase the effectiveness and achieve more success in farming preventative measures. In spite of consistency of the seropositivity, the involvement of animal contact and secretion exposure risk factors increase over the years (Fig. 4). It can be concluded that the history of tick bite has an essential role in involvement as a risk factor of CCHF seropositivity. These above findings are in agreement with the results of previous studies done by Gunes et al. (2009) and Izadi et al. (2006). The factors including history of tick bite (P = 0.002) or tick removal from the animals (P = 0.03), animal husbandry employment (P = 0.01) or farming (P = 0.02), keeping livestock at homes (P = 0.018) and age > 40 years (P < 0.001) were significantly associated with CCHF seropositivity (Gunes et al., 2009; Izadi et al., 2006). Another study also showed that age, location, and contact with donkeys was significantly associated with exposure to CCHFV (Lwande et al., 2012). Age (OR = 3.6, CI = 1.7–7.8, P-value = 0.026); locality (OR = 5.8, CI = 1.8–18.8, P- value = 0.003), tick number (OR = 4.6, CI = 1.4–9.8, P-value 0.04); tick control (OR = 2.2, CI, 1.1–4.4, Pvalue = 0.023) and livestock breeding (OR = 6.6, CI = 2.4–18.4, Pvalue = 0.001) were recorded as risk factors for contracting CCHF (Suliman et al., 2017). Several techniques have been used to measure the seroprevalence of CCHF including gel diffusion precipitation (AGDP), complement fixation (CF), enzyme linked immunosorbent assay (ELISA), immunofluorescence assay (IFA), reverse passive hemagglutination inhibition (RPHI) assay and virus neutralization assay (Spengler et al., 2016a). In general, the AGDP, virus neutralization, RPHI and CF are less commonly used analytical techniques (Spengler et al., 2016a; Tuncer et al.,

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2014) while IFA assay is used somewhat more frequently (Gergova and Kamarinchev, 2013; Mariner et al., 1995; Nemeth et al., 2013; Spengler et al., 2016a). The ELISA analytical methods (indirect or sandwich enzyme-linked immunoassays) tend to be the most commonly used in the reported literature (Albayrak et al., 2012; Andriamandimby et al., 2011; Bayram et al., 2017; Chinikar et al., 2008, 2012a; Chinikar et al., 2012b, c; Greiner et al., 2016; Lwande et al., 2012; Memish et al., 2011; Mostafavi et al., 2013a, 2012; Mostafavi et al., 2017; Muianga et al., 2017; Mustafa et al., 2011; Papa et al., 2016; Sadeuh-Mba et al., 2018; Sun et al., 2009; Xia et al., 2011). There are no data available to show that the analytical technique might impact the reported and this should be acknowledged in conducting such meta-analysis as is done here. To understand many new aspects of vertebrate involvement in the maintenance and spread of CCHFV and identify gaps in knowledge in a variety of wild and domestic animals (Spengler et al., 2016b), new experimental investigations through artificial feeding (Nasirian and Ladonni, 2006; Nasirian et al., 2008) are needed.

factors involved in CCHF seropositivity, animal contact, animal husbandry, farming, history of tick bite, housewife, hunting, miscellaneous, secretion exposure and slaughtering were the most frequent risk factors involved in CCHF seropositivity. Globally, the trend mean in seropositivity and risk factors involving CCHF seropositivity exhibit a slightly decreasing trend, suggesting that the seropositivity correlates with the risk factors involving CCHF seropositivity. Globally, the CCHF seroprevalence means and trends in animal populations especially camels, cattle, goats, sheep and livestock are about 5.0 fold more than normal human populations. These differences between seroprevalence of humans and animals are significant: vs camels (P = 0.043), cattle (P = 0.010), goats (P = 0.015), sheep (P = 0.005) and livestock (P = 0.017). The epidemiology of CCHF is very complicated. Various invertebrate ticks and several vertebrate animals are involved in the CCHF viral life cycle. So the control and prevention of CCHF disease is often difficult, because it requires the disruption of a complex transmission chain, involving vertebrate amplifying hosts and ticks as a reservoir and vector, which interact in a constantly changing environment.

4.4. CCHF epidemiology, control and prevention aspects Like cockroaches, leishmaniosis, myiasis, pediculosis and scabies (Davari et al., 2017b; Gholamian-Shahabad et al., 2018; Martínez-Girón et al., 2017; Nasirian, 2010, 2016, 2017a, b; Nasirian, 2019; Nasirian and Salehzadeh, 2019; Poudat and Nasirian, 2007; Schapheer et al., 2018; Soleimani-Ahmadi et al., 2009), tick-borne diseases threaten human health. The epidemiology of CCHF is very complicated. Various invertebrate ticks and several vertebrate animals are involved in the CCHF viral life cycle (Papa et al., 2015b). Many factors contribute to the emergence of CCHF and these factors have complex relationships with each other, which in turn affects both the emergence and the spread of the disease. When all these factors are evaluated, environmental and climate change and wild birds seem to have played key roles in the dissemination of the disease, while uncontrolled animal movements may have played a role in the spread within the country and to neighboring countries (Leblebicioglu et al., 2016b). In addition to the constraints related to their diagnosis and clinical management, the control and prevention of CCHF disease is often difficult, because it requires the disruption of a complex transmission chain, involving vertebrate amplifying hosts and ticks as a reservoir and vector, which interact in a constantly changing environment (Dantas-Torres et al., 2012). It is clear that control of tick populations in endemic regions will play an important role in reduction of CCHF incidence (Chinikar et al., 2010). Avoiding or minimizing exposure to the virus is the best form of prevention of CCHF disease, with body protection being the best way to safeguard humans against CCHF (Fazlalipour et al., 2016; Whitehouse, 2004). Although extensive studies have been conducted about CCHF epidemiology, there are many different aspects that affect the CCHF epidemiology which still remain unknown and more research is needed to fill in gaps in our understanding of CCHF epidemiology.

Conflict of interest The author declare no conflict of interest. Acknowledgments This work did not receive any technical or financial support from any institution and was done by the author at his own personal expense. Thanks to Professor K.N. Irvine, Nanyang Technological University, Singapore, for assistance in editing the manuscript. References Abbas, T., Younus, M., Muhammad, S.A., 2015. Spatial cluster analysis of human cases of Crimean Congo hemorrhagic fever reported in Pakistan. Infect. Dis. Poverty 4, 9. Adam, I.A., Mahmoud, M.A., Aradaib, I.E., 2013. A seroepidemiological survey of Crimean Congo hemorrhagic fever among Cattle in North Kordufan state, Sudan. Virol. J. 10, 178. Adams, M.J., Lefkowitz, E.J., King, A.M.Q., Harrach, B., Harrison, R.L., Knowles, N.J., Kropinski, A.M., Krupovic, M., Kuhn, J.H., Mushegian, A.R., Nibert, M., Sabanadzovic, S., Sanfacon, H., Siddell, S.G., Simmonds, P., Varsani, A., Zerbini, F.M., Gorbalenya, A.E., Davison, A.J., 2017. Changes to taxonomy and the international code of virus classification and nomenclature ratified by the international committee on taxonomy of viruses (2017). Arch. Virol. 162, 2505–2538. Akuffo, R., Brandful, J., Zayed, A., Adjei, A., Watany, N., Fahmy, N., Hughes, R., Doman, B., Voegborlo, S., Aziati, D., 2016. Crimean-Congo hemorrhagic fever virus in livestock ticks and animal handler seroprevalence at an abattoir in Ghana. BMC Infect. Dis. 16, 324. Al-Abri, S.S., Abaidani, I.A., Fazlalipour, M., Mostafavi, E., Leblebicioglu, H., Pshenichnaya, N., Memish, Z.A., Hewson, R., Petersen, E., Mala, P., Nhu Nguyen, T.M., Rahman Malik, M., Formenty, P., Jeffries, R., 2017. Current status of CrimeanCongo haemorrhagic fever in the World Health Organization Eastern Mediterranean region: issues, challenges, and future directions. Int. J. Infect. Dis. 58, 82–89. Al-Nakib, W., Lloyd, G., El-Mekki, A., Platt, G., Beeson, A., Southee, T., 1984. Preliminary report on arbovirus-antibody prevalence among patients in Kuwait: evidence of Congo/Crimean virus infection. Trans. R. Soc. Trop. Med. Hyg. 78, 474–476. Al-Yabis, A., Al-Thamery, A., Hasony, H., 2005. Seroepidemiology of Crimean-Congo haemorrhagic fever in rural community of Basrah. Med. J. Basrah. Univ. 23, 30–35. Alavi-Naini, R., Moghtaderi, A., Koohpayeh, H.-R., Sharifi-Mood, B., Naderi, M., Metanat, M., Izadi, M., 2006. Crimean-Congo hemorrhagic fever in Southeast of Iran. J. Infect. 52, 378–382. Albayrak, H., Ozan, E., Kurt, M., 2012. Serosurvey and molecular detection of CrimeanCongo hemorrhagic fever virus (CCHFV) in northern Turkey. Trop. Anim. Health Prod. 44, 1667–1671. Andriamandimby, S.F., Marianneau, P., Rafisandratantsoa, J.T., Rollin, P.E., Heraud, J.M., Tordo, N., Reynes, J.-M., 2011. Crimean-Congo hemorrhagic fever serosurvey in at-risk professionals, Madagascar, 2008 and 2009. J. Clin. Virol. 52, 370–372. Ansari, H., Mansournia, M.A., Izadi, S., Zeinali, M., Mahmoodi, M., Holakouie-Naieni, K., 2015. Predicting CCHF incidence and its related factors using time-series analysis in the southeast of Iran: comparison of SARIMA and Markov switching models. Epidemiol. Infect. 143, 839–850. Ansari, H., Shahbaz, B., Izadi, S., Zeinali, M., Tabatabaee, S.M., Mahmoodi, M., Holakouie-Naieni, K., Mansournia, M.A., 2014. Crimean-Congo hemorrhagic fever and its relationship with climate factors in southeast Iran: A 13-year experience. J. Infect. Dev. 8, 749–757. Aradaib, I.E., Erickson, B.R., Karsany, M.S., Khristova, M.L., Elageb, R.M., Mohamed, M.E., Nichol, S.T., 2011. Multiple Crimean-Congo hemorrhagic fever virus strains are associated with disease outbreaks in Sudan, 2008-2009. PLoS Negl. Trop. Dis. 5,

5. Conclusion CCHF is a virulent tick-borne viral zoonotic disease caused by CCHFV. The virus circulates in nature in an enzootic tick-vertebratetick cycle. A variety of domestic and wild animals provide asymptomatic hosts of CCHFV in an endemic CCHF cycle of transmission, critical to feeding ticks that are aiding in the transmission cycle to a new populations of ticks. The principal source of information and key to monitoring and elucidating areas with natural CCHF transmission and reservoirs are seroepidemiological, serosurveillance or serosurvey studies. Reports of detailed serosurveys have been published by several groups but they suffer from a focus that is too local and often highly variable. There is a lack of a comprehensive global overview and hence the need for the meta-analysis provided here. Globally, CCHF seroprevalence in at-risk professional populations are about 7.5 fold more than normal human populations. Among risk 116

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