Crimean-Congo hemorrhagic fever virus in Central, Eastern, and South-eastern Asia

Abstract

Crimean-Congo hemorrhagic fever (CCHF), caused by Crimean-Congo hemorrhagic fever virus (CCHFV), is endemic in Africa, Asia, and Europe, but CCHF epidemiology and epizootiology is only rudimentarily defined for most regions. Here we summarize what is known about CCHF in Central, Eastern, and South-eastern Asia. Searching multiple international and country-specific databases using a One Health approach, we defined disease risk and burden through identification of CCHF cases, anti-CCHFV antibody prevalence, and CCHFV isolation from vector ticks. We identified 2313 CCHF cases that occurred in 1944–2021 in the three examined regions. Central Asian countries reported the majority of cases (2,026). In Eastern Asia, China was the only country that reported CCHF cases (287). In South-eastern Asia, no cases were reported. Next, we leveraged our previously established classification scheme to assign countries to five CCHF evidence levels. Six countries (China, Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, and Uzbekistan) were assigned to level 1 or level 2 based on CCHF case reports and the maturity of the countries’ surveillance systems. Two countries (Mongolia and Myanmar) were assigned to level 3 due to evidence of CCHFV circulation in the absence of reported CCHF cases. Thirteen countries in Eastern and South-eastern Asia were categorized in levels 4 and 5 based on prevalence of CCHFV vector ticks. Collectively, this paper describes the past and present status of CCHF reporting to inform international and local public-health agencies to strengthen or establish CCHFV surveillance systems and address shortcomings.

Highlights

• •CCHF is endemic in Africa, Asia, and Europe, but the disease's epidemiology and epizootiology is only rudimentarily defined.
• •We identified 2313 cases of CCHF that occurred from 1944 to 2021 in Central, Eastern, and South-eastern Asia.
• •We identified six countries with clear evidence of occasional or frequent outbreaks; two countries with likely circulation of CCHFV; and thirteen countries in which CCHFVs vector tick is present.

1. Introduction

Crimean-Congo hemorrhagic fever (CCHF; ICD-11: 1D49 (World Health Organization International Classification of Diseases 11th Revision, 2022) is a tick-borne viral disease occurring across Africa, Asia, and Europe (Hoogstraal, 1979; Ergonul and Whitehouse, 2007; Pigott et al., 2017; Blair et al., 2019; Belobo et al., 2021; Temur et al., 2021). Crimean-Congo hemorrhagic fever virus (CCHFV), the etiologic agent of CCHF (Simpson et al., 1967; Woodall et al., 1967; Woodall, 2007), is a negarnaviricot bunyaviral classified as an orthonairovirus in family Nairoviridae (Garrison et al., 2020; Kuhn et al., 2021). Although likely encountered for many centuries (جرجانی ,1391; Миндерер, 1825; Салаев, 1825; Ходукин, 1952; 付滨等, 2007; Mozafari et al., 2016), CCHF was first systematically described after a 1944–45 outbreak among Soviet military personnel on the Soviet Crimean peninsula (Соколов и др., 1945). During the past decade, the number of CCHF cases (as well as the associated case fatality rate) appears to have increased (Nasirian, 2020). During the last two decades, emergence or reemergence has occurred in several countries, including Greece (2008), Georgia (2009), Spain (2016), and Turkey (2002) (Blair et al., 2019; Belobo et al., 2021; Fanelli and Buonavoglia, 2021). Southern (Afghanistan, Iran, and Pakistan) and Western Asian countries (Iraq and Turkey) consistently report the highest numbers among global cases (Blair et al., 2019; Belobo et al., 2021).

CCHFV is primarily transmitted to vertebrates, including humans, by ixodid ticks predominantly classified in genus Hyalomma. Among them, Hyalomma marginatum, H. turanicum, and H. rufipes ticks are the most prevalent CCHFV vectors (Hoogstraal, 1979; Nasirian, 2020; Okely et al., 2020). Conditions in which ticks multiply lead to more tick bites and, consequently, the emergence or sustained circulation of CCHFV. Human tick bites are the primary mode of CCHFV transmission (Chapman et al., 1991; Vonesch et al., 2019). Domestic animals, including sheep and cattle, can also be infected with CCHFV by ticks; these animals have transient viremia without signs of disease. Thus, unprotected human exposure to viremic animals, especially among, for instance, abattoir workers, may lead to CCHFV transmission (Williams et al., 2000; Keshtkar-Jahromi et al., 2013; Mostafavi et al., 2017; Kasi et al., 2020). Furthermore, human-to-human transmission has been observed in medical staff exposed to CCHFV through aerosols or body fluids (Whitehouse, 2004; Mardani et al., 2007, 2009; Celikbas et al., 2014). Therefore, CCHF outbreaks are dependent on tick distribution as well as human and animal exposure to CCHFV.

The majority of CCHFV infections is asymptomatic or cause mild clinical signs. Clinical symptoms/signs may be nonspecific for mild cases, including headaches, myalgia, joint pain, fever, nausea, and vomiting. Rare severe cases may present with sudden-onset bruising and bleeding at injection sites. The disease can be fatal within days of onset (Schwarz et al., 1997; Ergonul, 2007; Al-Abri et al., 2019; Tripathi et al., 2020). The case-fatality rate of CCHF (5–80%) is affected by several factors, such as age, pre-existing medical conditions, availability of supportive care, virus strain, and route of transmission (Leblebicioglu, 2010; Tezer et al., 2010; Akuffo et al., 2016).

The World Health Organization (WHO) includes CCHF as a Blueprint priority disease, i.e., as a disease to be prioritized in research and development in public health emergency contexts (World Health Organization, 2020). This article is the third of our publication series on global CCHFV distribution to inform assessments of CCHF epidemiology, disease burden, and need for further investigation (Blair et al., 2019; Temur et al., 2021). Central, Eastern, and South-eastern Asia were selected for this article due to a lack of organized published CCHF-relevant data for these geographical regions.

2. Methods

2.1. Database searching and criteria

We used the United Nations geoscheme for (current) country inclusion in literature searches: Central Asia—Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, and Uzbekistan; Eastern Asia—China, Democratic People's Republic of Korea, Japan, Mongolia, and Republic of Korea; and South-eastern Asia—Brunei Darussalam, Cambodia, Indonesia, Lao People's Democratic Republic, Malaysia, Myanmar, Philippines, Singapore, Thailand, East Timor, and Viet Nam (United Nations Statistics Division, 2020). We first searched Embase, GIDEON, Google Scholar, ProMED, PubMed, Scopus, and Web of Science to collect and review scientific literature for any evidence of CCHFV endemicity in Central, Eastern, and South-eastern Asia (1944–July 2022), followed by searches using country- and/or language-specific databases of national societies and/or libraries and publishers. In addition, if indexed, information was obtained from conference presentations. Also considered were unpublished data obtained through personal communications with public-health authorities and experts (Table 1). Search terms, used in Boolean combinations, included “CCHFV”, “CCHF”, “CHF”, “Crimean”, “Crimean-Congo”, “Congo-Crimean”, “Congo virus”, “Crimean hemorrhagic fever”, “Nairoviridae”, “nairovirus”, and “orthonairovirus” or their non-English cognates with the names of each of the countries (or their predecessor names). We specifically retrieved studies on CCHF cases, CCHFV-specific serological analyses of human and animal samples, data on CCHFV isolation from ticks, and information on established CCHFV surveillance systems. For documentation of CCHFV vector prevalence, we considered Hyalomma ticks, with specific attention to H. marginatum, H. turanicum, and H. rufipes ticks in light of their ability to transmit CCHFV transstadially, transovarianally, and to vertebrates (Okely et al., 2020). Manuscripts were reviewed and included independent of publication language; referenced manuscripts are cited in the original language to the best of our abilities to aid the interested reader with retrieval.

Table 1.

Summary of unpublished data on CCHFV circulation and CCHF cases obtained by personal communications.

Country	Unpublished Data
Indonesia	Nothing reported.
Japan	Nothing reported.
Kyrgyzstan	I. Fifteen confirmed CCHF cases were reported (2018–2021).
	II. An ELISA test revealed CCHFV Antigen in 2 out of 218 collected ticks (2021).
	III. CCHFV was detected in ticks by PCR (1980s).
	IV. Due to insufficient laboratory capabilities in this country, regular CCHF identification is impossible.
Singapore	Nothing reported.
Tajikistan	I. The Tajik Research Institute of Preventive Medicine (TRIPM) has been the lead institute for CCHF surveillance since 1944.
	II. From 1998 to 2009, 18 districts in southern Tajikistan recorded CCHF cases; this number increased to 32 districts by 2020.
	III. Newly reported districts are located near previously affected districts.
	IV. A total of 81 CCHF patients died (1944 and 2020).
Thailand	Nothing reported.
Turkmenistan	I. Per communications with the Turkmen Ministry of Health officials, CCHFV is listed as a monitored pathogen, but official situations reports are unavailable.
Uzbekistan	I. The Republican Specialized Center for Scientific and Practical Medicine of Epidemiology, Microbiology, Infectious and Parasitic Diseases (Республика ихтисослаштирилган эпидемиология, микробиология, юқумли ва паразитар касалликлар илмий-амалий тиббиëт маркази) maintains a CCHFV surveillance system through the country.

2.2. Classification standard for dividing investigated countries to five levels

Our team developed and applied a One Health country-level CCHFV evidence classification scheme in two previous articles (Blair et al., 2019; Temur et al., 2021). This classification system combines vector, animal, human, and virus data to identify CCHFV circulation within regions. Countries are classified as follows: level 1—CCHF cases have been reported annually regularly via an established surveillance system; level 2—CCHF cases have been reported intermittently in the absence of a surveillance system; level 3—no CCHF cases have been reported and no surveillance has been implemented, but available data point toward the possibility of unreported cases of CCHF (animal/human serology or CCHFV detected in Hyalomma ticks); level 4—no CCHF cases have been reported, no surveillance has been implemented, no epidemiologic/epizootiologic studies have been done, but Hyalomma ticks are present; and level 5—no data are available.

For this study, we classified countries of Central, Eastern, and South-eastern Asia into the classification system based on the evidence acquired. (Note that we were unable to establish a category for countries that reported negative results due to the relatively small number of such reports and publications.)

3. Results

3.1. CCHF cases and CCHFV detection

3.1.1. Central Asia

The first CCHF cases that were unambiguously described clinically occurred in the 1930s and 1940s in Central Asia (Иоффе, 1944; Сиповский, 1944; Миxайлов, 1946; Ходукин, 1952; Шапиро and Баркаган, 1960). The disease was often referred to under the umbrella term “Central Asian hemorrhagic fever” (“Среднеазиатская геморрагическая лихорадка”), various local terms, such as “Uzbekistan hemorrhagic fever” (“Узбекистанская геморрагическая лихорадка”), or less-specific terms, including “acute infectious capillarotoxicosis” (“острый инфекционный капилляротоксикоз”) (Gajdusek, 1962).

3.1.1.1. Kazakhstan

In the Kazakh Soviet Socialist Republic (Kazakh SSR, today's Kazakhstan), the first reported cases of CCHF were recorded in 1948 during an outbreak in the areas of Maktaaral and Keles, South Kazakhstan Region (later Chimkent Region; today's Turkistan Region) (Рыбалко и др., 1963; Добрица, 1965; Nurmakhanov et al., 2015). Kazakhstan has both ongoing historical CCHF experience (Реформатская и др., 1965; Nurmakhanov et al., 2015; Укибаева т.б., 2021) and an established surveillance system. In 1965, upon establishment of central records, a retrospective analysis was conducted to identify probable human CCHF cases that met a newly established definition (Nurmakhanov et al., 2015; Укибаева т.б., 2021). A total of 801 CCHF human cases (101 deaths) were identified as having occurred from 1948 through the end of 2021 (Table 2). Kazakhstan's knowledge of CCHFV is exemplified by numerous publications on human serology, animal serology, and virus isolation from ticks spanning 70 years (Table 3). Surveillance of CCHFV is guided by The Committee for Sanitary and Epidemiological Surveillance of the Ministry of Health (Қазақстан Республикасының Денсаулық сақтау министрлігінің Санитариялық-эпидемиологиялық бақылау комитеті). Local hospitals use algorithms to identify, manage, and report CCHF cases; patients are isolated to prevent nosocomial spread. Diagnosis is confirmed via laboratory tests on pre-acute and acute clinical specimens, in addition to recording symptoms of patients, medical and epidemiological history, and physical examination results. Laboratory data include nonspecific and specific tests. Nonspecific tests include complete blood count, urinalysis, coagulation markers, blood chemistry, and fecal occult blood test. Specific tests include complement fixation-based tests and, more recently, enzyme-linked immunosorbent assay (ELISA) and molecular diagnostics (including real-time reverse transcription polymerase chain reaction [RT-qPCR] and conventional RT-PCR) (Объединенная комиссия по качеству медицинских услуг министерства здравоохранения PK). CCHF cases occur seasonally in Kazakhstan, peaking April–June (Nurmakhanov et al., 2015). Almaty, Guryev/Atyrau, South Kazakhstan/Chimkent/Turkistan, Kzyl-Orda/Kyzylorda, and Zhambyl/Jambyl Regions are CCHFV-endemic areas associated with multiple outbreaks (Смирнова и др., 1972; Hoogstraal, 1979; Дерновой и др., 1996; Дурумбетов и др., 2001; Yegemberdiyeva and Tuleuov, 2006; Егембердиева and Шерметова, 2008; Абуова и др., 2012; RK-NCPH, 2020; International Society for Infectious Diseases, 2021). Increased tick populations and/or increased human exposure to ticks have been identified as the major risk factor associated with CCHFV infections (Knust et al., 2012; Head et al., 2020). Mitigation efforts have included tick-bite prevention education for at-risk workers (sheep-shearers in endemic areas) and encouraging people to seek medical help for appropriate tick removal (Head et al., 2018). Statistics show that 1135 people sought medical advice in Kyzylorda Region after being bitten by ticks in 2012, compared to 188 in 2007 (Nurmakhanov et al., 2015), suggesting that public-education campaigns are increasingly effective.

Table 2.

Total confirmed CCHF cases in Central Asia (1944–2021).

Country	Total confirmed cases	Total deaths	Year (s)	References
Kazakhstan	801	101	1948–2021	(Добрица, 1965; Чун-Сюн and Генис, 1965; Yegemberdiyeva and Tuleuov, 2006; Егембердиева и Шерметова, 2008; International Society for Infectious Diseases, 2014a, b, 2015; Nurmakhanov et al., 2015; Head et al., 2018; Abdiyeva et al., 2019; KTK, 2019; Турлиев и Усатаева, 2019; International Society for Infectious Diseases, 2020; RK-NCPH, 2020; International Society for Infectious Diseases, 2021)
Kyrgyzstan	19	NA	1948, 1951, 1953, 2018–21	(Прорешная, 1955; Hoogstraal, 1979)a
Tajikistan	527	81a	1944–2020	(Tishkova et al., 2012; Atkinson et al., 2013; Ince et al., 2014)a
Turkmenistan	14	10	1944, 1946	(Миxайлов, 1946; Hoogstraal, 1979)
Uzbekistan	665	66	1944–83, 1998–2007, 2001–4, 2013–15, 2017–18	(Ходукин, 1952; Мусабаев, 1961; Мусабаев и др., 1962; Мелиев, 1967; Kadyrov et al., 2007; Комілов та ін., 2009b; Комилов, 2010; Бутенко и Трусова, 2013; Ermakova et al., 2020)
Total	2026	258	1944–2021

Note: Total deaths are those among confirmed cases only. Therefore, fatality rate was not calculated. We were limited to available data, but this approach likely underestimates the true CCHF burden.

^aData collected by personal communication.

Table 3.

Evidence for CCHFV circulation in Central Asia (1944–2021).

Country	CCHF cases reported (year)	Human serology (year)	Animal serology (year)	Hyalomma ticks existence	CCHFV detected in ticks (year)	Level of evidence
Kazakhstan	1948–2013 (Nurmakhanov et al., 2015),	1955 (Чумаков и др., 1964), 1964–68 (Генис и др., 1971), 1973–74 (Hoogstraal, 1979), 1974 (Hoogstraal, 1979), 2014–15 (Abdiyeva et al., 2019), 2017 (Head et al., 2020), 2018 (Head et al., 2018)	1964 (Чун-Сюн и Генис, 1965), 1968 (Hoogstraal, 1979), 1964–68 (Генис и др., 1971), 1973–74 (Hoogstraal, 1979), 1974 (Каримов и др., 1975), 2017 (Bryant-Genevier et al., 2022)	Yes (Померанцев, 1950)	1946 (Чумаков, 1974), 1970–72 (Згурская и др., 1972), 1971 (Смирнова и др., 1971b), 1972 (Смирнова и др., 1972), 1971 (Семашко и др., 1975), 1973 (Семашко и др., 1975), 2001–2 (Онищенко и др., 2005), 2001 (Yashina et al., 2003), 2002 (Онищенко и др., 2005), 2015 (International Society for Infectious Diseases, 2015), 2018 (Head et al., 2018), 2009–18 (Турлиев и Усатаева, 2019)	1
	2014 (International Society for Infectious Diseases, 2014b, International Society for Infectious Diseases, 2014a),
	2015 (International Society for Infectious Diseases, 2015), 2014–15 (Abdiyeva et al., 2019),
	2016–18 (Турлиев и Усатаева, 2019),
	2018 (Head et al., 2018),
	2019 (КТК, 2019; International Society for Infectious Diseases, 2020),
	2020 (International Society for Infectious Diseases, 2020; RK-NCPH, 2020)
	2021 (International Society for Infectious Diseases, 2021)
Kyrgyzstan	1948, 1951, 1953, 2018–21 (Прорешная, 1955; Hoogstraal, 1979)a	2012 (Лещинская и др., 1969; Кутманова и др., 2013)	1971–72 (Тимофеев, 1973; Тимофеев и др., 1973)	Yes (Гребенюк, 1966; Циркин и др., 1971; Федорова, 2005)	1970–74 (Циркин и др., 1971; Карась и др., 1973; Чумаков и др., 1974b; Дандуров и др., 1975; Львов и др., 1975; Hoogstraal, 1979), 1980sa, 2021a	2
Tajikistan	1944–2009 (Atkinson et al., 2013), 1951–70 (Hoogstraal, 1979), 1967 (Бляхер и др., 1971), 1967–2012 (Deka, 2016), 1987 (Костюков и др., 1993), 1991 (Tishkova et al., 2012), 1991–94 (Пиров, 2005), 1993 (Tishkova et al., 2012), 1998–2013 (Ince et al., 2014), 2001 (Tishkova et al., 2012), 2005–14 (Рахманов и др., 2014), 2007 (Tishkova et al., 2012), 2008 (Tishkova et al., 2012), 2009 (Tishkova et al., 2012), 1944–2020a	1968 (Смирнова и др., 1971a), 1968–69 (Касымов и др., 1971b; Пак и др., 1971), 2010 (Atkinson et al., 2013), ≈2005 (Пиров, 2005)	1966–68 (Чунихин и др., 1969), 1968–72 (Пак, 1973), 1968 (Смирнова и др., 1969; Смирнова и др., 1971a; Хашимов и Михайлова, 1971), 1969 (Касымов и др., 1971b; Пак и др., 1971), 1968–69 (Пак и др., 1971), 1989b (Гордеева и др., 1990), 1943–70 (Пак, 1972)	Yes (Куйма, 1975, Куйма, 1971; Пиров, 2005; Tishkova et al., 2012)	1967 (Пак, 1975), 1968–72 (Пак, 1973), 1968–74 (Данияров и др., 1975), 1968–73 (Пак и др., 1974), 1969 (Чумаков и др., 1974b), (Данияров и др., 1975), (Касымов и др., 1971a), 1969–73 (Пак и др., 1974), 1969–70 (Пак и Михайлова, 1973), 1970–72 (Згурская и др., 1972), (Chumakov et al., 1973), 1971 (Чумаков и др., 1974b), (Цилинский и др., 1972), 1973–74 (Пак и др., 1975), 1973 (Пак и др., 1975), 2001–2 (Онищенко и др., 2005), 2001–3 (Туманова и др., 2006), 2009 (Петрова и др., 2013)	1
Turkmenistan	1944 (Миxайлов, 1946), 1946 (Hoogstraal, 1979; Смирнова и др., 1974)	1966–68 (Чунихин и др., 1969), 1967–68 (Hoogstraal, 1979), 1972–73 (Курбанов и др., 1974a), 1968–76 (Смирнова и др., 1978; Смирнова и др., 1978)	1966–67 (Смирнова и др., 1969), (Смирнова и др., 1971c), 1966–68 (Чунихин и др., 1969), 1968 (Смирнова и др., 1971c), 1969 (Смирнова и др., 1974), (Смирнова и др., 1971c), 1972–73 (Смирнова и др., 1978), 1973 (Смирнова и др., 1974), 1968–76 (Смирнова и др., 1978)	Yes (Бердыев, 1980)	1967–68 (Hoogstraal, 1979), 1969–74 (Львов и др., 1975), 1968–76 (Смирнова и др., 1978), (Смирнова и др., 1978), 1970 (Hoogstraal, 1979), 1970–72 (Згурская и др., 1972), (Аристова и др., 1973), 1972 (Hoogstraal, 1979), 1973 (Смирнова и др., 1974), (Курбанов и др., 1974b), 1974 (Hoogstraal, 1979), 1976 (Смирнова и др., 1978), 1978 (Hoogstraal, 1979), 1978–81 (Скворцова и др., 1982)	2
Uzbekistan	1944 (Ходукин, 1952),1948–63 (Мелиев, 1967), 1944–47 (Комилов, 2010), 1948–83 (Бутенко и Трусова, 2013), 1973 (Чумаков и др., 1974a), 1998–2007, (Комілов та ін, 2009b), 2001–4 (Kadyrov et al., 2007), 2013–15 (Ermakova et al., 2020), 2017 (Ermakova et al., 2020), 2018 (Ermakova et al., 2020)	1967 (Мелиев, 1967), 1967–71 (Максумов и др., 1973), 1968 (Генис и др., 1971), 2010–16 (Байназаров и др., 2018); 2013 (Юсупова и др., 2013)	1967 (Комилов, 2010), 1967–68 (Смирнова и др., 1969), 1966–68 (Чунихин и др., 1969), 1973 (Kadyrov et al., 2007), 1988–2007 (Комілов та ін, 2009a), 2001–4 (Kadyrov et al., 2007),	Yes (Ahmed et al., 2007; Rasulov, 2007)	1949 (Gajdusek, 1956), 1967 (Чумаков и др., 1971; Комилов, 2010), 1970–72 (Згурская и др., 1972), 1973 (Чумаков и др., 1974b), (Чумаков и др., 1974b), 1985 (Яшина и др., 2002), 2001–4 (Kadyrov et al., 2007), 2013 (Юсупова и др., 2013)	1
			2001–8 (Умурзaков ва дигарон., 2009), 2003–4 (Юсупова и др., 2013), 2013 (Юсупова и др., 2013)

Note: Years are listed if there is evidence of anti-CCHFV antibodies in humans or animals, CCHFV vector endemicity, or CCHFV antigen or genome detection. NA, no data available.

^aData collected by personal communication.

^bYear unclear per the cited publication.

3.1.1.2. Kyrgyzstan

There was scant information on CCHFV infection in the Kyrgyz SSR (today's Kyrgyzstan). The first probable human CCHF cases were recorded during the period 1948–53 (Прорешная, 1955), but the first virus isolation was confirmed during 1970–71 (Циркин и др., 1971; Карась и др., 1973). Four CCHF cases were recorded 1948–53 (Прорешная, 1955) and another 15 during 2018–21 (unpublished data collected by personal communication). The Laboratory of Virology of the Republican Center for Quarantine and Especially Dangerous Infections of the Ministry of Health and Social Development of Kyrgyz Republic (Кыргыз Республикасынын Саламаттык сактоо жана социалдык өнүктүрүү министрлигинин Карантиндик жана өтө коркунучтуу инфекциялар республикалык борборунун вирусологиялык лабораториясы) diagnoses CCHF and detects CCHFV in humans and ticks. Ticks collected from the northwest and southwest parts of southern Kyrgyzstan were found infected with the virus. For instance, in 2021, two of 218 collected ticks tested positive by ELISA (unpublished data collected by personal communication). Although several studies, including those resulting in virus isolations from ticks and animal serology data (Table 3), support ongoing CCHFV circulation in Kyrgyzstan, there is no established CCHFV surveillance. However, specimens from suspected cases may be sent to local laboratories for diagnostic evaluation. Lack of regulatory guidelines for CCHFV surveillance and the absence of routine tick testing for CCHFV are the main barriers to developing a surveillance system in the country. Furthermore, CCHF is not a reportable disease in Kyrgyzstan. The lack of regular CCHF identification is secondary to insufficient laboratory capabilities in this country (unpublished data collected by personal communication).

3.1.1.3. Tajikistan

In the Tajik SSR (today's Tajikistan), the first possible CCHF cases were described in 1944 (Иоффе, 1944; Сиповский, 1944; Черновский и др., 1968), whereas the first CCHFV isolation from ticks occurred in 1967 and the first CCHF-positive human serology data were obtained in 1968 (Смирнова и др., 1971a; Пак, 1975). Over the period 1944–2020, 527 CCHF human cases (81 deaths) were identified (Table 2). The Tajik Research Institute of Preventive Medicine (TRIPM) has been the sole authority responsible for CCHFV surveillance since 1944 (unpublished data collected by personal communication). Recent international collaborations have provided TRIPM with cutting-edge diagnostic capabilities. Hospitals in high-risk areas receive up-to-date information, raising awareness and prompting infection control. All hospitals and medical establishments are required to report any cases suspected to be CCHF to the TRIPM virology laboratory (unpublished data collected by personal communication). The annual number of cases fluctuates, with a range of 5–38. For the last 30 years, the majority of CCHF cases have occurred in the south. During 1998–2009, 18 districts recorded CCHF cases; this gradually increased to 32 districts in southern Tajikistan in 2020 (unpublished data collected by personal communication). The newly reporting districts are close in proximity to previously affected districts; reports are likely true first observations due to the recent rapid expansion of Hyalomma anatolicum ticks (unpublished data collected by personal communication). Hyalomma anatolicum ticks prefer drier and warmer conditions compared to H. marginatum ticks, the most common Hyalomma tick found in Europe (Atkinson et al., 2013). Indeed, >82% of ticks collected in endemic areas are H. anatolicum ticks. Most CCHF cases in Tajikistan have been traced back directly to tick bites and hence are thought to be due to H. anatolicum tick bites (Tishkova et al., 2012). No CCHF cases have been reported from the north of Tajikistan despite positive serology in animals; this lack of reporting is most likely due to lack of awareness of the disease among the population, low number of livestock population, and/or low human exposure to ticks (Atkinson et al., 2013).

3.1.1.4. Turkmenistan

In the Turkmen SSR (today's Turkmenistan), the first possible CCHF cases were described in 1946 (Миxайлов, 1946), whereas first serologic evidence of human CCHFV infections was obtained in 1966–68 (Миxайлов, 1946; Чунихин и др., 1969). At least 14 CCHF cases (10 deaths) were recorded in 1946 (Table 2). No additional CCHF cases have been reported since then. Thus, the current epidemiology of CCHFV is unknown. Per personal communication with the Turkmen Ministry of Health officials, a CCHFV surveillance system exists in the country, though we were unable to verify diagnostic capabilities and accuracy of this system.

3.1.1.5. Uzbekistan

In the Uzbek SSR (UzSSR, today's Uzbekistan), the first CCHF case was identified clinically in 1938, whereas the first CCHFV isolation from ticks occurred in 1949 (Ходукин, 1952; Gajdusek, 1956). During the period 1944–2018, 665 CCHF cases (66 deaths) were reported (Table 2). The Kyzylkum Desert has been the predominant CCHFV hotspot, with H. anatolicum ticks being the main reservoir (Hoogstraal, 1979). CCHFV has been spreading to new regions over the last two decades. By 1998, cases had been recorded in the Bukhara, Kashkadarya (Qashqadaryo), and Navoiy Regions; from 1998 onward, cases also occurred in Tashkent Region, followed by Jizzakh and Syrdarya Regions in 2001 and the Karakalpakstan Republic in 2003. Since 2012, 15–30 cases have been reported annually from this more-recently involved area. This rather impressive geographic spread of CCHFV could be due to tick expansion, increased human exposure, and/or improved diagnostic capability (Uzbek CDC, 2019). The Republican Specialized Center for Scientific and Practical Medicine of Epidemiology, Microbiology, Infectious and Parasitic Diseases (Республика ихтисослаштирилган эпидемиология, микробиология, юқумли ва паразитар касалликлар илмий-амалий тиббиëт маркази) maintains a CCHFV surveillance system, which has not yet been described in detail (personal communication).

3.1.2. Eastern and South-eastern Asia

3.1.2.1. China

In China, CCHF, under various names, has likely been known since the Hàn Dynasty (202 B.C.E. – 220 C.E.) (付滨等, 2007). “Xīnjiāng hemorrhagic fever (新疆出血热)” was the disease term first ascribed to cases of severe illness that occurred during 1959–66 in Maralbexi (Bāchǔ) County, Xīnjiāng Uygur Autonomous Region (新疆维吾尔自治区卫生防疫站, 1975; 柴君杰等, 2004a; 柴君杰等, 2004b; 冯崇惠等, 2004; 刘远恒等, 2004), which were later followed by sporadic cases mostly in the same and surrounding counties in and around the Tarim Basin of Xīnjiāng Uygur Autonomous Region (柴君杰等, 1985; 冯崇慧等, 1995; 唐青等, 1999; 柴君杰, 2004; Chai Junjie et al, 2004d, Chai Junjie et al, 2004c; 冯崇慧, 2004; 冯崇慧等, 2004; 刘远恒等, 2004; 阿不力提甫·阿不力孜等, 2005; Zhang et al., 2018). Characterization of the etiologic agent (冯崇慧, 1983; Yan Yuchen et al 1983a, Li Feng et al 1983; 严玉辰等, 1983a; 严玉辰等, 1983b) led to the identification of “Xīnjiāng hemorrhagic fever virus” as CCHFV in 1985 (Yen et al., 1985).

During the period 1964–2003, 287 CCHF cases (59 deaths) were identified in Xīnjiāng Uygur Autonomous Region (Table 4). CCHFV transmission in these areas occurred predominately through contact with livestock (Zhang et al., 2018); most CCHFV isolates come from desert areas especially in the south of Xīnjiāng Uygur Autonomous Region (Table 5). Therefore, the southern areas were the focus of past epidemiological surveys and increased surveillance. The main vectors of CCHFV in the southern region are H. asiaticum ticks (冯崇慧和白旭华, 1991; 戴翔等, 2006; Sun et al., 2009; Guo et al., 2017). Despite the presence of CCHFV RNA-positive H. asiaticum ticks in the Junggar Basin in the north of the region, no cases of CCHFV have been reported from there (Sun et al., 2009). No CCHF cases have been reported from China since 2003. However, several human and other animal serology studies and CCHFV isolation from ticks indicate that CCHFV circulation is ongoing and that CCHFV may be endemic in China beyond Xīnjiāng Uygur Autonomous Region (陈化新等, 1991; 侯宗柳等, 1992; 屠云人等, 1992; 蔡增林等, 1994a; 1994b; 1994c; 祁继深等, 1995; 任次早等, 1995; 邵锡如等, 1995; 黄好壮等, 1996; 李兆育等, 1998; 张婷等, 2007).

Table 4.

Total confirmed CCHF cases in Eastern and South-eastern Asia by country (1944–2021).

Country	Total confirmed cases	Total deaths	Year (s)	References
Brunei Darussalam	NA	NA	NA	NA
Cambodia	NA	NA	NA	NA
Chinab	287	59	1964–2003	(刘远恒等, 2004; 新疆维吾尔自治区卫生防疫站, 1975; 冯崇慧和白旭华, 1991; 唐青等, 1999; Papa et al., 2002; 柴君杰, 2004; 柴君杰等, 2004a; 柴君杰等, 2004c; 唐青等, 2005; Sun et al., 2009; Zhou et al., 2013; Zhang et al., 2018; Teng et al., 2022)c
Democratic People's Republic of Korea	NA	NA	NA	NA
Indonesia	0a	0a	NA	NA
Japan	0a	0a	NA	NA
Lao People's Democratic Republic	NA	NA	NA	NA
Malaysia	NA	NA	NA	NA
Mongolia	NA	NA	NA	NA
Myanmar	NA	NA	NA	NA
Philippines	NA	NA	NA	NA
Republic of Korea	NA	NA	NA	(Im et al., 2019)
Singapore	0a	0a	NA	NA
Thailand	0a	0a	NA	NA
East Timor	NA	NA	NA	NA
Viet Nam	NA	NA	NA	NA

Note: Total deaths are those among confirmed cases only. Therefore, fatality rate was not calculated. We were limited to available data, but this approach likely underestimates the true CCHF burden.

^aCommunication with local health authorities confirmed that there has not been any CCHF case reported in the country.

^bNo information was found in China Hong Kong Special Administrative Region and China Macao Special Administrative Region, and therefore they are not listed in the table. NA, no data available.

^cTeng et al. summarizes “331 cases” and “283 occurrence records of CCHFV” but no numbers of deaths.

Table 5.

Evidence for CCHFV circulation in South-eastern and Eastern Asia (1944–2021).

Country	CCHF cases reported (year)	Human serology (year)	Animal serology (year)	Hyalomma ticks	CCHFV detected in ticks (year)	Level of evidence
Brunei Darussalam	NA	NA	NA	NA	NA	5
Cambodia	NA	NA	NA	NA	NA	5
China	1959–73 (刘远恒等, 2004), 1965 (新疆维吾尔自治区卫生防疫站, 1975), 1966 (柴君杰, 2004, 柴君杰等, 2004a; Sun et al., 2009), 1968 (柴君杰, 2004, 柴君杰等, 2004c), 1978–80 (Sun et al., 2009), 1984 (唐青等, 1999, Papa et al., 2002), 1990 (柴君杰, 2004), 1997 (Papa et al., 2002), 2001–2 (唐青等, 2005), 2002 (Papa et al., 2002), 2004–5 (Sun et al., 2009; Zhou et al., 2013), 2016 (冯崇慧和白旭华, 1991; 柴君杰, 2004; Zhang et al., 2018)	1988–90 (侯宗柳等, 1992), 1992 (蔡增林等, 1994b, a, 蔡增琳等, 1994), 1992–93 (任次早等, 1995), 1997b (李兆育等, 1998), 2001–2 (Saijo et al., 2005), 2002–3 (张婷等, 2007), 2004–5 (戴翔等, 2006, Sun et al., 2009), 2008 (Xia et al., 2011)	1988 (陈化新等, 1991), 1988–90 (侯宗柳等, 1992), 1991–92 (屠云人等, 1992), 1992 (邵锡如等, 1995), 1993 (祁继深等, 1995), 1996 (黄好壮等, 1996), 2004–5 (Sun et al., 2009), 2001 (韩磊等, 2002; Qing et al., 2003), 2020 (Li et al., 2020)	Yes (邓国藩和姜在阶, 1991; Sun et al., 2009; Chen et al., 2010; Sheng et al., 2019; Zhao et al., 2020; Yang et al., 2021)	1966 (Liang et al., 2018), 1968 (Yen et al., 1985), 1984 (Papa et al., 2002), 2001–2 (唐青等, 2005), 2004 (吕新军等, 2005), 2004–5 (Sun et al., 2009), 2004–5 (戴翔等, 2006), 2008 (Xia et al., 2011), 2012–14 (韩辉等, 2016; 杨宇 等, 2018), 2015 (Kong et al., 2022), 2016 (Zhang et al., 2018), 2014–17 (Moming et al., 2018), 2017 (Guo et al., 2017)	2
Democratic People's Republic of Korea	NA	NA	NA	NA	NA	5
Indonesia	0a	NA	NA	NA	NA	5
Japan	0a	NA	NA	NA	NA	5
Lao People's Democratic Republic	NA	NA	NA	NA	NA	5
Malaysia	NA	NA	NA	NA	NA	5
Mongolia	NA	2010 (Wölfel et al., 2010), 2013–14 (Voorhees et al., 2018)	1987 (Чунихин и др., 1987)	Yes (Narankhajid et al., 2018; Voorhees et al., 2018; Černý et al., 2019; Von Fricken et al., 2020)	2013–14 (Voorhees et al., 2018)	3
Myanmar	NA	2016–18 (Evans et al., 2021)	NA	Yes (Robbins et al., 2002; Evans et al., 2021)	NA	3
Philippines	NA	NA	NA	NA	NA	5
Republic of Korea	NA (Im et al., 2019)	NA (Im et al., 2019)	NA (Im et al., 2019)	NA (Im et al., 2019)	NA (Im et al., 2019)	5
Singapore	0a	NA	NA	NA	NA	5
Thailand	0a	NA	NA	NA	NA	5
East Timor	NA	NA	NA	NA	NA	5
Viet Nam	NA	NA	NA	Yes (Колонин, 2003)	NA	4

Note: Years are listed if there is evidence of anti-CCHFV antibodies in humans or animals, CCHFV vector endemicity, or CCHFV antigen or genome detection.

^aCommunication with local health authorities confirmed that there has not been any CCHF case reported in the country. NA, no data available.

^bYear unclear per the cited publication.

3.1.2.2. Other countries

No CCHF cases have been reported from South-eastern Asia. Positive results in human/animal serology studies in Mongolia and Myanmar in the presence of Hyalomma ticks (Table 5) suggest local CCHFV circulation, indicating that the lack of reported cases could be due to lack of diagnostic and surveillance capabilities. Larger-scale investigations to screen symptomatic (acute febrile) cases in Mongolia and Myanmar are recommended to define CCHFV burden in the region. In Malaysia, a human serology study among healthy individuals conducted in 2012–13 yielded only one positive result in an indigenous person living in the forest fringe areas of peninsular Malaysia (Lani et al., 2015). However, Hyalomma ticks are not known to exist in Malaysia, and hence the status of CCHFV in Malaysia remains dubious.

To the best of our knowledge, there are no published studies reporting any evidence of CCHFV circulation in Brunei Darussalam, Cambodia, Democratic People's Republic of Korea, Indonesia, Japan, Lao People's Democratic Republic, Philippines, Republic of Korea (Im et al., 2019), Singapore, Thailand, East Timor, and Viet Nam. Among these countries, Hyalomma ticks have been reliably identified only in Viet Nam (Колонин, 2003).

3.2. CCHFV tick vector distribution

Hyalomma ticks of various species are broadly distributed in Central Asia but virtually absent in countries of South-eastern Asia. Western China, southern Kazakhstan, Kyrgyzstan, Tajikistan, and Turkmenistan have the highest diversity and abundance of Hyalomma ticks, including presence of one of the major vectors of CCHFV, H. turanicum (Померанцев, 1950; 邓国藩和姜在阶, 1991; Apanaskevich and Horak, 2008). Ticks of very few Hyalomma species, mostly of H. asiaticum and H. scupense, are found farther east (Mongolia, central China, and eastern China) (邓国藩和姜在阶, 1991; Филиппова и др., 1995). Most countries of South-eastern Asia apparently are not suitable for a majority of Hyalomma ticks and lay outside of the normal distribution of ticks of the genus. There are a few records of H. isaaci ticks from western Myanmar (one) and northern Viet Nam (two) (Robbins et al., 2002; Колонин, 2003; Apanaskevich and Horak, 2008). These are the only records despite the fact that many areas of South-eastern Asia are well-studied, confirming that Hyalomma ticks are almost absent from the region. We excluded recent records (Leliana and Rizalsyah, 2015; Temmam et al., 2019) of Hyalomma ticks from Indonesia and Thailand, because they were not verified and most likely based on misidentifications. For example, one research team (Temmam et al., 2019) also collected “Dermacentor marginatus” ticks in Thailand; however, these ticks are western Palearctic and do not reside in South-eastern Asia. Because clearly documented evidence of the presence of Hyalomma ticks in South-eastern Asian countries (except Myanmar and Viet Nam) has not yet been published, we considered them absent from there.

4. Discussion

Reported CCHF cases (2313; 1944–December 2021), positive human and other animal serology, and presence of CCHFV tick vector populations were considered supportive evidence of CCHFV endemicity. Based on that evidence (Table 2, Table 3, Table 4, Table 5, Fig. 1).

• 1.Kazakhstan, Tajikistan, and Uzbekistan are level 1 countries with diagnostic capabilities, which can provide immediate assistance during CCHF outbreaks. Field work to address the focal endemic ecology of CCHFV in the north may help to determine differences in tick or other reservoir host species and densities between the northern and southern regions—contributing to consistent and appropriate disease-control strategies. We suggest that these countries collaborate to strengthen their surveillance systems by setting up a regional diagnostic network and defining representative epidemiology of CCHF in Central Asia. This collaborative effort must also include active surveillance for CCHFV, including testing for CCHFV in Hyalomma ticks, human and animal serological testing, strengthening the healthcare infrastructure, providing information to communities on CCHFV transmission, and implementing protective measures in high-risk areas;
• 2.China, Kyrgyzstan, and Turkmenistan are level 2 countries that have reported cases intermittently, with supportive evidence confirming CCHFV circulation. Therefore, setting up a surveillance system would be beneficial to these countries;
• 3.Mongolia and Myanmar, with no confirmed cases but significant evidence of CCHFV circulation, are level 3 countries that would benefit from establishing a surveillance system to potentially identify human infections and conduct systematic studies, including human/animal serology and virus isolation from ticks, to better define CCHFV epidemiology and manage possible outbreaks;
• 4.Viet Nam is a level 4 country because Hyalomma ticks are present in the absence of proof of CCHFV circulation. This country would benefit from studies that include tick sampling and testing, as well as human and animal serological testing, to look for CCHFV footprints; and
• 5.All other examined countries are level 5 countries because Hyalomma ticks are practically absent.

Fig. 1.

One Health approach to understanding the burden of CCHF in Central, Eastern, and South-eastern Asia. CCHFV circulation is confirmed in countries of lower levels (1 and 2), but it is recommended that further investigation and surveillance need to be conducted in countries of higher levels (3, 4, and 5). This classification is based on potential policy implications for individual countries. A highlighted country's boundaries are unlikely to reflect the exact ecological distribution of CCHFV within the country. However, even a single focus of CCHFV activity within a country will require the entire country to respond to it. (There is no guarantee that depicted country boundaries accurately reflect the geographical area at risk, nor are they necessarily endorsed by the authors).

There are some limitations to our study. First, we searched public databases for indexed articles. Thus, we might have missed data that were not publicly available, such as those having circulated solely in official reports; but we also may have missed studies that were not indexed in the searched databases or studies that were not retrieved using our chosen keywords. Second, we assigned equal weight to all studies within each category (virus isolation, human serological testing, and animal serological investigations). However, the approaches and accuracy of the studies differ considerably among and within countries. Third, the creation of artificial geographic boundaries has no effect on viral ecology or transmission; however, ecological niches and ecotopes may differ substantially across adjacent regions. Consequently, CCHFV might be defined as endemic in two countries, with one having a homogenous virus distribution and the other only having a single hotspot. As a precaution, we assumed that countries adjacent to CCHFV-endemic countries might also be CCHFV-endemic, however, this may not to be the case. Fine-tuned ecological niche modeling (Pigott et al., 2017) may provide additional resolution, but it is out of the scope of this paper. Finally, we did not account for change in climate over time or altered biotopes due to human activity, both of which can affect migrations of CCHFV vectors and hosts, therefore changing prevalence.

5. Conclusions

Taken together, the data and recommendations presented here echo the call for further investigation on tick, human, and animal CCHFV surveillance by collaborating local governments and international public-health organizations (WHO and the World Organization for Animal Health) in Central, Eastern, and South-eastern Asia.

Conflict of interest

The authors declare no relevant financial or non-financial conflict of interests.