Médecine et maladies infectieuses 49 (2019) 574–585

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Review

Crimean-Congo hemorrhagic fever: An update

Fièvre hémorragique de Crimée-Congo: mise au point
P. Fillâtre a,∗ , M. Revest b , P. Tattevin b
a
Service de réanimation polyvalente, centre hospitalier St-Brieuc, 10, rue Marcel-Proust, 22000 St-Brieuc, France
b
Service des maladies infectieuses et de réanimation médicale, CHU de Rennes, Rennes, France

a r t i c l e i n f o a b s t r a c t

Article history: Crimean-Congo hemorrhagic fever (CCHF) is a severe form of hemorrhagic fever caused by a virus of the
Received 7 September 2018 genus Nairovirus. The amplifying hosts are various mammal species that remain asymptomatic. Humans
Received in revised form 22 October 2018 are infected by tick bites or contact with animal blood. CCHF has a broad geographic distribution and is
Accepted 3 September 2019
endemic in Africa, Asia (in particular the Middle East) and South East Europe. This area has expanded
Available online 10 October 2019
in recent years with two indigenous cases reported in Spain in 2016 and 2018. The incubation period is
short with the onset of symptoms in generally less than a week. The initial symptoms are common to
Keywords:
other infectious syndromes with fever, headache, myalgia and gastrointestinal symptoms. The hemor-
Crimean-Congo hemorrhagic fever
Viral hemorrhagic fever
rhagic syndrome occurs during a second phase with sometimes major bleeding in and from the mucous
Health professionals membranes and the skin. Strict barrier precautionary measures are required to prevent secondary and
Ribavirin nosocomial spread. CCHF may be documented by PCR detection of the virus genome during the first days
Ticks after the onset of illness, and then by serological testing for IgM antibodies as from the 2nd week after
infection. Patient management is mainly based on supportive care. Despite a few encouraging retrospec-
tive reports, there is no confirmed evidence that supports the use of ribavirin for curative treatment.
Nevertheless, the World Health Organization continues to recommend the use of ribavirin to treat CCHF,
considering the limited medical risk related to short-term treatment. The prescription of ribavirin should
however be encouraged post-exposure for medical professionals, to prevent secondary infection.
© 2019 Elsevier Masson SAS. All rights reserved.

r é s u m é

Mots clés : La fièvre hémorragique de Crimée-Congo (FHCC) est une forme sévère de fièvre hémorragique causée
Fièvre hémorragique de Crimée-Congo par un virus du genre Nairovirus. De nombreux mammifères peuvent être hôtes intermédiaires et restent
Fièvre hémorragique virale asymptomatiques. Les humains sont infectés par morsures de tiques ou par le contact avec du sang
Professionnels de santé animal. La FHCC a une large distribution géographique et est endémique en Afrique, en Asie (en particulier
Ribavirine
au Moyen-Orient) et dans le Sud-Est de l’Europe. Cette zone s’est étendue ces dernières années avec
Tiques
deux cas autochtones signalés en Espagne en 2016 et 2018. La période d’incubation est courte et les
symptômes apparaissent généralement en moins d’une semaine. Les symptômes initiaux sont communs
à d’autres syndromes infectieux tels que fièvre, céphalées, myalgies et troubles gastro-intestinaux. Le
syndrome hémorragique survient au cours d’une seconde phase avec parfois des saignements importants
cutanéomuqueux. Des mesures d’isolement strictes sont nécessaires pour prévenir les cas secondaires
nosocomiaux. La FHCC peut être documentée par détection en PCR du génome au cours des premiers
jours suivant l’apparition de la maladie, puis par sérologique avec la recherche d’anticorps IgM à compter
de la 2e semaine après l’infection. La gestion des patients repose principalement sur des traitements
symptomatiques. Malgré quelques séries rétrospectives encourageantes, il n’existe pas de haut niveau
de preuve en faveur de l’utilisation de la ribavirine pour le traitement curatif. Néanmoins, l’Organisation
mondiale de la santé continue de recommander l’utilisation de la ribavirine dans le traitement de la FHCC,
compte tenu du risque limité sur des traitements de courte durée. La prescription de ribavirine devrait
toutefois être encouragée en post-exposition pour les professionnels de la santé, afin de prévenir les
infections secondaires.
© 2019 Elsevier Masson SAS. Tous droits réservés.

∗ Corresponding author.
E-mail address: pierre.fillatre@ch-stbrieuc.fr (P. Fillâtre).
https://doi.org/10.1016/j.medmal.2019.09.005
0399-077X/© 2019 Elsevier Masson SAS. All rights reserved.
 P. Fillâtre et al. / Médecine et maladies infectieuses 49 (2019) 574–585
1. Introduction
Crimean-Congo hemorrhagic fever (CCHF) virus is one of the
most severe viral diseases for humans. Typically, the disease is ini-
tially characterized by unspecific signs and symptoms before the
onset of the hemorrhagic syndrome. A fatality rate of 5–30% is gen-
erally reported [1]. The present literature review discusses the most
recently published data on the epidemiology, mode of transmis-
sion, clinical forms and potential treatment options for the disease,
bearing in mind a possible outbreak of CCHF in mainland France.
2. Material and methods
The PubMed database was searched with the term “Crimean
Congo hemorrhagic fever” and the following filters: 1/articles in
English and French, and 2/articles published between January 1,
2000 and September 1, 2018. In all, 971 references were identified.
The number of articles used for this literature review was further
reduced by selection based on the title and abstract.
3. History of CCHF
Although several cases of illness that can probably be assimi-
lated to CCHF were described in Tajikistan from the 12th century
on, the first documented reports of the disease were described in
1944 when the Soviet armed forces engaged the Germany army
in Crimea [2]. Nearly 200 soldiers fell ill with a fever associated
with hemorrhagic syndrome and shock, with a mortality rate of
10% [1,3]. The disease was suspected to be due to a tick-borne
virus following the injection of a filtered suspension of ticks, at
the same time as antibiotics, to volunteer soldiers and psychiatric
patients [2]. The virus was not identified until 1967, when Chu-
makov, a Soviet scientist, isolated it in a patient from Uzbekistan
[4].
Independently, another virus causing similar clinical fea-
tures was isolated in 1956 from a child in the Democratic
Republic of Congo. Only in 1969 were the Congo and Uzbek-
istan strains described as displaying antigenic similarity. The
virus was then renamed Crimean-Congo hemorrhagic fever virus
[2,5].
Fig. 1. Risk areas for Crimean-Congo hemorrhagic fever (CCHF), adapted from [119].
Zones à risque de fièvre hémorragique Crimée-Congo (FHCC), issue de [119].
575
4. Taxonomy and phylogenetics
The CCHF virus belongs to the genus Nairovirus, of the order
Bunyaviridae. The Nairovirus genus comprises 34 different viruses
divided into 7 distinct serological subgroups. Only 3 viruses of this
genus can cause disease in humans, CCHF being of greater impor-
tance than Dugbe fever and Nairobi sheep fever [2]. The nairovirus
genome is structured into 3 segments of single-stranded RNA,
named L, M, and S based on their respective sizes, that are packaged
in an internal envelop formed by the NP nucleoprotein. The diame-
ter of the virion is approximately 90–120 nm. The virion consists of
a lipid envelop comprising the GN and GC glycoproteins which play
a key role in the cell adhesion process prior to endocytosis, hemag-
glutination and inducing a host immune response [1,6]. Because
the virus is highly contagious and causes severe disease, it should
only be handled in high-containment (BSL-4) laboratories.
Studies on the antigenic structure of the CCHF viral mem-
brane could not detect any differences between the Crimean and
African strains before 1967. Today, the viral RNA (in particular
the S segment) has been sequenced and 8 genetic lineages have
been identified. The first European lineage comprises the viruses
found in East Europe covering a region from the Balkan peninsula,
through Turkey and into Russia [2]. A second lineage, named AP92
and found mainly in Greece, forms an independent group and is
probably less pathogenic. The third lineage is present in Central
Asia (Kazakhstan, Tajikistan, Uzbekistan and China), and the fourth
in Pakistan, Madagascar and some of the strains found in Iran. The
fifth lineage consists of the remaining strains found in Iran, as well
as those found in Senegal and Mauritania. The other three lineages
are found only in Africa [1].
5. Epidemiology
CCHF has the most widespread geographical distribution of all
the tick-borne viruses that cause disease in humans, and the second
widest geographical distribution of all arboviruses, after Dengue
virus [1] (Fig. 1). During the 20th century, the main CCHF outbreaks
occurred in the ex-Soviet Union (e.g. Crimea, Rostov, Astrakhan), in
Bulgaria with 1105 cases reported between 1953 and 1974 [7], and
in China where 260 farmers were infected between 1965 and 1994
in the Xinjiang region, with a reported mortality of 80% (probably
576 P. Fillâtre et al. / Médecine et maladies infectieuses 49 (2019) 574–585

Table 1
Cases of Crimean-Congo hemorrhagic fever (CCHF) reported since 2000.
Cas de fièvre hémorragique Crimée-Congo (FHCC) publiés depuis 2000.

Country Screening method Period Reference Description

Europe
Kosovo – 2001 [120] 75 suspected cases, 5 deaths
Albania Serology 2001 [121] 8 cases, including 1 secondary case in a health professional
Bulgaria – 2000–2003 [7] 98 cases reported to the Ministry of Health over 4 years
Serology and PCR 2008 [122] 4 cases, including 1 secondary case in a health professional
PCR 2014 [123] 1 imported case in the United Kingdom from Bulgaria
Greece PCR 2008 [124] 1 death, a farmer from North-East Greece
Spain PCR 2016 [28] 1st indigenous case in Western Europe, and a secondary case in a
[29] health professional
2nd indigenous case in Spain due to a tick bite, Castile and Leon region
Georgia PCR 2009 [125] 1st case reported in the Tbilissi region
Serology 2008–2011 [126] 3 cases detected among 537 patients included for fever > 38 ◦ C and no
Serology and PCR 2014 [127] etiology after > 48 hours
22 cases reported to the Ministry of Health between January and
September 2014
Middle East
Turkey Serology and PCR 2002–2003 [128] 29 documented cases (9 PCR+, 25 IgM+) in the Black Sea region
PCR 2007 [129] 10 imported cases in Istanbul
– 2002–2017 [5] 10,000 cases reported to the Ministry of Health over 15 years.
Reported mortality rate: 4.6%
Iran – 2004 [130] 6 cases in a province in the North of Iran
Serology and PCR 1996–2006 [131] Pediatric series of 34 children and adolescents. Reported mortality
Serology and PCR 2000–2007 [132] rate: 26% (9/34)
397 cases confirmed by the Pasteur Institute in Tehran
Iraq Serology and PCR 1998–2010 [133] 43 confirmed cases over 13 years, mostly in the Ninawa province
Oman Serology 2011 [134] 1st confirmed case in Oman
Dubai PCR 2010 [135] 2 reported cases
Asia
Pakistan Serology and PCR 1997–2002 [136] 83 confirmed cases (9 PCR+, 74 seropositives), Balochistan province
Antigen, serology and 2005 [137] 8 cases in Karachi. Reported mortality rate: 75%
PCR 2005 [138] 1 case, Abbottabad province
PCR 2011 [139] 8 cases, Hazara province
– 2009 [140] 1 case in a 16-year boy in Karachi
PCR 2012 [141] 1 imported case in Glasgow (Scotland) in a patient who stayed in
PCR 2009 [142] Kabul for 3 weeks
PCR 1 imported case in Germany in a US soldier previously stationed in the
south of Afghanistan
Kazakhstan Serology and PCR 2000–2013 [36] 212 confirmed cases over 14 years
India PCR 2011 [143] First series of 5 confirmed cases in India
Africa
Kenya PCR 2002 [144] 1 isolated case
Senegal Serology and PCR 2003 [145] 1 isolated case
PCR 2004 [52] 1 imported case in Rennes (France) from Dakar
Mauritania Serology and PCR 2003 [146] 38 cases, including 15 secondary cases in health professionals
Sudan PCR 2008 [147] 8 confirmed cases including 4 secondary hospital-acquired cases
PCR 2009 [148] Outbreak in 7 patients in a region of South Sudan
Uganda PCR 2015 [149] 1 isolated case

biased because only the most severe cases were recorded) [1]. Most
of the cases described in the literature since January 1, 2020 are
listed in Table 1. Currently, the main outbreak sites are found in the
Middle East (Turkey and Iran), with over 10,000 cases documented
in Turkey since 2002 [5].
A large number of studies have been carried out to determine
the seropositivity rate and delimit the geographical area where the
virus is found. High seropositivity rates have been found in rumi-
nants (sheep, cows, goats), the amplifying hosts of CCHF and act
as reliable indicators of the presence of the virus in some regions.
There is a logical relationship between a high seropositivity rate in
animals in a given region and the incidence of the disease in humans
[8]. Indeed, in a study performed on 1,165 ruminants in Bulgaria and
Turkey, seropositivity rates of 26% and 57% were reported, respec-
tively, with major divergences from region to region: absence of
seropositivity in some western regions of Turkey but a seroposi-
tivity rate of up to 87% in regions near the Black Sea [8]. In Africa,
although compared with the Middle East less human cases of CCHF
are reported, the seropositivity rates are sometimes high in live-
stock with 1.6% in the Democratic Republic of Congo [9], 66% in
Mali [10], 67% in Mauritania [11] and 21% in dromedary camels in
Sudan [12] and reflect an important reservoir on the African con-
tinent. In Europe, the virus has been found in livestock in Bulgaria,
Hungary, Albania, Kosovo and Greece, although at lower levels, and
even in two bats in the south of France [13,14].
The vector of the disease is ticks of the genus Hyalomma, which
are found in Asia and Africa but also in Europe (Fig. 1). They have
been found on migrating birds in Italy [15], Germany [16], in the
south of France [17] and Spain [18]. The virus was first detected
in ticks collected on deer in Spain in 2002 [19]. The CCHF virus
detected was of African lineage and was phylogenetically related
to the lineage found in ticks that infest migratory birds in Morocco
[20]. To date, however, only very few ticks in Spain have been found
to carry the virus, between 0 and 3,2% [5,18].
6. CCHF virus life cycle
6.1. Ticks: host and vector
The CCHF virus has been found in about thirty different species
of ticks (Fig. 2). The most efficient vector belongs to the Ixodes genus,
the Hyalomma marginatum tick, because it can:
 P. Fillâtre et al. / Médecine et maladies infectieuses 49 (2019) 574–585
Fig. 2. Transmission of Crimean-Congo hemorrhagic fever, adapted from [5,21].
Transmission de la fièvre hémorragique de Crimée-Congo, adapté de [5,21].
• acquire the virus when feeding on an infected host. Inside the tick,
the virus replicates within the tick’s intestinal wall and spreads to
various tissue types, reaching the highest titers in salivary glands
and reproductive organs;
• transmit the virus vertically during its various life stages (larva,
nymph and adult);
• transmit the virus via its offspring via the transovarial pathway in
females. A female produces several thousand eggs, so even a low
transovarial transmission rate is likely to maintain a relatively
large population of infected ticks;
• and transmit the virus horizontally when several ticks are present
on a same host animal because infected ticks introduce the virus
into the host’s bloodstream immediately upon biting.
To fully engorge, female ticks can remain for several weeks on a
host. The likelihood of transmitting the virus to other ticks that feed
on the same animal is therefore increased [3,6,21]. Some Hyalomma
marginatum ticks carry the virus throughout their various life stages
and therefore are true natural CCHF reservoirs. Other tick species,
such as ticks of the Argasid genus, cannot maintain and transmit
the virus horizontally and vertically [3,22].
6.2. Amplifying hosts
Vertebrates are the amplifying hosts of CCHF and develop high
titers of the virus in less than 2 weeks following infection [21],
however there have been no reports of the virus causing symp-
toms in animals as of yet. Seropositivity rate investigations have
shown that large herbivores are most frequently infected. Birds
generally do not develop the virus, with the exception of ostriches
[3]. However, birds contribute to spreading the disease by carrying
CCHF-infected ticks over hundreds of kilometers [23]. Small verte-
brates such as hares and hedgehogs are important for maintaining
virus populations because often infested with larval stage ticks that
then transmit the virus vertically during their different life stages.
Large vertebrates that can be infested with several dozens of ticks at
the same time, can also amplify the virus by horizontal transmission
[6,21].
Due to [1] the very broad geographical distribution of the
Hyalomma vector, [2] the fact that a great many species of verte-
brates can act as amplifying hosts, and [3] the dry climate and long
577
hot seasons that enable the ticks to develop from larvae to adults,
as well as the favorable arid environment and vegetation found
in Mediterranean countries with large populations of both small
and large mammals, it is possible that the incidence of CCHF will
increase in upcoming years and spread to yet unaffected regions
[24]. Some authors even suggest that the future climate change
and spreading distribution area of the Hyalomma ticks, will result
in the emergence of CCHF in western Europe [25–27], with a num-
ber of cases far greater that the indigenous cases described in Spain
in 2016 and August 2018 [28,29]. In this setting, the CCHF virus
was classified as a priority zoonotic infection 10 years ago by Santé
Publique France (French Health Authority) that should be closely
monitored and investigated for efficient preventive and disease
control measures [30].
7. Transmission to humans
7.1. Livestock farming
Human infection usually occurs by a tick bite or by squashing
an infected tick with ungloved hands. Despite potential recall bias
and the fact that some tick bites can be missed if the tick remains
only for a short time on the host, tick bites are reported by 60 to
69% of patients [31,32]. An increase in the number of cases seems
to be recorded in the spring and the summer when adult Hyalomma
ticks require to feed to complete their life cycle [23], especially if
the previous winter was mild causing an increased survival rate of
infected ticks [33]. The capacity of Hyalomma ticks to transmit the
CCHF virus to humans also depends on the ecosystem in which they
develop. In regions where there are large numbers of both small
mammals such as hares and hedgehogs and large mammals such
as cattle and sheep, the virus seems to circulate silently with only
a few sporadic “accidental” human cases. In contrast, as seemed to
have been the case in Crimea in 1944 when wild hares had pro-
liferated on abandoned farms during the German occupation and
the number of farm animals had dropped significantly, the soldiers
and farm workers that repopulated the area indirectly represented
a new source of blood for the adult Hyalomma ticks, resulting in
a high incidence of human CCHF cases [3]. It is possible that the
same kind of circumstances could explain the outbreaks seen in
some regions of Turkey [23].
578 P. Fillâtre et al. / Médecine et maladies infectieuses 49 (2019) 574–585
Humans can also be infected by direct contact with animal blood
or other infected tissue, although muscle acidification following
death of the animal inactivates the virus. In a study describing a
series of 1820 cases registered in Turkey between 2002 and 2007,
patients reported that they had had close contact with animals in
62% of the cases [32]. In Turkey, nearly 90% of the cases reported
occurred in farmers, slaughterhouse workers or butchers [1]. It
has also been shown that the seropositivity rate for anti-CCHF
IgG antibodies is higher in elderly patients, as well as patients of
lower social-economic status, with a history of tick bites, regularly
remove ticks from animals, handle livestock, slaughter animals or
process meat and globally in contact with animals in endemic areas
[23,34–37]. Human cases are predominantly observed in men, but
this should be seen in correlation with farming activities that are
mostly performed by men in the countries the most at risk, as in
the Middle East.
The possible sexual transmission of CCHF should also be consid-
ered, although very few cases have been documented [38]. Several
cases of mother-to-child transmission have been reported, with
severe hemorrhagic syndromes in neonates and subsequent death
[5,39], although in other cases neonates are not infected which
suggests that the virus is not transmitted vertically in all cases
[40].
7.2. Transmission to health care professionals
The second category of people most affected by CCHF infec-
tion are health care professionals and laboratory workers. A great
many such cases have been described [28,41–46] with a few related
deaths. A large retrospective study was performed on 9 sites in
Turkey between 2002 and 2014 [47]. During that period, health pro-
fessionals cared for 4869 patients with confirmed CCHF infection.
There were 51 cases of accidental exposure of health professionals
over that period with 25 confirmed secondary cases and a mortal-
ity rate of 16%. In most cases, infection was due to a needlestick
injury (62.7%) followed by contact between infected biological flu-
ids and the health professional’s mucous membrane (23.5%). The
transmission rate following a needlestick injury was estimated
at 25%. Post-exposure prophylactic protocols with oral ribavirin
were implemented in the event of needlestick injuries with a
certain amount of success. For a total of 32 needlestick injuries,
no (0) secondary cases were seen in the 19 carers who received
prophylactic treatment, whereas 8 of the 13 carers who did not
receive prophylactic treatment developed the disease. Neverthe-
less, although certain experts recommend prophylactic treatment
with ribavirin, no well-documented studies have yet validated its
use [48].
The risk of transmission is maximal during the hemorrhagic
phase, i.e. the late stages of the disease, whereas no cases of sec-
ondary infection have been reported during the incubation phase.
The risk of contamination is highest in the event of needlestick
injuries and an absence of protective measures to avoid expo-
sure to blood and other infectious body fluids during care or
washing of a deceased patient [49]. In Russia, cases have been
documented in health professionals who were not in direct con-
tact with biological fluids, although the study did not describe
in detail possible contacts with contaminated materials. These
findings raise the question of possible airborne transmission, but
such cases seem only to occur on an exceptional basis [50]. This
mode of transmission has already been described for viral hemor-
rhagic fevers in primates in the event of prolonged contact without
any barrier precautions. It was also discussed in 1970 during an
outbreak of Lassa fever in Nigeria. Whatever the case, it would
probably only take place during the most advanced stages of the
disease [44].
8. Preventive measures
8.1. For travelers
The risk of contracting the disease during travel to an endemic
area, and therefore of importing the disease back to Europe, is con-
sidered to be very low. A comprehensive literature review revealed
that only 21 cases of such imported disease were reported between
1960 and 2016, albeit with 12 fatalities. Two cases were imported
into Western Europe from Bulgaria and three cases from Africa
[51]. Only one of these cases occurred in France, in Rennes at
the end of 2004, and was imported from Senegal, a country for
which no outbreaks were reported at that time [52]. Neverthe-
less, it seems important that people traveling to endemic areas
be properly informed about vector control measures against tick-
borne diseases (repellents, wearing long clothing), the need to wear
gloves to remove ticks, the risks of contamination via contact with
livestock and working with meat.
8.2. For health professionals
In mainland France, a patient returning from travel to an
endemic area with fever and thrombocytopenia is considerably
more likely to have contracted malaria or Dengue fever. A failure
to consider a diagnosis of CCHF would result in a risk of a hospi-
tal outbreak of the disease if adequate isolation and barrier nursing
techniques are not implemented. Therefore, the French operational
group for coordinating epidemic and biological risks (Coordination
opérationnelle en réseau du risque épidémique et biologique [COREB]),
together with expert advice from the infectious diseases depart-
ments of reference health facilities, has recently issued guidelines
for 1st-line health care providers for the management of patients
with suspected viral hemorrhagic fever [53]. These recommenda-
tions are in line with European guidelines on infection control in
the management of highly pathogenic infectious diseases [54].
The first crucial step for managing patients with CCHF is
to consider its diagnosis, which must result in the immediate
implementation of specific barrier precautions. Standard barrier
precautions seem sufficient for patients in the early stages of the
disease, with a first level of isolation via the use of an alcohol-
based hand sanitizer, level 2 face mask, disposable gown and non
sterile gloves. If the patient presents with body excretions (vom-
iting, profuse diarrhea, significant hemorrhagic syndrome, etc.)
then protective measures should be augmented with a splash-
resistant face mask, single-use scrub suits, a full length waterproof
gown/coverall, two pairs of non sterile nitrile gloves and eyeglasses
with side shields [53]. The patient should be cared for in a separate
isolation room, away from the main patient flow, because cases
of transmission in double patient rooms and to visitors have been
described [54,55]. If possible, the isolation room should have neg-
ative room pressure. Waste should be managed specifically and
incinerated. When the recommended confinement measures are
properly implemented, the risk of secondary infection in health
professionals is probably insignificant [56]. This is supported by
the absence of seroconversion in any of the health professionals
who cared for the unique case of imported CCHF in France in 2004,
despite confinement measures being initially limited to avoiding
direct contact [52,57,58].
8.3. Vaccination
Animal studies have given rise to divergent results. One team
succeeded in triggering both a cell-mediated and a humoral
immune response in mice using a vaccine strain, but this did not
reduce the fatality rate [59]. By using two doses of vaccine, the same
team then demonstrated reduced mortality in a mouse model [60].
 P. Fillâtre et al. / Médecine et maladies infectieuses 49 (2019) 574–585 579

Phase 1 vaccine trials are currently underway in humans, but the Table 2
Clinical signs reported in the literature.
antibodies produced only seem to have a limited virus neutraliza-
Signes cliniques rapportés dans la littérature.
tion capability [61].
Reported References
frequency, %
9. Clinical presentation
Common clinical signs
Pre-hemorrhagic phase
The largest series of clinical reports are from highly endemic Fever 43–98 [63,64]
countries (Iran and Turkey) and should be considered with caution Myalgia 54–93 [62,63]
because based on IgM seropositivity [31,62–65] rather than direct Headache 48–80 [31,65]
Nausea/vomiting 46–83 [63,64]
detection of the CCHF virus. Based on the very high seropositiv-
Diarrhea 31–44 [62,65]
ity rates found in some endemic areas, up to 27% in some regions Retro-orbital pain –
of Romania and Greece, a great many cases of CCHF are either Stiff neck –
asymptomatic or cause symptoms so limited that patients do not Hepatomegaly 30–37 [31,62]
Splenomegaly 14–37 [31,65]
seek medical care [66,67]. It is estimated that 88% of seropositive
Peripheral lymphadenopathy 13 [31]
patients in Turkey experienced only limited symptoms [68]. Hemorrhagic phase
The clinical features most commonly reported in the literature, Epistaxis 17–52 [31,63]
which are also the most extreme signs, are detailed in Table 2. The Hematemesis 8–31 [31,64]
mean incubation time is 2 to 7 days. Longer incubation times have Melena 1–20 [31,64]
Hemoptysia 6–9 [62,63,64]
been described in the literature. In a series of 312 patients with
Hematuria 15–37 [62,63,64]
CCHF after a tick bite in Turkey, 12 patients (3.8%) displayed an incu- Ecchymosis/Purpura 20–47 [62,63]
bation time > 12 days which is the generally accepted maximum Rare clinical signs
incubation time (longest: 53 days) [69]. These patients displayed Lungs
Alveolar hemorrhage [150,151]
less severe symptoms (less fever, less cytolysis and lower mortal-
Hemothorax [152,153]
ity). Heart
The disease can be divided into 3 phases, similarly to other viral Left ventricular dysfunction [154]
hemorrhagic fevers (Fig. 3). During the pre-hemorrhagic phase, Myocarditis [156]
symptoms are generally unspecific. The main symptom is high Pericardial effusion [154,157]
Pulmonary arterial hypertension [155,158]
fever, which can reach 39–41 ◦ C and usually lasts 4–5 days [1]. It
Bundle branch block or repolarization [158]
can be associated with myalgia, headache, retro-orbital pain and disturbance
sometimes a stiff neck. Gastrointestinal symptoms then occur with Eyes
nausea and/or vomiting and more rarely diarrhea [31,62–65]. The Retinal and subconjunctival hemorrhage [159]
Skin
pre-hemorrhagic phase is generally short but can last up to one
Erythema nodosum [160]
week [1]. Mobilliform eruption [161]
Infection with the CCHF virus results in endothelial dysfunc- Digestive system
tion and capillary leaking of red blood cells and plasma into tissue. Acalculous cholecystitis [162]
Endothelial damage leads to activation of the coagulation cascade Acute pancreatitis [163]
Ascites [164,165]
and thrombocytopenia, which increases bleeding [22]. The hemor-
Spontaneous retroperitoneal hematoma [166]
rhagic phase is characterized by mucous tissue bleeding: epistaxis, Urinary system
hematemesis, more rarely melena, hemoptysis and hematuria. Orchiepididymitis [167]
Bleeding into the skin (ecchymosis/purpura) is often observed ENT
[31,62–65]. Parotitis [168]
Endocrine system
During the first two phases, the main signs detected upon exam- Disturbed vasopressin secretion [169]
ination are hepatomegaly in approximately one third of cases, Adrenal gland failure [170]
splenomegaly and sometimes peripheral lymph node enlargement Brain
[31,62]. The clinical features associated with patient mortality are Acute subdural hematoma [171]
Kidneys
somnolence, gross hematuria, hematemesis and melena [1,70,71].
Proteinuria and elevated neutrophil [172]
A fatality rate of 5–30% is generally described with death occurring gelatinase-associated lipocalin (NGAL)
during the hemorrhagic phase. A mortality of 80% was reported in Bones and joints
the first series whereas in the most recent last Turkish series the Inflammatory arthralgia [173]
mortality rate was 4,6% [1,5].
The convalescence phase starts 10–20 days after the onset of
hepatocellular cytolysis are often observed (Fig. 3). Many studies
the first clinical symptoms [1]. Patients experience marked fatigue,
have demonstrated that the higher the degree of thrombocytope-
tachycardia with labile blood pressure, temporary alopecia and
nia, decreased PT, cytolysis, and longer aPTT and the poorer the
memory impairment. The convalescence phase usually lasts about
prognosis [72,73]. In rare cases, a macrophage activation syndrome
ten days [1].
enhances cytopenia [74–76]. Finally, elevated LDH and CK levels
are frequently observed [1].
10. Laboratory findings
10.2. Imaging features
10.1. Clinical chemistry
Unspecific abnormal features are observed using abdomi-
Thrombocytopenia is observed in almost all cases, as is a nal ultrasound [77,78], and chest [79] or abdominal CT [80].
decreased prothrombin time (PT), increased activated partial Evidence of deep lymph node enlargement, serous effusion, hep-
thromboplastin time (aPTT) and hypofibrinogenemia. These atosplenomegaly and pulmonary infiltration does not change
abnormalities are highest during the hemorrhagic phase before patient management. Systematic imaging provides no real benefit,
slowly regressing [1]. At the same time, transient leukopenia and especially since moving the patient increases the risk of secondary
580 P. Fillâtre et al. / Médecine et maladies infectieuses 49 (2019) 574–585
Fig. 3. Phases of Crimean-Congo hemorrhagic fever, adapted from [1].
Différentes phases de la fièvre hémorragique de Crimée-Congo.
contamination if containment measures are breached. European
guidelines even recommend to perform bedside chest X-rays, ultra-
sound with equipment used only in the isolation unit, and to
minimize the use of CT or MRI [54].
11. Diagnosis
11.1. Clinical chemistry
Patient samples should be considered as highly infectious and
represent a high risk for the laboratory technicians and pathologists
who handle them. Lab investigations should therefore be limited to
the tests strictly necessary to:
• confirm diagnosis;
• determine consequences (impaired hemostasis, electrolyte
imbalance);
• and allow alternative diagnosis.
CCHF virus isolation and culture in order to confirm diagnosis
should only be performed in a BSL-4 laboratory. Once inactivated,
other samples may be handled using BSL-3 biosafety precautions
[49].
11.2. Serology
Specific IgG and IgM antibodies can be detected by ELISA. IgM
antibodies are detected from the 5th to 7th day on [22], and disap-
pear 4 months after infection. However, specific IgGs are detected
for at least 5 years [23]. An acute phase infection may therefore be
documented by detecting IgMs (but not IgGs) in an initial serum
sample, then IgMs and IgGs at the same time, or seroconversion
with a four-fold increase in the antibody titer between two succes-
sive samples of serum [6]. The specificity of serological testing is
excellent, with no reported false positives or cross-reactivity with
other viruses. However, the sensitivity of IgM detection ranges from
87.8 to 100% [81,82].
11.3. Quantitative PCR
Molecular biology tests have now become the preferred meth-
ods for fast, exact diagnosis. Various different real-time PCR
methods have been described with primers common to all known
viral strains [22]. The quantitative PCR developed by Drosten [83]
can be used to detect the genomes of the Ebola, Marburg, Lassa,
CCHF, Rift valley fever, Dengue and yellow fever viruses in a single
assay, which may prove useful for travelers returning from an area
where several viral hemorrhagic fevers are found.
The main diagnostic challenge is caused by the very short win-
dow during which the virus can be detected in blood samples using
PCR. If symptomatic patients are not rapidly admitted to hospi-
tal, PCR results may be negative and serological testing required.
But IgM levels can remain high for several months and although
they demonstrate recent infection, they do not prove that the
symptoms are caused by the CCHF virus. The diagnostic value of
seropositivity therefore depends on the geographical region. In an
endemic area like Turkey, seropositivity may reflect recent CCHF
infection that caused limited symptoms, and the unspecific clin-
ical signs that have led the patient to seek care may be due to
a number of other potential diseases. Such symptoms may be
caused by other hemorrhagic fevers depending on the region vis-
ited, Rickettsial diseases, Q fever, leptospirosis, malaria, bacterial
sepsis, viral hepatitis and infective endocarditis, etc [1,23]. Due
to the null prevalence of CCHF in Western Europe, positive spo-
radic IgM results should however be considered as of diagnostic
relevance.
12. Severity scoring
Two different scoring systems have been proposed to assess
prognosis upon admission of patients with CCHF. Both systems are
estimated to predict the risk of unfavorable prognosis with a sensi-
tivity of 96–100% and a specificity of 93–100% [84,85] These scores
can help in predicting a patient’s clinical outcome and have been
developed for use in endemic countries. The first scoring system
was designed to help decide whether patients required transferring
to a reference center or whether they could be treated satisfacto-
rily in a local hospital [84]. The second system was developed in an
uncontrolled retrospective study to stratify patients based on the
risk of death, the patients at intermediate risk having benefited to
a greater degree from treatment with ribavirin [85]. Although not
included in the clinical scoring systems, a high viral load exceed-
ing 108 copies/mL was also independently associated with poor
prognosis [86–88].
 P. Fillâtre et al. / Médecine et maladies infectieuses 49 (2019) 574–585
13. Treatment options
13.1. Symptomatic care
Care for patients with CCHF is based on symptomatic treatment
[49]: correcting hypovolemia and electrolyte imbalance caused by
gastrointestinal disturbances, correcting hemostasis in the event
of bleeding (fresh frozen plasma, platelet transfusion), packed cell
transfusion [1,23]. Potential coinfection should be investigated and
treated because although rarely described, bacterial coinfection
[89,90] and concomitant malaria [91,92] have been reported in the
literature.
13.2. Ribavirin
Tests performed on ribavirin, a nucleoside analog, have demon-
strated that, in vitro, it inhibits CCHF virus replication and its
cytopathogenic effect in adrenal carcinoma cells [93]. Ribavirin
also seems to be able to decrease the mortality rate in a mouse
model, but only if administered at an early stage of the disease
[95]. Treatment with ribavirin is contraindicated in pregnant and
breast-feeding women, or in patients with pre-existing heart dis-
ease.
In the first years of the 21st century, ribavirin was therefore
recommended in various clinical guidelines, notably because ret-
rospective studies on cases in Turkey and Iran showed a lower
mortality rate [62,95], or even rapid recovery [96,97] in the patients
who received ribavirin, especially when administered at an early
stage (within 4 days of the onset of symptoms) [98,99]. In a recent
retrospective study adjusted using a severity score, ribavirin had
a protective effect against death with an odds ratio (OR) of 0.04
[0.004–0.48] [85], thus confirming the results of the earlier stud-
ies that demonstrated the efficacy of ribavirin for the most severe
cases [62]. In the literature review published in 2010 by Soares-
Weiser et al. [101] that included 11 observational studies and a
total of 955 patients, ribavirin was also shown to have a benefi-
cial effect on mortality, with a risk ratio (RR) of death estimated at
0.56 [0.35–0.90]. However, other retrospective studies have shown
a lack of effect [101–104], and some experts are convinced that
ribavirin is of no clinical value [105], all the more so after Bodur
et al. reported that the viral load in patients who received oral
ribavirin (n = 10) was not significantly reduced compared with
patients receiving only symptomatic treatment (n = 40) [106].
Studies with a higher level of evidence are rare and suggest a
lack of efficacy for ribavirin. In a randomized trial on the efficacy of
ribavirin [107], no differences were found between patients in the
ribavirin + symptomatic care group (n = 64) compared with patients
receiving only symptomatic care (n = 72) in terms of mortality,
length of hospital stay, need for transfusion and platelet count
recovery time. This unblinded study included all patients with the
clinical features of hemorrhagic fever suspected to be CCHF. Only
documented cases were included, but the population size required
to achieve a predefined power was not calculated so it is impossible
to draw meaningful conclusions from the findings.
Two meta-analyses that assessed the efficacy of the use of rib-
avirin to reduce mortality from CCHF concluded that too little data
had been published to determine whether ribavirin has a beneficial
effect or not [100,108]. Pending the results of a well-documented
study and because a lack of evidence does not necessarily imply a
lack of effect, WHO has based its guidelines on the efficacy demon-
strated in vitro and in animal models, as well as on the retrospective
data published and the low number of adverse effects, and recom-
mends that patients with CCHF be given an oral loading dose of 2 g
of ribavirin, followed by 1 g every 6 hours from day 1 to day 4 of
treatment, then 500 mg every 6 hours from day 5 to day 10. If intra-
venous treatment is possible (poor availability and very limited
581
temporary use authorization), WHO recommends 17 mg/kg (max-
imum dose: 1 g) every 6 hours from day 1 to day 4, then 8 mg/kg
(maximum dose: 500 mg) every 8 hours from day 5 to day 10 [109].
Based on encouraging retrospective data [47,110,111], some
authors recommend post-exposure treatment with ribavirin for
health professionals accidentally exposed to the virus, especially
in the event of needlestick injury [48]. A recent meta-analysis
estimated that such prophylactic post-exposure treatment signifi-
cantly reduced the risk of infection (OR 0.01 [0–0.003]) [112].
13.3. Other treatment options
The efficacy of favipiravir, a broad-spectrum viral polymerase
inhibitor was assessed in a mouse model and demonstrated superi-
ority over ribavirin and a persistent effect even when administered
at a late stage after the onset of symptoms [94]. However, too little
data is currently available to be able to recommend the routine use
of favipiravir to treat CCHF.
Other therapeutic options have been experimented. Of particu-
lar interest: plasmapheresis combined with ribavirin in patients
with severe CCHF in an attempt to reduce the proinflam-
matory cytokine load [113,114], high doses of corticosteroids
(5–30 mg/kg/day) to treat macrophage activation syndrome, poly-
valent immunoglobulins and fresh frozen plasma [115].
Two Iranian studies attempted to evaluate the potential ben-
efit of immunomodulatory therapy. The first study compared the
combined use of polyvalent immunoglobulins and ribavirin (n = 12)
with ribavirin alone (n = 28) and showed a beneficial effect of
polyvalent immunoglobulins in terms of time to recovery from
cytopenia and return to normal liver function. Unfortunately, the
study was not double-blinded [116]. The second trial was an
open, controlled, prospective study comparing the combined use
of ribavirin and 10 mg/kg/d corticosteroids (n = 13) with ribavirin
alone (n = 22). The corticosteroid group were found to have less
severe hemorrhagic syndrome, a reduced need for transfusion and
recovered faster from cytopenia. However, the mortality rate was
equivalent in both groups [117].
Another interesting option is worth mentioning even though
only preliminary findings are currently available: Kubar et al.
reported interesting results in CCHF patients with a high viral load
(n = 15) after administration of hyperimmune globulins prepared
from the serum of convalescent patients [118].
14. Conclusions
The presence of the ticks that vector CCHF in Western Europe
and the favorable climate make it plausible that indigenous cases
of CCHF will emerge in France in the future. Further investigation
of the contagiousness and severity of the CCHF virus are required
to better understand the disease and implement adequate patient
isolation measures in order to prevent the secondary infection of
health professionals.
Disclosure of interest
The authors declare that they have no competing interest.
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