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International Journal of Infectious Diseases (2009) 13, 380—386
http://intl.elsevierhealth.com/journals/ijid
The epidemiology of Crimean-Congo hemorrhagic
fever in Turkey, 2002—2007§
Gul Ruhsar Yilmaz a,*, Turan Buzgan a, Hasan Irmak a, Ahmet Safran a,
Ramazan Uzun a, Mustafa Aydin Cevik b, Mehmet Ali Torunoglu a
a
b
Ministry of Health, General Directorate of Primary Health Care, Mithatpasa Cad. 3, 06434 Sihhiye, Ankara, Turkey
Ankara Numune Training and Research Hospital, Ankara, Turkey
Received 23 March 2008; received in revised form 30 June 2008; accepted 11 July 2008
Corresponding Editor: William Cameron, Ottawa, Canada
KEYWORDS
Crimean-Congo
hemorrhagic fever;
Epidemiology;
Turkey
Summary
Background: Crimean-Congo hemorrhagic fever (CCHF) is a serious disease caused by the CCHF
virus of the Bunyaviridae family. The disease has been reported in 30 countries in Africa, Asia,
Eastern Europe, and the Middle East. It has been present in Turkey since 2002. In this study we
present and discuss the epidemiological features, clinical and laboratory findings, treatment, and
outcome of cases diagnosed with CCHF between 2002 and 2007 from the surveillance results of
the Turkish Ministry of Health (MoH).
Methods: According to the surveillance system of the MoH, data for patients with clinical,
laboratory, and epidemiological findings compatible with CCHF are recorded on case reporting
forms. These forms are submitted to the General Directorate of Primary Health Care of the MoH by
the city health directorates. All the surveillance data regarding CCHF were recorded on a
database (SSPS 11.0) established in the Communicable Diseases Department of the MoH.
Results: According to the surveillance reports of the Turkish MoH, between 2002 and 2007, 1820
CCHF cases occurred (150 in 2002—2003, 249 in 2004, 266 in 2005, 438 in 2006, and 717 in 2007). The
crude fatality rate was calculated to be 5% (92/1820). Two thirds of the CCHF cases were reported
from five cities located in the Mid-Eastern Anatolia region; 69.4% of the cases were from rural areas.
The male to female ratio was 1.13:1. Of all the reported cases, 68.9% had a history of tick-bite or tick
contact and 84.1% were seen in the months of May, June, and July. Of 1820 CCHF cases, three (0.16%)
were nosocomial infections.
Conclusions: CCHF appears to be a seasonal problem in the Mid-Eastern Anatolia region of Turkey.
The possible risk factors for transmission and the clinical and laboratory findings of patients with a
diagnosis of CCHF were found to be similar to those reported in the literature. The mean fatality
rate for Turkey is lower than the rate reported for other series from other parts of the world.
# 2008 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
§
In memory of Mustafa Aydin Cevik for all his support and guidance.
* Corresponding author. Tel.: +90 312 5851390; fax: +90 312 4322994.
E-mail address: [email protected] (G.R. Yilmaz).
1201-9712/$36.00 # 2008 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ijid.2008.07.021
The epidemiology of CCHF in Turkey, 2002-2007
Introduction
Crimean-Congo hemorrhagic fever (CCHF) is a viral infection
caused by a tick bite or transmitted through the blood or body
fluids of domestic animals or CCHF patients. It was first seen
in the Crimean Peninsula in 1940. Today, it is found in 30
countries located in Africa, Asia, Eastern Europe, and the
Middle East.
Despite the incidence of CCHF in Bulgaria, Russia, Iran,
and Iraq, countries neighboring Turkey, no case of CCHF was
reported from Turkey until 2002.1—4 Following a regional
epidemic in Turkey in 2003, the disease was determined to
be CCHF by laboratory confirmation, and several reports have
now been published.5—17 When considering the number of
CCHF cases reported to date worldwide,18 the highest number has been reported in Turkey.
In this study, the epidemiological features, clinical and
laboratory findings, treatment, and outcome of cases diagnosed with CCHF between 2002 and 2007 obtained from the
surveillance results of the Turkish Ministry of Health (MoH)
are discussed.
Materials and methods
Outbreak history
Turkey has a population of 70 million, and there are no
reports of CCHF occurring before 2002. In the spring and
summer of 2002, the first cases with clinical and laboratory
findings compatible with CCHF were reported from the city
of Tokat, located in the Middle Anatolia-Black sea region of
Turkey. In the spring and summer of 2003, cases with similar
clinical and laboratory findings were reported from Tokat
and its neighboring cities of Yozgat, Sivas, etc. In the same
year, a scientific commission set up by Turkish MoH described
the cases and developed a case report form, before the
diagnosis of the disease was established. The MoH demanded
that the approach to such cases be in compliance with these
case descriptions. In 2003, serum samples were found positive for the disease by the National Reference Center for
Arbovirus and Viral Hemorrhagic Fevers, Pasteur Institute,
Lyon, France.
CCHF surveillance system of the Turkish Ministry
of Health
CCHF has been listed as a notifiable disease since December
2003. In that year, the MoH ordered through a declaration
that all suspected cases of CCHF with specific clinical findings
compatible with the disease should be referred to a secondary healthcare center by the primary care centers, and that
notification of the case should come from the secondary care
center. The MoH has described the centers that can treat
patients according to their severity of disease, case definitions, and referral criteria. Treatment options, isolation
measures, suggestions for disinfection, and the approach
in handling the deceased were published in a small pamphlet
and sent to all health centers.
Patient data, including clinical, laboratory, and epidemiological findings compatible with CCHF, are recorded on MoH
surveillance forms. These forms, along with serum samples
381
obtained from suspected cases (the first sample), are submitted to the General Directorate of Primary Health Care,
Department of Communicable Diseases and Refik Saydam
Hygiene Center, Virology Laboratory of the MoH by the city
health directorates. It is required that all patients diagnosed
with CCHF based on case definition criteria be followed in
hospitals. The centers are also directed to collect a second
sample of blood from individuals with a prediagnosis or
definitive diagnosis of CCHF in the second week of the disease
or upon discharge, and to send these samples to the MoH.
Based on the notification system, epidemiological data
were collected starting from 2004 using the standard case
reporting forms developed by the CCHF scientific committee.
All the surveillance data were recorded on a database (SSPS
11.0) established in the Communicable Diseases Department
of the MoH. In the case of missing patient information,
contact was established with the city health directorates
and the information was obtained.
Case definition
Among the cases with epidemiological risk factors and clinical and laboratory findings compatible with CCHF, those with
confirmed CCHF virus RNA in blood or body fluid samples by
reverse transcriptase-polymerase chain reaction (RT-PCR)
evaluation or IgM and/or IgG positivity by ELISA were defined
as confirmed CCHF cases. Risk factors and findings compatible with CCHF were defined as follows: (1) epidemiological
risk factors: tick-bite or tick contact, involvement in animal
husbandry or farmer, contact with the body fluid of a CCHF
patient or working at a laboratory, and individuals with
similar complaints in the proximity of a CCHF patient; (2)
clinical findings: fever, hemorrhage, headache of acute
onset, myalgia/arthralgia, lethargy, nausea/vomiting, and
abdominal pain/diarrhea; (3) laboratory findings: thrombocytopenia (platelet count <150 109/l) and/or leukopenia
(white blood cell count <4 109/l) and elevated levels of
alanine aminotransferase (ALT), aspartate aminotransferase
(AST), lactate dehydrogenase (LDH), and creatine phosphokinase (CK).
Laboratory tests
Between 2002 and 2004, patient serum samples were collected and sent via the Refik Saydam Hygiene Center to the
National Reference Center for Arbovirus and Viral Hemorrhagic Fevers, Pasteur Institute, Lyon, France and the
National Center for Infectious Diseases (NCID), Special Pathogen Branch of the Division of Viral and Rickettsial Disease
(DVRD), CDC, Atlanta, USA. Between 2005 and 2007, serum
samples were studied by the virology laboratory of Refik
Saydam Hygiene Center. Patient serum samples were tested
for anti-CCHF IgM and IgG antibodies by ELISA. CCHF virus
RNA was investigated by RT-PCR, and direct sequence analysis
was performed in these centers.
Statistical analyses
Statistical analyses were performed using SPSS 11.0 package
program (SPSS Inc., Chicago, IL, USA). The Chi-square test
was used.
382
G.R. Yilmaz et al.
Results
Between 2002 and 2007, a total of 1820 CCHF cases occurred
(150 in 2002—2003, 249 in 2004, 266 in 2005, 438 in 2006, and
717 in 2007); 92 of these cases resulted in mortality. The
mean fatality rate was 5% (4.5—6.2%).
Because the case report form was only prepared in 2003
and the patient demographic data only collected from 2004,
the tables presented in this report do not contain the data for
2002—2003. Of the CCHF cases, 53% were male and 47%
were female. The mean age of the patients was 44 years
Table 1
(range 1—92 years). Evaluation of the age distribution of the
patients showed that fewer patients were aged under 10
years or over 80 years. The distribution of patients according
to occupation showed that most were homemakers (36.4%),
followed by farmers (34.1%), and those working in the animal
husbandry sector (6.6%). The disease was most common in
the months of June and July (Table 1).
Of the CCHF cases, 68.9% had a history of tick-bite or tick
contact and 61.7% had a history of close contact with animals. One case was a baby who was infected through breastfeeding (Table 2). Fatigue, fever, myalgia, and headache
The epidemiological characteristics of patients with a diagnosis of Crimean-Congo hemorrhagic fever.
Gender
Male
Female
Age groups (years)
0—9
10—19
20—29
30—39
40—49
50—59
60—69
70—79
80—89
90—99
Location of residence
Village
Town
City center
Occupation
Undeclared
Farmer
Homemaker
Student or government worker
Worker
Working in animal husbandry
or as a shepherd
Unemployed
Child
Other, retired, butcher
Healthcare workera
Month of disease incidence
March
April
May
June
July
August
September
October
Total
2004, n (%)
2005, n (%)
2006, n (%)
2007, n (%)
Total, n (%)
131 (52.6)
118 (47.4)
130 (48.9)
136 (51.1)
249 (56.8)
189 (43.2)
375 (52.3)
342 (47.7)
885 (53.0)
785 (47.0)
25
102
85
96
108
128
106
56
10
1
59
210
206
230
268
285
254
136
20
2
5
29
32
30
44
39
48
21
0
1
(2.0)
(11.6)
(12.9)
(12.0)
(17.7)
(15.7)
(19.3)
(8.4)
(0.0)
(0.4)
14
25
35
38
35
48
39
30
2
0
(5.3)
(9.4)
(13.1)
(14.3)
(13.1)
(18.0)
(14.7)
(11.3)
(0.8)
(0.0)
15
54
54
66
81
70
61
29
8
0
(3.4)
(12.3)
(12.3)
(15.1)
(18.5)
(16.0)
(13.9)
(6.6)
(1.8)
(0.0)
(3.5)
(14.2)
(11.9)
(13.4)
(15.1)
(17.9)
(14.8)
(7.8)
(1.4)
(0.1)
(3.5)
(12.6)
(12.3)
(13.8)
(16.0)
(17.1)
(15.2)
(8.1)
(1.2)
(0.1)
183 (73.5)
48 (19.3)
18 (7.2)
185 (69.5)
50 (18.8)
31 (11.7)
298 (68.0)
97 (22.1)
43 (9.8)
493 (68.8)
154 (21.5)
70 (9.7)
15
85
105
11
3
14
(6.0)
(34.1)
(42.2)
(4.4)
(1.2)
(5.6)
7
85
115
14
2
14
(2.6)
(32.0)
(43.2)
(5.3)
(0.8)
(5.3)
46
165
140
31
2
24
(10.5)
(37.7)
(32.0)
(7.1)
(0.5)
(5.5)
65
234
248
41
10
59
(9.1)
(32.6)
(34.6)
(5.7)
(1.4)
(8.2)
133
569
608
97
17
111
(8.0)
(34.1)
(36.4)
(5.8)
(1.0)
(6.6)
(3.2)
(0.4)
(2.8)
(0.0)
7
15
5
2
(2.6)
(5.6)
(1.9)
(0.8)
17
5
6
2
(3.9)
(1.1)
(1.4)
(0.5)
15
16
27
2
(2.1)
(2.2)
(3.8)
(0.3)
47
37
45
6
(2.8)
(2.2)
(2.7)
(0.4)
8
1
7
0
2
8
37
66
105
28
2
1
249
(0.8)
(3.2)
(14.9)
(26.5)
(42.2)
(11.2)
(0.8)
(0.4)
(100.0)
0
10
40
72
99
36
4
5
266
(0.0)
(3.8)
(15.0)
(27.1)
(37.2)
(13.5)
(1.5)
(1.9)
(100.0)
4
31
56
183
128
35
1
0
438
(0.9)
(7.1)
(12.8)
(41.8)
(29.2)
(8.0)
(0.2)
(0.0)
(100.0)
3
27
150
259
210
53
15
0
717
(0.4)
(3.8)
(20.9)
(36.1)
(29.3)
(7.4)
(2.1)
(0.0)
(100.0)
1159 (69.4)
349 (20.9)
162 (9.7)
9
76
283
580
542
152
22
6
1670
(0.5)
(4.6)
(16.9)
(34.7)
(32.5)
(9.1)
(1.3)
(0.4)
(100.0)
a
In 2005, a nurse and healthcare technician contracted the disease by contamination via blood and body fluids. Both cases recovered. In 2006,
a nurse contracted the disease by contact and died; the other case was a healthcare worker who had a history of tick-bite, thus, there was no
nosocomial infection. In 2007, neither of the two healthcare workers had a history of contact with a CCHF patient; one had a history of tick-bite
and the other had a history of living in rural areas. To sum up, starting from 2004, three nosocomial infection cases were reported to the MoH.
The epidemiology of CCHF in Turkey, 2002-2007
383
Table 2 Possible risk factors for transmission and clinical and laboratory findings in patients with a diagnosis of Crimean-Congo
hemorrhagic fever.
Possible risk factors for transmission
Tick-bite or tick contact
Close contact with animals
Contact with animal blood, tissue,
or body fluids
Contact with the body fluid of
a CCHF patient or working at
a laboratory a
Individuals with similar complaints
in the proximity of a CCHF patient
2004
(N = 249)
n (%)
2005
(N = 266)
n (%)
2006
(N = 438)
n (%)
2007
(N = 717)
n (%)
Total
(N = 1670)
n (%)
137 (55.0)
140 (56.2)
32 (12.9)
169 (63.5)
177 (66 .5)
13 (4.9)
309 (70.5)
282 (64.4)
65 (14.8)
535 (74.6)
432 (60.3)
55 (7.7)
1150 (68.9)
1031 (61.7)
165 (9.9)
2 (0.8)
3 (1.1)
1 (0.2)
0 (0)
6 (0.4)
16 (6.4)
11 (4.1)
16 (3.7)
10 (1.4)
53 (3.2)
Clinical findings
Fever
Headache
Myalgia
Fatigue
Nausea
Vomiting
Abdominal pain
Diarrhea
Hemorrhagic findings b
221
185
196
239
193
142
120
91
93
(88.8)
(74.3)
(78.7)
(96.0)
(77.5)
(57.0)
(48.2)
(36.5)
(37.3)
230
164
167
253
161
112
79
79
90
(86.5)
(61.7)
(62.8)
(95.1)
(60.5)
(42.1)
(29.7)
(29.7)
(33.8)
396
300
318
399
274
196
138
98
106
(90.4)
(68.5)
(72.6)
(91.1)
(62.6)
(44.7)
(31.5)
(22.4)
(24.2)
646
489
483
651
452
266
212
146
95
(90.1)
(68.2)
(67.4)
(90.8)
(63.0)
(37.1)
(29.6)
(20.4)
(13.2)
1493
1138
1164
1542
1080
716
549
414
384
(89.4)
(68.1)
(69.7)
(92.3)
(64.7)
(42.9)
(32.9)
(24.8)
(23.0)
Laboratory findings
Leukopenia
Thrombocytopenia
Elevated AST and ALT
Elevated LDH
Elevated CK
221
239
226
202
183
(88.8)
(96.0)
(90.8)
(81.1)
(73.5)
236
249
235
219
189
(88.7)
(93.6)
(88.3)
(82.3)
(71.1)
387(88.4)
397 (90.6)
365 (83.3)
325 (74.2)
291 (66.4)
640
672
608
520
437
(89.3)
(93.7)
(84.8)
(72.5)
(60.9)
1484
1557
1434
1266
1100
(88.9)
(93.2)
(85.9)
(75.8)
(65.9)
CCHF, Crimean-Congo hemorrhagic fever; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; CK,
creatine phosphokinase.
a
Three of six cases were healthcare workers with nosocomial infections, two cases were siblings, and one case was the breastfed baby of
a nursing mother with a diagnosis of CCHF.
b
p < 0.05.
were the most common clinical findings. Hemorrhagic findings were detected in 23.0% of the patients.
IgM seropositivity was 65.1% in first blood samples and 86.4%
in second blood samples. RT-PCR positivity was 45.3% in first
blood samples and 24.7% in second blood samples. According to
the case reporting forms, oral ribavirin treatment was applied
in 67.9% of the CCHF cases in 2004. This rate was 21.8% in 2005,
16.2% in 2006, and 11.8% in 2007 (Table 3).
Discussion
In Turkey, the first cases with findings compatible with CCHF
were reported to the Turkish MoH from the city of Tokat in
2002.16 In 2003, the disease was determined to be CCHF by
laboratory confirmation. In 2004, the total number of cases
was 249, which increased to 266 in 2005, 438 in 2006, and 717
in 2007. The gradual increase in the number of cases over the
latter two years may have been associated with regional
dispersion of the disease as well as increased awareness of
healthcare personnel and the public about the disease. These
data show that Turkey has become the country with the
highest number of CCHF cases among those countries that
report CCHF cases annually. Despite reports of the disease
from the neighboring countries of Iran (mostly from the areas
closer to the Pakistani border), Russia, and Bulgaria, the
number of reported cases from these countries is much
smaller than that reported from Turkey.1—3
The mean fatality rate for Turkey is about 5%. This rate has
not changed over the years and is lower than the rate
reported for other series from other parts of the world.
The lower fatality rate in Turkey compared to the rates
reported by other countries may be due to a better surveillance system, which facilitates the detection of cases with
mild to moderate clinical findings, and the relatively better
treatment facilities. In the regions where the disease is
endemic, diagnosis of cases with mild clinical findings due
to education and increased awareness of the healthcare
personnel and public may have contributed to the low fatality
rate. In addition, the CCHF strain determined in our country
is significantly homologous with the strain detected in Russia
and Kosovo (the old Yugoslavia).5 In CCHF cases caused by
similar strains, the fatality rate has been found to be lower
than those of other regions.19,20
384
Table 3
G.R. Yilmaz et al.
The prognosis and treatment of patients with a diagnosis of Crimean-Congo hemorrhagic fever.
2004
(N = 249)
n (%)
2005
(N = 266)
n (%)
2006
(N = 438)
n (%)
2007
(N = 717)
n (%)
Total
(N = 1670)
n (%)
Outcome
Cured
Died
236 (94.8)
13 (5.2)
253 (95.1)
13 (4.9)
411 (93.8)
27 (6.2)
684 (95.4)
33 (4.6)
1584 (94.9)
86 (5.1)
Treatment
Ribavirin
Supportive
Untreated
No data
169
37
14
29
58
106
2
100
71
94
0
273
85
615
4
13
(67.9)
(14.9)
(5.6)
(11.6)
(21.8)
(39.8)
(0.8)
(37.6)
The majority of cases in our country were from 15
cities in Kelkit Canyon and its environs, particularly the
cities of Tokat, Sivas, Yozgat, Çorum, and Erzurum from
which two thirds of cases were reported (Figure 1). With
these characteristics, the disease is in an endemic state
that is limited to a certain region. This has been associated
with factors such as climatic features (temperature, humidity, etc.), geographical conditions, flora and wild life, the
Figure 1
2007.
(16.2)
(21.5)
(0)
(62.3)
(11.8)
(85.8)
(0.6)
(1.8)
383
852
20
415
(22.9)
(51.0)
(1.2)
(24.9)
animal husbandry sector, and increased contact with animals and ticks.21 In a study by Tonbak et al. from our
country, 47% of the tick species collected from domestic
animals were Rhipicephalus bursa and 46% were Hyalomma
marginatum marginatum. In the same study CCHF was
detected in 9.09% of the R. bursa pool and 3.22% of the
H. m. marginatum pool.9 Both tick species play a role in
CCHF transmission.22
Incidence rates (number of cases/100 000) of Crimean-Congo hemorrhagic fever in the cities with the highest prevalence,
The epidemiology of CCHF in Turkey, 2002-2007
Evaluation of the epidemiological characteristics of 1670
cases (2004—2007) showed that the female to male ratio was
similar. The disease is common in the rural areas of the region
and in the actively working age group. Nearly two thirds of
the patients were farmers and homemakers in the rural
areas. In Turkey, the population defined as homemakers in
rural areas is made up of active workers in the agricultural
and animal husbandry sectors. The occupations at risk for
CCHF have primarily been those that are engaged in animal
husbandry and farming, which involve the risk of contact with
ticks.8,23—26
The incidence rate of the disease among healthcare workers is very low in Turkey. The number of cases with nosocomial
CCHF infection has been limited to three. This might have
been due to high compliance of healthcare workers in the
region with the established standard measures and isolation
methods for protection from the disease.
In Turkey, the disease occurs between the months of March
and October with peak levels in June and July. Nearly 70% of
the cases were reported in the months of June and July,
which are the months of intensive work for those working in
agriculture and the animal husbandry sector. In the earlier
years, the peak number of cases occurred in July; however, in
the last two years (2006 and 2007) this peak occurred in June.
This may be associated with earlier activation of the tick
population due to global warming. Evaluation of transmission
routes has shown that nearly 70% of cases had a history of tick
contact. Strikingly, the same rate was found in those with a
history of close contact with animals and/or animal blood or
body tissue. As is known, infection progresses asymptomatically in domestic animals such as sheep, goats, and cattle,
and close contact with animals in the viremic stage has been
established in the literature as one of the transmission
routes.22,27,28 In our country, the primary route of transmission in cases with no history of tick contact is close contact
with animals. Contact with a patient’s blood or excretions is
another route of transmission. In the literature, epidemics by
this transmission route have been reported.29—31 In Turkey,
there have been six reported cases, three in healthcare
workers, two in siblings, and one in a breastfed baby of a
nursing mother with CCHF; all had a history of contact with a
CCHF patient.
Evaluation of clinical findings showed that the most common symptoms were fatigue, fever, myalgia, and headache.
The most common symptoms reported in the literature have
been fever, fatigue, headache, loss of appetite, and myalgia.3,8,22,32,33 In the cases from our country, hemorrhagic
findings were detected in almost a quarter of cases. The
rate of cases with hemorrhagic findings has gradually
decreased over the years ( p < 0.05; Table 2), and this may
be attributed to diagnosis of cases with mild to moderately
severe findings due to increased awareness of healthcare
personnel and patients about the disease.
Primary laboratory findings in patients diagnosed with
CCHF are thrombocytopenia, leukopenia, and increased
levels of transaminases.1,7,8,22,27 In the cases from our country, thrombocytopenia was the most common laboratory
finding (in 93.2% of cases). This was followed by leukopenia
(88.9%) and elevated levels of transaminase (85.9%).
Ribavirin treatment was started in nearly one third of the
patients with data for treatment options on their reporting
forms. Despite some missing data, ribavirin use for treatment
385
purposes has gradually decreased over the years. Currently,
there are no Food and Drug Administration approved antiviral
agents for the treatment of CCHF.22 Ribavirin has been shown
to inhibit in vitro viral replication.18,34 In Turkey, it has been
in use in clinical practice by some centers for treatment purposes. The treatment efficacy of ribavirin in CCHF
remains unclear. Nevertheless, the literature reveals studies
reporting its efficiency in treatment and prophylaxis.31,35—38
Some studies from our country have reported a decreased
mortality rate among severe cases who were given oral
ribavirin treatment, while other studies have reported that
ribavirin has no effects on mortality.6,8,39
CCHF remains a seasonal problem in the Mid-Eastern
Anatolia region of Turkey. The Turkish Ministry of Health
has been conducting studies on the reporting, diagnosis,
and treatment of the disease. We believe that the data
collected in Turkey on CCHF will significantly contribute to
the literature.
Conflict of interest: No conflict of interest to declare.
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