The n e w e ng l a n d j o u r na l
Brief Report
The authors’ full names, academic de-
grees, and affiliations are listed in the
Appendix. Address reprint requests to Dr.
Arribas at the High Level Isolation Unit,
Hospital Universitario La Paz, Idipaz,
Castellana 261 28046, Madrid, Spain, or
at ­joser​.­arribas@​­salud​.­madrid​.­org.
* A complete list of the members of the
Crimean Congo Hemorrhagic Fever@
Madrid Working Group is provided in
the Supplementary Appendix, available
at NEJM.org.
Drs. Negredo and de la Calle-Prieto con-
tributed equally to this article.
N Engl J Med 2017;377:154-61.
DOI: 10.1056/NEJMoa1615162
Copyright © 2017 Massachusetts Medical Society.
154
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of m e dic i n e
Autochthonous Crimean–Congo
Hemorrhagic Fever in Spain
A. Negredo, F. de la Calle‑Prieto, E. Palencia‑Herrejón, M. Mora‑Rillo,
J. Astray‑Mochales, M. P. Sánchez‑Seco, E. Bermejo Lopez, J. Menárguez,
A. Fernández‑Cruz, B. Sánchez‑Artola, E. Keough‑Delgado, E. Ramírez de Arellano,
F. Lasala, J. Milla, J.L. Fraile, M. Ordobás Gavín, A. Martinez de la Gándara,
L. López Perez, D. Diaz‑Diaz, M.A. López‑García, P. Delgado‑Jimenez,
A. Martín‑Quirós, E. Trigo, J.C. Figueira, J. Manzanares, E. Rodriguez‑Baena,
L. Garcia‑Comas, O. Rodríguez‑Fraga, N. García‑Arenzana, M.V. Fernández‑Díaz,
V.M. Cornejo, P. Emmerich, J. Schmidt‑Chanasit, and J.R. Arribas,
for the Crimean Congo Hemorrhagic Fever@Madrid Working Group*​​
Sum m a r y
Crimean–Congo hemorrhagic fever (CCHF) is a widely distributed, viral, tickborne
disease. In Europe, cases have been reported only in the southeastern part of the
continent. We report two autochthonous cases in Spain. The index patient ac-
quired the disease through a tick bite in the province of Ávila — 300 km away
from the province of Cáceres, where viral RNA from ticks was amplified in 2010.
The second patient was a nurse who became infected while caring for the index
patient. Both were infected with the African 3 lineage of this virus. (Funded by
Red de Investigación Cooperativa en Enfermedades Tropicales [RICET] and Effi-
cient Response to Highly Dangerous and Emerging Pathogens at EU [European
Union] Level [EMERGE].)
C
CHF is a severe viral disease caused by a nairovirus of the bunya-
viridae family. Humans become infected through tick bites or contact with
viremic patients or animals. Clinically, CCHF is characterized by fever,
coagulopathy, and hepatitis.1 The disease is widespread geographically and has
been identified in more than 30 countries in Africa, Asia, the Middle East, and
Europe. In Europe, CCHF has been reported only in countries located in the south-
eastern part of the continent: Russia, Georgia, Ukraine, Bulgaria, Albania, Kosovo,
Greece, and Turkey.2 Here we report the epidemiologic and clinical course of two
patients who contracted the disease autochthonously in Spain.
C a se R ep or t s
Index Patient
A 62-year-old man who had a history of hypertension and obstructive sleep apnea
and had been living in Madrid presented to the Infanta Leonor University Hospital
with a 2-day history of high fever, abdominal pain, malaise, nausea, and diarrhea.
During the ensuing hours, purpuric lesions and hematomas developed at veni-
puncture sites. The next day, the patient was transferred to the intensive care unit
(ICU) because of severe coagulopathy, with macroscopic hematuria, purpuric skin
n engl j med 377;2 nejm.org  July 13, 2017
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 Brief Report
lesions and hematomas, a low platelet count, and
prolonged prothrombin and partial-thrombo-
plastin times. The patient’s family reported that
four days before admission, while visiting relatives,
the patient had walked through the fields in San
Juan del Molinillo, a small village located in
Ávila, a province of central-western Spain (Fig. 1).3
When he returned to his relatives’ home, he
noticed a tick on his left knee. The patient lived
and worked in Madrid and had not traveled
abroad. After learning that the patient may have
had a tick bite, clinicians initiated treatment
with doxycycline.
On the seventh day of illness, the patient’s
clinical condition deteriorated rapidly. He had
macroscopic hematuria, worsening of purpuric
skin lesions and hematomas, fulminant hepatic
failure, severe respiratory insufficiency, encepha-
lopathy, hypoglycemia, and severe metabolic
acidosis. Later that day, he was transferred to
the ICU at Gregorio Marañón University General
Hospital to be evaluated for liver transplantation.
During the next 24 hours, the patient had dis-
tributive shock, oliguric renal failure, very high
liver-enzyme levels, and persistent metabolic
acidosis. All tests for routine infections were
negative. The patient died on the ninth day of
illness. The family consented to necropsy. Data
regarding treatment, laboratory analyses, and
clinical variables are provided in Figure S3 and
Tables S1, S2, and S3 in the Supplementary Ap-
pendix, available with the full text of this article
at NEJM.org.
Analysis of serum samples obtained on the
sixth and eighth days of the patient’s illness re-
vealed 1.0×108 and 1.2×109 viral copies per milli-
liter, respectively. The CCHF virus was isolated
by means of in vitro cell cultures of the first
plasma sample obtained. No antibodies against
the virus were detected on the sixth day of ill-
ness. (Details are provided in the Supplementary
Appendix.)
We performed necropsy using routine protec-
tion with gloves, goggles, water-repellent gowns,
and surgical masks. Gross examination revealed
generalized visceral edema, with substantial
amounts of serohematic ascitic fluid and dis-
seminated cutaneous and visceral hemorrhages.
The liver was normal in both weight and size,
with a brownish appearance and softened con-
sistency. Representative samples were processed
and stained with hematoxylin and eosin.
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We did not identify cytopathic cellular inclu-
sions or inflammatory infiltrates in any of the
organs examined, and endothelial swelling was
not a prominent feature. There was massive hepa-
tocyte necrosis, with sparing of narrow peripor-
tal and pericentral rims, and mild sinusoidal
congestion. No Kupffer-cell hyperplasia or inflam-
matory infiltrates were observed. The hepato-
cytes had a swollen appearance and widespread
necrosis. In general, the hepatocytes contained
cytoplasmic macro- and microvesiculation (Fig. 2D
and 2E, respectively). Although most mucosae
were preserved, the appearance of the colon was
striking owing to its complete epithelial denuda-
tion. The crypts were filled with basophilic mu-
coid material and walled by sloughed apoptotic
cells, again without inflammatory infiltrates
(Fig. 2A and 2B). Occasional microthrombi were
observed. The bone marrow showed hemorrhages
and a preserved megakaryocyte population with
a normal morphologic appearance. The spleen
showed slight lymphoid depletion and hemor-
rhage but no necrotic areas.
Second Patient
A 50-year-old female nurse was the second patient.
On August 23, 2016 (Fig. 1), she had assisted
with the endotracheal intubation of the index
patient and with the insertion of femoral venous
and arterial catheters. Profuse bleeding compli-
cated placement of the catheters, and the nurse’s
hands were in direct contact with the patient’s
blood, although the skin was not punctured. The
nurse lived and worked in Madrid and reported
no recent travel abroad or to the countryside.
She had had no recent tick bites.
On the first day of her illness, August 27, fever,
asthenia, and arthromyalgias developed (Fig. 1).
On the second day, the patient was admitted to
the ICU at Infanta Leonor University Hospital
owing to the presence of petechiae, thrombocy-
topenia, and a mild increase in aminotransferase
levels. On the third day of illness, vaginal bleed-
ing started, coinciding with expected time of her
normal menstruation period. On the fourth day
of illness, CCHF was suspected. Empiric treat-
ment with ribavirin was started, with an oral
dose of 1000 mg administered every 6 hours and
continued for the next 24 hours. The drug was
administered intravenously thereafter. On the
sixth day of illness, the dose of ribavirin was
reduced to 500 mg every 8 hours, in keeping
155
 The n e w e ng l a n d j o u r na l of m e dic i n e

A Timeline Involving Patients and Contacts

Orotracheal intubation
Travel to Ávila Central venous catheter Contact Tracing and Surveillance
Tick bite placement
Transfer to GMUH HLIU health care workers
Onset of symptoms

Death Family, ILUH, and GMUGH

ILUH admission Necropsy health care workers

Follow-up visit
DOI 0 DOI 9

Index Case Onset of symptoms First blood RT-PCR negative

ILUH ICU Aminotransferase level
admission starts to decline HLIU discharge
CCHF diagnosis
Transfer to HLIU Platelet count starts Hospital discharge
to increase

DOI 0 DOI 9 DOI 11 DOI 20

Second Case
13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 1 2 6
August 2016 September 2016 October 2016

B Locations of CCHF Worldwide

50° North latitude: Limit for geographic distribution of genus hyalomma ticks

Hyalomma tick vector presence

CCHF virologic or serologic
evidence and vector presence
5–49 CCHF cases reported each year
2 ≥50 CCHF cases reported each year
3

Figure 1. Clinical Events and Locations.

Panel A shows a timeline of events related to the two patients and their contacts. The color blue denotes the day of infection for each
patient. Panel B shows the geographic location of Crimean–Congo hemorrhagic fever (CCHF) worldwide and in Spain, according to the
World Health Organization. Circle 1 marks the geographic area (39.63° north and 7.33° west), where hyalomma ticks infected with the
CCHF virus have previously been identified.3 Circle 2 marks San Juan del Molinillo (Ávila), where the index patient became infected.
Circle 3 marks Madrid, where the first and second cases were detected and where the patients received the diagnosis and were treated.
DOI denotes day of illness, GMUGH Gregorio Marañón University General Hospital, HLIU high-level isolation unit, ICU intensive care
unit, ILUH Infanta Leonor University Hospital, and RT-PCR reverse-transcriptase–polymerase chain reaction.

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 Brief Report

A B C

D E

Figure 2. Necropsy Findings for the Index Patient.

Panel A shows the colonic mucosa, in which the surface and crypt epithelium is completely sloughed (black arrow) and walled by apop-
totic cells (yellow arrow). The lamina propria is preserved (blue arrow). Panel B also shows the colonic mucosa. Epithelial-cell remnants
(arrows), which are apparently apoptotic, have been shed. There is no inflammation. Panel C shows bone marrow that is slightly hypo-
cellular. All hematopoietic-cell lineages can be seen, including two megakaryocytes (arrows). Hemorrhage (yellow arrow) and edema
(blue arrow) are also present. Panel D shows the liver, with a preserved portal tract at the center (in white) that is surrounded by massive
hepatocellular necrosis, congestion, and hemorrhage. Panel E also shows the liver. Most hepatocytes are necrotic, with cytoplasmic
vacuolar changes (arrows). All sections were stained with hematoxylin and eosin.

with the protocol for the treatment of CCHF
from the World Health Organization.4 The pa-
tient was subsequently transferred to the high-
level isolation unit at La Paz University Hospital.
On admission to this unit, the patient was
awake, alert, and fully oriented to time and
place. Physical examination revealed subcon-
junctival hemorrhage in the right eye, cutaneous
petechiae on pressure areas, and vaginal bleed-
ing. Hypoxemic respiratory failure associated
with a moderately sized pleural effusion in the
right lung led to treatment with oxygen by nasal
cannula until the 15th day of illness. On the 9th
day of illness, vaginal bleeding stopped. Levels
of aminotransferase and lactate dehydrogenase
began to decrease on the 9th day of illness, and
platelet levels began to increase on the 11th day.
Mild renal impairment persisted until the 20th
day. Complete data regarding the administered
treatment, laboratory results, and clinical vari-
ables are available in Tables S4 through S7 in the
Supplementary Appendix.
On the 9th day of illness, we discontinued
treatment with ribavirin because severe hemo-
lytic anemia was suspected. The patient received
transfusions of a total of 5 units of platelets
before we performed any invasive procedures
and when the platelet count fell below 10,000
per cubic millimeter. The transfusions took place
on the 6th and 8th days of illness.
Levels of CCHF virus in the blood were high-
est in a stored sample obtained on the 2nd day
of illness, at 3.6×107 copies per milliliter. We
also cultured the virus from a plasma sample on
the 7th day of illness. The first negative result for
viremia, obtained by means of real-time reverse-
transcriptase–polymerase-chain-reaction (RT-PCR)
assay, was observed on the 20th day of illness
(Fig. 3). Anti-CCHF virus antibodies were not
detectable on the 2nd day of illness. IgM titers
increased to 1:640 on the 6th day of illness and
started to decrease after the 15th day. The titer
for IgG antibodies remained constant (1:640),
with the exception of an isolated decrease that
was probably the result of a technical issue. RT-PCR
assays of several fluid samples were performed;

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 The n e w e ng l a n d j o u r na l of m e dic i n e

8 1:1280
Plasma viral RNA
7 IgG
1:640

6
Log10 Viral RNA (copies/ml)

Vaginal viral RNA 1:320

5

Titer
4 1:160

3 IgM
1:80
Saliva viral
2 RNA

Ribavirin 1:40
1

0 0
0 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Day of Illness

Figure 3. Timeline for CCHF Viral Load, Antibody Levels, and Ribavirin Administration in the Second Patient.
The y axis at left shows the viral RNA load (solid lines), and the y axis at right shows antibody titers (dashed lines).
The gray, horizontal, dashed line indicates the lower limit for the detection of viral RNA on RT-PCR assay. From the
eighth day of illness onward, several different body fluids were tested for CCHF RNA, and the viral load was mea-
sured if CCHF RNA was detected. Urine and sweat were always negative for CCHF RNA. Nasal (the 11th day of ill-
ness), conjunctival (the 13th day of illness), and rectal swabs (13th day of illness) were each weakly positive once.
Saliva (green) and vaginal (purple) swabs were positive and showed quantifiable levels of CCHF RNA. The solid
gray bar shows the duration of ribavirin therapy.

vaginal fluid was positive on the 4th day of ill- National Center for Biotechnology Information
ness, saliva on the 8th day, and conjunctival, with the use of the Basic Local Alignment Search
nasal, and rectal swabs were sporadically posi- Tool (BLAST), and the sequences showed a 99%
tive, with very low viral titers. After the 14th day identity with those from the African 3 lineage,
of illness, RT-PCR assays of all body fluids were such as the Mauritania ArD39554 (GenBank acces-
negative. On the 22nd day of illness, the mea- sion number, DQ211641) strain of the CCHF virus.5
sures taken in the high-level isolation unit were Phylogenetic analysis also revealed 99% identity
discontinued when two consecutive RT-PCR as- with African 3 lineage sequences (GenBank ac-
says of the blood were negative. cession numbers, KY492289 and KY492290) (Fig.
S2 in the Supplementary Appendix).
Iden t ific at ion of V irus
a nd C on tac t T r acing Contact Tracing
The Public Health Service from Comunidad de
Identification of Virus Madrid and the occupational health services at
We used two PCR methods designed to amplify each hospital performed contact tracing to iden-
two different targets of the CCHF viral genome tify all persons exposed to either patient. Con-
(Fig. S1 in the Supplementary Appendix). The tacts took their body temperature twice daily for
sequences in the plasma samples (592 bp of the 14 days after exposure. Among the 437 people
S segment) obtained from both patients were who were exposed, 386 were classified as having
100% identical. Nucleotide sequences were com- a high risk of acquiring the infection and 51 as
pared with those available in the database of the having a low risk (definitions are available in the

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 Brief Report
Supplementary Appendix). In addition, 59 health
care workers in the high-level isolation unit had
protected exposures while caring for the second
patient. None contracted symptomatic CCHF.
Serologic testing was not performed in contacts
to rule out asymptomatic disease.
Discussion
These autochthonous cases of CCHF represent a
change in the geographic distribution of the
disease. Given the expanding distribution of the
main vector,3,6-8 the appearance of these two
cases in a previously unaffected region of Europe
reinforces the notion that CCHF is a reemerging
infectious disease.
The index patient acquired CCHF through a
tick bite in the province of Ávila. The southern
region of this province shares a border with the
province of Cáceres, where the nucleic acid of
the CCHF virus was detected in Hyalomma lusitani-
cum ticks obtained from deer in 2010.3 The viral
nucleic acids amplified in the blood of both pa-
tients were identical and shared a genetic foot-
print with viruses of the African 3 lineage but
not with sequences from Eastern Europe (Fig. S2
in the Supplementary Appendix). The region of
the CCHF virus sequenced from infected ticks in
Cáceres3 (positions 115 through 326 in the S frag-
ment) is typically amplified by means of an
in-house RT-nested PCR analysis (positions 123
through 764). The amplification of sequences in
samples from ticks and from the case patients
showed that the sequences were nearly identical
to the ArD39554 strain — 98% for the ticks and
99% for the patients. We therefore conclude that
our index patient was probably infected by the
same CCHF virus that was detected in ticks in
2010. This particular strain could have arrived in
Spain through infected ticks carried by north-
ward migrating birds from Morocco, the live-
stock trade, the movement of infected animals,
or other means.8,9
We did not suspect CCHF until the second
patient presented with a clinical picture similar
to that of the index patient. It is very likely that
in the absence of a second case, this outbreak of
CCHF would not have been discovered. Thus, it is
possible that other cases of CCHF may have oc-
curred in Spain in recent years. In our circum-
stance, more than 400 people — primarily
health care workers — may have been exposed
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Copyright © 2017 Massachusetts Medical Society. All rights reserved.
to the CCHF virus while not wearing the appro-
priate personal protective equipment. Although
the nosocomial transmission of CCHF has been
previously described,10 we have not detected any
additional cases beyond that of the second patient,
whose exposure to the virus was substantial.
Both patients fulfilled the criteria for severe
CCHF.11,12, Although in the second patient we
observed a rapid decline of viremia with the con-
comitant use of intravenous ribavirin, its efficacy
for the treatment of CCHF remains controversial
— a meta-analysis did not reveal evidence in
favor of its use for this disease.13
The second case allowed us to study various
body fluids for the presence of the CCHF virus,
an aspect of infection for which there are very
few data. Unlike Ebola virus disease (EVD),14 in
CCHF the genetic material in all fluids cleared
before the viremia did. Although the viral load
in the second patient was low during the last
week of infection, she did have viremia for 20
days, a fact that delayed her discharge from our
high-level isolation unit. At this time, it is unclear
whether patients who are clinically well but still
have positive results on RT-PCR for the CCHF
virus in their blood can be safely treated without
the use of the precautions taken in the high-
level isolation unit. In Turkey, patients are routine­
ly discharged after improvement in the clinical
picture and in laboratory results without confir-
mation of clearance of the viremia.15 However,
there has been no evidence of subsequent spread
of the CCHF virus in Turkey, where these dis-
charge criteria are observed.
Our investigation of these cases provided us
with the rare opportunity to perform a human
necropsy — albeit inadvertently — in a case of
CCHF.16-18 Massive liver necrosis in the absence
of inflammatory infiltrates is consistent with the
findings reported in other hemorrhagic fevers.19-21
No cytopathic inclusions have been reported in
cases of CCHF,17 a finding that is in contrast
with the Cowdry type A intranuclear inclusions
seen in cases of Rift Valley fever19 and the cyto-
plasmic eosinophilic inclusions reported in cases
of EVD21 and Marburg virus disease.22 In CCHF,
the appearance of hepatocytes and the absence
of inflammatory infiltrates provide support for
the view that there is a primary cytopathic patho-
genic effect.
An unexpected finding in the necropsy was
the selective and complete apoptosis of colonic
159
 The n e w e ng l a n d j o u r na l of m e dic i n e

enterocytes in the absence of inflammatory in- In conclusion, we report two autochthonous

filtrates. This feature of the disease is unusual
because it is not accompanied by multiorgan
failure and suggests massive, viral-induced cell
damage. The in vitro activation of apoptotic path-
ways by the virus or by host cells has been re-
ported.23 Similar findings have been described in
cases of early infection with the simian immuno-
deficiency virus.24 It is possible that specific co-
lonic targeting is typical of this particular strain.
This characteristic would partly explain the ionic
imbalances and diarrhea. The colonic epithelium
could constitute a viral replication site. Findings
from bone marrow provide support for a periph-
eral pathogenic mechanism for thrombocytope-
nia, as has been described in association with
other viral infections.25
cases of CCHF occurring in Spain. Our observa-
tions highlight the importance of routine surveil-
lance of vectors capable of spreading CCHF.
When CCHF nucleic acid is amplified from in-
fected ticks in geographic areas that have previ-
ously been unaffected by CCHF, clinicians should
remain alert to the possibility of human cases.
Supported by Red de Investigación Cooperativa en Enferme-
dades Tropicales (RICET grant, RD12/0018/0023) and EMERGE
(Efficient Response to Highly Dangerous and Emerging Patho-
gens at EU [European Union] Level), a joint action funded under
the third EU Health Program (677066),.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Julio Farias of the Pathology Department at Gregorio
Marañón University General Hospital and Maria José Buitrago
and the rest of the members of the Grupo de Respuesta Rápida
of the Centro Nacional de Microbiología for their help.

Appendix
The authors’ full names and academic degrees are as follows: Anabel Negredo, Ph.D., Fernando de la Calle‑Prieto, M.D., Eduardo
Palencia‑Herrejón, M.D., Marta Mora‑Rillo, M.D., Jenaro Astray‑Mochales, M.D., Ph.D., María P. Sánchez‑Seco, Ph.D., Esther Bermejo
Lopez, M.D., Javier Menárguez, M.D., Ph.D., Ana Fernández‑Cruz, M.D., Ph.D., Beatriz Sánchez‑Artola, M.D., Elena Keough‑Delgado,
M.B., B.S., Eva Ramírez de Arellano, Ph.D., Fátima Lasala, Ph.D., Jakob Milla, M.D., Ph.D., Jose L. Fraile, M.D., Maria Ordobás Gavín,
M.D., Ph.D., Amalia Martinez de la Gándara, M.D., Lorenzo López Perez, M.D., Domingo Diaz‑Diaz, M.D., M. Aurora López‑García,
M.D., Pilar Delgado‑Jimenez, M.D., Alejandro Martín‑Quirós, M.D., Elena Trigo, M.D., Juan C. Figueira, M.D., Jesús Manzanares, M.D.,
Elena Rodriguez‑Baena, M.D., Luis Garcia‑Comas, Ph.D., Olaia Rodríguez‑Fraga, M.D., Nicolás García‑Arenzana, M.D., Ph.D., Maria V.
Fernández‑Díaz, B.S.N., Victor M. Cornejo, B.S.N., Petra Emmerich, Ph.D., Jonas Schmidt‑Chanasit, M.D., and Jose R. Arribas, M.D.
The authors’ affiliations are as follows: the Arbovirus and Imported Viral Diseases Unit, Centro Nacional de Microbiología, Instituto
de Salud Carlos III (A.N., M.P.S.-S., E.R.A., F.L.), Red de Investigación Colaborativa en Enfermedades Tropicales (A.N., M.P.S.-S.,
E.R.A., F.L.), High Level Isolation Unit (F.C.-P., M.M.-R., A.M.-Q., E.T., J.C.F., J. Manzanares, O.R.-F., V.M.C., J.R.A.) and Departments
of Preventive Medicine (N.G.-A.) and Occupational Health (M.V.F.-D.), La Paz University Hospital, Intensive Care Unit (E.P.-H., A.M.G.,
L.L.P., D.D.-D., M.A.L.-G.) and Departments of Internal Medicine (B.S.-A.), Emergency (J.L.F.), and Occupational Health (P.D.-J.), Infanta
Leonor University Hospital, Epidemiology Area of the Autonomous Community of Madrid (J.A.-M., M.O.G., E.R.-B., L.G.-C.), Intensive
Care Unit (E.B.L., E.K.-D.) and Departments of Pathology (J. Menárguez, J. Milla) and Clinical Microbiology and Infectious Diseases
(A.F.-C.), Gregorio Marañón University General Hospital, and Instituto de Investigación Sanitaria Gregorio Marañón, Complutense
University (J. Menárguez, J. Milla, A.F.-C.) — all in Madrid; and the World Health Organization Collaborating Center for Arbovirus and
Hemorrhagic Fever Reference and Research, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany (P.E., J.S.-C.).

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