¿Qué hemos aprendido de la fiebre hemorrágica de Crimea-Congo? · 2018. 6. 26. · 3 1944-1945. 200 cases in soldiers Des-población incremento de vectores y reservorios Re-población

¿Qué hemos aprendido de la fiebre hemorrágica de Crimea-Congo?

Dr. Jose R Arribas

@jrarribas

2

HistoryHistory

Qué hemos aprendido de la fiebre hemorrágica de Crimea-Congo

3

1944-1945. 200 cases in soldiers

Des-población

incremento de vectores y reservorios

Re-población

Población susceptible


Source: Önder Ergonül, Chris A. Whitehouse. CRIMEAN-CONGO HEMORRHAGIC FEVER. A Global Perspective. Springer. ISBN 978-1-4020-6105-9 (HB).

4Qué hemos aprendido de la fiebre hemorrágica de Crimea-Congo

1944, península de Crimea

1956, Congo

5

1967 ¿Congo-Crimean or Crimean-Congo?


Source: https://en.wikipedia.org/.

Mikhail Petrovich Chumakov

(1909-1993)

Jordi Casals i Ariet

(1911- 2004)John Payne Woodall

(1935- 2014)

6

VirologyVirology


7

Single-stranded negative strand RNA Viruses

Source: Scie mEcker DJ, et al BMC Microbiol 2005;5:19.


Source: Estrada-Peña A, Palomar AM, Santibáñez P, Sánchez N, Habela MA, Portillo A, et al. Crimean-Congo hemorrhagic fever virus in ticks, Southwestern Europe, 2010. Emerging Infect Dis 2012; 18:179–180.

Crimean-Congo Hemorrhagic Fever Virus in Ticks, SouthwesternEurope, 2010


Source: https://www.msssi.gob.es/profesionales/saludPublica/ccayes/analisisituacion/doc/crimeaCongo.pdf

Informe de Situación y Evaluación del Riesgo de Transmisión de Fiebre Hemorrágica de Crimea-Congo (FHCC) en España. Octubre 2011


Source: Negredo A, et al. N Engl J Med 2017; 377:154–161.

Reemerging Infectious Diseases. 2016: CCHF


Phylogenetic tree


12

Vector (and reservoir)Vector (and reservoir)



Source: Önder Ergonül, Chris A. Whitehouse. CRIMEAN-CONGO HEMORRHAGIC FEVER. A Global Perspective. Springer. ISBN 978-1-4020-6105-9 (HB)

> 30 species of ticks15 minutes (Powasan)

Ixodidae (hard ticks)Hyalomma marginatum, lusitanicum

14

Hyalomma distributionHyalomma distribution


Geographic distribution of CCHF - 1


Geographic distribution of CCHF - 2


Source: https://ecdc.europa.eu/en/publications-data/hyalomma-marginatum-current-known-distribution-europe-october-2017

Arrival to Spain


Source: Palomar AM et al. Crimean-Congo Hemorrhagic Fever Virus in ticks from migratory birds, Morocco. Em Infec Dis 2013. 19:260-3


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ExtremaduraCastilla La ManchaCastilla y LeónMadrid7/11 comarcas

Todas las garrapatas positivas han sido capturadas sobre animales silvestres, fundamentalmente ciervos Hyalomma Lusitanicum

19

Lyfe cycleLyfe cycle


Life cycle


Life cycle


5,6: Transtadial7: Venereal8: Vertical10: Horizontal

Person to person transmission


• Blood

• Bodily fluids

Source: Perspectives in Medical Virology, Elsevier, 2006, Volume 16, Pages 299-324

23

Clinical FeaturesClinical Features


2424

Source Ergönül Ö. Crimean-Congo haemorrhagic fever. The Lancet Infectious Diseases 2006; 6:203–214.

Clinical and laboratory course of CCHF

Max 13


2525

Source Ergönül Ö. Crimean-Congo haemorrhagic fever. The Lancet Infectious Diseases 2006; 6:203–214.

Hemorrhagic Period


13 14 15 19 23 25

Travel to San Juan del Molinillo. Walk through the field.

Posible tick bite, not attached.

Hospital Infanta Leonor (Madrid): Fever, mild diarrhea and malaise

•On admission: Platelets 30.000. Cr 1.63 mg/dl, Lactate 1.45. CPK 311, LDH

746, GPT 88, GOT 203.

•24h later: Platelets 9.000, INR 1.93.

August

ICU admision: thrombocytopenia and severe coagulopathy

Inotropic treatment, hemofiltration, empiric antibiotics

18

DOI: day of illness

Index case

Qué hemos aprendido de la fiebre hemorrágica de Crimea-Congo 26

27

Index case

Liver Function Test CoagulationBlood Cell Counts

1 2 3 4 5 6 7 8 9

Hemoglobin (g/dL) 13,4 13,3 12,5 11,4 10,1 9,3 5,3 7 7,9

White cells (×10−3/mm3) 13,92 11,39 11,25 6,7 7,19 18,58 10,6 11,1 3,8

Platelets (×10−3/mm3) 30 9 6 9 7 123 66 150 62

0

20

40

60

80

100

120

140

160

0

2

4

6

8

10

12

14

16

18

20

Pla

tele

ts(x

10

3/u

L

Hae

mo

glo

bin

(mg/

dL)

Leu

cocy

tes

(x1

03/u

L)

Day of Illness

Hemoglobin (g/dL) White cells (×10−3/mm3) Platelets (×10−3/mm3)


CoagulationBlood Cell Counts Liver Function Test

28

Index case

Day of Illness 1 2 3 4 5 6 7 8 9

AST (U/liter) 203 289 374 717 1.922 12.142 10.479 19.389 17.516

ALT (U/liter) 88 85 113 234 579 3.538 2.842 5.206 4.300

Bilirubin (mg/dL) 0.9 0.7 0.5 0.9 2.1 5.5 4.2 4.3 4.2

GGT (U/L) 431 449 500

LDL (U/L) 746 1.375 10.220 17.427

CPK (U/L) 311 412 594 731 1.101 2.250 1.801 5.216 68.168


29

Index case

Blood Cell Counts Liver Function Test Coagulation

Day of Illness 1 2 3 4 5 6 7 8 9

INR 1.47 1.93 1.51 1.35 1.54 2.33 2.24 2.68 2.81

Prothrombin Time (sec) 18.1 22.7 18.5 16.7 18.2 27.8 28.1 33.9 35.7

Prothrombin activity (%) 52.8 37.7 51 60 49.1 31

APTT (sec) 55.4 93.9 92 85.9 76.6 77.4 64.2 77 63.6

Fibrinogen (mg/dL) 200 < 150 < 150 < 150 < 150 < 150 96 73 104

D-dimer (mcg/L) > 30.000 80.000


30

Index case

• Massive hepatocyte necrosis sparingnarrow periportal and pericentral rims.

• Hepatocytes showed a swollenappearance but strikingly, cellremnants stayed in place, a proportionof them with ghostly nuclei.

• Councilman-like bodies could be easilyspotted.

• Hepatocytes contained cytoplasmicmacro and microvesiculation.

• Although sinusoidal congestion waspresent it wasn’t a prominent feature.

Liver


31

Prognostic FactorsPrognostic Factors


3232

∼Turkey: 15 years experience: ∼ 10.000 cases

Source: Leblebicioglu H, Ozaras R, Irmak H, Sencan I. Antiviral Research. ANTIVIRAL RESEARCH 2016; 126:21–34..


3333

Clinical Spectrum

Source: Leblebicioglu H, Ozaras R, Irmak H, Sencan I. Antiviral Research. ANTIVIRAL RESEARCH 2016; 126:21–34..


ASYMPTOMATIC INFECTION (seroprevalence studies)

MILD symptomatic infection

MODERATE symptomatic infection

SERIOUS symptomatic infection

FATAL symptomatic infection

3434

Predicitve score

7

Source: Duh D, Saksida A, Petrovec M, Ahmeti S, Dedushaj I, Panning M, et al. Viral load as predictor of Crimean-Congo hemorrhagic fever outcome. Emerging Infect Dis 2007; 13:1769–1772.


3535

Predicitve score



36

CCHF: Viral Loads of Fatal and Non-fatal Patients

Source: Hasanoglu et al. J Clin Virol 2016; 75:42–46.


3737

Viral Load as Predictor of Crimean-Congo Hemorrhagic Fever Outcome


“It was shown that viral load of >108 copies/mL is a strong factor (p<0.001) for differentiating CCHF patientswho died from those who survived”

Index case: 108 & 109

Secondary case: 107


38

TreatmentTreatment



4040

Source: Ascioglu S, Leblebicioglu H, Vahaboglu H, Chan KA. Ribavirin for patients with Crimean-Congo haemorrhagic fever: a systematic review and meta-analysis. Journal of Antimicrobial Chemotherapy 2011; 66:1215–1222.


4141

The Role of Ribavirin in CCHF

PLTs

Incubation3-7 days

Prehemorrhagic period1-7 days

Hemorrhagic period

2-3 days

Convelescence

AST and ALT

Fatality

7 d 10 d days

Disseminated Intravascular Coagulation

viremia

EARLYPHASE

LATEPHASE

CYTOKINES

Ribavirin could be more effective in early phaseSource: Ergonul O. Treatment of CCHF, Antivir Res 2008.


4242

Secondary Case – August 2016

• 50 years-old male• ICU Nurse


4343

The role of Ribavirin in CCHF


4444

Animal Model


4545

Hematologic support

Sangrado masivo agudo con shock hipovolémico

Pacientes con cifra de plaquetas por debajo de 50.000/mm3 y diátesis

hemorrágica

Pacientes con cifra de plaquetas por debajo de 50.000/mm3 y que requieren una

cirugía urgente o intervención invasiva

Pacientes con cifra de plaquetas por debajo de 20.000/mm3 y que presentan

fiebre y alteraciones de la coagulación

Pacientes con cifra de plaquetas por debajo de 10.000/mm3

Source: de la Calle F et al Manejo terapéutico de la fiebre hemorrágica de crimea congo. Enf Inf Microbiol Clin. En prensa


4646

Secondary Case – August 2016

• 50 years-old male• ICU Nurse

CCHF PCR Positive

Homozygous rs1127354 & Heterozygousrs7270101 (Inosine Triphosphatase alleles)

Platelets infusion


47

Risk for health care workersRisk for health care workers


4848

Transmission in the community


Source: Koksal et all. The seroprevalance of Crimean-Congo haemorrhagic fever in people living in the same environment with Crimean-Congo haemorrhagic fever patients in an endemic region in TurkeyI.Epidemiol. Infect. (2014), 142, 239–245

4949

Investigation of Crimean-Congo Hemorrhagic Fever Virus Transmissionfrom Patients to Relatives: A Prospective Contact Tracing Study

Source: Gozel MG, Bakir M, Oztop AY, Engin A, Dokmetas I, Elaldi N. Investigation of Crimean-Congo Hemorrhagic Fever Virus Transmission from Patients to Relatives: A Prospective Contact TracingStudy. American Journal of Tropical Medicine and Hygiene 2014; 90:160–162.

0/116 with serological evidencie of CCHF


5050

Crimean-Congo Hemorrhagic Fever among Health Care Workers

Cortesia: Dr Ö Ergonul. In press


5151

Riks for Health Care Workers


La Paz- Carlos III University Hospital, Madrid (Spain)

Hitit University Hospital, Çorum (Turquía)

52

European Network of Infectious Disease (EUNID) recommendations forcare of patients with known viral infections

Details Risk group Human-to-humanspread

EUNID recommendations

Minimun Optimun

Phleboviruses

Rift Valley fever virus Mosquito borne 3 None Standard ..

Togoviruses

Venezuelan equine encephalomyelitis

Mosquito borne 3 None Standard ..

Chikungunya virus Mosquito borne 3Yes, one suspected hospital- adquiredinfection by contact

Standard ..

Bunyaviruses

Hantaan virusesHaemorrhagic fever with renalsyndrome, and other Puumala, Seoul, and Sin nombre virus

4 Yes Droplet Airborne

Congo-Crimean heamorrhagicfever virus

.. 4 Yes HLIU ..

Paramyxoviruses

Hendra and Hendra-like virus Equine morbillivirus encephalitis 3 Unknown Airborne HLIU

Rhabdoviruses

Vesicular stomatitis virus 3Highly contagious bycontact

Airborne HLIU

Source: Brouqui P, Puro V, Fusco FM, Bannister B, Schilling S, Follin P, et al. Infection control in the management of highly pathogenic infectious diseases: consensus of theEuropean Network of Infectious Disease. The Lancet Infectious Diseases 2009; 9:301–311


53

Unidad de Aislamiento de Alto Nivel

3r Congreso

AEBioS


5454

Contactos

• 437 exposed subjects,

– 386: high risk

– 51: low risk

• 2 contacts admitted to HLIU

• None contracted symptomatic CCHF



Comunicación 0457Comunicación 0457

5656

Occupational exposure to CCHF

• 437 exposed subjects,

– 386: high risk

– 51: low risk

• 2 contacts admitted to HLIU

• None contracted symptomatic CCHF

Source: Emerg Infect Dis 2014Qué hemos aprendido de la fiebre hemorrágica de Crimea-Congo

57

Index case

ILUH: Infanta Leonor University Hospital; GMUH: Gregorio Marañon University Hospital; ICU: Intensive Care Unit; CCHF: CrimeanCongo Haemorrhagic Fever; HLIU: High Level Isolation Unit; DOI: day of illness


58

DischargeDischarge


5959

Multi-center prospective evaluation of discharge criteria forhospitalized patients with Crimean-Congo Hemorrhagic Fever

Source: Leblebicioglu H, Sunbul M, Barut S, Buyuktuna SA, Ozkurt Z, Yapar D, et al. Multi-center prospective evaluation of discharge criteria for hospitalized patients withCrimean-Congo Hemorrhagic Fever. ANTIVIRAL RESEARCH 2016; 133:9–13.


6060

0

1

2

3

4

5

6

0

1

2

3

4

5

6

7

8

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

Tite

r

Log

10

Vir

al R

NA

(co

pie

s/m

L)

Day of Illness

Plasma Viral RNA

IgG

IgM

Vaginal Viral RNA

Saliva ViralRNA

1/1280

1/320

1/160

1/80

1/40

1/640

Ribavirine


61

PreparednessPreparedness


62

Top Emerging Pathogens Likely to Cause Severe Outbreaks in the Near Future

Source: Røttingen J-A, Gouglas D, Feinberg M, Plotkin S, Raghavan KV, Witty A, et al. New Vaccines against Epidemic Infectious Diseases. N Engl J Med 2017; :NEJMp1613577.


6363

Protocolo de vigilancia de la Fiebre Hemorrágica Crimea-Congo

Source: https://goo.gl/Ca8hcs


6464

UAAN en España


MADRIDHULP/CIIIHGD

CATALUÑACLINIC

PAIS VASCODONOSTI

C. VALENCIANALA FE

ANDALUCIAVIRGEN DEL ROCIO

CANARIASVIRGEN DE LA CANDELARIA

6565

Agradecimientos: UAAN. La Paz/CIII

High Level Isolation Unit. Hospital Universitario La Paz: Bouchra Alami Tajri, Ana María Alba Suarez, Mª Elena Aldeanueva Serrano, Jesus Jose Alonso Domingo, Elena Aparicio Plaza, Omar Arabi Fernández, Marta Arsuaga Vicente, Maritza Olimpia Armijo Castillo, Rosa Mª Avila Borja, María Isabel Barrientos Martínez, Pilar Borrego Prieto, Marta Bretín Zornoza, Mª Luisa Cabildo Fajardo, Lucía Cachafeiro Fuciños, Encarnación Del Campo Ortún, Juan Eduardo Campos Higueras, Lorena Casado Fernández, Ana Mercedes Castaño Carmona, Carolina Castillo Portellano, Alicia Cerón Serrano, Yolanda Cuesta Herrero, Mª Del Carmen De Dompablo Ferrándiz, Marta Díaz Menendez, Victor Enriquez Calatrava, Belen Fernández Puntero, Eva Maria Flores Cabeza, Marta Galvez Charro, Ricardo García Hernandez, Miguel Angel García Expósito, Crsitina GarciaGonzalez, Mireia García Sánchez , Ana María Gómez Campos, Emilia Gómez Rodríguez, Elena Gómez Del Pulgar Carrillo, Miguel Angel González Herrero , Itziar González Herrezuelo, Antonio González Navarro, Ana Isabel González Del Castillo, Santiago González Espinosa, Juan Carlos Gracia Pasamar, Raul Granizo Lopez, Caroline GutierrezPlana, María Gutierrez Prieto, Jorge Hermida Rodriguez, Monica Hernández Bernal, Carmen Herrero Benito, María Teresa Herrero Alonso, Paulina Andres Jara Orozco, Rafael Jiménez Castellano, Mercedes León Pérez, Pedro López Lorente, Cristina López Alvir, Yolanda López Díaz-Plaza, Carmen Lorenzo Velez, Vanesa Lucas Burgos, Beatriz Machón Rodríguez, Felipe Mármol Martínez, Cristina Marote Martín, Concepción Martínez Corral, Silvia Antonia Martínez Nieto, Jose Iván Martínez Quintana, Cristina MolinsBustamante, Erica Moreno Lozano, Cristina Moreno Martinez, Mª Del Carmen Muñoz Gil, Carmen Ortega Lucena, Pedro Antonio Patrón Barambio, Melania Perez Pacheco, María Del Rosario Rivero Gómez, Rocio Rodriguez Diez, Ana San Juan Rodríguez, Vanesa Sanchez Arroyo, Miriam Sanchez Villarejo, Ana I Silva Montero, Mªdel Carmen Solera Martin De Nicolas, Miguel Angel Soriano Sánchez , Mary Rosa Tapia García, Adrián Torres Hidalgo

Marta ArsuagaFernando de la CalleMarta Diaz MenéndezMarta MoraAlejandro Martín QuirosElena Trigo


6666

Agradecimientos

Anabel Negredo (1), Fernando de la Calle-Prieto (2), Eduardo Palencia-Herrejón (3), Marta Mora-Rillo (2), Jenaro Astray-Mochales (4), María Paz Sánchez-Seco (1), Esther Bermejo Lopez (5), Javier Menárguez (6), Ana Fernández-Cruz (7) Beatriz Sánchez-Artola (8), Elena Keough-Delgado (5), Eva Ramírez de Arellano (1), Fátima Lasala (1), Jakob Milla (6), Jose Luis Fraile (9), Maria Ordobás Gavín (4), Amalia Martinez de la Gándara (3), Lorenzo López Perez (3), Domingo Diaz-Diaz (3), Mª Aurora López-García (3), Pilar Delgado-Jimenez (10), Alejandro Martín-Quirós (2), Elena Trigo (2), Juan Carlos Figueira (2) Jesús Manzanares (2), Elena Rodriguez-Baena (4), Luis Garcia-Comas (4), Olaia Rodríguez-Fraga (2), Nicolás García-Arenzana (11), Victoria Fernández-Díaz (12), Victor Manuel Cornejo (2), Jonas Schmidt-Chanasit (13), Petra Emmerich (13) for the Crimean Congo Hemorrhagic Fever @Madrid working group*1. Arbovirus Laboratory, Centro Nacional de Microbiología, Instituto de Salud Carlos III: Ana Vázquez, Lourdes Hernández, Laura Herrero, Francisca Molero.2. Preventive Medicine Department. Hospital Universitario La Paz: Ana Robustillo Rodela, Pilar Elola Vicente4. Internal Medicine Department. Hospital Universitario La Paz: Francisco Arnalich5. Laboratory Medicine, Hospital Universitario La Paz: Antonio Buño Soto6. Intensive Care Unit. Hospital Universitario La Paz: Abelardo García de Lorenzo7. Department of Occupational Health. Hospital Universitario La Paz: Concepción Núñez, Consuelo Rodrigo Garcia-Pando , Gabriela MartinsMuñoz, Sofia Gabriela Velasquez-Alcala8. Department of Nursing. Hospital Universitario La Paz: Mª Ángeles Sánchez-Castillo, Esther Rey-Cuevas, Mª Del Rosario Férnandez-Acevedo9. Pharmacology Deparmtent. Hospital Universitario La Paz: Alberto Borobia10. Epidemiology Area of the Autonomous Community of Madrid: Ramón Aguirre Martín-Gil, Mª Carmen Alvarez-Castillo, Andrés Aragón-Peña, Carmen de Burgos-Lunar, Esther Córdoba-Deorador, Juan Carlos Diezma-Criado, Felicitas Domínguez -Berjón, Mª Jose Esteban-Niveiro, Jose Bernardo-Ferrer Simó, Carmen Yolanda Fuentes-Rodriguez, Fernando Fuster, Isabel Garcia-Mañosa, Elisa Gil-Montalbán, Consuelo Ibáñez-Martí, Ester InsuaMarisquerena, Maria Dolores Lasheras-Carbajo ,Pello Latasa-Zamalloa, Mª Angeles Lópaz-Perez, Eloy Marino, Fernando Martin-Martínez, Manuel Martinez-Vidal, Jose Ignacio de Miguel-Moro, Alba Nieto-Juliá, Rosa Noguerales- De la Obra, Honorato Ortiz-Marrón, Mª Teresa Palomino-Lopez, Jesús Sanchez-Diaz, ,Amaya Sánchez-Gómez ,Mª José Torrijano-Castillo, Irene Wijers11. Ministry of Health: Maria José Sierra-Matamoros, Fernando Simón-Soria12. Pathology Department. Hospital Universitario Gregorio Marañón: Julio García Bordas13. Microbiology Department. Hospital Universitario Gregorio Marañon: Patricia Muñoz García, Roberto Alonso Fernández, María José Goyanes, Paloma Gijón Vidaurreta, Pablo Martín-Rabadán, Carlos Sánchez Carrillo, Emilio Bouza14. Intensive Care Unit. Hospital Universitario Gregorio Marañon: Juan Camilo Barrios, Jose Eugenio Guerrero15. Emergency Department. Hospital Universitario Infanta Leonor: Carlos Bibiano, Pablo Medina Iglesias, Rodrigo Pacheco Puig, Jose Luis Aguilar Huertas, Elena Sanz de Miguel16. Department of Occupational Health. Hospital Universitario Infanta Leonor: Marta de Sansegundo Reyes, Irene Camacho Muñoz17. Central Laboratory of the Autonomous Community of Madrid: Fernando Cava


67

Enveloped particles with a tripartite, single-stranded RNA genome of negative

Source: Ergonul O. Crimean-Congo haemorrhagic fever. Lancet Infect Dis 2006; 6:203–14Anagnostou V, Papa A. Evolution of Crimean-Congo Hemorrhagic Fever virus. Infection, Genetics and Evolution. 2009. 9:948-53.http://ecdc.europa.eu/en/healthtopics/emerging_and_vector-borne_diseases/tick_borne_diseases/crimean_congo/pages/index.aspx



Source: http://wysinfo.com/Migratory_Birds/Migratory_Birds_Without_Boundaries.htmhttp://www.seen-net.eu

6969

Supportive treatment. Secondary case


Documents

¿Qué hemos aprendido de la fiebre hemorrágica de Crimea-Congo? · 2018. 6. 26. · 3 1944-1945. 200 cases in soldiers Des-población incremento de vectores y reservorios Re-población