05 FISIOPATOLOGIA_miercoles 14-08-13.ppt

8/11/2019 05 FISIOPATOLOGIA_miercoles 14-08-13.ppt

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Inaparente Fiebreindiferenciada Dengue y

dengue grave

Dengue es una solaENFERMEDAD


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N % N % N % N %

19 32.8 57 39.9 66 78.6 14 93.3

12 20.69 27 18.88 49 58.33 7 46.675 8.62 22 15.38 40 47.62 1 6.67

1 1.72 3 2.10 11 13.1 2 13.33

3 5.17 3 2.10 6 7.14 2 13.33

FHD(84) SCD(15)

Derrame pleural bilateral

Derrame pericrdico

FD(58) FD+H(143)

Edema pared vesicular y

AscitisDerrame pleural derecho

lquido perivesicular

(Garca M, Stgo de Cuba, 1997)

Cuadro 5.14


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.

Rev. Soc. Bras. Med. Trop Rev. Soc. Bras. Med. Trop 2008 ;41(1):6-10.

IL-6, TNF-alpha and IFN-gamma in dengue infection.

No statistically significant

differences were found betweenclinical forms,although IL-6 and IFN-gamma levels were higher in dengue fever casesand TNF-alpha levels were higher in dengue hemorrhagic fever (gradesI-II) than in dengue fever.
http://portal.revistas.bvs.br/transf.php?xsl=xsl/titles.xsl&xml=http://catserver.bireme.br/cgi-bin/wxis1660.exe/?IsisScript=../cgi-bin/catrevistas/catrevistas.xis|database_name=TITLES|list_type=title|cat_name=ALL|from=1|count=50&lang=pt&comefrom=home&home=false&task=show_magazines&request_made_adv_search=false&lang=pt&show_adv_search=false&help_file=/help_pt.htm&connector=ET&search_exp=Rev.%20Soc.%20Bras.%20Med.%20Trophttp://portal.revistas.bvs.br/transf.php?xsl=xsl/titles.xsl&xml=http://catserver.bireme.br/cgi-bin/wxis1660.exe/?IsisScript=../cgi-bin/catrevistas/catrevistas.xis|database_name=TITLES|list_type=title|cat_name=ALL|from=1|count=50&lang=pt&comefrom=home&home=false&task=show_magazines&request_made_adv_search=false&lang=pt&show_adv_search=false&help_file=/help_pt.htm&connector=ET&search_exp=Rev.%20Soc.%20Bras.%20Med.%20Trophttp://portal.revistas.bvs.br/transf.php?xsl=xsl/titles.xsl&xml=http://catserver.bireme.br/cgi-bin/wxis1660.exe/?IsisScript=../cgi-bin/catrevistas/catrevistas.xis|database_name=TITLES|list_type=title|cat_name=ALL|from=1|count=50&lang=pt&comefrom=home&home=false&task=show_magazines&request_made_adv_search=false&lang=pt&show_adv_search=false&help_file=/help_pt.htm&connector=ET&search_exp=Rev.%20Soc.%20Bras.%20Med.%20Trophttp://portal.revistas.bvs.br/transf.php?xsl=xsl/titles.xsl&xml=http://catserver.bireme.br/cgi-bin/wxis1660.exe/?IsisScript=../cgi-bin/catrevistas/catrevistas.xis|database_name=TITLES|list_type=title|cat_name=ALL|from=1|count=50&lang=pt&comefrom=home&home=false&task=show_magazines&request_made_adv_search=false&lang=pt&show_adv_search=false&help_file=/help_pt.htm&connector=ET&search_exp=Rev.%20Soc.%20Bras.%20Med.%20Trophttp://portal.revistas.bvs.br/transf.php?xsl=xsl/titles.xsl&xml=http://catserver.bireme.br/cgi-bin/wxis1660.exe/?IsisScript=../cgi-bin/catrevistas/catrevistas.xis|database_name=TITLES|list_type=title|cat_name=ALL|from=1|count=50&lang=pt&comefrom=home&home=false&task=show_magazines&request_made_adv_search=false&lang=pt&show_adv_search=false&help_file=/help_pt.htm&connector=ET&search_exp=Rev.%20Soc.%20Bras.%20Med.%20Trophttp://portal.revistas.bvs.br/transf.php?xsl=xsl/titles.xsl&xml=http://catserver.bireme.br/cgi-bin/wxis1660.exe/?IsisScript=../cgi-bin/catrevistas/catrevistas.xis|database_name=TITLES|list_type=title|cat_name=ALL|from=1|count=50&lang=pt&comefrom=home&home=false&task=show_magazines&request_made_adv_search=false&lang=pt&show_adv_search=false&help_file=/help_pt.htm&connector=ET&search_exp=Rev.%20Soc.%20Bras.%20Med.%20Trophttp://portal.revistas.bvs.br/transf.php?xsl=xsl/titles.xsl&xml=http://catserver.bireme.br/cgi-bin/wxis1660.exe/?IsisScript=../cgi-bin/catrevistas/catrevistas.xis|database_name=TITLES|list_type=title|cat_name=ALL|from=1|count=50&lang=pt&comefrom=home&home=false&task=show_magazines&request_made_adv_search=false&lang=pt&show_adv_search=false&help_file=/help_pt.htm&connector=ET&search_exp=Rev.%20Soc.%20Bras.%20Med.%20Trophttp://portal.revistas.bvs.br/transf.php?xsl=xsl/titles.xsl&xml=http://catserver.bireme.br/cgi-bin/wxis1660.exe/?IsisScript=../cgi-bin/catrevistas/catrevistas.xis|database_name=TITLES|list_type=title|cat_name=ALL|from=1|count=50&lang=pt&comefrom=home&home=false&task=show_magazines&request_made_adv_search=false&lang=pt&show_adv_search=false&help_file=/help_pt.htm&connector=ET&search_exp=Rev.%20Soc.%20Bras.%20Med.%20Trophttp://portal.revistas.bvs.br/transf.php?xsl=xsl/titles.xsl&xml=http://catserver.bireme.br/cgi-bin/wxis1660.exe/?IsisScript=../cgi-bin/catrevistas/catrevistas.xis|database_name=TITLES|list_type=title|cat_name=ALL|from=1|count=50&lang=pt&comefrom=home&home=false&task=show_magazines&request_made_adv_search=false&lang=pt&show_adv_search=false&help_file=/help_pt.htm&connector=ET&search_exp=Rev.%20Soc.%20Bras.%20Med.%20Trophttp://portal.revistas.bvs.br/transf.php?xsl=xsl/titles.xsl&xml=http://catserver.bireme.br/cgi-bin/wxis1660.exe/?IsisScript=../cgi-bin/catrevistas/catrevistas.xis|database_name=TITLES|list_type=title|cat_name=ALL|from=1|count=50&lang=pt&comefrom=home&home=false&task=show_magazines&request_made_adv_search=false&lang=pt&show_adv_search=false&help_file=/help_pt.htm&connector=ET&search_exp=Rev.%20Soc.%20Bras.%20Med.%20Trophttp://portal.revistas.bvs.br/transf.php?xsl=xsl/titles.xsl&xml=http://catserver.bireme.br/cgi-bin/wxis1660.exe/?IsisScript=../cgi-bin/catrevistas/catrevistas.xis|database_name=TITLES|list_type=title|cat_name=ALL|from=1|count=50&lang=pt&comefrom=home&home=false&task=show_magazines&request_made_adv_search=false&lang=pt&show_adv_search=false&help_file=/help_pt.htm&connector=ET&search_exp=Rev.%20Soc.%20Bras.%20Med.%20Trophttp://portal.revistas.bvs.br/transf.php?xsl=xsl/titles.xsl&xml=http://catserver.bireme.br/cgi-bin/wxis1660.exe/?IsisScript=../cgi-bin/catrevistas/catrevistas.xis|database_name=TITLES|list_type=title|cat_name=ALL|from=1|count=50&lang=pt&comefrom=home&home=false&task=show_magazines&request_made_adv_search=false&lang=pt&show_adv_search=false&help_file=/help_pt.htm&connector=ET&search_exp=Rev.%20Soc.%20Bras.%20Med.%20Trop


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The systemic hostinflammatory and coagulationactivation response occursearly in patients with dengueviral infection in the absence of

severe hemorrhagicmanifestationsAvila-Aguero ML et al, 2004


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Dengue tambien es unaenfermedad SISTEMICA


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Dengue es SISTEMICO

durante la fase virmica el virucirculante puede alojarseencualquier rgano, y a ese nivel

generar alguna de lasmanifestaciones clnicas de laenfermedad.


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Tambin el carcter

sistmico de la enfermedadest determinado por la

respuesta del hospedero.

Dengue es SISTEMICO


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. De la interaccin virus-hospedero se

generan diversos mecanismos,que actan de manera conjunta en unsujeto que, a su vez, tiene

particularidades genticasespecficas

(de Kruif, 2008).

Dengue es SISTEMICO


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-liberacin de citoquinas (Avila Agero, 2004; Perez etal, 2010)

,-diversas respuestas inmunopatologicas(Matthews y Rothman, 2008),

-induccin de apoptosis (Brown, 2009)-y la aparicin de fenmenos transitorios deautoinmunidad (Dejnirattisai et al, 2010)

Dengue es SISTEMICO


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y es una enfermedadSISTEMICA

y DINAMICA


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DENGUEEs una enfermedad

DINAMICA

Asintomtico InespecficosDengue

sin signosde Alarma

Denguecon signosde Alarma

Denguegrave


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Febril CRITICA RecuperaooFases da doena1 ao 7 dia 3 ao 6 dia > 5 diaPerodo

Viremia Extrav. plasmtico ReabsoroFisiopatologia

Pele Mucosas Grave (Macisa))Hemorragia

Sinais de alarmeClnica

HemoconcentraoDerrame cavitrio

Edema intersticial pulmonar

Febre

Dor corpo

Rash

Sint digestivos

Riscos Desidratao CHOQUE Dano multiple dergos

Desconforto resp.

Sepse bacteriana

Pneumonia

Fatores de risco Comorbidade, idade, fator social

Hepatite, encefalite, miocardite, pancreatite


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The cytokine profile patterns

discovered between the differentphases of illness indicate anessential role in dengue

pathogenesis RATHAKRISHNAN ET AL, 2012

Dengue es DINAMICO


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LOS ACTORES factores virales y del husped

LOS MECANISMOS inmunidad innatainmunopatologia de celulas T

apoptosisautoimmunidad

LOS EFECTOS extravasacion plasmatica sangrados

afectacion de organos

FISIOPATOLOGIA


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The pathogenesis of Dengue and

Severe Dengue involves viralvirulence factors and detrimental

host responses.By ro n EEM, et al. Clin Mic ro bi ol R ev 2009, 22(4): 564-581


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NS-3 specific immunostaining support roles for

infected phagocytes, hepatocytes and

endothelial cells .

Salgado DM, Eltit JM, Mansfield K, Panqueba C, Castro D, Vega MRet al. Pediat Infect Dis J 2010, 29(3):238-42 .

Balsitis SJ, Coloma J, Castro G, Alava A, Flores D,McKerow JH, et al. Am J Trop Med Hyg 2009, 80(3):416-424.

Vigorous infection of heart tissues in vivo and

striated skeletal cells has been shown .


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Cells infected with dengue virus release a high

proportion of immature prM-containing virions.

During a secondary infection or primary

infection of infants born to dengue-immune

mothers, immature particles have the potential

to be highly infectious and hence may contribute

to the development of severe disease

Rodenhuis-Zybert IA; van der Schaar HM; da SilvaVoorham JM; van der Ende-Metselaar H; Lei HY;Wilschut J; Smit JM. PLoS Pathog ;6(1):e1000718, 2010Jan 1553-7374.
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La patogenicidaddel virus

CARGA VIRAL VIRULENCIA DE LA CEPA


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Viral load correlates withthrombocytopaenia and vascular leak

Libraty et al, JID, 2002


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Comparison of Southeast (SE) Asian and

other genotypes viruses (American,

Indian, and West African) showed

significant differences in magnitude

and duration of viremia and rash , withSE Asia viruses always being highest.

Mota J, Rico-Hesse R. J Virol 2009, 83(17):8638-45.


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Circulating heterotypic antibodies at

enhancing concentrations continue being a

recurrent explanation of severe dengue .

Halstead SB. Ann N Y Acad Sci 2009, 171 Suppl 1:E48-56. Pierson TC. Cell Host Microbe 2010, 7(2):85-6. Zellweger RM, Prestwood TR, Shresta S. Cell Host Microbe 2010, 7(2):128. Balsitis SJ, Williams KL, Lachica R, Flores D, Kyle JL, Mehihop E, et al. PLoS Pathog2010, 6(2):e1000790. Published on line 2010 February 12.doi.- Dejnirattisai W,Jumnainsong A, Onsirisakut N, Fitton P, Vasanawathana S, Limpitijulk W, et al. Science2010, 328:745-49.


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- La teora secuencial por infeccin secundaria (Halstea

Inmuno-amplificacin de lainfeccin, o amplificacindependiente de anticuerpos

(ADA)

- Por sustancias biolgicamente activas (bacterianas parasitarias) que pueden aumentar la replicacin de Vy producir cantidades significativas de virus (Hotta).


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FcRECEPTOR

DENGUEVIRUS

Ac. Ampl.

CEL

CEL

AMPLIFICACIN DEPENDIENTE DE ANTICUERPOADE

VIRUS

MAYOR REPLICACIONVIRAL


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Despite decades of investigation ,no i n v ivo model for antibody enhancement

of dengue disease severity has beendescribed .

Passive administration of anti-DV antibodies is sufficient to

enhance DV infection and disease in mice: Antibody-enhancedlethal disease featured many of the hallmarks of severe denguedisease in humans , including thrombocytopenia, vascularleakage, elevated serum cytokine levels, and increased

systemic viral burden in serum and tissue phagocytes.

PLoS Pathog. 2010 February;6(2): Published online 2010February 12. doi:

10.1371/journal.ppat.1000790 .


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Lin CF, Wan SW, Chen MC, Lin SC, Cheng CC, Chiu SC et al. Lab Invest 2008, 88: 1079 1089

In vitro studies have suggested a mechanism of

MOLECULAR MIMICRYin which antibodies directed

against dengue virus (DV) nonstructural protein 1(NS1) cross-reacted with endothelial cells and

caused inflammatory activation and apoptosis


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Strong emphasis has recently been made on

genetic polymorphisms that confer DENprotection versus susceptibility to severe DEN a

balance between protective and pathologic

immune responses.

Tan G K, Alonso, S. Current Opinion Infect Dis 2009,22(3):302-08 .


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EXISTE DEMOSTRACININMUNOLGICA DE LAS FUNCIOPROTECTORA Y PATOGNICA DE CLULAST CD8DE REACCIN

CRUZADA.


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LA RESPUESTA INMUNOLOGICA A LAINFECCION POR VIRUS DENGUE PUEDE

y conducir a la curacin, o

y conducir a la gravedad y a la muerte.


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Memory DEN specific T-cells

DENV specific T cells from a priorinfection respond with alteredcytokine production to heterologous

DENV serotypeRothman AI. Current Topics in Microbiology and Immunology 338, Springer Verlag Berlin Heidelberg 2010. P.83-98


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The interleukin-1 receptor-like-1 protein (IL1RL1), also known

as ST2 has been shown to regulate T-cell function and is

produced by T cells and endothelial cells

Seet RC, Chow AW, Chan YH, Lim EC.. Int J Infect Dis 2009,13(5):e248-53.

Houghton-Trivio N, Salgado DM, Rodrguez JA, Bosch I,Castellanos JE. J Gen Virol 2010, 91(Pt 3):697-7062010 Jan1553-7374.

Vascular endothelial growth factor (VEGF) and its soluble

receptor assessed in adult confirmed dengue patients

highlight the importance of vascular permeability cytokines

in the pathogenesis of DHF .


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The complement system, that links the innate ad

adaptative immune responses, can be a a key

component in dengue pathogenesis.

Nascimento EJ, Silva AM, Cordero MT, Brito CA, GilLH, Braga-Neto U, Marques ET. PloS One 2009,4(8):e6782


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Pro-inflammatory cytokines released by

DENV serotype memory T cells could

explain the severe course in some patientsafter DENV reinfection. . On the contrary, thehomologous re-challenge triggered an opposite pattern

dominated by regulatory cytokines.

Sierra B, Perez AB, Vogt K, Garcia G, Schmolke K, Aguirre E, etal. Cell Immunol 2010, 262:134-140.


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Ladis-regulacin de larespuesta inmunolgica delhusped es de tipo transitoria eincluye:

- inversin de la relacin CD4/CD8

- cambio de la respuesta tipo T H1hacia la respuesta tipo T H2, e

- superproduccin de citoquinas.


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T4 EC

plasma

leakage

T8

T4

Mo

MoT8

IFNg IL-2TNF a TNF b

TNF a

TNF a

complement

C3aC5a

+

+

lysis

EC

MoEC

Ab

DV

MHC I

MHC II

DV peptides

DV receptor

Fc gR

monocyte

endothelial cell

T cell receptor

Segn Rothman, 2001


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La fuga plasmtica en elDengue y Dengue Grave estasociada con niveles elevados decitoquinas en plasma.


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EL MICROAMBIENTE DE CITOQUCONSTITUYE UNO DE LOS FACTOMAS IMPORTANTES EN LA INDUCDE UNA RESPUESTA INMUNE Y E

DIRECCION HACIA TH1 TH2.


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% TH1 TH0 TH2

Polos de la respuesta T H a nivel efector

Activacin deMacrfagos

Ac. Opsonizantes

Cel. T, NK y LAK Activacin de IgEEosinfilos

Mastocitos

Infeccin porVirus Dengue

CARGAVIRAL


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% TH1 TH0 TH2

Polos de la respuesta T H a nivel efector

Activacin deMacrfagos

Ac. Opsonizantes

Cel. T, NK y LAK Activacin de IgEEosinfilos

Mastocitos

Infeccin porVirus Dengue

CARGAVIRAL


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Antibody-enhanced dengue virus infection of

the FcR-bearing mast cell/basophil KU812

cell line results in a massive inductionof apoptosis . It was found to be caspase-dependent, involving global caspase

activation .Brown MG, Huang YY, Marshall JS, King CA, HoskinDW, Anderson R.. J Leukoc Biol 2009, 85(1):71-80.


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PBMCs isolated from Severe Dengue patients underwent

apoptosis at a significantly higher rate than thosesuffering Dengue. This suggests that the severity of natural

DENV infection correlates with PMBC apoptosis. This cell

death was induced not only by DENV itself, but

also by the apoptotic activities of pro-

inflammatory cytokines , such as TNF-alpha, and IL-1beta that were upregulated in Severe Dengue patients .

Jaiven Y, Masrinoul P, Kalayanarooj S, PulmanausahakulR, Ubol S. Microbiol Immunol 2009, 53(8):442-50.

DENGUE Y DENGUE GRAVE


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DENGUE Y DENGUE GRAVEMECANISMOS FISIOPATOLGICOS: SINTESIS

endotelio - plaquetashgado - mdula seaganglios linfticos - bazocorazn - cerebro - pulmn

VIRUS

muerte celularpor

APOPTOSIS

LINFOCITO T

CITOTXICO

Induccinde

APOPTOSIS

MONOCITO

CITOQUINAS

ANTICUERPOS

accincruzada

protenasdel huesped

activacin delCOMPLEMENTO

anafilatoxinas


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AFECTACION DE ORGANOS:hgado, cerebro, corazn, rin, pulmn. otros

AFECTACION A LINFOCITOS TMANIFESTACIONES OCULARES

SANGRADOS

EXTRAVASACION DE PLASMA


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- Progressive increase in hematocri

PLEURAL ANDPERICARDIAL EFUSSION

HEMOCONCENTRATIO

HYPOALBUMINEMIA

ASCITIS


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TNF-alpha and dengue virus infectiondecrease synergistically the

transendothelial electrical resistancevalue of endothelial cells

Dewi BE, Takasaki T, Kurane I. In vitro assessment of human endothelial cell permeability:

effects of inflammatory cytokines and dengue virus infection. J Virol Methods. 2004 Nov;121(2):171-80.


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Anti DV nonstructural protein 1 (NS1)

antibodies generated in mice have been

shown previously to cross react with humanfibrinogen, platelets, and endothelial cells.

The cross reactivity of dengue patient sera

with endothelial cells has also been

demonstrated.. Cheng HJ, Lin CF, Lei HY, Liu HS, Yeh TM, Luo YS, Lin YS. Exp Biol Med 2009,


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Cortesia del Prof. J. Bellassai, Paraguay


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Mid-zonal hepatonecrosis


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Mice inoculated by the intravenous route presented

extensive damage areas in the liver tissue. Hepatic

injury was noted mainly around the central vein and

portal tracts. Damages consist of hepatocyte injury,including steatosis, swelling and necrosis. Further,

erythrophagocytosis, intercellular edema and vascular

damages were evident, including hemorrhage , which

is characteristic of the dengue-induced hepatitis in

human liver.

Lin CF, Wan SW, Chen MC, Lin SC, Cheng CC, Chiu SC et

al.. Lab Invest 2008, 88: 1079

1089


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- Massive hepatocyte infection

- A relative minimal role for cytokine producion in the liver

- Minimal inflammatory infiltrate (as Ebola and YF)

- Marked hepatocyte necrosis (not always)

- Mid-zonal perisinusoidal edema

-Carvalho de Macedo F et al, Diag Mol Pathol, 2006


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Immunoperoxidase stain positive in TUNEL assay showed picnosis and

nuclear fragmentation in focal hepatonecrosis. 200 x .


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APOPTOSIS VS NECROSIS ?

- La apoptsis: fenmeno biolgico mucho msprevalente que la necrosis.

- Pueden ocurrir apoptsis y necrosis de manerasimultnea.- La apoptsis, la mayora de las veces, precede a lanecrosis.

- La apoptsis: primer paso del proceso que conduce ala necrosis.


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The DENV-infected myotubes had increases in

intracellular Ca2+ concentration.

Derangements of Ca2+ storage in the infected cells

may directly contribute to the presentation of

myocarditis in pediatric patients .

Salgado DM, Eltit JM, Mansfield K, Panqueba C, CastroD, Vega MR et al. Pediatr Infect Dis J 2010, 29(3):238-42.


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Cortesia de la Prof V. Capo, IPK


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Lung epithelial cell is a possible target of

dengue viruses and IL-6 and RANTES may

play pivotal roles in lung related immuno-

pathogenesis.

Lee YR et al. Virus Res 2007; 126(216-25)


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Interstitial pneumonia (mononuclear cells) Focal alterations of the blood-exchange

barrier Endothelial cells of blood capillaries

exhibited PHYLOPODIA suggestingactivation by presence of dengue virus

Ferreira Barreto et al. Mem Inst. Osswaldo Cruz 102, 2, Mar2007.


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Acute kidney injury is an uncommon

complication but renal dysfunction has

been associated with various ViralHemorrhagic Fevers, particularly

dengue and yellow fever .

Lima EQ, Nogueira ML.. Semin Nephrol 2008,28(4):409-15


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AFECTACION RENAL

Se encontrapoptosis enclulas epiteliales deltbulo proximal en cuatrode siete nios fallecidospor FHDSCD.

(Ana C. Polanco, HNNBM, El Salvador, 2000)


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En la FHD se ha demostrado mediante mtodos noinvasivos (espectroscopia de impedanciabioelctrica) que en la defervescencia existeaumento del agua extracelularrespecto al aguaintracelular lo cual se correlacion con la severidad

de la enfermedad (FHD > FD + H > FD).EL AUMENTO DEL AGUAEXTRACELULAR SE DEBI

PRINCIPALMENTE A DISMINUCINDEL ACLARAMIENTO RENAL.Libraty, 2002


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En el estudio de cerebros de casos fatales se hanidentificado antgenos virales de dengue mediantetcnicas de inmunoperoxidasa e inmunohistoqumica:

(Miagostovich y col, FIOCRUZ, Ro de Janeiro)


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En el estudio de cerebros de casos fatales se hanidentificado antgenos virales de dengue mediantetcnicas de inmunohistoqumica:

- en macrfagos CD68+ (espacios de Virchow Robin(Miagostovich y col, IPK, FIOCRUZ, Ro de Janeiro)- en neuronas

(Cap y col, IPK, La Habana)


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En el estudio de cerebros de casos fatales se hanidentificado antgenos virales de dengue mediantetcnicas de inmunohistoqumica:

- en macrfagos CD68+ (espacios de Virchow Robin(Miagostovich y col, IPK, FIOCRUZ, Ro de Janeiro)- en neuronas

(Cap y col, IPK, La Habana)

Y muerte neuronal por apoptosisen humanos

D. Limonta et al. / Journal of Clinical Virology 40 (2007) 50 54


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gy ( )


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- Endothelial cell injury- Release of proquagulant components- Activation of the coagulation cascade with trombin generation- Increased antifibrinolytic factors and consumption of natural

anticoagulants

EACH APPEARED TO PLAY AN IMPORTANT ROLE IN DEVELOMET OF HEMORRHAGE IN DENGUE

Sosothikul D et al. Tromb Haemost 2007; 97(4):627-34


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TNF-alpha in tissues correlated with cell apoptosis and hemorrhage

CONTRIBUTION OF THE INNATE IMM

RESPONSE TO DENGUE HEMORRHAG

Chen HC et al. J Virol 2007; 81 (11): 5518-26


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Thrombocytopenia, increased partialthromboplastin times and reduced fibrinogen

concentrations were apparent from an early stage in

dengue cases and correlated strongly with the severity

and timing of vascular leakage but not bleeding.

There was little evidence of procoagulant activation .

Wills B, Tran VN, Nguyen TH, Truong TT, Tran TN,Nguyen MD, Tran VD, Nguyen VV, Dinh TT, Farrar J. AmJ Trop Med Hyg 2009, 81(4):638-44.

.


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The platelet counts were not predictive

The duration of shock (OR, 2.11; 95% CI, 1.13 t3.92; P =.019) and low-normal hematocrit at thetime of shock (OR, 0.72; 95% CI, 0.55 to 0.95; P=.020) were risk factors of severe hemorrhage

Lum, L. C. |Goh AY |Chan PW |El-Amin AL |Lam SK.Risk factors for hemorrhage in severe dengue infections.J Pediatr. 2002 May; 140(5):629-31

bleeding


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LATROMBOCITOPENIA EN ELDENGUE ES RESULTADO LISIS DE PLAQUETAS PERIFERIA POR UN FENM

INMUNO-MEDIADO.Oishi K et al, J Med Virol, 2003Saito M et al, Clin Exp Immunol, 2004


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.

J Im m uno l 2009, 183: 1797 1803

Los Anticuerpos (Ac) contra la proteina noestructural 1 (NS1) del virus dengue (VD) tienen

reaccion cruzada con las plaquetas e inhiben suagregacion.

La disfuncion plaquetaria y la tendencia a sangrarson inducidos por Ac contra DV NS1

full-length

pero no por Ac anti-C NS1

REACCION CRUZADA DE ANTICUERPOS CON LASPLAQUETAS


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.

Increased adherence of platelets to stimulatedendothelial cells(by dengue-2 virus) couldcontribute to thethrombocytopenia observedduring infection.

Am J Trop Med Hyg, 2002; 66(4):435-441


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No existe diferencia estadsticamente significativen cuanto a la incidencia de sangramientos enpacientes con dengue y trombocitopenia respectoa los no trombocitopnicos.

Las hemorragias en eldengue son un fenmenomulticausal: vasculopata,trombocitopenia, trastornosde la coagulacin y otros.


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En pacientes conFHD/SCD se haevidenciado que algunascitoquinas estnasociadas con marcadoresde activacin de lacoagulacin y lafibrinolisis. La hemostasiadepende del balance

entre la coagulacin y lafibrinolisis.

E l i t g FHD d i


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En los pacientes graves con FHD se producira undisbalance entre la efectividad de los mecanismosde coagulacin y la fibrinolisis, con predominio deestos ltimos.


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La proliferacin de linfocitos T enetapas tempranas de la infeccin

por dengue est acompaada deuna APOPTOSIS MASIVA que estransitoria (2 semanas ).

(Mongkolsapaya y col, julio 2003)


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Hemorragia supeficial retiniana

Manchas algodonosas

Dilatacion y tortuosidad de los vasos

Retinopatia (exudados, y todo lo demas)

Harpreet K.K et al. Can J Ophthalmol 2006;41:741-6

ALTERACIONES DEL SEGMENTOPOSTERIOR


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Dengue-associated ocular inflammation is an

emerging ophthalmic condition and often involves

the posterior segment. Prognosis is variable.

Patients usually regain good vision but may

retain persistent scotomata even at 2 years

despite clinical resolution of the disease. Optical

coherence tomography showed 3 patterns ofmaculopathy.

Teoh SC; Chee CK; Laude A; Goh KY; Barkham T;Ang BS;. Retina 2010;30(3):390-8.
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Vita Wendell Paiva; Nicolai, Ceclia Carmen de Araujo; Azevedo, Marina Baptista de; Souza,MarcelleFernandes de; Baran, Meri. Rev. Soc. Bras. Cln. Md ;7(1):11-14, 2009.

fatores preditivos de mauprogn stico os sinais e sintomas :dor abdominal, hipotenso postural, manifesta eshemorr gicase extravasamento plasm tico.

, ,
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N % N %56 84,85 10 15,15

14 93,33 1 6,67

9 75,00 3 25

2 66,67 1 33,33

SONOGRAFA

SIGNOS

Letargia

Dolor abdominal intenso

Vmitos persistentes

Irritabilidad

CLNICOS DE ALARMA

POSITIVO NEGATIVO

(Garca M, Stgo de Cuba, 1997)

INNATE IMMUNITY AND


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Plasma levels of IL-6 and IL-8 were significantly higher (P < and P = 0.001, in children with severe clinically infection (DWSD) compared to children with mild dengue (DEN)

However,there were no significant differencesbetween the two severity groups of dengue (DWand SD) for any of the tested cytokines.

Cytokine 61 (2013) 766 771

INNATE IMMUNITY AND

WARNING SIGNS


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POR ACUMULO DELIQUIDO EN ELRETROPERINEO ?

Dolor abdominal intenso enel dengue

( S ti )


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n = 73 casos

ALTERACION NO GRAVES GRAVES

Derrame pleural 30 % 95 %Ascitis 31 95Engrosamiento pared

vescula biliar 32 95Hepatomegalia 49 56Esplenomegalia 16 16Aumento del pncreas 14 44

Coleccin lquida pararrenaly perirrenal 77

Coleccin lquida subcapsularheptica y esplnica 9

(segn Setiawan)


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POR EDEMA DE LA VESICULA BILIAR Y DE LAPARED INTESTINAL DE INSTALACION SUBITA ?

05 FISIOPATOLOGIA_miercoles 14-08-13.ppt

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