Rabia

Sergio Recuenco Cabrera MD MPH DrPHCentro Nacional de Salud Puacuteblica

Instituto Nacional de Salud

La Rabia

Enfermedad conocida por gt 5000 antildeos

1930 AC Codice Eshunna Iraq

1885 Vacuna antirraacutebica Pasteur

Genus Lisavirus

14 especies Virus Rabia Lagos bat virus Mokola virus

Duvenhage virus Aravan virus IrkutVirus Khujand virus

European bat lyssavirus 1 European bat lyssavirus 2

West Caucasian bat virus Australian bat lyssavirus

Shimoni bat virus Ikoma virus y Bokeloh bat lyssavirus

Reservorios

Perros Virus Rabia

Murcieacutelagos Todos los lisavirus excepto Mokola

Otros animales silvestres

Todos los mamiacuteferos pueden ser infectados y pueden transmitirla

En el Siglo 21 sigue siendo un problema

~70000 victimas cada antildeo

PEP vacuna + inmunoglobulina disponible pero con

acceso limitado en muchos paiacuteses en desarrollo

Banyard et al 2011

Banyard et al 2011

Virus de la Rabia

Familia Rhabdoviridae

Genus Lyssavirus

Virus ARN

Interfase animal para rabia humana en SA

Gato

Murcielago vampiro

Otros murcielagos

Mono Saguumli

Monos

Alpaca

Burro

Kinkajou

Zorro gris

Ganado Mas

Rabia Canina

Presence of dog-transmitted human rabies cases at the first subnational level Latin America and the

Caribbean 2005ndash2007Source PAHO based on SIRVERA Database PAHOPANAFTOSA

Epizootiologiacutea de la RabiaRESERVORIOS DE RABIA

RABIA URBANARABIA SILVESTRE

Rabia Enzooacutetica

Rabia asociada con carniacutevoros terrestres

Especies susceptibles (ldquodead endsrdquo)

Gato

VECTORES

Huroacuten

Perros

Canes Vampiro Murcieacutelago Ali-oscuro

(Big brown bat)

Murcieacutelago pelo plateado

(Silver hair bat)

Murcieacutelago cola peluda rojizo

(Red bat)

Murcieacutelago cola suelta

(Free taiedl bat)

Mapaches

Mapaches Zorro gris

Zorrillo listado(Stripped skunk)

Zorrillo manchado(Spotted skunk)

Zorro del AacuterticoCoyotes

Mangostas(Mongooses)

Rabia asociada con murcieacutelagos

Bovinos Caprinos y ovinos

Humanos y equinosCerdo

Castores ymarmotas

ldquoPerro mapacherdquo

CDC

Desmodus rotundus

Rabia en Sudamerica Progreso importante hacia la

eliminacion de la rabia canina

La rabia transmitida por

murcielagos hematofagos (R

Silvestre) ha pasado a ser la

mayor fuente de casos

humanos

Desmodus rotundus

Region amazonica es la mas

afectada

Foco de mayor actividad

Condorcanqui Amazonas Peru

Brotes frecuentes 2007-2011

Rabia silvestre

Source MINSA-DGE-DGSP RH

Rabia CaninaUrbana

Animal

surveillance

Rabies in cattle

transmitted by

vampire bats

Rabies incidence

density and

relationship with

landscape

Map CDC-Rabies

Data SENASA-Peru

Peru

RS es un problema

Amazonico

La RS esta en aumento

Respuesta lentatardia

Intervencion costosa

Vector omnipresente

Vigilancia en ganado

Exposicion masiva vacunacion

masiva

Barreras para control

Barreras para el diagnostico

RS Factores reconocidos

Baja educacioacuten Encuesta CAP Peruacute 2010

Lenguaje 370 grupos eacutetnicos

Acceso geograacutefico vacunas servicios de

salud

Vivienda modificacioacuten es posible se

requiere programa masivo con poliacuteticas

de gobierno

Exposicioacutenmordeduras alta frecuencia

Vacunas $ cadena de frio abandonos

faltano uso de RIG

Poliacuteticas lento reconocimiento de la

situacioacuten uacutenica de la RS como

enfermedad emergente en Amazonia

Loreto

Madre De Dios

Temporary workers

home

La rabia

Una vez que ingresa el virus ldquoviajardquo

por el tejido nervioso hasta llegar al

cerebro

Incubacioacuten

Tiempo que demora en llegar al cerebro

~45 diacuteas (7dias-3 meses)

excepcionalmente antildeos

No contagia durante incubacioacuten

Aun se puede vacunarhellip urgentemente

Inicio de siacutentomas

Encefalitis fiebre alteracioacuten de conciencia

Hidrofobia salivacioacuten

Una vez iniciadohellipmuerte en 5-15 diacuteas

Exposicion ne Enfermedad Clinica

Laboratorio

Animales sospechosos

Exposicion

(mordeduras)

Presentacioacuten

Cliacutenica

Autopsia

Confirmacioacuten

de laboratorio

Post-mortem

Vacuna +RIG

OK

Rabia

detenida

Sin Vacuna

Confirmacioacuten

de laboratorio

Pre-mortem

Mordeduras

Dog bite

Rat bite

Mordeduras

Profilaxis Antirraacutebica Humana

Para evitar la progresioacuten de la infeccioacuten (inoculacioacuten viral por

mordedura) al cuadro cliacutenico de la rabia

La necesidad de profilaxis esta determinada por la evaluacioacuten de

riesgo de cada caso individual

Indicada tan pronto como se establece la necesidad despueacutes de la

evaluacioacuten de riesgo

No esta indicado cuando ya hay signos de encefalitis y se sospecha rabia

Existen recomendaciones emitidas por la OMSOPS

Rabies Vaccines WHO position paper (2010)

Consulta de Expertos en Rabia Segundo reporte OMS 2013

Vacunas

httpwwwwhointimmunization_standardsvaccine_qualityPQ_vaccine_list_enen

1 Chiron Behring Vaccines Private Ltd India 1 dose Vial

2 Novartis Vaccines and Diagnostics Germany 1 dose

Vial

3 Sanofi Pasteur France 1 dose Vial

4 Serum Institute of India Ltd India India 1 dose Vial

5 Zydus Cadila India 1 dose Vial 1 dose Vial

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

La Rabia

Enfermedad conocida por gt 5000 antildeos

1930 AC Codice Eshunna Iraq

1885 Vacuna antirraacutebica Pasteur

Genus Lisavirus

14 especies Virus Rabia Lagos bat virus Mokola virus

Duvenhage virus Aravan virus IrkutVirus Khujand virus

European bat lyssavirus 1 European bat lyssavirus 2

West Caucasian bat virus Australian bat lyssavirus

Shimoni bat virus Ikoma virus y Bokeloh bat lyssavirus

Reservorios

Perros Virus Rabia

Murcieacutelagos Todos los lisavirus excepto Mokola

Otros animales silvestres

Todos los mamiacuteferos pueden ser infectados y pueden transmitirla

En el Siglo 21 sigue siendo un problema

~70000 victimas cada antildeo

PEP vacuna + inmunoglobulina disponible pero con

acceso limitado en muchos paiacuteses en desarrollo

Banyard et al 2011

Banyard et al 2011

Virus de la Rabia

Familia Rhabdoviridae

Genus Lyssavirus

Virus ARN

Interfase animal para rabia humana en SA

Gato

Murcielago vampiro

Otros murcielagos

Mono Saguumli

Monos

Alpaca

Burro

Kinkajou

Zorro gris

Ganado Mas

Rabia Canina

Presence of dog-transmitted human rabies cases at the first subnational level Latin America and the

Caribbean 2005ndash2007Source PAHO based on SIRVERA Database PAHOPANAFTOSA

Epizootiologiacutea de la RabiaRESERVORIOS DE RABIA

RABIA URBANARABIA SILVESTRE

Rabia Enzooacutetica

Rabia asociada con carniacutevoros terrestres

Especies susceptibles (ldquodead endsrdquo)

Gato

VECTORES

Huroacuten

Perros

Canes Vampiro Murcieacutelago Ali-oscuro

(Big brown bat)

Murcieacutelago pelo plateado

(Silver hair bat)

Murcieacutelago cola peluda rojizo

(Red bat)

Murcieacutelago cola suelta

(Free taiedl bat)

Mapaches

Mapaches Zorro gris

Zorrillo listado(Stripped skunk)

Zorrillo manchado(Spotted skunk)

Zorro del AacuterticoCoyotes

Mangostas(Mongooses)

Rabia asociada con murcieacutelagos

Bovinos Caprinos y ovinos

Humanos y equinosCerdo

Castores ymarmotas

ldquoPerro mapacherdquo

CDC

Desmodus rotundus

Rabia en Sudamerica Progreso importante hacia la

eliminacion de la rabia canina

La rabia transmitida por

murcielagos hematofagos (R

Silvestre) ha pasado a ser la

mayor fuente de casos

humanos

Desmodus rotundus

Region amazonica es la mas

afectada

Foco de mayor actividad

Condorcanqui Amazonas Peru

Brotes frecuentes 2007-2011

Rabia silvestre

Source MINSA-DGE-DGSP RH

Rabia CaninaUrbana

Animal

surveillance

Rabies in cattle

transmitted by

vampire bats

Rabies incidence

density and

relationship with

landscape

Map CDC-Rabies

Data SENASA-Peru

Peru

RS es un problema

Amazonico

La RS esta en aumento

Respuesta lentatardia

Intervencion costosa

Vector omnipresente

Vigilancia en ganado

Exposicion masiva vacunacion

masiva

Barreras para control

Barreras para el diagnostico

RS Factores reconocidos

Baja educacioacuten Encuesta CAP Peruacute 2010

Lenguaje 370 grupos eacutetnicos

Acceso geograacutefico vacunas servicios de

salud

Vivienda modificacioacuten es posible se

requiere programa masivo con poliacuteticas

de gobierno

Exposicioacutenmordeduras alta frecuencia

Vacunas $ cadena de frio abandonos

faltano uso de RIG

Poliacuteticas lento reconocimiento de la

situacioacuten uacutenica de la RS como

enfermedad emergente en Amazonia

Loreto

Madre De Dios

Temporary workers

home

La rabia

Una vez que ingresa el virus ldquoviajardquo

por el tejido nervioso hasta llegar al

cerebro

Incubacioacuten

Tiempo que demora en llegar al cerebro

~45 diacuteas (7dias-3 meses)

excepcionalmente antildeos

No contagia durante incubacioacuten

Aun se puede vacunarhellip urgentemente

Inicio de siacutentomas

Encefalitis fiebre alteracioacuten de conciencia

Hidrofobia salivacioacuten

Una vez iniciadohellipmuerte en 5-15 diacuteas

Exposicion ne Enfermedad Clinica

Laboratorio

Animales sospechosos

Exposicion

(mordeduras)

Presentacioacuten

Cliacutenica

Autopsia

Confirmacioacuten

de laboratorio

Post-mortem

Vacuna +RIG

OK

Rabia

detenida

Sin Vacuna

Confirmacioacuten

de laboratorio

Pre-mortem

Mordeduras

Dog bite

Rat bite

Mordeduras

Profilaxis Antirraacutebica Humana

Para evitar la progresioacuten de la infeccioacuten (inoculacioacuten viral por

mordedura) al cuadro cliacutenico de la rabia

La necesidad de profilaxis esta determinada por la evaluacioacuten de

riesgo de cada caso individual

Indicada tan pronto como se establece la necesidad despueacutes de la

evaluacioacuten de riesgo

No esta indicado cuando ya hay signos de encefalitis y se sospecha rabia

Existen recomendaciones emitidas por la OMSOPS

Rabies Vaccines WHO position paper (2010)

Consulta de Expertos en Rabia Segundo reporte OMS 2013

Vacunas

httpwwwwhointimmunization_standardsvaccine_qualityPQ_vaccine_list_enen

1 Chiron Behring Vaccines Private Ltd India 1 dose Vial

2 Novartis Vaccines and Diagnostics Germany 1 dose

Vial

3 Sanofi Pasteur France 1 dose Vial

4 Serum Institute of India Ltd India India 1 dose Vial

5 Zydus Cadila India 1 dose Vial 1 dose Vial

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Banyard et al 2011

Virus de la Rabia

Familia Rhabdoviridae

Genus Lyssavirus

Virus ARN

Interfase animal para rabia humana en SA

Gato

Murcielago vampiro

Otros murcielagos

Mono Saguumli

Monos

Alpaca

Burro

Kinkajou

Zorro gris

Ganado Mas

Rabia Canina

Presence of dog-transmitted human rabies cases at the first subnational level Latin America and the

Caribbean 2005ndash2007Source PAHO based on SIRVERA Database PAHOPANAFTOSA

Epizootiologiacutea de la RabiaRESERVORIOS DE RABIA

RABIA URBANARABIA SILVESTRE

Rabia Enzooacutetica

Rabia asociada con carniacutevoros terrestres

Especies susceptibles (ldquodead endsrdquo)

Gato

VECTORES

Huroacuten

Perros

Canes Vampiro Murcieacutelago Ali-oscuro

(Big brown bat)

Murcieacutelago pelo plateado

(Silver hair bat)

Murcieacutelago cola peluda rojizo

(Red bat)

Murcieacutelago cola suelta

(Free taiedl bat)

Mapaches

Mapaches Zorro gris

Zorrillo listado(Stripped skunk)

Zorrillo manchado(Spotted skunk)

Zorro del AacuterticoCoyotes

Mangostas(Mongooses)

Rabia asociada con murcieacutelagos

Bovinos Caprinos y ovinos

Humanos y equinosCerdo

Castores ymarmotas

ldquoPerro mapacherdquo

CDC

Desmodus rotundus

Rabia en Sudamerica Progreso importante hacia la

eliminacion de la rabia canina

La rabia transmitida por

murcielagos hematofagos (R

Silvestre) ha pasado a ser la

mayor fuente de casos

humanos

Desmodus rotundus

Region amazonica es la mas

afectada

Foco de mayor actividad

Condorcanqui Amazonas Peru

Brotes frecuentes 2007-2011

Rabia silvestre

Source MINSA-DGE-DGSP RH

Rabia CaninaUrbana

Animal

surveillance

Rabies in cattle

transmitted by

vampire bats

Rabies incidence

density and

relationship with

landscape

Map CDC-Rabies

Data SENASA-Peru

Peru

RS es un problema

Amazonico

La RS esta en aumento

Respuesta lentatardia

Intervencion costosa

Vector omnipresente

Vigilancia en ganado

Exposicion masiva vacunacion

masiva

Barreras para control

Barreras para el diagnostico

RS Factores reconocidos

Baja educacioacuten Encuesta CAP Peruacute 2010

Lenguaje 370 grupos eacutetnicos

Acceso geograacutefico vacunas servicios de

salud

Vivienda modificacioacuten es posible se

requiere programa masivo con poliacuteticas

de gobierno

Exposicioacutenmordeduras alta frecuencia

Vacunas $ cadena de frio abandonos

faltano uso de RIG

Poliacuteticas lento reconocimiento de la

situacioacuten uacutenica de la RS como

enfermedad emergente en Amazonia

Loreto

Madre De Dios

Temporary workers

home

La rabia

Una vez que ingresa el virus ldquoviajardquo

por el tejido nervioso hasta llegar al

cerebro

Incubacioacuten

Tiempo que demora en llegar al cerebro

~45 diacuteas (7dias-3 meses)

excepcionalmente antildeos

No contagia durante incubacioacuten

Aun se puede vacunarhellip urgentemente

Inicio de siacutentomas

Encefalitis fiebre alteracioacuten de conciencia

Hidrofobia salivacioacuten

Una vez iniciadohellipmuerte en 5-15 diacuteas

Exposicion ne Enfermedad Clinica

Laboratorio

Animales sospechosos

Exposicion

(mordeduras)

Presentacioacuten

Cliacutenica

Autopsia

Confirmacioacuten

de laboratorio

Post-mortem

Vacuna +RIG

OK

Rabia

detenida

Sin Vacuna

Confirmacioacuten

de laboratorio

Pre-mortem

Mordeduras

Dog bite

Rat bite

Mordeduras

Profilaxis Antirraacutebica Humana

Para evitar la progresioacuten de la infeccioacuten (inoculacioacuten viral por

mordedura) al cuadro cliacutenico de la rabia

La necesidad de profilaxis esta determinada por la evaluacioacuten de

riesgo de cada caso individual

Indicada tan pronto como se establece la necesidad despueacutes de la

evaluacioacuten de riesgo

No esta indicado cuando ya hay signos de encefalitis y se sospecha rabia

Existen recomendaciones emitidas por la OMSOPS

Rabies Vaccines WHO position paper (2010)

Consulta de Expertos en Rabia Segundo reporte OMS 2013

Vacunas

httpwwwwhointimmunization_standardsvaccine_qualityPQ_vaccine_list_enen

1 Chiron Behring Vaccines Private Ltd India 1 dose Vial

2 Novartis Vaccines and Diagnostics Germany 1 dose

Vial

3 Sanofi Pasteur France 1 dose Vial

4 Serum Institute of India Ltd India India 1 dose Vial

5 Zydus Cadila India 1 dose Vial 1 dose Vial

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Interfase animal para rabia humana en SA

Gato

Murcielago vampiro

Otros murcielagos

Mono Saguumli

Monos

Alpaca

Burro

Kinkajou

Zorro gris

Ganado Mas

Rabia Canina

Presence of dog-transmitted human rabies cases at the first subnational level Latin America and the

Caribbean 2005ndash2007Source PAHO based on SIRVERA Database PAHOPANAFTOSA

Epizootiologiacutea de la RabiaRESERVORIOS DE RABIA

RABIA URBANARABIA SILVESTRE

Rabia Enzooacutetica

Rabia asociada con carniacutevoros terrestres

Especies susceptibles (ldquodead endsrdquo)

Gato

VECTORES

Huroacuten

Perros

Canes Vampiro Murcieacutelago Ali-oscuro

(Big brown bat)

Murcieacutelago pelo plateado

(Silver hair bat)

Murcieacutelago cola peluda rojizo

(Red bat)

Murcieacutelago cola suelta

(Free taiedl bat)

Mapaches

Mapaches Zorro gris

Zorrillo listado(Stripped skunk)

Zorrillo manchado(Spotted skunk)

Zorro del AacuterticoCoyotes

Mangostas(Mongooses)

Rabia asociada con murcieacutelagos

Bovinos Caprinos y ovinos

Humanos y equinosCerdo

Castores ymarmotas

ldquoPerro mapacherdquo

CDC

Desmodus rotundus

Rabia en Sudamerica Progreso importante hacia la

eliminacion de la rabia canina

La rabia transmitida por

murcielagos hematofagos (R

Silvestre) ha pasado a ser la

mayor fuente de casos

humanos

Desmodus rotundus

Region amazonica es la mas

afectada

Foco de mayor actividad

Condorcanqui Amazonas Peru

Brotes frecuentes 2007-2011

Rabia silvestre

Source MINSA-DGE-DGSP RH

Rabia CaninaUrbana

Animal

surveillance

Rabies in cattle

transmitted by

vampire bats

Rabies incidence

density and

relationship with

landscape

Map CDC-Rabies

Data SENASA-Peru

Peru

RS es un problema

Amazonico

La RS esta en aumento

Respuesta lentatardia

Intervencion costosa

Vector omnipresente

Vigilancia en ganado

Exposicion masiva vacunacion

masiva

Barreras para control

Barreras para el diagnostico

RS Factores reconocidos

Baja educacioacuten Encuesta CAP Peruacute 2010

Lenguaje 370 grupos eacutetnicos

Acceso geograacutefico vacunas servicios de

salud

Vivienda modificacioacuten es posible se

requiere programa masivo con poliacuteticas

de gobierno

Exposicioacutenmordeduras alta frecuencia

Vacunas $ cadena de frio abandonos

faltano uso de RIG

Poliacuteticas lento reconocimiento de la

situacioacuten uacutenica de la RS como

enfermedad emergente en Amazonia

Loreto

Madre De Dios

Temporary workers

home

La rabia

Una vez que ingresa el virus ldquoviajardquo

por el tejido nervioso hasta llegar al

cerebro

Incubacioacuten

Tiempo que demora en llegar al cerebro

~45 diacuteas (7dias-3 meses)

excepcionalmente antildeos

No contagia durante incubacioacuten

Aun se puede vacunarhellip urgentemente

Inicio de siacutentomas

Encefalitis fiebre alteracioacuten de conciencia

Hidrofobia salivacioacuten

Una vez iniciadohellipmuerte en 5-15 diacuteas

Exposicion ne Enfermedad Clinica

Laboratorio

Animales sospechosos

Exposicion

(mordeduras)

Presentacioacuten

Cliacutenica

Autopsia

Confirmacioacuten

de laboratorio

Post-mortem

Vacuna +RIG

OK

Rabia

detenida

Sin Vacuna

Confirmacioacuten

de laboratorio

Pre-mortem

Mordeduras

Dog bite

Rat bite

Mordeduras

Profilaxis Antirraacutebica Humana

Para evitar la progresioacuten de la infeccioacuten (inoculacioacuten viral por

mordedura) al cuadro cliacutenico de la rabia

La necesidad de profilaxis esta determinada por la evaluacioacuten de

riesgo de cada caso individual

Indicada tan pronto como se establece la necesidad despueacutes de la

evaluacioacuten de riesgo

No esta indicado cuando ya hay signos de encefalitis y se sospecha rabia

Existen recomendaciones emitidas por la OMSOPS

Rabies Vaccines WHO position paper (2010)

Consulta de Expertos en Rabia Segundo reporte OMS 2013

Vacunas

httpwwwwhointimmunization_standardsvaccine_qualityPQ_vaccine_list_enen

1 Chiron Behring Vaccines Private Ltd India 1 dose Vial

2 Novartis Vaccines and Diagnostics Germany 1 dose

Vial

3 Sanofi Pasteur France 1 dose Vial

4 Serum Institute of India Ltd India India 1 dose Vial

5 Zydus Cadila India 1 dose Vial 1 dose Vial

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Rabia Canina

Presence of dog-transmitted human rabies cases at the first subnational level Latin America and the

Caribbean 2005ndash2007Source PAHO based on SIRVERA Database PAHOPANAFTOSA

Epizootiologiacutea de la RabiaRESERVORIOS DE RABIA

RABIA URBANARABIA SILVESTRE

Rabia Enzooacutetica

Rabia asociada con carniacutevoros terrestres

Especies susceptibles (ldquodead endsrdquo)

Gato

VECTORES

Huroacuten

Perros

Canes Vampiro Murcieacutelago Ali-oscuro

(Big brown bat)

Murcieacutelago pelo plateado

(Silver hair bat)

Murcieacutelago cola peluda rojizo

(Red bat)

Murcieacutelago cola suelta

(Free taiedl bat)

Mapaches

Mapaches Zorro gris

Zorrillo listado(Stripped skunk)

Zorrillo manchado(Spotted skunk)

Zorro del AacuterticoCoyotes

Mangostas(Mongooses)

Rabia asociada con murcieacutelagos

Bovinos Caprinos y ovinos

Humanos y equinosCerdo

Castores ymarmotas

ldquoPerro mapacherdquo

CDC

Desmodus rotundus

Rabia en Sudamerica Progreso importante hacia la

eliminacion de la rabia canina

La rabia transmitida por

murcielagos hematofagos (R

Silvestre) ha pasado a ser la

mayor fuente de casos

humanos

Desmodus rotundus

Region amazonica es la mas

afectada

Foco de mayor actividad

Condorcanqui Amazonas Peru

Brotes frecuentes 2007-2011

Rabia silvestre

Source MINSA-DGE-DGSP RH

Rabia CaninaUrbana

Animal

surveillance

Rabies in cattle

transmitted by

vampire bats

Rabies incidence

density and

relationship with

landscape

Map CDC-Rabies

Data SENASA-Peru

Peru

RS es un problema

Amazonico

La RS esta en aumento

Respuesta lentatardia

Intervencion costosa

Vector omnipresente

Vigilancia en ganado

Exposicion masiva vacunacion

masiva

Barreras para control

Barreras para el diagnostico

RS Factores reconocidos

Baja educacioacuten Encuesta CAP Peruacute 2010

Lenguaje 370 grupos eacutetnicos

Acceso geograacutefico vacunas servicios de

salud

Vivienda modificacioacuten es posible se

requiere programa masivo con poliacuteticas

de gobierno

Exposicioacutenmordeduras alta frecuencia

Vacunas $ cadena de frio abandonos

faltano uso de RIG

Poliacuteticas lento reconocimiento de la

situacioacuten uacutenica de la RS como

enfermedad emergente en Amazonia

Loreto

Madre De Dios

Temporary workers

home

La rabia

Una vez que ingresa el virus ldquoviajardquo

por el tejido nervioso hasta llegar al

cerebro

Incubacioacuten

Tiempo que demora en llegar al cerebro

~45 diacuteas (7dias-3 meses)

excepcionalmente antildeos

No contagia durante incubacioacuten

Aun se puede vacunarhellip urgentemente

Inicio de siacutentomas

Encefalitis fiebre alteracioacuten de conciencia

Hidrofobia salivacioacuten

Una vez iniciadohellipmuerte en 5-15 diacuteas

Exposicion ne Enfermedad Clinica

Laboratorio

Animales sospechosos

Exposicion

(mordeduras)

Presentacioacuten

Cliacutenica

Autopsia

Confirmacioacuten

de laboratorio

Post-mortem

Vacuna +RIG

OK

Rabia

detenida

Sin Vacuna

Confirmacioacuten

de laboratorio

Pre-mortem

Mordeduras

Dog bite

Rat bite

Mordeduras

Profilaxis Antirraacutebica Humana

Para evitar la progresioacuten de la infeccioacuten (inoculacioacuten viral por

mordedura) al cuadro cliacutenico de la rabia

La necesidad de profilaxis esta determinada por la evaluacioacuten de

riesgo de cada caso individual

Indicada tan pronto como se establece la necesidad despueacutes de la

evaluacioacuten de riesgo

No esta indicado cuando ya hay signos de encefalitis y se sospecha rabia

Existen recomendaciones emitidas por la OMSOPS

Rabies Vaccines WHO position paper (2010)

Consulta de Expertos en Rabia Segundo reporte OMS 2013

Vacunas

httpwwwwhointimmunization_standardsvaccine_qualityPQ_vaccine_list_enen

1 Chiron Behring Vaccines Private Ltd India 1 dose Vial

2 Novartis Vaccines and Diagnostics Germany 1 dose

Vial

3 Sanofi Pasteur France 1 dose Vial

4 Serum Institute of India Ltd India India 1 dose Vial

5 Zydus Cadila India 1 dose Vial 1 dose Vial

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Epizootiologiacutea de la RabiaRESERVORIOS DE RABIA

RABIA URBANARABIA SILVESTRE

Rabia Enzooacutetica

Rabia asociada con carniacutevoros terrestres

Especies susceptibles (ldquodead endsrdquo)

Gato

VECTORES

Huroacuten

Perros

Canes Vampiro Murcieacutelago Ali-oscuro

(Big brown bat)

Murcieacutelago pelo plateado

(Silver hair bat)

Murcieacutelago cola peluda rojizo

(Red bat)

Murcieacutelago cola suelta

(Free taiedl bat)

Mapaches

Mapaches Zorro gris

Zorrillo listado(Stripped skunk)

Zorrillo manchado(Spotted skunk)

Zorro del AacuterticoCoyotes

Mangostas(Mongooses)

Rabia asociada con murcieacutelagos

Bovinos Caprinos y ovinos

Humanos y equinosCerdo

Castores ymarmotas

ldquoPerro mapacherdquo

CDC

Desmodus rotundus

Rabia en Sudamerica Progreso importante hacia la

eliminacion de la rabia canina

La rabia transmitida por

murcielagos hematofagos (R

Silvestre) ha pasado a ser la

mayor fuente de casos

humanos

Desmodus rotundus

Region amazonica es la mas

afectada

Foco de mayor actividad

Condorcanqui Amazonas Peru

Brotes frecuentes 2007-2011

Rabia silvestre

Source MINSA-DGE-DGSP RH

Rabia CaninaUrbana

Animal

surveillance

Rabies in cattle

transmitted by

vampire bats

Rabies incidence

density and

relationship with

landscape

Map CDC-Rabies

Data SENASA-Peru

Peru

RS es un problema

Amazonico

La RS esta en aumento

Respuesta lentatardia

Intervencion costosa

Vector omnipresente

Vigilancia en ganado

Exposicion masiva vacunacion

masiva

Barreras para control

Barreras para el diagnostico

RS Factores reconocidos

Baja educacioacuten Encuesta CAP Peruacute 2010

Lenguaje 370 grupos eacutetnicos

Acceso geograacutefico vacunas servicios de

salud

Vivienda modificacioacuten es posible se

requiere programa masivo con poliacuteticas

de gobierno

Exposicioacutenmordeduras alta frecuencia

Vacunas $ cadena de frio abandonos

faltano uso de RIG

Poliacuteticas lento reconocimiento de la

situacioacuten uacutenica de la RS como

enfermedad emergente en Amazonia

Loreto

Madre De Dios

Temporary workers

home

La rabia

Una vez que ingresa el virus ldquoviajardquo

por el tejido nervioso hasta llegar al

cerebro

Incubacioacuten

Tiempo que demora en llegar al cerebro

~45 diacuteas (7dias-3 meses)

excepcionalmente antildeos

No contagia durante incubacioacuten

Aun se puede vacunarhellip urgentemente

Inicio de siacutentomas

Encefalitis fiebre alteracioacuten de conciencia

Hidrofobia salivacioacuten

Una vez iniciadohellipmuerte en 5-15 diacuteas

Exposicion ne Enfermedad Clinica

Laboratorio

Animales sospechosos

Exposicion

(mordeduras)

Presentacioacuten

Cliacutenica

Autopsia

Confirmacioacuten

de laboratorio

Post-mortem

Vacuna +RIG

OK

Rabia

detenida

Sin Vacuna

Confirmacioacuten

de laboratorio

Pre-mortem

Mordeduras

Dog bite

Rat bite

Mordeduras

Profilaxis Antirraacutebica Humana

Para evitar la progresioacuten de la infeccioacuten (inoculacioacuten viral por

mordedura) al cuadro cliacutenico de la rabia

La necesidad de profilaxis esta determinada por la evaluacioacuten de

riesgo de cada caso individual

Indicada tan pronto como se establece la necesidad despueacutes de la

evaluacioacuten de riesgo

No esta indicado cuando ya hay signos de encefalitis y se sospecha rabia

Existen recomendaciones emitidas por la OMSOPS

Rabies Vaccines WHO position paper (2010)

Consulta de Expertos en Rabia Segundo reporte OMS 2013

Vacunas

httpwwwwhointimmunization_standardsvaccine_qualityPQ_vaccine_list_enen

1 Chiron Behring Vaccines Private Ltd India 1 dose Vial

2 Novartis Vaccines and Diagnostics Germany 1 dose

Vial

3 Sanofi Pasteur France 1 dose Vial

4 Serum Institute of India Ltd India India 1 dose Vial

5 Zydus Cadila India 1 dose Vial 1 dose Vial

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Desmodus rotundus

Rabia en Sudamerica Progreso importante hacia la

eliminacion de la rabia canina

La rabia transmitida por

murcielagos hematofagos (R

Silvestre) ha pasado a ser la

mayor fuente de casos

humanos

Desmodus rotundus

Region amazonica es la mas

afectada

Foco de mayor actividad

Condorcanqui Amazonas Peru

Brotes frecuentes 2007-2011

Rabia silvestre

Source MINSA-DGE-DGSP RH

Rabia CaninaUrbana

Animal

surveillance

Rabies in cattle

transmitted by

vampire bats

Rabies incidence

density and

relationship with

landscape

Map CDC-Rabies

Data SENASA-Peru

Peru

RS es un problema

Amazonico

La RS esta en aumento

Respuesta lentatardia

Intervencion costosa

Vector omnipresente

Vigilancia en ganado

Exposicion masiva vacunacion

masiva

Barreras para control

Barreras para el diagnostico

RS Factores reconocidos

Baja educacioacuten Encuesta CAP Peruacute 2010

Lenguaje 370 grupos eacutetnicos

Acceso geograacutefico vacunas servicios de

salud

Vivienda modificacioacuten es posible se

requiere programa masivo con poliacuteticas

de gobierno

Exposicioacutenmordeduras alta frecuencia

Vacunas $ cadena de frio abandonos

faltano uso de RIG

Poliacuteticas lento reconocimiento de la

situacioacuten uacutenica de la RS como

enfermedad emergente en Amazonia

Loreto

Madre De Dios

Temporary workers

home

La rabia

Una vez que ingresa el virus ldquoviajardquo

por el tejido nervioso hasta llegar al

cerebro

Incubacioacuten

Tiempo que demora en llegar al cerebro

~45 diacuteas (7dias-3 meses)

excepcionalmente antildeos

No contagia durante incubacioacuten

Aun se puede vacunarhellip urgentemente

Inicio de siacutentomas

Encefalitis fiebre alteracioacuten de conciencia

Hidrofobia salivacioacuten

Una vez iniciadohellipmuerte en 5-15 diacuteas

Exposicion ne Enfermedad Clinica

Laboratorio

Animales sospechosos

Exposicion

(mordeduras)

Presentacioacuten

Cliacutenica

Autopsia

Confirmacioacuten

de laboratorio

Post-mortem

Vacuna +RIG

OK

Rabia

detenida

Sin Vacuna

Confirmacioacuten

de laboratorio

Pre-mortem

Mordeduras

Dog bite

Rat bite

Mordeduras

Profilaxis Antirraacutebica Humana

Para evitar la progresioacuten de la infeccioacuten (inoculacioacuten viral por

mordedura) al cuadro cliacutenico de la rabia

La necesidad de profilaxis esta determinada por la evaluacioacuten de

riesgo de cada caso individual

Indicada tan pronto como se establece la necesidad despueacutes de la

evaluacioacuten de riesgo

No esta indicado cuando ya hay signos de encefalitis y se sospecha rabia

Existen recomendaciones emitidas por la OMSOPS

Rabies Vaccines WHO position paper (2010)

Consulta de Expertos en Rabia Segundo reporte OMS 2013

Vacunas

httpwwwwhointimmunization_standardsvaccine_qualityPQ_vaccine_list_enen

1 Chiron Behring Vaccines Private Ltd India 1 dose Vial

2 Novartis Vaccines and Diagnostics Germany 1 dose

Vial

3 Sanofi Pasteur France 1 dose Vial

4 Serum Institute of India Ltd India India 1 dose Vial

5 Zydus Cadila India 1 dose Vial 1 dose Vial

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Rabia en Sudamerica Progreso importante hacia la

eliminacion de la rabia canina

La rabia transmitida por

murcielagos hematofagos (R

Silvestre) ha pasado a ser la

mayor fuente de casos

humanos

Desmodus rotundus

Region amazonica es la mas

afectada

Foco de mayor actividad

Condorcanqui Amazonas Peru

Brotes frecuentes 2007-2011

Rabia silvestre

Source MINSA-DGE-DGSP RH

Rabia CaninaUrbana

Animal

surveillance

Rabies in cattle

transmitted by

vampire bats

Rabies incidence

density and

relationship with

landscape

Map CDC-Rabies

Data SENASA-Peru

Peru

RS es un problema

Amazonico

La RS esta en aumento

Respuesta lentatardia

Intervencion costosa

Vector omnipresente

Vigilancia en ganado

Exposicion masiva vacunacion

masiva

Barreras para control

Barreras para el diagnostico

RS Factores reconocidos

Baja educacioacuten Encuesta CAP Peruacute 2010

Lenguaje 370 grupos eacutetnicos

Acceso geograacutefico vacunas servicios de

salud

Vivienda modificacioacuten es posible se

requiere programa masivo con poliacuteticas

de gobierno

Exposicioacutenmordeduras alta frecuencia

Vacunas $ cadena de frio abandonos

faltano uso de RIG

Poliacuteticas lento reconocimiento de la

situacioacuten uacutenica de la RS como

enfermedad emergente en Amazonia

Loreto

Madre De Dios

Temporary workers

home

La rabia

Una vez que ingresa el virus ldquoviajardquo

por el tejido nervioso hasta llegar al

cerebro

Incubacioacuten

Tiempo que demora en llegar al cerebro

~45 diacuteas (7dias-3 meses)

excepcionalmente antildeos

No contagia durante incubacioacuten

Aun se puede vacunarhellip urgentemente

Inicio de siacutentomas

Encefalitis fiebre alteracioacuten de conciencia

Hidrofobia salivacioacuten

Una vez iniciadohellipmuerte en 5-15 diacuteas

Exposicion ne Enfermedad Clinica

Laboratorio

Animales sospechosos

Exposicion

(mordeduras)

Presentacioacuten

Cliacutenica

Autopsia

Confirmacioacuten

de laboratorio

Post-mortem

Vacuna +RIG

OK

Rabia

detenida

Sin Vacuna

Confirmacioacuten

de laboratorio

Pre-mortem

Mordeduras

Dog bite

Rat bite

Mordeduras

Profilaxis Antirraacutebica Humana

Para evitar la progresioacuten de la infeccioacuten (inoculacioacuten viral por

mordedura) al cuadro cliacutenico de la rabia

La necesidad de profilaxis esta determinada por la evaluacioacuten de

riesgo de cada caso individual

Indicada tan pronto como se establece la necesidad despueacutes de la

evaluacioacuten de riesgo

No esta indicado cuando ya hay signos de encefalitis y se sospecha rabia

Existen recomendaciones emitidas por la OMSOPS

Rabies Vaccines WHO position paper (2010)

Consulta de Expertos en Rabia Segundo reporte OMS 2013

Vacunas

httpwwwwhointimmunization_standardsvaccine_qualityPQ_vaccine_list_enen

1 Chiron Behring Vaccines Private Ltd India 1 dose Vial

2 Novartis Vaccines and Diagnostics Germany 1 dose

Vial

3 Sanofi Pasteur France 1 dose Vial

4 Serum Institute of India Ltd India India 1 dose Vial

5 Zydus Cadila India 1 dose Vial 1 dose Vial

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Rabia silvestre

Source MINSA-DGE-DGSP RH

Rabia CaninaUrbana

Animal

surveillance

Rabies in cattle

transmitted by

vampire bats

Rabies incidence

density and

relationship with

landscape

Map CDC-Rabies

Data SENASA-Peru

Peru

RS es un problema

Amazonico

La RS esta en aumento

Respuesta lentatardia

Intervencion costosa

Vector omnipresente

Vigilancia en ganado

Exposicion masiva vacunacion

masiva

Barreras para control

Barreras para el diagnostico

RS Factores reconocidos

Baja educacioacuten Encuesta CAP Peruacute 2010

Lenguaje 370 grupos eacutetnicos

Acceso geograacutefico vacunas servicios de

salud

Vivienda modificacioacuten es posible se

requiere programa masivo con poliacuteticas

de gobierno

Exposicioacutenmordeduras alta frecuencia

Vacunas $ cadena de frio abandonos

faltano uso de RIG

Poliacuteticas lento reconocimiento de la

situacioacuten uacutenica de la RS como

enfermedad emergente en Amazonia

Loreto

Madre De Dios

Temporary workers

home

La rabia

Una vez que ingresa el virus ldquoviajardquo

por el tejido nervioso hasta llegar al

cerebro

Incubacioacuten

Tiempo que demora en llegar al cerebro

~45 diacuteas (7dias-3 meses)

excepcionalmente antildeos

No contagia durante incubacioacuten

Aun se puede vacunarhellip urgentemente

Inicio de siacutentomas

Encefalitis fiebre alteracioacuten de conciencia

Hidrofobia salivacioacuten

Una vez iniciadohellipmuerte en 5-15 diacuteas

Exposicion ne Enfermedad Clinica

Laboratorio

Animales sospechosos

Exposicion

(mordeduras)

Presentacioacuten

Cliacutenica

Autopsia

Confirmacioacuten

de laboratorio

Post-mortem

Vacuna +RIG

OK

Rabia

detenida

Sin Vacuna

Confirmacioacuten

de laboratorio

Pre-mortem

Mordeduras

Dog bite

Rat bite

Mordeduras

Profilaxis Antirraacutebica Humana

Para evitar la progresioacuten de la infeccioacuten (inoculacioacuten viral por

mordedura) al cuadro cliacutenico de la rabia

La necesidad de profilaxis esta determinada por la evaluacioacuten de

riesgo de cada caso individual

Indicada tan pronto como se establece la necesidad despueacutes de la

evaluacioacuten de riesgo

No esta indicado cuando ya hay signos de encefalitis y se sospecha rabia

Existen recomendaciones emitidas por la OMSOPS

Rabies Vaccines WHO position paper (2010)

Consulta de Expertos en Rabia Segundo reporte OMS 2013

Vacunas

httpwwwwhointimmunization_standardsvaccine_qualityPQ_vaccine_list_enen

1 Chiron Behring Vaccines Private Ltd India 1 dose Vial

2 Novartis Vaccines and Diagnostics Germany 1 dose

Vial

3 Sanofi Pasteur France 1 dose Vial

4 Serum Institute of India Ltd India India 1 dose Vial

5 Zydus Cadila India 1 dose Vial 1 dose Vial

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

RS Factores reconocidos

Baja educacioacuten Encuesta CAP Peruacute 2010

Lenguaje 370 grupos eacutetnicos

Acceso geograacutefico vacunas servicios de

salud

Vivienda modificacioacuten es posible se

requiere programa masivo con poliacuteticas

de gobierno

Exposicioacutenmordeduras alta frecuencia

Vacunas $ cadena de frio abandonos

faltano uso de RIG

Poliacuteticas lento reconocimiento de la

situacioacuten uacutenica de la RS como

enfermedad emergente en Amazonia

Loreto

Madre De Dios

Temporary workers

home

La rabia

Una vez que ingresa el virus ldquoviajardquo

por el tejido nervioso hasta llegar al

cerebro

Incubacioacuten

Tiempo que demora en llegar al cerebro

~45 diacuteas (7dias-3 meses)

excepcionalmente antildeos

No contagia durante incubacioacuten

Aun se puede vacunarhellip urgentemente

Inicio de siacutentomas

Encefalitis fiebre alteracioacuten de conciencia

Hidrofobia salivacioacuten

Una vez iniciadohellipmuerte en 5-15 diacuteas

Exposicion ne Enfermedad Clinica

Laboratorio

Animales sospechosos

Exposicion

(mordeduras)

Presentacioacuten

Cliacutenica

Autopsia

Confirmacioacuten

de laboratorio

Post-mortem

Vacuna +RIG

OK

Rabia

detenida

Sin Vacuna

Confirmacioacuten

de laboratorio

Pre-mortem

Mordeduras

Dog bite

Rat bite

Mordeduras

Profilaxis Antirraacutebica Humana

Para evitar la progresioacuten de la infeccioacuten (inoculacioacuten viral por

mordedura) al cuadro cliacutenico de la rabia

La necesidad de profilaxis esta determinada por la evaluacioacuten de

riesgo de cada caso individual

Indicada tan pronto como se establece la necesidad despueacutes de la

evaluacioacuten de riesgo

No esta indicado cuando ya hay signos de encefalitis y se sospecha rabia

Existen recomendaciones emitidas por la OMSOPS

Rabies Vaccines WHO position paper (2010)

Consulta de Expertos en Rabia Segundo reporte OMS 2013

Vacunas

httpwwwwhointimmunization_standardsvaccine_qualityPQ_vaccine_list_enen

1 Chiron Behring Vaccines Private Ltd India 1 dose Vial

2 Novartis Vaccines and Diagnostics Germany 1 dose

Vial

3 Sanofi Pasteur France 1 dose Vial

4 Serum Institute of India Ltd India India 1 dose Vial

5 Zydus Cadila India 1 dose Vial 1 dose Vial

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

La rabia

Una vez que ingresa el virus ldquoviajardquo

por el tejido nervioso hasta llegar al

cerebro

Incubacioacuten

Tiempo que demora en llegar al cerebro

~45 diacuteas (7dias-3 meses)

excepcionalmente antildeos

No contagia durante incubacioacuten

Aun se puede vacunarhellip urgentemente

Inicio de siacutentomas

Encefalitis fiebre alteracioacuten de conciencia

Hidrofobia salivacioacuten

Una vez iniciadohellipmuerte en 5-15 diacuteas

Exposicion ne Enfermedad Clinica

Laboratorio

Animales sospechosos

Exposicion

(mordeduras)

Presentacioacuten

Cliacutenica

Autopsia

Confirmacioacuten

de laboratorio

Post-mortem

Vacuna +RIG

OK

Rabia

detenida

Sin Vacuna

Confirmacioacuten

de laboratorio

Pre-mortem

Mordeduras

Dog bite

Rat bite

Mordeduras

Profilaxis Antirraacutebica Humana

Para evitar la progresioacuten de la infeccioacuten (inoculacioacuten viral por

mordedura) al cuadro cliacutenico de la rabia

La necesidad de profilaxis esta determinada por la evaluacioacuten de

riesgo de cada caso individual

Indicada tan pronto como se establece la necesidad despueacutes de la

evaluacioacuten de riesgo

No esta indicado cuando ya hay signos de encefalitis y se sospecha rabia

Existen recomendaciones emitidas por la OMSOPS

Rabies Vaccines WHO position paper (2010)

Consulta de Expertos en Rabia Segundo reporte OMS 2013

Vacunas

httpwwwwhointimmunization_standardsvaccine_qualityPQ_vaccine_list_enen

1 Chiron Behring Vaccines Private Ltd India 1 dose Vial

2 Novartis Vaccines and Diagnostics Germany 1 dose

Vial

3 Sanofi Pasteur France 1 dose Vial

4 Serum Institute of India Ltd India India 1 dose Vial

5 Zydus Cadila India 1 dose Vial 1 dose Vial

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Exposicion ne Enfermedad Clinica

Laboratorio

Animales sospechosos

Exposicion

(mordeduras)

Presentacioacuten

Cliacutenica

Autopsia

Confirmacioacuten

de laboratorio

Post-mortem

Vacuna +RIG

OK

Rabia

detenida

Sin Vacuna

Confirmacioacuten

de laboratorio

Pre-mortem

Mordeduras

Dog bite

Rat bite

Mordeduras

Profilaxis Antirraacutebica Humana

Para evitar la progresioacuten de la infeccioacuten (inoculacioacuten viral por

mordedura) al cuadro cliacutenico de la rabia

La necesidad de profilaxis esta determinada por la evaluacioacuten de

riesgo de cada caso individual

Indicada tan pronto como se establece la necesidad despueacutes de la

evaluacioacuten de riesgo

No esta indicado cuando ya hay signos de encefalitis y se sospecha rabia

Existen recomendaciones emitidas por la OMSOPS

Rabies Vaccines WHO position paper (2010)

Consulta de Expertos en Rabia Segundo reporte OMS 2013

Vacunas

httpwwwwhointimmunization_standardsvaccine_qualityPQ_vaccine_list_enen

1 Chiron Behring Vaccines Private Ltd India 1 dose Vial

2 Novartis Vaccines and Diagnostics Germany 1 dose

Vial

3 Sanofi Pasteur France 1 dose Vial

4 Serum Institute of India Ltd India India 1 dose Vial

5 Zydus Cadila India 1 dose Vial 1 dose Vial

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Mordeduras

Dog bite

Rat bite

Mordeduras

Profilaxis Antirraacutebica Humana

Para evitar la progresioacuten de la infeccioacuten (inoculacioacuten viral por

mordedura) al cuadro cliacutenico de la rabia

La necesidad de profilaxis esta determinada por la evaluacioacuten de

riesgo de cada caso individual

Indicada tan pronto como se establece la necesidad despueacutes de la

evaluacioacuten de riesgo

No esta indicado cuando ya hay signos de encefalitis y se sospecha rabia

Existen recomendaciones emitidas por la OMSOPS

Rabies Vaccines WHO position paper (2010)

Consulta de Expertos en Rabia Segundo reporte OMS 2013

Vacunas

httpwwwwhointimmunization_standardsvaccine_qualityPQ_vaccine_list_enen

1 Chiron Behring Vaccines Private Ltd India 1 dose Vial

2 Novartis Vaccines and Diagnostics Germany 1 dose

Vial

3 Sanofi Pasteur France 1 dose Vial

4 Serum Institute of India Ltd India India 1 dose Vial

5 Zydus Cadila India 1 dose Vial 1 dose Vial

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Mordeduras

Profilaxis Antirraacutebica Humana

Para evitar la progresioacuten de la infeccioacuten (inoculacioacuten viral por

mordedura) al cuadro cliacutenico de la rabia

La necesidad de profilaxis esta determinada por la evaluacioacuten de

riesgo de cada caso individual

Indicada tan pronto como se establece la necesidad despueacutes de la

evaluacioacuten de riesgo

No esta indicado cuando ya hay signos de encefalitis y se sospecha rabia

Existen recomendaciones emitidas por la OMSOPS

Rabies Vaccines WHO position paper (2010)

Consulta de Expertos en Rabia Segundo reporte OMS 2013

Vacunas

httpwwwwhointimmunization_standardsvaccine_qualityPQ_vaccine_list_enen

1 Chiron Behring Vaccines Private Ltd India 1 dose Vial

2 Novartis Vaccines and Diagnostics Germany 1 dose

Vial

3 Sanofi Pasteur France 1 dose Vial

4 Serum Institute of India Ltd India India 1 dose Vial

5 Zydus Cadila India 1 dose Vial 1 dose Vial

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Profilaxis Antirraacutebica Humana

Para evitar la progresioacuten de la infeccioacuten (inoculacioacuten viral por

mordedura) al cuadro cliacutenico de la rabia

La necesidad de profilaxis esta determinada por la evaluacioacuten de

riesgo de cada caso individual

Indicada tan pronto como se establece la necesidad despueacutes de la

evaluacioacuten de riesgo

No esta indicado cuando ya hay signos de encefalitis y se sospecha rabia

Existen recomendaciones emitidas por la OMSOPS

Rabies Vaccines WHO position paper (2010)

Consulta de Expertos en Rabia Segundo reporte OMS 2013

Vacunas

httpwwwwhointimmunization_standardsvaccine_qualityPQ_vaccine_list_enen

1 Chiron Behring Vaccines Private Ltd India 1 dose Vial

2 Novartis Vaccines and Diagnostics Germany 1 dose

Vial

3 Sanofi Pasteur France 1 dose Vial

4 Serum Institute of India Ltd India India 1 dose Vial

5 Zydus Cadila India 1 dose Vial 1 dose Vial

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Vacunas

httpwwwwhointimmunization_standardsvaccine_qualityPQ_vaccine_list_enen

1 Chiron Behring Vaccines Private Ltd India 1 dose Vial

2 Novartis Vaccines and Diagnostics Germany 1 dose

Vial

3 Sanofi Pasteur France 1 dose Vial

4 Serum Institute of India Ltd India India 1 dose Vial

5 Zydus Cadila India 1 dose Vial 1 dose Vial

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Vaccineshelliplike in the old timeshellip

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Categoriacuteas de Exposicioacuten OMS

Categoriacutea I Tocar o alimentar animales

Lameduras en piel intacta

Contacto de piel intacta con secreciones o excreciones de un animal o persona con

la rabia

NO se consideran exposiciones

No PEP

Categoriacutea II Mordisqueo de piel descubierta

Arantildeazos menores o raspados sin sangrado

PEP (vacuna) inmediatamente

Categoriacutea III Una o muacuteltiples mordeduras o arantildeazos transdeacutermicos

Lamedura en piel con aberturas o cortes

Contaminacioacuten de membrana mucosa con saliva de lameduras

Exposicioacuten a murcieacutelagos

PEP (vacuna+RIG)

PEP

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

PEP

Indicado en caso de mordeduras arantildeazos y exposicioacuten de

mucosa o aberturascortes de la piel a la saliva de un animal

con la rabia

Evaluacioacuten de riesgo caso por caso

Componentes Lavado de herida eneacutergicamente con agua corriente y jaboacuten ~10 minutos

RIG Infiltrado en la herida e IM Evitar el mismo brazo de la vacuna

HRIG 20 UIkg de peso en el diacutea 0

ERIG 40 UIkg de peso en el diacutea 0

Cuatro a cinco dosis de vacuna antirraacutebica IM o esquema ID

Refuerzos En individuos previamente vacunados

Dos dosis de vacuna IM Diacuteas 0 y 3

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Esquemas de PEP recomendados

IM [Cada dosis de vacuna 1 ml o 05 ml (VeroRab)]+RIG(Day 0)

Essen (1-1-1-1-1) Una dosis administrada en los diacuteas 03714 y

28 cinco dosis en total

Essen acortado (1-1-1-1-0) Una dosis administrada en los diacuteas

037 y 14 cuatro dosis en total (EEUU) Personas en buen

estado de salud

Zagreb (2-1-1) Dos dosis en el diacutea 0 y una dosis en los diacuteas 7 y

21 cuatro dosis en total (Brasil Francia)

ID [Cada dosis de vacuna 01 ml]+RIG (Day 0)

Cruz Roja Tailandesa (2-2-2-0-2) Dos dosis en dos lugares

diferentes los diacuteas 037 y 28

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

PEP

Lavado de herida+RIG+Vacuna

(ACIP-EEUU)

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

PEP Indicacioacuten

(ACIP-EEUU)

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Pre-EP

Indicacioacuten

Riesgo ocupacional

Viaje a zonas endeacutemicas

Poblacioacuten de aacutereas de alto riesgo

Componentes

Tres dosis de vacuna antirraacutebica de 1 ml IM diacuteas 0 7 y 2128

Lugar brazo aacuterea deltoidea

No hay necesidad de administrar HRIG

Refuerzos

Una dosis de vacuna antirraacutebica de 1 mL IM

Administrada cuando la indicacioacuten persiste y los RVNA detectados por RFFIT

baja a menos del nivel adecuado (15 diluciones en suero)

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Pre-EP Vacuna (HRIG no es

necesaria)

(ACIP-EEUU)

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Pre-EP Indicacioacuten

(ACIP-EEUU)

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Vacuna Antirraacutebica Humana

Vacunas de cultivo celular disponibles

HDCV Vacuna de Ceacutelulas Diploides Humanas Imovax reg (Sanofi-Pasteur) cada dosis IM 1mL

PCECV Vacuna de Ceacutelulas de Embrioacuten de Pollo Purificada Rabipurreg RabAvertreg(Novartis)

Vial para una dosis IM 1mL

PVCV Vacuna de Ceacutelulas Vero Purificada VeroRabreg (Sanofi-Pasteur)

Vial para una dosis IM 05 mL

PDEV₮ Vacuna de Ceacutelulas de Embrioacuten de Pato Purificada Lyssavac N reg (Berna B)

Vial para una dosis IM 1 mL

Vacunas precalificadas por la OMS 2013 ₮ En texto de WHO Rabies Expert Cons 2013

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Vial de 1mL(1 dosis IM por vial)

Vial de 05 mL(1 dosis IM por vial)

HDCV

PCECVPVCV

PDEV

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Dos ejemplos de HRIGs disponiblendash Inmunoglobulina antirraacutebica (Human) USP Imogamreg Rabies ndash HT

(Sanofi-Pasteur)

ndash Inmunoglobulina antirraacutebica (Human) - HyperRABreg SDSolventDetergent Treated Rabies ndash HT (Talecris)

ndash Presentacioacuten Viales de 2mL y 10mL Uso IM

Inmunoglobulina Antirraacutebica Humana

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Inmunoglobulina Antirraacutebica

Heteroacuteloga

ERIG disponible en la

actualidad esta purificado

Menos reacciones

adversas que en ERIG

anteriores

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Vacunacioacuten

antirraacutebica Intradeacutermica

Permite ahorrar vacuna (01 ml por dosis vs 1mL o 05 mL en IM)

Utilizado en Asia exitosamente

Requiere garantizar administracioacuten

correcta (Tecnica de Mantoux)

PCECV y PVCV

Tratamiento antimalaacuterico con cloroquina

interfiere en la respuesta inmuneOMS

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Desviaciones comunes

Indicacioacuten incorrecta de la PEP

Vacuna o RIG administrado subcutaacuteneamente

Dosis incorrecta de HRIG

Vacuna y RIG administrada en el mismo brazo

Paciente perdido al seguimiento o faltando a las fecha

de las dosis

HRIG no disponible el diacutea 0 pero disponible despueacutes

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Vacuna ideal

Termoestable

Faacutecil de aplicar

Una sola dosis

Bajo costo

Miacutenimas reacciones

adversas

Tecnologiacuteas existen pero

aun no estaacuten combinadas

en un productoi Adaptadorinyector jet ID

ii Cristalizacioacuten

iii NanoparchesNanoagujas

iv Vacunas recombinantes

v Modificacioacuten geneacutetica viral

vi Disentildeo geneacutetico viral

Investigacioacuten y desarrollo

en proceso

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Adaptador de Jeringa

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

NanoPass

MicronJet

(MJ600)

Debiotech

Nanoject

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Vacuna Influenza ID

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Bioinyector

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Parches de Microagujas

James J Norman Jaya M Arya Maxine A McClain Paula M Frew Martin I Meltzer Mark R Prausnitz

Microneedle patches Usability and acceptability for self-vaccination against influenza

Vaccine Volume 32 Issue 16 2014 1856 - 1862

httpdxdoiorg101016jvaccine201401076

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Resumen

ANTES CRL

Inyeccioacuten periumbilical

subcutanea

Volumen 2 ml

7 dosis diarias + 3 refuerzos

Vacuna nacional uacutenica

ESAVI severos esperadas

116000 dosis

AHORA VCC

Inyeccioacuten aacuterea deltoidea

intramuscular

Volumen 05 ml o 1ml

5 dosis Diacuteas 0371428

Tres opciones de vacunas

pre calificadas por OMS

Importadas

ESAVIS severos esperadas

11Milloacuten de dosis

bull Cambio de vacuna a cultivo celular es

irreversible

bull Hay nuevas opciones y promesas de nuevos

bioloacutegicos a futuro pero es necesario centildeirse a

normas y directivas nacionales NT ESAVI

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

M

ors

ihellip ~

45

hellip J

ou

r 0

Jo

ur

3 J

ou

r 7

Jo

ur

14

Jo

ur

28

VNA

Sin

VNA

05 IU

Periodo de incubacioacuten

RIG

Vacuna

Mo

rded

ura

Diacutea

Diacutea

Diacutea

Diacutea

Diacutea

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Diagnoacutestico

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Table 183-2 Comparison of human rabies cases and non-rabies cases sorted by frequency of signs and symptoms in confirmed cases

Unites States 1960-2010

Variable Positive N=108 Negative N=144 Odds Ratio P-value

n() n () (95 CI)

Mean age (range) 3435 (2ndash82) 3072 (lt1ndash78) 0173

Male gender 83 (769) 87 (626) 198 (113ndash349) 0019dagger

Fever 90 (833) 113 (785) 137 (072ndash261) 0422

Confusion or

delirium 67 (620) 123 (854) 028 (015ndash051) lt0001dagger

Agitation or

combativeness 55 (509) 86 (597) 070 (042ndash116) 02

Paresthesia or

localized pain 54 (500) 21 (146) 586 (322ndash1064) lt0001dagger

Dysphagia 53 (491) 43 (299) 226 (135ndash380) 0003dagger

Muscle spasm 45 (417) 59 (410) 103 (062ndash171) 1

Localized weakness 44 (407) 34 (236) 222 (129ndash383) 0004dagger

Malaise or fatigue 39 (361) 101 (701) 024 (014ndash041) lt0001dagger

Nausea or vomiting 38 (352) 66 (458) 064 (038ndash107) 009

Hydrophobia 36 (333) 9 (63) 750 (342ndash1643) lt0001dagger

Anxiety 33 (306) 51 (354) 080 (047ndash137) 05

Headache 29 (269) 90 (625) 022 (013ndash038) lt0001dagger

Autonomic

instability 29 (269) 47 (326) 076 (044ndash131) 034

Hypersalivation 28 (259) 38 (264) 098 (055ndash172) 1

Seizures 27 (250) 79 (549) 027 (016ndash047) lt0001dagger

Hallucinations 26 (241) 42 (192) 077 (044ndash136) 039

Ataxia 20 (185) 38 (264) 063 (034ndash117) 017

Anorexia 19 (176) 37 (257) 062 (033ndash115) 017

Insomnia 11 (102) 27 (188) 049 (023ndash104) 017

Aerophobia 10 (93) 1 (07) 1459 (184ndash11583) 0001dagger

Priapism or

spontaneous

ejaculation 4 (37) 2 (14) 273 (050ndash1519) 041

CI = Confidence interval dagger Statistically significant Adapted from Petersen B and Rupprecht C Human Rabies Epidemiology and Diagnosis Chapter 11 in Non-Flavivirus

Encephalitis Edited by S Tkachev Intech 2011

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Siacutentomas

pediaacutetricos

Capitulo 183 Rabia Recuenco S et al Feigin and Cherry

Texbook of Pediatric Infectious Diseases 7ma ed

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Diagnostico

Muy difiacutecil

Suele confundirse con otras

enfermedades

Diferenciales

Enf Virales

Enf Siquiatricas

Enf Autoinmune

Considerar contexto cultural

Recordar epidemiologia localregional

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

DiseaseCondition Differentiating SignsSymptoms Differentiating Tests

Herpes simplex virus infection

Does not show the

relapsingremitting pattern of

mental lucidity seen in rabies

HSV is detected in CSF by PCR

with gt95 sensitivity

Enterovirus

meningoencephalitis

May show similar profound

dysautonomia with

cardiomyopathy

Enteroviruses are detected in

CSF by PCR with gt95

sensitivity

West Nile virus encephalitis

History of a mosquito bite

Generally shows more

parkinsonian findings or general

body rigidity than rabies

West Nile virus-specific IgM in

CSF is diagnostic

Other arbovirus encephalitides

History of a mosquito bite

Generally show more

parkinsonian findings or general

body rigidity than rabies

Serum anti-arboviral antibodies

are positive

Rocky Mountain spotted fever

and rickettsial encephalitis

Petechial rashes or eschars are

present

WBC count usually low

Rocky Mountain spotted fever

and other rickettsial serologies

are diagnostic

Japanese encephalitis

Parkinsonian symptoms are

common

Patients develop hyperreflexia

Presence of Japanese

encephalitis virus RNA in

tissue blood or CSF is

diagnostic

Japanese encephalitis virus

antibodies may be detected in

CSF or serum

CSF shows elevated protein

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Guillain-Barre syndrome

Acute flaccid paralysis is similar

to paralysis seen in rabies

especially paralytic rabies

Sphincter involvement is rare

There is no fever

with a normal cell count

(albuminocytologic

dissociation)

Nerve conduction studies

show slowing of nerve

conduction velocities

Limbic encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are very similar to

rabies Seizures are common

with limbic encephalitis with N-

methyl-D-aspartate glutamate

receptor (NMDAR) antibodies

Serum antibodies to N-methyl-

D-aspartate (NMDA)

glutamate receptor may be

positive

Acute disseminated

encephalitis

Aerophobia and hydrophobia

are absent but other clinical

features are similar to rabies

Brain MRI shows white matter

lesions

Tetanus

Aerophobia hydrophobia and

mental state changes are

absent

The main sign is trismus (which

results in a grimace described

as risus sardonicus or

sardonic smile) associated with

muscle rigidity spasms

respiratory embarrassment

dysphagia or autonomic

dysfunction

Detection of tetanus toxin in

plasma or clostridial culture

from wound swab

CSF is normal

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

dysfunction

Bartonella encephalitis Associated with lymphadenitisBartonella serologies are

diagnostic

Delirium tremens

History of chronic alcohol use

and either reduction or

cessation of drinking before

presentation

Prodromal illness is absent

Fever is rare

The diagnosis is clinical

Cocaine overdose History of cocaine use

Cocaine may be detected in

urine blood or gastric

contents The half-life in blood

is short

Amphetamine overdose History of amphetamine abuseUrine is positive for

amphetamines

Acute psychosis

Main symptoms are

hallucinations delusions and

thought disorder possibly

accompanied by agitation The

prodrome and physical

manifestations of rabies are

absent

Other clinical features depend

on the cause

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Manejo clinico

Manejo de complicaciones

Sedacion

Paleativo

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Protocolo de Milwaukee y Recife

Tratamiento experimental

Ketamina coma inducido sedacion

2004primer sobreviviente

2009 Colombia

2010 Brasil Recife

2010 Peru

Extremadamente caro

Requiere equipo medico

especializado y comprometido 247

Manejo de caso de rabia es de

Medicina Intensiva

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Protocolo de Milwaukee

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Pediatr Infect Dis J 2014 Nov 18 [Epub ahead of print]

Virology Immunology and Pathology of Human Rabies during Treatment

Caicedo Y1 Paez A Kuzmin I Niezgoda M Orciari LA Yager PA Recuenco S Franka R Velasco-

Villa A Willoughby RE Jr

Author information

Abstract

BACKGROUND

Rabies is an acute fatal encephalitis caused by all members of the Lyssavirus genus The first

human rabies survivor without benefit of prior vaccination was reported from Milwaukee in 2005

We report a second unvaccinated patient who showed early recovery from rabies and then died

accidentally during convalescence providing an unparalleled opportunity to examine the

histopathology as well as immune and virological correlates of early recovery from human rabies

METHODS

Case report rapid fluorescent focus inhibition test enzyme-linked immunosorbent assay indirect

and direct fluorescent antibody assays reverse-transcriptase polymerase chain

reaction phylogenetic reconstruction isolation in tissue culture pathology and

immunohistochemistry

RESULTS

The 9 year old died 76 days after presenting with rabies of vampire bat phylogeny transmitted by

cat bite Antibody response in serum and CSF was robust and associated with severe cerebral

edema No rabies virus was cultured at autopsy Rabies virus antigen was atypical in size and

distribution Rabies virus genome was present in neocortex but absent in brainstem

CONCLUSIONS

Clinical recovery was associated with detection of neutralizing antibody and clearance of infectious

rabies virus in the CNS by 76 days but not clearance of detectable viral subcomponents such as

nucleoprotein antigen or RNA in brain

Rabia Abortiva y recuperacioacuten

espontanea Muy raro

Texas 2010

California 2011

Inmunidad adquirida

Preguntas

Gracias

Gracias

Preguntas

Tarapoto Peru 2010

Inmunidad adquirida

Preguntas

Gracias

Gracias

Preguntas

Tarapoto Peru 2010

Preguntas

Gracias

Gracias

Preguntas

Tarapoto Peru 2010

Gracias

Preguntas

Tarapoto Peru 2010