<?xml version="1.0" encoding="ISO-8859-1"?><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance">
<front>
<journal-meta>
<journal-id>0034-8376</journal-id>
<journal-title><![CDATA[Revista de investigación clínica]]></journal-title>
<abbrev-journal-title><![CDATA[Rev. invest. clín.]]></abbrev-journal-title>
<issn>0034-8376</issn>
<publisher>
<publisher-name><![CDATA[Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán]]></publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id>S0034-83762005000500007</article-id>
<title-group>
<article-title xml:lang="es"><![CDATA[Agentes del bioterrorismo: preparándose para lo impensable]]></article-title>
<article-title xml:lang="en"><![CDATA[Bioterrorism agents: getting ready for the unthinkable]]></article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Franco-Paredes]]></surname>
<given-names><![CDATA[Carlos]]></given-names>
</name>
<xref ref-type="aff" rid="A01"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Rodríguez-Morales]]></surname>
<given-names><![CDATA[Alfonso]]></given-names>
</name>
<xref ref-type="aff" rid="A02"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Santos-Preciado]]></surname>
<given-names><![CDATA[José Ignacio]]></given-names>
</name>
<xref ref-type="aff" rid="A01"/>
</contrib>
</contrib-group>
<aff id="A02">
<institution><![CDATA[,Universidad de Los Andes Centro Trujillano de Investigaciones J. W. Torrealba ]]></institution>
<addr-line><![CDATA[ Trujillo]]></addr-line>
<country>Venezuela</country>
</aff>
<aff id="A01">
<institution><![CDATA[,Hospital Infantil de México, Federico Gómez  ]]></institution>
<addr-line><![CDATA[México D.F.]]></addr-line>
</aff>
<pub-date pub-type="pub">
<day>00</day>
<month>10</month>
<year>2005</year>
</pub-date>
<pub-date pub-type="epub">
<day>00</day>
<month>10</month>
<year>2005</year>
</pub-date>
<volume>57</volume>
<numero>5</numero>
<fpage>695</fpage>
<lpage>705</lpage>
<copyright-statement/>
<copyright-year/>
<self-uri xlink:href="http://www.scielo.org.mx/scielo.php?script=sci_arttext&amp;pid=S0034-83762005000500007&amp;lng=en&amp;nrm=iso"></self-uri><self-uri xlink:href="http://www.scielo.org.mx/scielo.php?script=sci_abstract&amp;pid=S0034-83762005000500007&amp;lng=en&amp;nrm=iso"></self-uri><self-uri xlink:href="http://www.scielo.org.mx/scielo.php?script=sci_pdf&amp;pid=S0034-83762005000500007&amp;lng=en&amp;nrm=iso"></self-uri><abstract abstract-type="short" xml:lang="en"><p><![CDATA[The September 11, 2001 terrorist attacks in the USA demonstrated our vulnerability to terrorist raids. Furthermore, in the same year inhalational anthrax cases in humans caused by the international release of Bacillus anthracis spores via the USA postal system inflicted a lot of panic and terror over the civilian population. The succeeding terrorist events scattered in several other countries are continous reminders of our failness and of the risk that terrorists attempts in the future may be implemented by means of deliberate evil release of biological agents. These events may be perpetrated by either the release of an infectious agent or any of its products in order to spread death or sickness in humans, animals, or plants with the obnoxius purpose of scaring governments and societies for the profit of particular ideological causes. In the current article, we present a review of the main bioterrorism agents, as well as a historical and clinical aspects and their significance for public health preparedness and response.]]></p></abstract>
<abstract abstract-type="short" xml:lang="es"><p><![CDATA[Los eventos terroristas del 11 de septiembre del 2001 en Estados Unidos de América (EUA) cambiaron para siempre nuestra percepción de la vulnerabilidad a los ataques terroristas. Aunado a esto, los primeros casos de ántrax en humanos ocasionados por la liberación intencional de esporas de Bacillus anthracis a través del sistema postal de EUA infligieron pánico y terror en la población general. Los subsecuentes eventos de terrorismo ocurridos en diversos países son recordatorios continuos de nuestra fragilidad y del riesgo que futuros ataques terroristas pudieran organizarse a través de liberación intencional de agentes biológicos. El bioterrorismo consiste en el uso intencional o amenaza de utilizar agentes biológicos; ya sea el propio agente infeccioso o sus productos para causar la muerte o enfermedad en humanos, animales o plantas con el objetivo de intimidar a gobiernos y sociedades en beneficio de causas ideológicas particulares. En el presente artículo se hace una revisión de los principales agentes del bioterrorismo, aspectos históricos, clínicos y terapéuticos, así como su prevención e importancia para la salud pública mundial.]]></p></abstract>
<kwd-group>
<kwd lng="en"><![CDATA[Bioterrorism]]></kwd>
<kwd lng="en"><![CDATA[Biological weapons]]></kwd>
<kwd lng="en"><![CDATA[Public health]]></kwd>
<kwd lng="es"><![CDATA[Bioterrorismo]]></kwd>
<kwd lng="es"><![CDATA[Armas biológicas]]></kwd>
<kwd lng="es"><![CDATA[Salud pública]]></kwd>
</kwd-group>
</article-meta>
</front><body><![CDATA[ <p align="justify"><font face="verdana" size="4">Art&iacute;culo de revisi&oacute;n</font></p>     <p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     <p align="center"><font face="verdana" size="4"><b>Agentes del bioterrorismo: prepar&aacute;ndose para lo impensable</b></font></p>     <p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     <p align="center"><font face="verdana" size="3"><b>Bioterrorism agents: getting ready for the unthinkable</b></font></p>     <p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     <p align="center"><font face="verdana" size="2"><b>Carlos Franco&#150;Paredes,* Alfonso Rodr&iacute;guez&#150;Morales,** Jos&eacute; Ignacio Santos&#150;Preciado*</b></font></p>     <p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     <p align="justify"><font face="verdana" size="2"><i>* Hospital Infantil de M&eacute;xico, Federico G&oacute;mez.</i></font></p>     <p align="justify"><font face="verdana" size="2"><i>** Centro Trujillano de Investigaciones J. W. Torrealba. Universidad de Los Andes. Trujillo, Venezuela.</i></font></p>     ]]></body>
<body><![CDATA[<p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     <p align="justify"><font face="verdana" size="2"><b>Sobretiros:</b><i>    <br>   </i><i>Dr. Carlos Franco&#150;Paredes<b>    <br>   </b>Hospital Infantil de M&eacute;xico, Federico G&oacute;mez,    <br>   Dr. M&aacute;rquez No. 162, Col. Doctores    <br>   06720, M&eacute;xico, D.F.    <br>   Tel: 5761&#150;0181 y 5761&#150;1963</i>    <br> Correo electr&oacute;nico: <a href="mailto:cfranco@sph.emory.edu">cfranco@sph.emory.edu</a></font></p>     <p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     <p align="justify"><font face="verdana" size="2">Recibido el 11 de junio de 2004.     ]]></body>
<body><![CDATA[<br>   Aceptado el 17 de marzo de 2005.</font></p>     <p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     <p align="justify"><font face="verdana" size="2"><b><i>ABSTRACT</i></b></font></p>     <p align="justify"><font face="verdana" size="2"><i>The September 11, 2001 terrorist attacks in the USA demonstrated our vulnerability to terrorist raids. Furthermore, in the same year inhalational anthrax cases in humans caused by the international release of Bacillus anthracis spores via the USA postal system inflicted a lot of panic and terror over the civilian population. The succeeding terrorist events scattered in several other countries are continous reminders of our failness and of the risk that terrorists attempts in the future may be implemented by means of deliberate evil release of biological agents. These events may be perpetrated by either the release of an infectious agent or any of its products in order to spread death or sickness in humans, animals, or plants with the obnoxius purpose of scaring governments and societies for the profit of particular ideological causes. In the current article, we present a review of the main bioterrorism agents, as well as a historical and clinical aspects and their significance for public health preparedness and response.</i></font></p>     <p align="justify"><font face="verdana" size="2"><b><i>Kew words. </i></b><i>Bioterrorism. Biological weapons. Public health.</i></font></p>     <p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     <p align="justify"><font face="verdana" size="2"><b>RESUMEN</b></font></p>     <p align="justify"><font face="verdana" size="2">Los eventos terroristas del 11 de septiembre del 2001 en Estados Unidos de Am&eacute;rica (EUA) cambiaron para siempre nuestra percepci&oacute;n de la vulnerabilidad a los ataques terroristas. Aunado a esto, los primeros casos de &aacute;ntrax en humanos ocasionados por la liberaci&oacute;n intencional de esporas de <i>Bacillus anthracis </i>a trav&eacute;s del sistema postal de EUA infligieron p&aacute;nico y terror en la poblaci&oacute;n general. Los subsecuentes eventos de terrorismo ocurridos en diversos pa&iacute;ses son recordatorios continuos de nuestra fragilidad y del riesgo que futuros ataques terroristas pudieran organizarse a trav&eacute;s de liberaci&oacute;n intencional de agentes biol&oacute;gicos. El bioterrorismo consiste en el uso intencional o amenaza de utilizar agentes biol&oacute;gicos; ya sea el propio agente infeccioso o sus productos para causar la muerte o enfermedad en humanos, animales o plantas con el objetivo de intimidar a gobiernos y sociedades en beneficio de causas ideol&oacute;gicas particulares. En el presente art&iacute;culo se hace una revisi&oacute;n de los principales agentes del bioterrorismo, aspectos hist&oacute;ricos, cl&iacute;nicos y terap&eacute;uticos, as&iacute; como su prevenci&oacute;n e importancia para la salud p&uacute;blica mundial.</font></p>     <p align="justify"><font face="verdana" size="2"><b>Palabras clave. </b>Bioterrorismo. Armas biol&oacute;gicas. Salud p&uacute;blica.</font></p>     <p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     ]]></body>
<body><![CDATA[<p align="justify"><font face="verdana" size="2"><b>INTRODUCCI&Oacute;N</b></font></p>     <p align="justify"><font face="verdana" size="2">Los eventos terroristas del 11 de septiembre del 2001 en Estados Unidos de Am&eacute;rica (EUA) cambiaron para siempre nuestra percepci&oacute;n de la vulnerabilidad a los ataques terroristas.<sup>1&#150;</sup><sup>4</sup> Aunado a esto, los primeros casos de &aacute;ntrax en humanos ocasionados por la liberaci&oacute;n intencional de esporas de <i>Bacillus anthracis </i>a trav&eacute;s del sistema postal de EUA infligieron p&aacute;nico y terror en la poblaci&oacute;n general.<sup>5&#150;</sup><sup>9</sup> Los subsecuentes eventos de terrorismo ocurridos en Arabia Saudita, Indonesia, Turqu&iacute;a y m&aacute;s recientemente en Espa&ntilde;a e Inglaterra son recordatorios continuos de nuestra fragilidad y del riesgo que futuros ataques terroristas pudieran perpetrarse a trav&eacute;s de liberaci&oacute;n intencional de agentes biol&oacute;gicos.<sup>10</sup> El bioterrorismo consiste en el uso intencional o amenaza de utilizar agentes biol&oacute;gicos, ya sea el propio agente infeccioso o sus productos para causar la muerte o enfermedad en humanos, animales o plantas con el objetivo de intimidar a gobiernos y sociedades en beneficio de causas ideol&oacute;gicas particulares.<sup>3</sup> En principio, cualquier organismo puede ser usado como arma biol&oacute;gica. No obstante, las caracter&iacute;sticas que ciertos agentes infecciosos<sup>2&#150;</sup><sup>4</sup> deben poseer para ser considerados como armas biol&oacute;gicas incluyen:</font></p>     <p align="justify"><font face="verdana" size="2">1. Que causen elevada morbilidad y mortalidad.</font></p>     <p align="justify"><font face="verdana" size="2">2. Que se transmitan de persona a persona.</font></p>     <p align="justify"><font face="verdana" size="2">3. Que tengan una baja dosis infecciosa.</font></p>     <p align="justify"><font face="verdana" size="2">4. Que sean altamente infectantes al ser diseminados como aerosol y, por tanto, tengan la capacidad para causar grandes brotes.</font></p>     <p align="justify"><font face="verdana" size="2">5. Que no exista una vacuna contra el agente o que &eacute;sta sea de disponibilidad limitada.</font></p>     <p align="justify"><font face="verdana" size="2">6. Que exista el potencial para ser producido a gran escala.</font></p>     <p align="justify"><font face="verdana" size="2">7. Que se trate de un agente estable en el medio ambiente.</font></p>     <p align="justify"><font face="verdana" size="2">Los agentes que cumplen con estos criterios son denominados "clase A" (<a href="/img/revistas/ric/v57n5/a7c1.jpg" target="_blank">Cuadro 1</a>).<sup>2,4</sup></font></p>     ]]></body>
<body><![CDATA[<p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     <p align="justify"><font face="verdana" size="2"><b>ANTECEDENTES HIST&Oacute;RICOS DEL BIOTERRORISMO</b></font></p>     <p align="justify"><font face="verdana" size="2">La perversa idea de utilizar agentes infecciosos para producir efectos similares a los de las grandes epidemias ha sido considerada por el hombre desde hace muchos a&ntilde;os y existen descripciones en distintos periodos de la historia.<sup>11&#150;</sup><sup>14</sup> Es as&iacute; como, cuando se produce la invasi&oacute;n de la ciudad de Kaffa (actualmente Crimea) durante la segunda pandemia de peste en 1346, la Armada t&aacute;rtara coloc&oacute; cad&aacute;veres de gente que hab&iacute;a sucumbido de peste, en las entradas de la ciudad. En forma similar, el Ej&eacute;rcito brit&aacute;nico distribuy&oacute; mantas contaminadas de soldados enfermos con viruela entre indios norteamericanos entre 1754&#150;1767. En el siglo XX el Ej&eacute;rcito alem&aacute;n desarroll&oacute; arsenales biol&oacute;gicos durante la Primera Guerra Mundial. Jap&oacute;n tambi&eacute;n desarroll&oacute; armas biol&oacute;gicas durante su ocupaci&oacute;n en Manchuria desde 1932 hasta el final de la Segunda Guerra Mundial.<sup>11</sup></font></p>     <p align="justify"><font face="verdana" size="2">En EUA la producci&oacute;n de armas biol&oacute;gicas se inicia en 1942 con misiles cargados con <i>B. </i><i>anthracis</i><sup>2,3,11</sup> Corea es acusado por el uso de armas biol&oacute;gicas.<sup>15</sup> Por su parte, EUA acusa a la Uni&oacute;n Sovi&eacute;tica de la utilizaci&oacute;n de micotoxinas de <i>Fusarium </i>en Laos y Afganist&aacute;n. Estas alegaciones conducen en 1972 a la Convenci&oacute;n Internacional para la Prohibici&oacute;n del Desarrollo de Armas Biol&oacute;gicas, lo cual conlleva a que el presidente Richard Nixon ordene la destrucci&oacute;n del arsenal biol&oacute;gico en EUA.<sup>2,16</sup> En teor&iacute;a, esto tambi&eacute;n deber&iacute;a haber ocurrido en otros pa&iacute;ses, no obstante, continu&oacute; la sospecha de la producci&oacute;n de armas biol&oacute;gicas por la Uni&oacute;n Sovi&eacute;tica debido a un brote de &aacute;ntrax en 1979 entre civiles cerca de esta base militar en Sverdlovsk, Rusia.<sup>16&#150;</sup><sup>18</sup> En 1992, el Presidente Boris Yeltsin reconoce que se hab&iacute;a debido a la liberaci&oacute;n no intencional de &aacute;ntrax de esta planta militar.<sup>16</sup> En las &uacute;ltimas d&eacute;cadas, fan&aacute;ticos religiosos han utilizado de manera intencional agentes biol&oacute;gicos. En 1984, en Oregon, EUA, un culto religioso hind&uacute; contamin&oacute; supermercados y dep&oacute;sitos de agua con <i>Salmonella typhimurium.</i><sup>19</sup> Asimismo, en Jap&oacute;n, en 1995, el culto Aum Shinrikyo, responsable de la liberaci&oacute;n del gas sar&iacute;n en el tren de la ciudad de Tokio, intent&oacute; por lo menos en ocho ocasiones distintas ataques con &aacute;ntrax;<sup>20</sup> Se sabe que este culto tambi&eacute;n intent&oacute; obtener virus &eacute;bola en Zaire para desarrollar armas biol&oacute;gicas en el a&ntilde;o 2001.<sup>20</sup></font></p>     <p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     <p align="justify"><font face="verdana" size="2"><b>AGENTES DEL BIOTERRORISMO (<a href="/img/revistas/ric/v57n5/a7c2.jpg" target="_blank">Cuadro 2</a>)</b></font></p>     <p align="justify"><font face="verdana" size="2"><b>Viruela (virus <i>Variola)</i></b></font></p>     <p align="justify"><font face="verdana" size="2">La viruela resulta de la infecci&oacute;n con el virus <i>Variola, </i>el cual pertenece al g&eacute;nero de los <i>Orthopoxvirusy </i>familia <i>Poxviridae.</i><sup>21&#150;27</sup> Existen dos formas cl&iacute;nicas de la viruela, la mayor y la menor. La viruela mayor es la forma m&aacute;s grave, manifest&aacute;ndose con un exantema m&aacute;s extenso. La transmisi&oacute;n de la viruela ocurre a trav&eacute;s de gotas generadas de las mucosas oral, nasal y far&iacute;ngea de pacientes infectados y que subsecuentemente son inhaladas por personas susceptibles. El paciente se vuelve infeccioso con la aparici&oacute;n del exantema. El periodo de incubaci&oacute;n es de doce d&iacute;as (ocho a 19 d&iacute;as). Durante el estadio prodr&oacute;mico aparece abruptamente fiebre (39&#150;40 &deg;C), cefalea, mialgias, postraci&oacute;n, n&aacute;usea, v&oacute;mito y dolor de espalda. Esta forma presenta diversas variedades cl&iacute;nicas. Adem&aacute;s, existen dos clasificaciones de la viruela, una por Dixon en 1962 y una por Rao en 1967 (<a href="/img/revistas/ric/v57n5/a7c3.jpg" target="_blank">Cuadro 3</a>).<sup>21&#150;25</sup></font></p>     <p align="justify"><font face="verdana" size="2">El diagn&oacute;stico en un paciente que presenta lesiones sugestivas de viruela requiere descartar infecci&oacute;n por <i>Varicella&#150;Zoster </i>y proceder a la b&uacute;squeda de <i>Orthopoxvirus </i>a trav&eacute;s de microscop&iacute;a electr&oacute;nica del contenido pustular o por la detecci&oacute;n de los cuerpos de Guarnieri en secciones de tejido por microscop&iacute;a de luz. El aislamiento respiratorio y de contacto es fundamental en los casos en los cuales se sospecha viruela. El manejo m&eacute;dico es principalmente de apoyo evitando sobreinfecci&oacute;n bacteriana y el mantener estados de hidrataci&oacute;n para evitar insuficiencia renal.<sup>2,25</sup> Recientemente se ha sugerido que el antiviral cidofovir pudiera ser &uacute;til, sin embargo, no existe ninguna experiencia cl&iacute;nica confirmatoria de su efectividad.<sup>25,28,29</sup></font></p>     <p align="justify"><font face="verdana" size="2">Gracias al programa intensificado de erradicaci&oacute;n de la viruela por la Organizaci&oacute;n Mundial de la Salud (OMS) el &uacute;ltimo caso de viruela en el mundo fue diagnosticado en octubre de 1977 en Somalia. El 8 de mayo de 1980 la Asamblea Mundial de la OMS certific&oacute; la erradicaci&oacute;n.<sup>30&#150;</sup><sup>37</sup> A partir de entonces, la OMS decidi&oacute; el almacenamiento de 200 millones de dosis de vacuna antivariolosa, pero a principios de los a&ntilde;os 90's por cuestiones financieras se vio obligada a s&oacute;lo almacenar 50 millones de dosis. Por disposici&oacute;n de la OMS se acord&oacute; que s&oacute;lo dos laboratorios en el mundo mantuvieran los restos del virus, uno en EUA (en el Centers for Disease Control &#91;CDC&#93;, Atlanta) y uno en la Uni&oacute;n Sovi&eacute;tica (en el Centro Estatal de Investigaciones en Virolog&iacute;a en Koltsovo).<sup>39&#150;</sup><sup>41</sup> El debate continu&oacute; en torno a la destrucci&oacute;n del virus en estos laboratorios, lo cual se hab&iacute;a programado para diciembre del 2002. Pero como resultado de los eventos ocurridos en el a&ntilde;o 2001, estos planes se vieron nuevamente truncados. El plan estrat&eacute;gico ahora consiste en la producci&oacute;n masiva de vacunas y el establecimiento de planes de respuesta de emergencia.<sup>29,</sup><sup>35,38,</sup><sup>41</sup></font></p>     ]]></body>
<body><![CDATA[<p align="justify"><font face="verdana" size="2">La vacuna actualmente disponible es la vacuna viva atenuada del virus <i>Vaccinia.</i><sup>38,</sup><sup>41</sup> Las complicaciones asociadas a esta vacuna incluyen el eczema vaccinatum, vaccinia generalizada, vaccinia progresiva y la encefalitis posvacunal.<sup>36,</sup><sup>37,42&#150;</sup><sup>45</sup> Sin embargo, una vacuna desarrollada en cultivos celulares producida por laboratorios Acambis est&aacute; siendo evaluada para su posible utilizaci&oacute;n, la cual pudiera tener un mejor perfil de seguridad.<sup>39</sup> Las estrategias de vacunaci&oacute;n contenidas en los planes de respuesta para contrarrestar un posible ataque bioterrorista con el virus <i>Variola </i>se encuentran divididos en la vacunaci&oacute;n preexposici&oacute;n y la vacunaci&oacute;n postexposici&oacute;n.<sup>27,</sup><sup>46&#150;</sup><sup>48</sup> Tan r&aacute;pido como se considere el diagn&oacute;stico de viruela a nivel intrahospitalario, el paciente debe ser aislado y todos los contactos deben ser vacunados y colocados bajo vigilancia m&eacute;dica.<sup>2,</sup><sup>28</sup></font></p>     <p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     <p align="justify"><font face="verdana" size="2"><b>&Aacute;ntrax <i>(Bacillus anthracis)</i></b></font></p>     <p align="justify"><font face="verdana" size="2"><i>Bacillus anthracis </i>es un bacilo grampositivo formador de esporas que recibe su nombre de la palabra griega <i>anthrakis </i>(carb&oacute;n), por la coloraci&oacute;n negruzca de las lesiones que produce en piel. Los seres humanos adquieren la infecci&oacute;n a trav&eacute;s de contacto directo con la piel de animales infectados o productos animales.<sup>2</sup> La transmisi&oacute;n de persona a persona nunca ha sido documentada. Una vez que las esporas son introducidas al cuerpo por inhalaci&oacute;n, ingeridas a trav&eacute;s del tubo digestivo o por contacto con la piel, son fagocitadas por macr&oacute;fagos que viajan a los ganglios linf&aacute;ticos en donde germinan hacia formas bacilares. El bacilo produce una c&aacute;psula antifagoc&iacute;tica y tres prote&iacute;nas: el ant&iacute;geno protector, el factor letal y el factor edematoso; &eacute;stas se combinan para formar la toxina edematosa, la cual bloquea la activaci&oacute;n de linfocitos y macr&oacute;fagos.<sup>5,</sup><sup>9,49</sup> En octubre del 2001, el CDC report&oacute; 18 casos confirmados de &aacute;ntrax asociados a la liberaci&oacute;n intencional de sus esporas. Del total de casos, 11 fueron por inhalaci&oacute;n y siete fueron cut&aacute;neos. De los casos de &aacute;ntrax por inhalaci&oacute;n, cinco pacientes murieron.<sup>5&#150;</sup><sup>9</sup></font></p>     <p align="justify"><font face="verdana" size="2">El &aacute;ntrax cut&aacute;neo abarca 95% de los casos que ocurren naturalmente de la enfermedad. Despu&eacute;s de la exposici&oacute;n a las esporas se forma una m&aacute;cula que progresa hacia ves&iacute;cula en 1&#150;2 d&iacute;as y es seguida de ulceraci&oacute;n y necrosis con la formaci&oacute;n de una escara negruzca no dolorosa. Los pacientes pueden tener fiebre, debilidad, cefalea y linfadenopat&iacute;a. La tasa de letalidad es de 20% sin tratamiento y disminuye a menos de 1% con tratamiento antimicrobiano. El &aacute;ntrax gastrointestinal es una forma rara que ocurre por la ingesta de carne bovina contaminada y se asocia a dolor abdominal, fiebre, anorexia, n&aacute;usea, v&oacute;mito y diarrea sanguinolenta en muchos casos. La tasa de fatalidad es de 25&#150;60%.<sup>2,</sup><sup>5&#150;10,16</sup> La forma m&aacute;s severa est&aacute; representada en el &aacute;ntrax por inhalaci&oacute;n, y la dosis letal por inhalaci&oacute;n es de 2,500 a 55,000 esporas. El periodo de incubaci&oacute;n var&iacute;a de dos a 60 d&iacute;as y tiene una presentaci&oacute;n cl&iacute;nica bif&aacute;sica, en la cual durante la primera fase existen s&iacute;ntomas inespecificos y dos a cuatro d&iacute;as m&aacute;s tarde aparecen s&iacute;ntomas respiratorios, falla hemodin&aacute;mica y edema pulmonar. Adem&aacute;s, 50% de estos pacientes presentan meningitis hemorr&aacute;gica. Cl&iacute;nicamente, existe ensanchamiento del mediastino dada por adenopat&iacute;as, as&iacute; como por derrames pleurales e infiltrados evidenciables en las radiograf&iacute;as de t&oacute;rax. A pesar de que la presentaci&oacute;n bif&aacute;sica no fue observada en los casos de &aacute;ntrax por liberaci&oacute;n intencional en el 2001, la mayor&iacute;a de los s&iacute;ntomas estuvieron presentes, adem&aacute;s se identific&oacute; leucocitosis y elevaci&oacute;n de transaminasas.<sup>7,</sup><sup>9,16</sup></font></p>     <p align="justify"><font face="verdana" size="2">La confirmaci&oacute;n de &aacute;ntrax por laboratorio se realiza a trav&eacute;s de estudios de inmunohistoqu&iacute;mica, prueba de reacci&oacute;n en cadena de la polimerasa (PCR) y cultivos de sangre, l&iacute;quido&#150;cefalorraqu&iacute;deo, as&iacute; como de secreciones proveniente de las lesiones cut&aacute;neas. En cultivos las colonias son descritas como no pigmentadas y no mucoides presentando una morfolog&iacute;a describible como <i>"cabeza </i>de medusa". El tratamiento de cualquiera de las formas de &aacute;ntrax es con ciprofloxacina, penicilina o doxiciclina. En mujeres embarazadas penicilina V o amoxicilina son preferidas. En el escenario de exposici&oacute;n a bioterrorismo la terapia antimicrobiana debe continuarse por 60 d&iacute;as porque es el tiempo requerido por las esporas para germinar. Para las formas por inhalaci&oacute;n y gastrointestinal, se recomienda la ciprofloxacina intravenosa y/o doxiciclina intravenosa a veces asociada a otros antibi&oacute;ticos como son: rifampicina, imipenem, vancomicina, clindamicina, claritromicina o penicilina.<sup>16</sup> Existe una vacuna adsorbida contra &aacute;ntrax que est&aacute; disponible en EUA para la profilaxis preexposici&oacute;n, la cual es producida por filtrados libres de las c&eacute;lulas inactivadas de una cepa avirulenta de <i>B. anthracis. </i>Se utilizan dosis de 0.5 mL en seis intervalos, a las cero, dos y cuatro semanas y despu&eacute;s de los seis, 12 y 18 meses. Adem&aacute;s, se recomienda dosis de refuerzo cada a&ntilde;o.<sup>2,5&#150;</sup><sup>9</sup></font></p>     <p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     <p align="justify"><font face="verdana" size="2"><b>Botulismo <i>(Clostridium botulinum)</i></b></font></p>     <p align="justify"><font face="verdana" size="2">El botulismo es causado por la infecci&oacute;n o presencia de la toxina de <i>Clostridium botulinum, </i>bacteria anaer&oacute;bica obligada formadora de esporas. Existen siete diferentes tipos antig&eacute;nicos de la toxina botul&iacute;nica, designados por las letras A&#150;G.<sup>2</sup> Las variedades que ocurren m&aacute;s frecuentemente son la A, B y G. La toxina botul&iacute;nica es probablemente la toxina m&aacute;s letal conocida, aproximadamente 100,000 veces m&aacute;s t&oacute;xica que el gas sar&iacute;n.<sup>50&#150;</sup><sup>51</sup> <i>Clostridium botulinum</i>o sus toxinas tienen la capacidad de ingresar al cuerpo humano a trav&eacute;s de tres diferentes v&iacute;as: inhalaci&oacute;n, ingesti&oacute;n y por contaminaci&oacute;n de heridas. Las dos rutas m&aacute;s comunes que pudieran ser utilizadas en eventos de liberaci&oacute;n intencional son la contaminaci&oacute;n de alimentos y la aerosolizaci&oacute;n.<sup>52&#150;</sup><sup>53</sup> La toxina se transporta a las terminales sin&aacute;pticas perif&eacute;ricas colin&eacute;rgicas, particularmente a la uni&oacute;n neuromuscular en donde se une en forma irreversible y se bloquea la liberaci&oacute;n de acetilcolina. Esto se manifiesta con una par&aacute;lisis fl&aacute;cida descendente sim&eacute;trica que usualmente se inicia con la afectaci&oacute;n de los pares craneales y manifest&aacute;ndose como diplop&iacute;a, visi&oacute;n borrosa, ptosis palpebral, disfon&iacute;a y disartria. Debe diferenciarse de la <i>miastenia gravis, </i>del s&iacute;ndrome de Miller&#150;Fisher y otras enfermedades neurol&oacute;gicas que afectan al tallo cerebral.<sup>2,51</sup> A pesar de que existen pruebas confirmatorias de laboratorio, la sospecha cl&iacute;nica es fundamental, ya que las pruebas requieren tiempo para sus resultados. El cultivo y la detecci&oacute;n de toxinas pueden realizarse en heces fecales, aspirado g&aacute;strico, v&oacute;mito y en alimentos contaminados. La prueba para la detecci&oacute;n de toxinas es un bioensayo en ratones que tarda de seis a 96 horas para completarse.<sup>51</sup> El tratamiento m&eacute;dico es de soporte y la inmunizaci&oacute;n pasiva es con antitoxina equina. Es fundamental el manejo ventilatorio, la prevenci&oacute;n de infecciones secundarias y cuidados intensivos en general. Si la bacteria es aislada, se recomienda la utilizaci&oacute;n de penicilina o metronidazol. En EUA existe una toxina pentavalente en proceso de investigaci&oacute;n que se utiliza para la vacunaci&oacute;n preexposici&oacute;n y existe una antitoxina trivalente (A, B y E) disponible a trav&eacute;s del CDC.<sup>2,51</sup></font></p>     <p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     ]]></body>
<body><![CDATA[<p align="justify"><font face="verdana" size="2"><b>Peste ( <i>Yersinia pestis)</i></b></font></p>     <p align="justify"><font face="verdana" size="2">La peste o peste bub&oacute;nica es una infecci&oacute;n bacteriana producida por <i>Yersinia pestis, </i>un cocobacilo gramnegativo que pertenece a la familia de las enterobacterias. Se considera una infecci&oacute;n enzoon&oacute;tica de perros, ratas y ardillas. La transmisi&oacute;n a seres humanos ocurre por pulgas provenientes de roedores y por secreciones respiratorias de animales o humanos.<sup>54&#150;</sup><sup>62</sup> Como un prefacio a las epidemias humanas, la muerte masiva de ratas infestadas con pulgas contaminadas con <i>Y. pestis, </i>precipita el movimiento de pulgas hacia los seres humanos.<sup>54</sup> Durante la segunda Guerra Mundial, Jap&oacute;n investig&oacute; el uso de la peste como un arma biol&oacute;gica. En los EUA tambi&eacute;n se investig&oacute; a <i>Y. pestis </i>como una potencial arma biol&oacute;gica en la d&eacute;cada de los 50s. En otros pa&iacute;ses como Rusia e Irak tambi&eacute;n se ha sospechado el posible desarrollo de armas biol&oacute;gicas con <i>Y. pestis.</i><sup>54&#150;</sup><sup>59</sup></font></p>     <p align="justify"><font face="verdana" size="2">Las tres formas cl&iacute;nicas de la peste son la forma bub&oacute;nica, la neumon&iacute;a secundaria y la neumon&iacute;a primaria, siendo la &uacute;ltima la m&aacute;s frecuente en caso de un evento de bioterrorismo. En la peste bub&oacute;nica, las personas afectadas se presentan con fiebre, fatiga y desarrollo de linfadenopat&iacute;as dolorosas cerca del sitio de picadura de la pulga; lo m&aacute;s frecuente (cerca de 90%) es que se afecten los ganglios linf&aacute;ticos inguinales. Algunos desarrollan peste septic&eacute;mica, la cual se caracteriza por bacteriemia, en ocasiones meningitis y choque s&eacute;ptico. La neumon&iacute;a secundaria se origina por diseminaci&oacute;n hemat&oacute;gena del bacilo hacia los pulmones y se manifiesta con disnea, dolor tor&aacute;cico, hemoptisis y bronconeumon&iacute;a severa. La neumon&iacute;a primaria y la meningitis por peste son formas generalmente mortales que progresan r&aacute;pidamente hacia el choque s&eacute;ptico. Cuando la peste bub&oacute;nica no es tratada la letalidad puede alcanzar hasta 50%.<sup>58&#150;</sup><sup>62</sup></font></p>     <p align="justify"><font face="verdana" size="2">El diagn&oacute;stico de peste bub&oacute;nica se realiza por la caracter&iacute;stica identificaci&oacute;n por tinci&oacute;n del bacilo gramnegativo con morfolog&iacute;a de pasador y por su tinci&oacute;n bipolar con las coloraciones de Wright o Giemsa, as&iacute; como cultivos de esputo, sangre o aspirado de ganglio linf&aacute;tico. Tambi&eacute;n la detecci&oacute;n directa por t&eacute;cnicas de inmunohistoqu&iacute;mica en tejidos o serolog&iacute;a son &uacute;tiles.<sup>60</sup> Los pacientes diagnosticados con neumon&iacute;a por peste deben ser aislados. Antiguamente exist&iacute;a una vacuna para la preexposici&oacute;n, la cual fue retirada del mercado, sin embargo, una nueva vacuna que protege contra la neumon&iacute;a por peste est&aacute; siendo desarrollada por la Armada de EUA.<sup>58&#150;</sup><sup>62</sup> Desde el punto de vista terap&eacute;utico, se recomienda gentamicina o estreptomicina, como agentes de primera l&iacute;nea. Alternativamente podr&iacute;a emplearse doxiciclina o ciprofloxacina. Para la quimioprofilaxis se recomienda de primera l&iacute;nea doxiciclina o alternativamente ciprofloxacina.<sup>54,62</sup></font></p>     <p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     <p align="justify"><font face="verdana" size="2"><b>Tularemia <i>(Francisella tularensis)</i></b></font></p>     <p align="justify"><font face="verdana" size="2">La tularemia es causada por la infecci&oacute;n por <i>Francisella tularensis, </i>una bacteria con morfolog&iacute;a de cocobacilo gramnegativo aer&oacute;bico, que tiene dos subespecies: <i>Francisella tularensis </i>biovar <i>tula</i><i>rensis, </i>la cual es altamente virulenta en humanos; y <i>Francisella tularensis </i>biovar <i>paleartica, </i>relativamente avirulenta en humanos. Esta bacteria produce una enfermedad zoon&oacute;tica en &aacute;reas rurales. La infecci&oacute;n es adquirida a trav&eacute;s de la inoculaci&oacute;n de secreciones de animales contaminados o a trav&eacute;s de la mordedura de artr&oacute;podos. Una vez que ocurre la inoculaci&oacute;n, el microorganismo se disemina a ganglios linf&aacute;ticos. La aerosolizaci&oacute;n de <i>Francisella tularensis </i>ser&iacute;a la forma m&aacute;s eficiente de ser utilizada en un evento de bioterrorismo.<sup>2,63 </sup>Las presentaciones cl&iacute;nicas de la tularemia incluyen: las formas ulceroglandular, oculoglandular, orofar&iacute;ngea y la forma neum&oacute;nica. La forma ulceroglandular se manifiesta por una p&aacute;pula que se convierte a un estadio pustular para subsecuentemente ulcerarse. La variedad oculoglandular ocurre por la contaminaci&oacute;n directa del ojo con ulceraciones conjuntivales, quemosis, vasculitis y linfadenopat&iacute;a regional. El tipo orofar&iacute;ngeo se adquiere por la ingesta de agua o alimentos contaminados y produce una faringoamigdalitis exudativa. La neumon&iacute;a por tularemia es causada por la inhalaci&oacute;n de aerosoles o por diseminaci&oacute;n secundaria por v&iacute;a hemat&oacute;gena y se puede manifestar como bronquiolitis, bronconeumon&iacute;a o pleuroneumonitis con adenopat&iacute;a hiliar. La tasa de letalidad por tularemia es aproximadamente de 35%.<sup>63</sup></font></p>     <p align="justify"><font face="verdana" size="2">El organismo se identifica directamente en secreciones o exudados de biopsias a trav&eacute;s de tinciones inmunohistoqu&iacute;micas. El diagn&oacute;stico definitivo se realiza a trav&eacute;s del cultivo. Una vez que se ha establecido el diagn&oacute;stico de tularemia, se debe proceder a las precauciones universales con desinfecci&oacute;n de objetos, ropas y s&aacute;banas con cloro a 10%. La quimioprofilaxis con doxiciclina o ciprofloxacina durante el periodo de incubaci&oacute;n y tomados por dos semanas previene la ocurrencia de la enfermedad. El tratamiento de elecci&oacute;n es la estreptomicina o gentamicina por 10 d&iacute;as, sin embargo, las tetraciclinas, fluoroquinolonas y el cloranfenicol son terapias alternativas, pero en general no son utilizadas por la alta tasa de reca&iacute;da asociada a su utilizaci&oacute;n. No existe vacuna disponible para tularemia hasta este momento.<sup>2,63</sup></font></p>     <p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     <p align="justify"><font face="verdana" size="2"><b>Fiebres hemorr&aacute;gicas virales</b></font></p>     ]]></body>
<body><![CDATA[<p align="justify"><font face="verdana" size="2"><b><i>(Filoviridae, Arenaviridae, </i></b><b><i>Bunyaviridae, Flavivirida&eacute;)</i></b></font></p>     <p align="justify"><font face="verdana" size="2">El grupo de las fiebres hemorr&aacute;gicas virales est&aacute; constituido por una variedad de entidades cl&iacute;nicas caracterizadas por fiebre y hemorragias en diversas partes del cuerpo, asociadas a la infecci&oacute;n por virus ARN. Estos virus pertenecen a cuatro distintas familias de virus: filovirus, arenavirus, bunyavirus y flavivirus (<a href="/img/revistas/ric/v57n5/a7c4.jpg" target="_blank">Cuadro 4</a>). Las fiebres hemorr&aacute;gicas son trasmitidas a los humanos a trav&eacute;s del contacto con animales infectados o artr&oacute;podos, con excepci&oacute;n de los filovirus para los cuales los reservorios y vectores de transmisi&oacute;n son desconocidos.<sup>64</sup></font></p>     <p align="justify"><font face="verdana" size="2">Algunos de los virus del grupo de las fiebres hemorr&aacute;gicas cumplen con muchos de los criterios para ser considerados como armas biol&oacute;gicas, incluyendo a los filovirus (&eacute;bola y Marburg), arenavirus (fiebre de Lassa y los arenavirus del nuevo mundo), bunyavirus (fiebre del Valle Rift) y flavivirus (fiebre amarilla, fiebre hemorr&aacute;gica de Omsk y la fiebre de la selva de Kyasanur).<sup>64&#150;</sup><sup>80</sup> Los virus causantes de las fiebres hemorr&aacute;gicas virales han sido utilizados para la producci&oacute;n de armas biol&oacute;gicas por la Uni&oacute;n Sovi&eacute;tica y EUA. Existen reportes que Corea del Norte ha escalado la producci&oacute;n del virus de fiebre amarilla como arma biol&oacute;gica.<sup>65&#150;</sup><sup>67</sup> Se sabe que la Uni&oacute;n Sovi&eacute;tica produjo hasta 1992 grandes cantidades de los virus Marburg, &eacute;bola, Lassa y de arenavirus del nuevo mundo, especialmente de los virus Junin y Machupo.<sup>66&#150;</sup><sup>68</sup> Por otra parte, el virus de la fiebre amarilla y del Valle Rift fueron producidos en grandes cantidades por los EUA.<sup>2,65&#150;</sup><sup>69,80&#150;92</sup></font></p>     <p align="justify"><font face="verdana" size="2">Las manifestaciones cl&iacute;nicas var&iacute;an con el origen del virus (<a href="/img/revistas/ric/v57n5/a7c5.jpg" target="_blank">Cuadro 5</a>). Los bunyavirus y los flavivirus producen s&iacute;ndromes caracterizados por enfermedad febril aguda asociada a debilidad, postraci&oacute;n e incremento en la permeabilidad vascular, incluyendo hemorragias conjuntivales y d&eacute;rmicas de caracter&iacute;sticas petequiales e hipotensi&oacute;n arterial. Estos s&iacute;ndromes pueden evolucionar hacia choque y hemorragia generalizada de mucosas e involucra a los sistemas hematopoy&eacute;ticos, neurol&oacute;gicos y pulmonares. La mortalidad var&iacute;a de 15 a 25% en casos de fiebre de Lassa hasta 90% en pacientes infectados con &eacute;bola.<sup>64,69,89&#150;92</sup> El diagn&oacute;stico virol&oacute;gico espec&iacute;fico se realiza por captura de ant&iacute;genos por t&eacute;cnica de ELISA o detecci&oacute;n por PCR. Cuando la identidad del virus no es conocida en el estudio de fiebres hemorr&aacute;gicas, se recomienda el aislamiento en cultivos seguidos de visualizaci&oacute;n directa con microscop&iacute;a electr&oacute;nica e identificaci&oacute;n inmunol&oacute;gica en laboratorios de bioseguridad nivel 4.<sup>64,80&#150;</sup><sup>84,90&#150;</sup><sup>92</sup></font></p>     <p align="justify"><font face="verdana" size="2">El diagn&oacute;stico diferencial de un paciente que se presenta con fiebre y hemorragia incluye una gran variedad de enfermedades virales y bacterianas.<sup>1,64 </sup>Estos incluyen infecciones virales como dengue hemorr&aacute;gico, meningococcemia, ricketsiosis, leptospirosis, paludismo severo, rub&eacute;ola, sarampi&oacute;n y viruela hemorr&aacute;gica. Dentro de las causas no infecciosas se tratamiento m&eacute;dico de las fiebres hemorr&aacute;gicas virales involucra manejo intrahospitalario y manejo de apoyo generalmente en terapias intensivas.<sup>1,64</sup> Dado el riesgo elevado de complicaciones hemorr&aacute;gicas se recomienda no utilizar medidas invasivas como cat&eacute;teres venosos centrales. La infusi&oacute;n de l&iacute;quidos intravenosos es fundamental, aunque existe riesgo de edema pulmonar por el incremento de la permeabilidad vascular. La utilizaci&oacute;n de ribavirina se recomienda en pacientes en los cuales se sospecha fiebre de Lassa y es tambi&eacute;n efectiva en la profilaxis postexposici&oacute;n. Existen estudios preliminares de la Armada de los EUA que han demostrado efectividad de la vacuna contra la fiebre hemorr&aacute;gica Argentina. Es tambi&eacute;n de uso com&uacute;n la vacuna 17D contra la fiebre amarilla con gran efectividad.<sup>64,68&#150;79,90,93</sup> Todos los casos  sospechosos o compatibles con fiebres hemorr&aacute;gicas deben de ser reportados a las autoridades de epidemiolog&iacute;a hospitalaria de la instituci&oacute;n, as&iacute; como a las autoridades correspondientes de la Secretar&iacute;a de Salud (Direcci&oacute;n General de Epidemiolog&iacute;a, SSA). Las medidas de aislamiento y control de infecciones en estos casos requieren de un apego estricto e incluyen: adherencia estricta al lavado de manos, aislamiento de contacto con uso de guantes, aislamiento respiratorio, protecci&oacute;n de ojos, utilizaci&oacute;n de batas impermeables, m&aacute;scaras N&#150;95 y el equipo m&eacute;dico individualizado.<sup>64</sup></font></p>     <p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     <p align="justify"><font face="verdana" size="2"><b>CONCLUSIONES</b></font></p>     <p align="justify"><font face="verdana" size="2">A pesar de que la mayor&iacute;a de los actos de terrorismo ocurren por motivos pol&iacute;ticos, es en el &aacute;rea del bioterrorismo donde la comunidad cient&iacute;fica y particularmente el personal m&eacute;dico y de salud p&uacute;blica juegan un papel fundamental. Es indudable que vivimos en una nueva etapa de la salud p&uacute;blica mundial, en donde ha surgido un replanteamiento con los eventos terroristas obligando a considerar el riesgo de nuevas amenazas de bioterrorismo.<sup>94&#150;</sup><sup>96</sup> Se requiere de estrategias precisas de prevenci&oacute;n para responder ante un evento de esta naturaleza. Debe existir un liderazgo organizado de las instituciones de salud y de las instituciones acad&eacute;micas para el establecimiento de planes de respuesta, para el fortalecimiento de los sistemas de vigilancia epidemiol&oacute;gica, disponibilidad de recursos e investigaci&oacute;n operacional de los sistemas de respuesta ante alguna de las posibles cat&aacute;strofes.</font></p>     <p align="justify"><font face="verdana" size="2">&nbsp;</font></p>     <p align="justify"><font face="verdana" size="2"><b>REFERENCIAS</b></font></p>     ]]></body>
<body><![CDATA[<!-- ref --><p align="justify"><font face="verdana" size="2">1. Varkey P, Poland GA, Cockerill F, et al. Confronting bioterrorism.  Physicians  on the front line. <i>Mayo Clin Proceed </i>2002; 77:   661&#150;72.</font>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;[&#160;<a href="javascript:void(0);" onclick="javascript: window.open('/scielo.php?script=sci_nlinks&ref=6765366&pid=S0034-8376200500050000700001&lng=','','width=640,height=500,resizable=yes,scrollbars=1,menubar=yes,');">Links</a>&#160;]<!-- end-ref --><!-- ref --><p align="justify"><font face="verdana" size="2">2. Lane CH, Fauci AS. Bioterrorism on the home front. 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