WORLD TRADE CENTER TRAGEDY AND BIOTERRORISM

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ALIGN="bottom" WIDTH="195" HSPACE="0" VSPACE="0"></tD> </tR> </TABLE></div> <div>               </div> </td> <td valign="top" BGCOLOR="#FFFFFF" TEXT="#080000" bgproperties="fixed" background="115f0f03.jpg"> <div> <I>WORLD TRADE CENTER TRAGEDY AND BIOTERRORISM</I></div> <div> <B><U>DEALING WITH THE TRAGEDY</U></B></div> <div> <A HREF="http://www.kidshealth.org/breaking_news/terrorist_attacks_EE_link.html" TARGET="_top" TITLE="http://www.kidshealth.org/breaking_news/"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Helping Your Child Deal With the Terrorist Tragedy</U></A></div> <div> <A HREF="http://www.kidshealth.org/parent/misc/attacks_help_EE_link.html" TARGET="_top" TITLE="http://www.kidshealth.org/parent/misc/at"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">How to Help After the Terrorist Attacks - for Parents</U></A></div> <div> <A HREF="http://www.kidshealth.org/parent/misc/teachers_tragedies_EE_link.html" TARGET="_top" TITLE="http://www.kidshealth.org/parent/misc/te"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">For Teachers: Talking About the Terrorist Attack</U></A></div> <div> <A HREF="http://www.news.cornell.edu/releases/Sept01/Garbarino.kids.bombing.lgk.html" TARGET="_top" TITLE="http://www.news.cornell.edu/releases/Sep"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Cornell expert advises parents on how to help children cope with news of terrorist attacks</U></A></div> <div> <A HREF="id92.htm" TARGET="_top" TITLE="Recommendations from Oklahoma City: Bere"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">a comprehensive book list on dealing with this type of tragedy recommended by Oklahoma city bookstores</U></A></div> <div> <B><U>BIO TERRORISM: THE FACTS</U></B></div> <div> <A HREF="#by_randolph_e__schmid_associated_press" TITLE="WORLD TRADE CENTER TRAGEDY AND BIOTERROR"><U><IMG BORDER="0" SRC="Symb075c00b700f099006600.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">serious reaactions with the new anthrax vaccine</U></A></div> <div> <A HREF="#us_releases_new_smallpox_response_plan" TITLE="WORLD TRADE CENTER TRAGEDY AND BIOTERROR"><U><IMG BORDER="0" SRC="Symb075c00b700f099006600.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">US Releases New Smallpox Response Plan</U></A></div> <div> <A HREF="#antibodies_show_early_promise_for" TITLE="WORLD TRADE CENTER TRAGEDY AND BIOTERROR"><U><B><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">NEW ANTHRAX TREATMENT</B></U></A></div> <div> <A HREF="#fewer_shots_for_new_anthrax_vaccine_" TITLE="WORLD TRADE CENTER TRAGEDY AND BIOTERROR"><U><B><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">newer anthrax vaccine</B></U></A></div> <div> <A HREF="http://www.bt.cdc.gov/" TARGET="_top" TITLE="http://www.bt.cdc.gov/"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">cdc update</U></A></div> <div> <A HREF="#1025_update_o_cases_of_anthrax_in_the" TITLE="WORLD TRADE CENTER TRAGEDY AND BIOTERROR"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">ANTHRAX UPDATE ON CASES AS OF  10/25</U></A></div> <div> <A HREF="http://www.cdc.gov/ncidod/dbmd/diseaseinfo/anthrax_g.htm" TARGET="_top" TITLE="http://www.cdc.gov/ncidod/dbmd/diseasein"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">ANTHRAX FACTS</U></A></div> <div> <A HREF="#a_primer_on_anthrax_separating_facts" TITLE="WORLD TRADE CENTER TRAGEDY AND BIOTERROR"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">A PRIMER ON ANTHRAX</U></A></div> <div> <A HREF="http://www.nlm.nih.gov/medlineplus/news/fullstory_4221.html" TARGET="_top" TITLE="http://www.nlm.nih.gov/medlineplus/news/"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">ANTHRAX TESTS</U></A></div> <div> <A HREF="#from_the_center_for_disease_control_cdc" TITLE="WORLD TRADE CENTER TRAGEDY AND BIOTERROR"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">FROM THE CDC ON ANTHRAX</U></A></div> <div> <A HREF="#_new_england_journal_review_article_on" TITLE="WORLD TRADE CENTER TRAGEDY AND BIOTERROR"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">NEW ENGLAND JOURNAL REVIEW ARTICLE ON ANTHRAX</U></A></div> <div> <A HREF="http://www.anthrax.osd.mil/" TARGET="_top" TITLE="http://www.anthrax.osd.mil/"><U><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"><IMG SRC="1cf0a0a0.png" border=0 width="10" height="10" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></U></U></A><FONT SIZE="2" COLOR="#660099" FACE="Arial" ><A HREF="http://www.anthrax.osd.mil/" TARGET="_top" TITLE="http://www.anthrax.osd.mil/"><U><U>anthrax immunizations program(DOD)</U></U></A></FONT></div> <div> <A HREF="http://www.aap.org/advocacy/releases/smlpoxanthrax.htm" TARGET="_top" TITLE="http://www.aap.org/advocacy/releases/sml"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">AAP POSITION ON SMALLPOX AND ANTHRAX</U></A></div> <div> <A HREF="http://www.immunizationinfo.org/newsbriefs/newsbriefDetail.cfm?id=6331" TARGET="_top" TITLE="http://www.immunizationinfo.org/newsbrie"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">SMALLPOX VACCINE NEWS</U></A></div> <div> <A HREF="#there_is_no_treatment_for_smallpox_but" TITLE="WORLD TRADE CENTER TRAGEDY AND BIOTERROR"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">TREATMENT FOR SMALLPOX?</U></A></div> <div> <A HREF="#progress_made_in_anthrax_cure" TITLE="WORLD TRADE CENTER TRAGEDY AND BIOTERROR"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Progress Made in Anthrax Cure Search</U></A></div> <div> <A HREF="#new_anthrax_vaccine_from_india_ready" TITLE="WORLD TRADE CENTER TRAGEDY AND BIOTERROR"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">New Anthrax Vaccine From India Ready for Trials</U></A></div> <div> <A HREF="#indian_drugmaker_offers_new_safer" TITLE="WORLD TRADE CENTER TRAGEDY AND BIOTERROR"><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">indian Drugmaker Offers New, Safer Anthrax Vaccine</U></A></div> <div> <A HREF="http://www.emedicine.com/cgi-bin/foxweb.exe/searchengine@/em/searchengine?query=ANTHRAX&book=derm&book=emerg&book=med&book=neuro&book=oph&book=orthoped&book=ent&book=ped&book=pmr&book=plastic&book=radio&book=sports&maxhits=80&sortorder=hits" TARGET="_top" TITLE="http://www.emedicine.com/cgi-bin/foxweb."><U><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">BIOTERRORISM DISEASES ARTICLES</U></A></div> <div> <IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The CDC has classified a number of infectious diseases as "Category A," or "high-priority" agents that, when in the wrong hands, could pose a risk to national security. These are: </div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700dc99006600.png" HEIGHT="15" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">anthrax,   smallpox,  </B><A HREF="http://www.emedicine.com/med/topic238.htm" TARGET="_top" TITLE="http://www.emedicine.com/med/topic238.ht"><U><B>botulism</B></U></A><B>,   plague,  </B><A HREF="http://www.emedicine.com/ped/topic2327.htm" TARGET="_top" TITLE="http://www.emedicine.com/ped/topic2327.h"><U><B>tularemia</B></U></A><B>  </B><B>viral hemorrhagic feve</B><FONT SIZE="2" COLOR="#660099" FACE="Arial" ><B>r</B></FONT></div> <bR> <div> The Postal Service hired a second company to cleanse the mail by irradiating it. Facilities in Bridgeport, N.J. and Lima, Ohio, now are tackling that massive effort. Each site is expected to cleanse about 750,000 pieces of mail a day, most coming from Washington, New Jersey and New York, where anthrax contamination was confirmed in some post offices. </div> <bR> <bR> <bR> <bR> <bR> <bR> <div> <I> <A NAME="by_randolph_e__schmid_associated_press"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></I><I>By RANDOLPH E. SCHMID, Associated Press Writer</I> </div> <div> WASHINGTON -<B> </B><FONT SIZE="3" COLOR="#660099" FACE="arial" ><B>Three serious reaction</B>s have been reported out of more than 100,000 military vaccinations against smallpox, the Army's deputy director for military vaccines said Thursday. </FONT></div> <div> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="12" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 19 WIDTH="4"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="19" ALIGN="bottom" WIDTH="4" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="1"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="19" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0"></tD> </tR> </TABLE></div> <div> Col. John D. Grabenstein told an Institute of Medicine (<FONT SIZE="3" COLOR="#0000FF" FACE="arial" ><U>news</U></FONT> - <FONT SIZE="3" COLOR="#0000FF" FACE="arial" ><U>web sites</U></FONT>) panel there have been two cases of encephalitis and one heart infection associated with the vaccinations. All three people have recovered and returned to duty, he said. </div> <div> "We're seeing a rash of rashes," Grabenstein said, but overall bad reactions are occurring at a lower rate than had been expected. </div> <div> Off to a slower start is the civilian smallpox program, with just 1,043 people vaccinated as of Feb. 11, said Joe Henderson, associate director of terrorism preparedness and response at the Centers for Disease Control and Prevention (<FONT SIZE="3" COLOR="#0000FF" FACE="arial" ><U>news</U></FONT> - <FONT SIZE="3" COLOR="#0000FF" FACE="arial" ><U>web sites</U></FONT>). </div> <div> He said no serious reactions have been reported in this group, mainly public health and safety personnel. </div> <div> Henderson said he was not surprised by the low number of vaccinations and predicted substantial increases over the next few weeks as more states get involved. </div> <div> Concerns about liability and compensation for people who suffer reactions have slowed the civilian program, but Henderson said only one state, Michigan, has declined to take part until that is resolved. </div> <div> When the national smallpox vaccination program was announced, as preparation for a potential attack, the rate of serious reactions was estimated at about 40 per million people being vaccinated for the first time, with one or two deaths. </div> <div> Routine smallpox vaccinations were discontinued in the 1970s. People born before that probably had a vaccination, while younger people will be vaccinated for the first time. The reaction rate is expected to be lower for people being revaccinated. </div> <div> In the 1970s, the only remaining stocks of the variola virus that causes smallpox were kept in Russia and the United States. But concerns have risen in recent years that some of the virus may have fallen into the hands of terrorists or countries such as Iraq. </div> <div> Grabenstein said 63 percent of those vaccinated in the military program are getting it the vaccine for the first time. </div> <div> In addition to the three cases classified as serious, Grabenstein said there have been seven cases of generalized vaccinia — a widespread rash — and a variety of minor complaints including fever, malaise, swollen lymph nodes and swelling at the site of the vaccination. </div> <div> Overall, he said, 4 percent to 5 percent of people receiving a first vaccination have missed a day or more or work, compared with 1 percent to 2 percent of those being revaccinated. </div> <div> Of the serious reactions reported, one encephalitis case and the heart infection were from new vaccinations, both involving people in this country. The other encephalitis case, treated in Germany, was a revaccination, he said. </div> <div> Henderson characterized the civilian program as a success despite the low number vaccinated so far, noting that the main effort has been in providing vaccine to the states and setting up education programs and infrastructure for the work to proceed. </div> <div> "We're much better prepared than we were even three weeks ago," he said. </div> <div> The CDC is also working with state health departments to collect information about those receiving the vaccine and, if any refuse it, why, he said. </div> <div> The vaccination uses the live vaccinia virus, a less potent cousin of smallpox, and people receiving it need to keep the site covered until it heals to avoid passing it along to others. </div> <div> Noting that concern, Grabenstein said the most commonly asked question among the military receiving the vaccine is whether they can have sex afterward. </div> <div> The answer? Sure, but "wear a T-shirt," he said. </div> <div> The Institute of Medicine is a branch of the National Academies, an independent organization chartered by Congress to advise the government on scientific issues</div> <bR> <bR> <div> <B><U> <A NAME="fewer_shots_for_new_anthrax_vaccine_"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></U></B><B><U>Fewer Shots for New Anthrax Vaccine </U></B></div> <div> Thu Oct 3, 6:01 PM ET</div> <div> By LAURA MECKLER, Associated Press Writer </div> <bR> <div> WASHINGTON (AP) - The government has created a new, genetically engineered anthrax vaccine that promises to cut in half the six shots now needed for protection, and chosen a pair of biotechnology companies to begin testing it. </div> <bR> <bR> <div> The contracts, awarded Thursday for $22.5 million, will allow California-based VaxGen Inc. and Britain's Avecia to test the experimental vaccine on people to see if it is safe and, if so, to see if it provides protection against the deadly bacteria. </div> <bR> <div> Federal authorities hope that together, the two companies will pave the way toward Food and Drug Administration ( news - web sites) approval for the vaccine. Eventually, the government wants 25 million doses manufactured and added to the National Pharmaceutical Stockpile. </div> <bR> <div> VaxGen said it plans to begin testing for safety by mid-2003 and finish by the end of next year. </div> <bR> <div> The current anthrax vaccine works well, experts say, but it requires six shots over 18 months plus an annual booster and it causes certain side effects. Last spring, a scientific advisory panel endorsed the existing shots, but recommended development of the next generation of vaccine, one that would require fewer shots and cause fewer side effects. </div> <bR> <div> The search for a replacement took on new urgency after last fall's anthrax attacks, discovered a year ago Friday when health officials announced that a Florida man had mysteriously contracted the disease. Later, as more cases emerged, investigators learned that the spores were being spread through the mail. </div> <bR> <div> "There is an urgent need to devise more effective measures to protect U.S. citizens from the harmful effects of anthrax spores used as instruments of terror," Health and Human Services ( news - web sites) Secretary Tommy Thompson said in a statement Thursday announcing his agency's grants. </div> <bR> <div> Federal scientists working at the Army's lab at Ft. Detrick, Md., have already developed the science behind the promising new vaccine. There are three proteins that make anthrax deadly, and all must work in concert to cause infection. The experimental vaccine engineers one of them, called protective antigen, which stimulates the body's immune system so that it can recognize and fight anthrax should the person actually be infected later. </div> <bR> <div> The private companies must now try and translate this technology into a practical vaccine. They must create samples for testing, then test the vaccine on a few people to see if it is safe. If these so-called Phase I trials work, the vaccine would be tested on larger groups of people to ensure it protects against infection — steps vital for FDA to ultimately approve its sale. </div> <bR> <div> On Thursday's news, VaxGen stock rose 13 percent, or $1.17 per share, to close at $10.17 in trading on the Nasdaq Stock Market. Avecia is privately held. </div> <bR> <div> The vaccine is not currently offered to civilians who have not been exposed to anthrax. It is, however, routinely used by the Pentagon ( news - web sites). </div> <bR> <div> All existing vaccine was under control of the Defense Department until this summer, when HHS and the Pentagon agreed to split the stockpile and each take half. </div> <bR> <div> It's not clear if the vaccine could protect even if administered after exposure to anthrax. Still, federal health workers offered it to congressional staffers and postal workers who were exposed during last fall's attacks in hopes it might offer greater protection than antibiotics alone. Only about 100 people opted to receive it, though. </div> <bR> <div> That's partly because the government gave no recommendation about the vaccine, leaving it up to each person to decide whether to get the shots. That caused a lot of confusion, something officials said Thursday they are trying to avoid as they plan to eventually offer a vaccine against another potential bioterror agent — smallpox. </div> <bR> <div> For smallpox, debate centers on how many Americans should be offered the shots — which carry rare but serious risks, including death. The plan now on the table would eventually offer the shots to everyone. </div> <bR> <div> An important, related issue is whether to specifically recommend that people get the shots, or just offer them and let people decide on their own, said Dr. Anthony Fauci, the National Institutes of Health ( news - web sites)'s infectious disease director. </div> <bR> <div> After the anthrax attacks, officials simply left it up to each person to decide. </div> <bR> <div> "We were criticized right, left and center for putting it out in this way," said Dr. D.A. Henderson, a top HHS bioterrorism adviser. "We didn't know really what to say." </div> <bR> <div> ___ </div> <bR> <div> Associated Press Medical Writer Lauran Neergaard contributed to this story.</div> <bR> <bR> <div> <B><U> <A NAME="us_releases_new_smallpox_response_plan"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></U></B><B><U>US Releases New Smallpox Response Plan</U></B></div> <div> Reuters Health Information 2002. © 2002 Reuters Ltd.</div> <div> Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.</div> <div> WASHINGTON (Reuters) Sept 23 - The US government issued guidelines on Monday for quickly vaccinating millions of people in case of a smallpox outbreak. </div> <div> The plan was drawn up amid fears that the disease, which was eradicated worldwide in 1979, could be used as a biological weapon against the US. </div> <div> Under the plan, up to 75 million doses of vaccine could be shipped in a single day, with 280 million doses going out from the National Pharmaceutical Stockpile "within 5 to 7 days." </div> <div> A manual was sent to health commissioners in all 50 states and posted on the US Centers for Disease Control and Prevention's Web site at <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>http://www.cdc.gov</U></FONT>. </div> <div> It details logistics for distributing the vaccine, specifying the types of coolers in which it would be stored and shipped in, how many doses would go to each clinic and at what temperature it should be kept refrigerated. </div> <div> Security must be in place, with "locked, limited access" to the vials of vaccine, the plan notes. Health experts fear any outbreak could trigger a panic, with millions struggling for protection. </div> <div> Because a smallpox vaccine is not currently approved by the US Food and Drug Administration, individuals will be required to sign an informed consent form before they are vaccinated. </div> <div> People receiving the vaccine would have to be monitored for side effects. The vaccine is contraindicated for HIV-infected patients, some cancer patients, and people with certain types of eczema. </div> <div> In the wake of the September 11th attacks, the US Health and Human Services Department scrambled to find enough smallpox vaccine to cover the population, and also conducted studies to see if existing vaccine stocks could be diluted and still provide protection. </div> <div> HHS Secretary Tommy Thompson has promised enough doses of vaccine would be produced to cover every "man, women and child" in the country. </div> <div> Two companies--Acambis Plc and Baxter International Inc.--won a contract to produce more vaccine to supplement the supply of Wyeth's DryVax vaccine. The US also bought 90 million doses that French vaccine maker Aventis-Pasteur found in storage. </div> <div> The government has been reluctant to vaccinate the entire US population as a precaution because the process is expensive and the vaccine can cause severe side effects. </div> <div> "Our impression is the public doesn't understand the side effects of smallpox," Dr. Walter Orenstein, director of the CDC's National Immunization Program, said in a recent interview. </div> <bR> <bR> <bR> <bR> <div> <B> <A NAME="antibodies_show_early_promise_for"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B><U>Antibodies Show Early Promise for Treating Anthrax</U></B><FONT SIZE="3" COLOR="#660099" FACE="Arial" ><U> </U></FONT></div> <div> <I>Fri May 31, 5:26 PM ET</I>  <I>By Amy Norton</I> </div> <div> NEW YORK (Reuters Health) - In early findings that could lead to a new treatment for anthrax infection, scientists have engineered several antibodies that neutralize toxins generated by the anthrax bacterium. </div> <div> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="12" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 19 WIDTH="4"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="19" ALIGN="bottom" WIDTH="4" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="1"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="19" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0"></tD> </tR> </TABLE></div> <div> One of these antibodies, referred to as 1H, was found to offer the best protection against anthrax toxin in experiments with cells and rats. A "humanized" version of this antibody has already been developed and will eventually be tested in primates, according to the study's lead author, Dr. George Georgiou of the University of Texas in Austin. </div> <bR> <div> He told Reuters Health that the main goal is to develop a therapy for later-stage inhalation anthrax infection, when the toxin level in the body is high. Currently, antibiotics are used to treat inhalation anthrax--the deadliest form of the disease--but the drugs must be given early on to be effective. This is a significant obstacle, as many cases of inhalation anthrax are not apparent until the later stages. </div> <bR> <div> The anthrax bacterium uses toxins to inflict its damage. These toxins consist of several proteins, one of which is called protective antigen (PA). Once a person is infected with anthrax, PA binds to target cells, gaining entry for other toxic anthrax proteins. Georgiou's team developed antibodies that bind to PA, thereby preventing it from latching onto cells. Their findings are published in the June issue of Nature Biotechnology. </div> <div> Besides the potential for the 1H antibody to become an anthrax treatment, Georgiou said it might offer an alternative to long courses of antibiotic treatment for the prevention of anthrax disease in people potentially exposed to the bacterium. </div> <bR> <div> In the wake of the anthrax attacks last year in the US, about 10,000 people were advised to go on a 60-day, preventive course of antibiotics due to possible anthrax exposure. </div> <bR> <div> SOURCE: Nature Biotechnology 2002;20:597-601. </div> <bR> <bR> <bR> <bR> <bR> <div> <B><U> <A NAME="new_anthrax_vaccine_from_india_ready"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></U></B><FONT SIZE="3" COLOR="#660099" FACE="Arial" ><B><U>New Anthrax Vaccine From India Ready for Trials</U></B></FONT></div> <div> Updated: Fri, Nov 02 5:27 PM EST By Subhadra Menon, PhD</div> <bR> <div> NEW DELHI (Reuters Health) - A new, experimental human anthrax vaccine developed in India is ready and waiting for clinical trials, according to Dr. Rakesh Bhatnagar, chairman of the Center for Biotechnology (CBT) at the Jawaharlal Nehru University in New Delhi. The research behind this recombinant technology vaccine will be presented in December at the Annual Meeting of the American Society for Cell Biology in Washington, DC.</div> <bR> <div> This type of vaccine has not been available until now, Bhatnagar told Reuters Health, although it has not yet been tested in humans. Questions have been raised over the safety of current anthrax vaccines, he noted.</div> <bR> <div> "This work is very important for India, not just in the current world scenario, but also because anthrax has always been a common problem in the country," said Dr. V. K. Vinayak, advisor at the Department of Biotechnology (DBT), Government of India.</div> <bR> <div> "The vaccine that is developed is not intended for the general public, and is only meant for special groups, such as the forces," Vinayak told Reuters Health.</div> <bR> <div> The CBT team genetically engineered Escherichia coli (E. coli) bacteria <FONT SIZE="1" COLOR="#800080" FACE="Arial" >to produce harmless, mutant forms of the three key proteins (the lethal factor, the edema factor and the protective antigen) found in Bacillus anthracis, the bacterium that causes anthrax.</FONT></div> <bR> <div> Bhatnagar and his team are now ready to hand the technology over to industry to produce large quantities of the vaccine for use in human trials. Those trials would determine if the vaccine is safe and effective in humans.</div> <bR> <div> The researchers developed the vaccine with a total grant of roughly $250,000 from India's DBT over the last 7 years. In studies, the investigators found the mutated proteins were good candidates for an anthrax vaccine. The mutation does not affect their molecular shapes, which meant they retained their original ability to generate specific protective antibodies.</div> <bR> <div> "We have so optimized this technology that 30% of the protein that is expressed from the recombined E. coli genome is the protective antigen of anthrax, whereas its expression has been negligible in the past," Bhatnagar said.</div> <bR> <div> Having applied for an Indian patent, Bhatnagar is now negotiating the transfer of his vaccine technology with industry and hopes that if there are no glitches, his anthrax vaccine should be in the market in a year or a little over.</div> <bR> <div> "Mass immunisation with a safe and effective anthrax vaccine could thwart attempts of terrorists to use anthrax as a biological warfare agent," according to The American Society for Cell Biology.</div> <bR> <div> "In 1994-1995 we decided to initiate a programme on recombinant vaccine development for anthrax and under this the technology developed by Dr. Rakesh Bhatnagar and his team is excellent. There is no other group (in India) working on vaccine development in anthrax," Vinayak said.</div> <bR> <div> "Research into infectious diseases has always been a priority area for us in India, and we at DBT have always given special emphasis to the same," Vinayak added.</div> <bR> <div> <B><U> <A NAME="indian_drugmaker_offers_new_safer"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></U></B><B><U>Indian Drugmaker Offers New, Safer Anthrax Vaccine</U></B></div> <div> Updated: Tue, Nov 06 7:40 AM EST By Sitaraman Shankar</div> <bR> <div> BOMBAY (Reuters) - An Indian drugmaker Tuesday said it could begin producing next year "hundreds of millions of dosages per month" of a new, cheaper and safer anthrax vaccine.</div> <bR> <div> Monday the Indian government announced its scientists had developed a new, high-yield vaccine that could be on the market in six to nine months.</div> <bR> <div> The vaccine was developed jointly by Jawaharlal Nehru University in New Delhi and the state-run Center for Biochemical Technology, and licensed to little-known Panacea Biotec Ltd., a New Delhi-based drugmaker.</div> <bR> <div> "The vaccine is currently under commercial-scale development, and if the United States approaches us we will be able to supply large quantities once we start production," Panacea's marketing director Rajesh Jain told Reuters from New Delhi.</div> <bR> <div> India's minister for science and technology Murli Manohar Joshi told a news conference Monday that the Indian vaccine avoided toxic effects common with existing anthrax vaccines such as redness of the skin, flu-like symptoms and itching.</div> <bR> <div> "Vaccines are available even now but they have strong side effects, they need boosters and are expensive," Joshi said. "The recombinant process through which Indian scientists have now developed a vaccine avoids toxic effects."</div> <bR> <div> Scientists said the vaccine, which had been more than six years in development, had been tested on mice and guinea pigs and would be tested on other animals and humans in the next six months under a fast-track process used in emergency situations.</div> <bR> <div> Fears of germ warfare have spread around the world since the September 11 attacks on the United States. Over the past month there have been 17 confirmed cases of anthrax in the United States and four people have died.</div> <bR> <div> Anthrax is spread by spores. Without quick antibiotic treatment, more than 80 percent of people who become ill after inhaling the spores die.</div> <bR> <div> CHEAPER TO PRODUCE</div> <bR> <div> The new Indian-developed vaccine "is much easier to produce and the cost of production would be very low," Joshi said. He gave no details of pricing.</div> <bR> <div> Currently only the United States, Britain and Russia have anthrax vaccines but they use an older manufacturing process. The Indian technique employs newer, gene recombinant technology, Joshi said.</div> <bR> <div> The Indian method focuses on extracting from the anthrax bacilli the gene responsible for making a protective antigen, a protein which guards against anthrax. The antigen is then grown in E. coli, a commonly found bacteria, producing the protein which goes into the vaccine.</div> <bR> <div> The method has resulted in very high yields, and five grams of the antigen can produce millions of doses of the vaccine, Joshi said.</div> <bR> <div> "This is among the highest yields of the protective antigen anybody has got anywhere in the world," V.K. Vinayak, medical advisor to the Indian government's department of biotechnology, told Reuters.</div> <bR> <div> Panacea's Jain said the vaccine would be made at a new facility the company was setting up at Lalru in Punjab state in northern India.</div> <bR> <div> Jain said the facility will have a 5,000-liter fermentation capacity, and as the anthrax vaccine had a two-week production cycle, Panacea could technically produce "hundreds of millions of dosages per month."</div> <bR> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"><A NAME="1025_update_o_cases_of_anthrax_in_the"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A>10/25 UPDATE O CASES OF ANTHRAX IN THE US</div> <div> Since the anthrax-by-mail crisis began, there have been six cases of inhaled anthrax, the most serious form of the disease. Two postal workers in Washington and a tabloid photo editor in Florida have died. </div> <div> There are 15 patients in the Washington area with symptoms suggestive of anthrax and all may linked to a letter sent to Senate Majority Leader Tom Daschle and handled in mail facilities from Trenton, N.J., to Capitol Hill. However, investigators have not ruled out the possibility there was other anthrax-laced mail that has not been found. </div> <div> Six cases of skin anthrax, a less dangerous form of the disease, have been diagnosed and there is a suspected case reported at the New York Post. These mostly are connected to mail sent to TV networks or to newspapers. </div> <div> Officials said a female employee of an electronic news organization was being treated for possible inhalation anthrax was outside Daschle's office the day the tainted letter was received - the first time they have said a possible case of inhalation anthrax may have come from exposure inside the Capitol complex. </div> <bR> <bR> <div>  <A NAME="there_is_no_treatment_for_smallpox_but"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A>There is no treatment for smallpox but a small California biotechnology company, Gilead, has a drug for a virus known as cytomegalovirus called cidofovir, which works in animals infected with pox viruses related to smallpox. </div> <div> Gilead said last week it had no plans to develop cidofovir, sold under the brand-name Vistide, as a treatment for smallpox. but Dr. Anthony Fauci, head of the National Institute of Allergies and Infectious Diseases, told reporters last week he was keeping an eye on it as a possibility.</div> <bR> <div>  </div> <bR> <div>     </div> <bR> <div>  <A NAME="from_the_center_for_disease_control_cdc"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A><FONT SIZE="3" COLOR="#660099" FACE="Arial" ><B>FROM THE CENTER FOR DISEASE CONTROL CDC</B></FONT></div> <div> <B>Facts about Anthrax</B></div> <div>  </div> <div> Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. Anthrax most commonly occurs in hoofed mammals and can also infect humans. </div> <div>  </div> <div> Symptoms of disease vary depending on how the disease was contracted, but usually occur within 7 days after exposure. The serious forms of human anthrax are inhalation anthrax, cutaneous anthrax, and intestinal anthrax. </div> <bR> <div> Initial symptoms of inhalation anthrax infection may resemble a common cold. After several days, the symptoms may progress to severe breathing problems and shock. Inhalation anthrax is often fatal. </div> <bR> <div> The intestinal disease form of anthrax may follow the consumption of contaminated food and is characterized by an acute inflammation of the intestinal tract. Initial signs of nausea, loss of appetite, vomiting, and fever are followed by abdominal pain, vomiting of blood, and severe diarrhea.</div> <bR> <div> Direct person-to-person spread of anthrax is extremely unlikely, if it occurs at all. Therefore, there is no need to immunize or treat contacts of persons ill with anthrax, such as household contacts, friends, or coworkers, unless they also were also exposed to the same source of infection.</div> <div>  </div> <div> In persons exposed to anthrax, infection can be prevented with antibiotic treatment. </div> <div>  </div> <div> Early antibiotic treatment of anthrax is essential–delay lessens chances for survival. Anthrax usually is susceptible to penicillin, doxycycline, and fluoroquinolones. </div> <div>  </div> <div> An anthrax vaccine also can prevent infection. Vaccination against anthrax is not recommended for the general public to prevent disease and is not available. </div> <bR> <div>  </div> <bR> <bR> <div>  <A NAME="a_primer_on_anthrax_separating_facts"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A>A primer on anthrax: Separating facts from speculation<FONT SIZE="2" COLOR="#660099" FACE="Verdana" > </FONT></div> <div> <I>By Paul Reid, Palm Beach Post Staff Writer</I></div> <div> Wednesday, October 10, 2001</div> <div> How did Robert Stevens of suburban Lantana get a lethal dose of anthrax bacteria? </div> <div> That's the question the FBI wants to answer. </div> <div> Until then, here is an anthrax primer: </div> <div> <B>What is anthrax? </B></div> <div> A disease caused by a bacterium: Bacillus anthracis. In its dormant state, the bacterium forms spores. When the spores enter the right nutritional environment, they germinate and multiply. Massive colonies of bacteria will then release toxins into the infected environment. The germs can enter through skin (cutaneous anthrax) or by ingestion or inhalation. </div> <div> <B>What kind of anthrax killed Sun photo assistant Robert Stevens? </B></div> <div> Inhalation anthrax. </div> <div> <B>What is inhalation or pulmonary anthrax? </B></div> <div> It is a virulent infection of the lungs or brain lining, or both. The name derives from the same ancient Greek word root as anthracite: black. It refers to the skin lesions caused by cutaneous anthrax, which is not as lethal as pulmonary anthrax but is far more common. </div> <div> <B>How can I get pulmonary anthrax?</B> </div> <div> By breathing large amounts of B. anthracis spores, which are found in the soil or on infected animals such as livestock, sheep or goats. The animals become infected from breathing the spores. Contact with them can result in one of the forms of anthrax. </div> <div> <B>How common is inhalation anthrax?</B> </div> <div> So rare as to be almost nonexistent. But it has been chronicled since biblical times. Only 18 Americans contracted the disease in the 20th century. Thirteen of these worked in goat hair factories, where studies showed they breathed large amounts of the spores day in and day out. Yet thousands and thousands of fellow workers never got sick. Two of the other victims worked in laboratories, where bacterial concentrations were likely high. The last case -- before Robert Stevens -- was reported in 1978, according to The Journal of the American Medical Association. </div> <div> <B>Is inhalation anthrax always fatal?</B> </div> <div> If not treated with antibiotics before symptoms appear, it is fatal more than 85 percent of the time. But that rate is based on cases chronicled before antibiotics were widely used and before microbiology diagnostic labs were as efficient as they are now. </div> <div> <B>What are the symptoms?</B> </div> <div> Early symptoms can include sore throat, muscle aches, mild fever, cough, headache, and vomiting. Later symptoms can include stupor, delirium, shock and loss of breathing functions. </div> <div> <B>Can inhalation anthrax be treated?</B> </div> <div> It can be treated with antibiotics after exposure and before onset of symptoms, but once symptoms appear, treatment is not likely to succeed. </div> <div> <B>Can inhalation anthrax be prevented?</B> </div> <div> It is hard to prevent because the anthrax bacterium is odorless and its distribution occurs silently and invisibly. But preventive antibiotics (Cipro is most common), taken before or immediately following exposure to the anthrax bacterium, will block or knock the disease down. The problem is, you shouldn't take these antibiotics unless public health officials determine a clear and present danger exists. One case does not create that condition. Even two cases may not, because rare diseases often happen in groups. Remember Legionnaires' disease or E. coli outbreaks. </div> <div> <B>Is there a vaccine?</B> </div> <div> Yes. It was licensed in 1970 and is produced by a Michigan company. Almost 600,000 doses have been given to armed forces personnel. Its effectiveness diminishes with time, it is expensive and the government and scientists feel it is not, at this time, practical to manufacture and distribute enough for nationwide vaccination. Certain antibiotics rather than a vaccine would be the recommended course to follow if an outbreak was thought probable. But most experts agree that the anthrax bacterium used in a terrorist attack would be genetically altered to be resistant to penicillin, the workhorse of the antibiotic family. The bacterium can be altered, but not synthesized or man-made. </div> <div> <B>What would it mean if test showed the anthrax to be genetically altered?</B> </div> <div> An altered bacterium would point to a criminal act. Most experts believe the anthrax germs used in a terrorist attack would be genetically altered by the scientists who cultured them overseas. However, U.S. intelligence does not know with certainty if anthrax bacteria supplies overseas are always genetically altered. Experts also think that the more the bacterium is altered, the less virulent it may become. So, the detection of genetically altered anthrax bacteria would not be a good sign, but would not necessarily be a cataclysmic finding. It would be significant because it clearly would indicate human intervention. </div> <div> <B>Where overseas is anthrax bacterium cultivated?</B> </div> <div> The former Soviet Union experimented with anthrax bacterium. One factory was on an island in the Aral Sea. The Soviets abandoned that factory about a decade ago. It is now unguarded. Iraq almost definitely had or has a bio-weapons program. Western nations, including the United States, furnished Iraq with the necessary technical supplies and anthrax cultures before an export ban was imposed in the mid-1980s.<B> </B></div> <div> <B>Is inhalation anthrax contagious?</B> </div> <div> NO. It is an infectious disease, but not contagious. </div> <div> <B>What's the difference between infectious and contagious?</B> </div> <div> An infectious illness spreads and grows within your body: For example, from lungs to blood to spinal fluid. A contagious illness spreads from person to person. Some bacterial and viral illnesses are both contagious and infectious: AIDS, the common cold, certain staph infections that can be transferred through person-to-person contact. But pulmonary anthrax, though an infectious disease, is NOT contagious. </div> <div> <B>What is aerosolization, and how does it contribute to the spread of anthrax?</B> </div> <div> Aerosol is the crucial component to the spread of pulmonary anthrax. Here's why: </div> <div> In order to get pulmonary anthrax, a person has to: </div> <div> 1. Breathe more than 3,000 B. anthracis spores per hour for a prolonged period, up to a day. These concentrations are not normally found in nature. That's why the disease is so rare. </div> <div> 2. The spores have to be less than 5 microns in diameter, small enough to get past your body's defense and into the lungs. </div> <div> 3. The concentration of spores per cubic yard of air must be artificially raised far beyond natural concentrations (except those rarest of rare natural circumstances, the ones chronicled since biblical times). </div> <div> 4. Then, if the first three steps are met, the concentrated spores must be aerosolized and sprayed. Even a small garden sprayer can provide a lethal aerosol but to a very limited area for a very limited time. Once the spores fall to the ground -- or onto any surface -- they are virtually harmless, even if highly concentrated. Infection by secondary aerosolization -- kicking up the soil to get spores back into the air -- is considered by experts to be a virtual impossibility. </div> <div> <B>Who says?</B> </div> <div> The Journal of the American Medical Association did a report on anthrax in 1999. A critical piece of information was a 1979 anthrax outbreak in Russia, the result of an aerosol plume accidentally released from a Soviet bio-research factory. Seventy-nine people got sick, 68 died. All of the sick people were accounted for within the plume of the bacterial cloud on the day and time of the accident. Since then, not a single case has been reported in the area. One million people live in the city, and spore levels in the ground remain much higher than normal. </div> <div> <B>How many spores would a terrorist need to kill people?</B> </div> <div> A kilogram (2.2 pounds) of spores, aerosolized and released under ideal conditions -- at night because sunlight kills spores, and in near windless air -- could prove lethal to thousands of people downwind. But the spores would all fall to the ground within hours or up to a day and give up their aerosolized lethality. </div> <div> <B>What if someone just dumped a pound of spores on the ground? Would they blow away in a fatal cloud?</B> </div> <div> Highly doubtful. The Journal cited Army tests conducted with soldiers exercising heavily -- noses to the ground -- on dirt infected by 2 million spores per square meter. The tests concluded that the soldiers might breathe a lethal dose. The simulation was meant to determine how safe runways and roads might be after an anthrax attack. But soldiers under those attack conditions would have been immunized and would be wearing gas masks. Again, the conclusion is: Those concentrations of spores would not exist naturally. You need aerosol delivery to infect large numbers of people. </div> <div> <B>Could an envelope carry anthrax</B> <B>germs?</B> </div> <div> Theoretically. Someone could put a large quantity of the spores into any container. But you'd have to snort the contents to have devastating results. It's not the way to make large numbers of people sick. </div> <div> <B>So what was the source of Robert Stevens' infection?</B> </div> <div> That's what the FBI and public health officials want to know. An FBI agent -- speaking without attribution -- said the FBI would scrutinize Stevens' movements and contacts. Clearly, he encountered a lethal dose of the germs. But was it introduced into his life by human intervention? Too early to say. If it was introduced, how? Speculation. </div> <div> <B>Could bacteria have been put into the air conditioner?</B> </div> <div> Speculation. Air conditioners can nurture and disperse germs (such as Legionnaires' disease), but the facts about anthrax indicate far more illness would be found throughout any building contaminated by the dispersal of bacteria via the air conditioning system. Stevens was the only case. That points to a concentrated dose, but not an aerosolized dose. That is a critical piece of logic. It implies that any spores found in the American Media building were carried there, on clothing, for example. The fact that one other person in the building -- 73-year-old mailroom employee Ernesto Blanco -- was found to have a spore in his nostril does not, with certainty, prove aerosolization. Investigators are looking for a uniform distribution of the bacteria throughout the building. </div> <div> <B>What if the FBI finds an unusually large sampling in the air conditioning system?</B> </div> <div> Then it's a whole new ballgame. The FBI would conduct a massive Unabomber-type of investigation: Research labs around the country -- any place with access to the anthrax bacterium -- would be investigated. The FBI would look at past and present employees, reported thefts of the anthrax bacterium, unusual requests for samples or the equipment needed to ferment and culture the germ. Anyone with modest laboratory supplies and technical expertise could culture the bacterium from samples found in their back yard. Mass-producing enough for an attack is a different matter. Very difficult. </div> <div> <B>Could the Sept. 11 terrorists have done a small-scale test? They rented planes in Lantana after all. They asked about crop dusting planes. Or is there a Unabomber-type lunatic out there?</B> </div> <div> Speculation. But all the experts agree that the transport and dispersal of the anthrax bacterium are dangerous, considered to be beyond the capacities of low-tech terrorists. The FBI might try to determine if any of the hijackers sought a prescription for Cipro or other antibiotics. That would indicate something interesting, not definitive, but very interesting. Anybody handling a concentrated amount of the bacterium without that preventive measure could contract the sickness themselves. The real -- and only -- question the FBI and doctors are asking now is: What is the source of Stevens' illness? Once they answer that question, they can look at how the source and Stevens came into contact. Only then would they have an idea about possible human intervention, malevolent or accidental. </div> <div> paul_reid@pbpost.com </div> <bR> <bR> <bR> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b7011899006600.png" HEIGHT="19" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"><A NAME="progress_made_in_anthrax_cure"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></U></B><B><U>Progress Made in Anthrax Cure Search</U></B><FONT SIZE="1" COLOR="#660099" FACE="Arial" >Updated: Wed, Oct 17 2:15 AM EDT By DANIEL Q. HANEY, AP Medical Editor </FONT></div> <bR> <div> The search for novel treatments to cure gravely ill victims of inhaled anthrax has taken on new urgency, but experts caution they are still probably years away from useful new medicines. </div> <bR> <div> The research targets the most insidious aspect of this frightening disease: By the time symptoms start, it is often too late to do anything. </div> <bR> <div> By then, anthrax bacteria have flooded the bloodstream with deadly poison. Killing the germs with antibiotics may not help much, because the damage is already done. </div> <bR> <div> Scientists are working on ways to block this toxin so it does not enter blood cells after being released by the bacteria. Several teams are working on competing approaches, and researchers say they have made significant headway in recent months. </div> <bR> <div> If the treatments work in people as well as they seem to in lab animals, they will probably be given along with antibiotics in the future as a one-two punch. </div> <bR> <div> The search for new anthrax treatments "has always been of great interest, but it obviously will get ratcheted up," Dr. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, said Tuesday. </div> <bR> <div> His agency and the Defense Department have financed most of the research. He said they hope to back more research, as well as speed up testing of any new drugs that are discovered. </div> <bR> <div> "The fact that somebody has died from inhalation of anthrax spores for the first time in 25 years has certainly galvanized a lot of people into action," said Dr. Robert Liddington, who studies the poison's atom-by-atom structure at the Burnham Institute in San Diego. </div> <bR> <div> If anthrax enters the body through a break in the skin, it causes a sore that is easily cured with antibiotics. Bacteria inhaled deep into the lungs are far more serious. They can lead to a bloodstream infection that begins with vague, flu-like symptoms and quickly progresses to shock and death. </div> <bR> <div> "You feel a little sick one day, and the next they put you on a ventilator," said Dr. Philip Hanna of the University of Michigan. </div> <bR> <div> By the time the first symptoms appear, the bacteria have already spewed out their toxin. This poison seeps into blood cells called macrophages. There it prompts the cells to manufacture normally useful disease-fighting substances, then kills them, releasing the substances in dangerously high quantities. </div> <bR> <div> To block this process, scientists at the U.S. Army Medical Research Institute of Infectious Diseases at Fort Detrick, Md., have screened dozens of antibodies against the poison. Two that seem to work are being investigated at the University of Texas at Austin. </div> <bR> <div> The bacteria actually make three different proteins to poison cells. One is called protective antigen. (It got that deceptively innocent name because it is also part of the anthrax vaccine reserved for military use.) The other two are edema factor and lethal factor. </div> <bR> <div> Protective antigen starts the process. It hooks onto blood cells and opens a hole that lets edema factor and the even more deadly lethal factor ooze inside. The antibodies block this by covering up the spot the protective antigen uses to anchor itself on the cells. </div> <bR> <div> Dr. John Collier of Harvard Medical School developed another approach. He makes slightly altered forms of protective antigen. It takes seven good copies of the antigen to make the hole for poison to enter cells. He found that even one bogus copy of the antigen keeps the hole from forming. </div> <bR> <div> Both the antibodies and the fake antigen have been found to protect lab animals from the effects of anthrax toxin, and experts say the next step will be against the actual bacteria, which can only be done at high-security labs. Nevertheless, Collier says human testing could start within a year. </div> <bR> <div> --- </div> <bR> <div> Medical Editor Daniel Q. Haney is a special correspondent for The Associated Press. </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">  Volume 341:815-826  September 9, 1999  Number 11 </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Anthrax</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Terry C. Dixon, B.S., Matthew Meselson, Ph.D., Jeanne Guillemin, Ph.D., and Philip C. Hanna, Ph.D. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">      </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"><A NAME="_new_england_journal_review_article_on"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> NEW ENGLAND JOURNAL REVIEW ARTICLE ON ANTHRAX</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Anthrax is an often fatal bacterial infection that occurs when Bacillus anthracis endospores enter the body through abrasions in the skin or by inhalation or ingestion.1 It is a zoonosis to which most mammals, especially grazing herbivores, are considered susceptible. Human infections result from contact with contaminated animals or animal products, and there are no known cases of human-to-human transmission. Human anthrax is not common, and only one of us has seen a case. Cutaneous anthrax, the most common form, is usually curable. A small percentage of cutaneous infections become systemic, and these can be fatal. Systemic infection resulting from inhalation of the organism has a mortality rate approaching 100 percent, with death usually occurring within a few days after the onset of symptoms.2 The rate of mortality among persons with infection resulting from ingestion is variable, depending on the outbreak, but it may also approach 100 percent. Whatever the portal of entry, systemic anthrax involves massive bacteremia and toxemia with nondescript initial symptoms until the onset of hypotension, shock, and sudden death. Manifestations of advanced disease, including shock and sudden death, are believed to result from the action of the exotoxin complex secreted by anthrax bacilli.1,3 The efficacy of therapy, if initiated during the incubation period, and the rapid course of the disease once symptoms appear make early intervention an absolute necessity. Inglesby et al. have provided a description of the policies and strategies for dealing with anthrax as a biologic weapon.4 The goal of this article is to familiarize physicians with the current understanding of the pathogenesis, diagnosis, prevention, and treatment of anthrax. </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Pathogenesis</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Anthrax infections are initiated by endospores of B. anthracis, a gram-positive soil organism. Anthrax endospores do not divide, have no measurable metabolism, and are resistant to drying, heat, ultraviolet light, gamma radiation, and many disinfectants.5 In some types of soil, anthrax spores can remain dormant for decades. Their hardiness and dormancy have allowed anthrax spores to be developed as biologic weapons by a number of nations, although their only known use in war was by the Japanese army in Manchuria in the 1940s.6 All known anthrax virulence genes are expressed by the vegetative form of B. anthracis that results from the germination of spores within the body. </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The course of infection and clinical manifestations are depicted in Figure 1. Endospores introduced into the body by abrasion, inhalation, or ingestion are phagocytosed by macrophages and carried to regional lymph nodes. Endospores germinate inside the macrophages and become vegetative bacteria7,8; the vegetative bacteria are then released from the macrophages, multiply in the lymphatic system, and enter the bloodstream, until there are as many as 107 to 108 organisms per milliliter of blood, causing massive septicemia. Once they have been released from the macrophages, there is no evidence that an immune response is initiated against vegetative bacilli. Anthrax bacilli express virulence factors, including toxin and capsule.1 The resulting toxemia has systemic effects that lead to the death of the host. </div> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">View larger version (87K):</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">[in this window]</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">[in a new window]</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">   Figure 1. Pathophysiology of Anthrax.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Pathogenic Bacillus anthracis endospores reach a primary site in the subcutaneous layer, gastrointestinal mucosa, or alveolar spaces. For cutaneous and gastrointestinal anthrax, low-level germination occurs at the primary site, leading to local edema and necrosis. Endospores are phagocytosed by macrophages and germinate. Macrophages containing bacilli detach and migrate to the regional lymph node. Vegetative anthrax bacilli grow in the lymph node, creating regional hemorrhagic lymphadenitis. Bacteria spread through the blood and lymph and increase to high numbers, causing severe septicemia. High levels of exotoxins are produced that are responsible for overt symptoms and death. In a small number of cases, systemic anthrax can lead to meningeal involvement by means of lymphatic or hematogenous spread. In cases of pulmonary anthrax, peribronchial hemorrhagic lymphadenitis blocks pulmonary lymphatic drainage, leading to pulmonary edema. Death results from septicemia, toxemia, or pulmonary complications and can occur one to seven days after exposure.</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The inset shows the effects of anthrax exotoxins on macrophages. Vegetative anthrax bacilli secrete two exotoxins that are active in host cells. Edema toxin is a calmodulin-dependent adenylate cyclase that increases intracellular levels of cyclic AMP (cAMP) on entry into most types of cell. This is believed to alter water homeostasis, resulting in massive edema. Lethal toxin is a zinc metalloprotease that causes a hyperinflammatory condition in macrophages, activating the oxidative burst pathway and the release of reactive oxygen intermediates, as well as the production of proinflammatory cytokines, such as tumor necrosis factor  (TNF-) and interleukin-1ß, that are responsible for shock and death. MAPKK denotes mitogen-activated protein kinase kinase.</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The major virulence factors of B. anthracis are encoded on two virulence plasmids, pXO1 and pXO2. The toxin-bearing plasmid, pXO1, is 184.5 kilobase pairs (kbp) in size and codes for the genes that make up the secreted exotoxins. The toxin-gene complex is composed of protective antigen, lethal factor, and edema factor.9 The three exotoxin components combine to form two binary toxins. Edema toxin consists of edema factor, which is a calmodulin-dependent adenylate cyclase,10,11 and protective antigen, the binding moiety that permits entry of the toxin into the host cell. Increased cellular levels of cyclic AMP upset water homeostasis and are believed to be responsible for the massive edema seen in cutaneous anthrax. Edema toxin inhibits neutrophil function in vitro,12 and neutrophil function is impaired in patients with cutaneous anthrax infection.13 Lethal toxin consists of lethal factor, which is a zinc metalloprotease14,15,16 that inactivates mitogen-activated protein kinase kinase in vitro,17,18 and protective antigen, which acts as the binding domain. Lethal toxin stimulates the macrophages to release tumor necrosis factor  and interleukin-1ß, which are partly responsible for sudden death in systemic anthrax (Figure 1, inset).3,15,19 </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The smaller capsule-bearing plasmid, pXO2, is 95.3 kbp in size and codes for three genes (capB, capC, and capA) involved in the synthesis of the polyglutamyl capsule.20 The exotoxins are thought to inhibit the immune response mounted against infection, whereas the capsule inhibits phagocytosis of vegetative anthrax bacilli. The expression of all known major virulence factors is regulated by host-specific factors such as elevated temperature (37°C) and carbon dioxide concentration (5 percent), and by the presence of serum components.21,22 Regulation of the expression of the toxin and capsule genes is mediated by the transcriptional activator AtxA, whose activity appears to be affected by the previously mentioned environmental conditions.23,24,25 Expression of the capsule gene is also controlled by its own transcriptional regulator, AcpA.26 Both plasmids are required for full virulence; the loss of either one results in an attenuated strain. Historically, bacterial strains for anthrax vaccine were made by rendering virulent strains free of one or both plasmids. Pasteur, an avirulent pXO2-carrying strain, is encapsulated but does not express exotoxin components.1 Sterne, an attenuated strain that carries pXO1, can synthesize exotoxin components but does not have a capsule.1 </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Clinical Manifestations</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Cutaneous Anthrax</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Cutaneous anthrax accounts for 95 percent of all anthrax infections in the United States.27,28,29,30 The name anthrax (from the Greek for coal) refers to the typical black eschar that is seen on affected areas (Figure 2). Patients often have a history of occupational contact with animals or animal products. The most common areas of exposure are the head, neck, and extremities, although any area can be involved. Pathogenic endospores are introduced subcutaneously through a cut or abrasion. There are a few case reports of transmission by insect bites, presumably after the insect fed on an infected carcass.31,32 The primary skin lesion is usually a nondescript, painless, pruritic papule that appears three to five days after the introduction of endospores. In 24 to 36 hours, the lesion forms a vesicle that undergoes central necrosis and drying, leaving a characteristic black eschar surrounded by edema and a number of purplish vesicles. The edema is usually more extensive on the head or neck than on the trunk or extremities.33 The common description "malignant pustule" is actually a misnomer, because the cutaneous lesion is not purulent and is characteristically painless. A painful, pustular eschar in a febrile patient indicates a secondary infection, most often with staphylococcus or streptococcus.34 </div> <bR> <bR> <bR> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">View larger version (109K):</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">[in this window]</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">[in a new window]</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">   Figure 2. Cutaneous Anthrax Infection of the Hand and Cheek.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Panel A shows the characteristic blackened eschar surrounded by eroded areas and massive edema. These lesions are painless. The areas of "dried skin" represent resolving edema. Lesions continue to progress despite rigorous antibiotic treatment. Cutaneous anthrax can be self-limiting, and the lesions resolve without scarring. About 10 percent of untreated cutaneous anthrax infections progress to systemic anthrax. Panels B, C, and D show changes in the lesion on the cheek over a seven-day period. The characteristic blackened eschar is present on day 0 (Panel B). Facial edema and ulceration occur by the second day (Panel C). On day 7, the lesion is beginning to heal, and the facial edema is resolving (Panel D). The photograph in Panel A was kindly provided by Drs. Wilhelm Kobuch and P.C.B. Turnbull. The photographs in Panels B, C, and D are reprinted from Smego et al.33 with the permission of the publisher.</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Although cutaneous anthrax can be self-limiting, antibiotic treatment is recommended. Lesions resolve without complications or scarring in 80 to 90 percent of cases. Malignant edema is a rare complication characterized by severe edema, induration, multiple bullae, and symptoms of shock.35,36 Malignant edema involving the neck and thoracic region often leads to breathing difficulties that require corticosteroid therapy or intubation. A few cases have been reported of temporal arteritis associated with cutaneous anthrax infection and of corneal scarring from palpebral cutaneous anthrax.37,38 Histologic examination of anthrax skin lesions shows necrosis and massive edema with lymphocytic infiltrates. There is no liquefaction or abscess formation, indicating that the lesions are not suppurative. Focal points of hemorrhage are evident, with some thrombosis.39 Gram's staining reveals bacilli in the subcutaneous tissue.39 </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Gastrointestinal and Oropharyngeal Anthrax</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Gastrointestinal anthrax, which can be fatal, has not been reported in the United States. The symptoms appear two to five days after the ingestion of endospore-contaminated meat from diseased animals.40 Therefore, multiple cases can occur within individual households.40,41 An unusually prolonged outbreak was attributed to the consumption of stored meat products.42 It is presumed that bacterial inoculation takes place at a breach in the mucosal lining, but exactly where the endospores germinate is unknown. On pathological examination, bacilli can be seen microscopically in the mucosal and submucosal lymphatic tissue, and there is gross evidence of mesenteric lymphadenitis.43 Ulceration is always seen. It is not known whether ulceration occurs only at sites of bacterial infection or is distributed more diffusely as a result of the action of anthrax toxin.43,44,45 Microscopical examination of affected tissues reveals massive edema and mucosal necrosis at infected sites.45 Inflammatory infiltrates are seen that are similar to those in cutaneous anthrax. Gram's staining of peritoneal fluid may reveal numerous large gram-positive bacilli.40,46 </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Although mediastinal widening is considered pathognomonic of inhalational anthrax, it has also been reported in a case of gastrointestinal anthrax.47 Associated symptoms include fever and diffuse abdominal pain with rebound tenderness. There are reports of both constipation and diarrhea; the stools are either melenic or blood-tinged.46,48 Because of ulceration of the gastrointestinal mucosa, patients often vomit material that is blood-tinged or has a coffee-ground appearance. Ascites develops with concomitant reduction in abdominal pain two to four days after the onset of symptoms. The appearance of the ascites fluid ranges from clear to purulent, and it often yields colonies of B. anthracis when cultured. Morbidity is due to blood loss, fluid and electrolyte imbalances, and subsequent shock. Death results from intestinal perforation or anthrax toxemia. If the patient survives, most of the symptoms subside in 10 to 14 days.48 </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Oropharyngeal anthrax is less common than the gastrointestinal form. It is also associated with the ingestion of contaminated meat. Initial symptoms include cervical edema and local lymphadenopathy, which cause dysphagia and respiratory difficulties. Lesions can be seen in the oropharynx and usually have the appearance of pseudomembranous ulcerations. This form is milder than the classic gastrointestinal disease and has a more favorable prognosis.34,48 </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Inhalational Anthrax</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Inhalational anthrax is rare, usually occurring after the inhalation of pathogenic endospores from contaminated animal hides or products. Before the introduction of hygienic measures in the 1960s, including vaccination, workers in goat-hair mills, for example, were regularly exposed to high concentrations of viable anthrax spores. Nevertheless, for reasons that are not understood, few cases of inhalational anthrax occurred among them.49,50,51 When dispersed in the atmosphere as an aerosol, anthrax spores can present a respiratory hazard even far downwind from the point of release, as demonstrated by animal tests on Gruinard Island in the United Kingdom,52,53,54,55 and by an accidental release from a military biologic facility in the city of Sverdlovsk in the former Soviet Union.2,56,57,58 </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Inhalational anthrax is usually fatal, even with aggressive antimicrobial therapy. It appears that only about one fifth of those who contracted inhalational anthrax in Sverdlovsk recovered.2 Anthrax spores are about 1 to 2 µm in diameter, a size that is optimal for inhalation and deposition in the alveolar spaces.51,59,60,61 Although the lung is the initial site of contact, inhalational anthrax is not considered a true pneumonia. In most but not all cases, there is no infection in the lungs.58,62 Rather, the endospores are engulfed by alveolar macrophages and transported by them to the mediastinal and peribronchial lymph nodes, with the spores germinating en route. Anthrax bacilli multiply in the lymph nodes, causing hemorrhagic mediastinitis, and spread throughout the body in the blood.43,62 </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Data from the Sverdlovsk outbreak indicate a modal incubation time of approximately 10 days for inhalational anthrax. However, the onset of symptoms occurred up to six weeks after the reported date of exposure.2,57 Such long incubation times presumably reflect the ability of viable anthrax spores to remain in the lungs for many days.51,63,64 Longer incubation periods may be associated with smaller inocula. </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The initial symptoms most often reported are fever, nonproductive cough, myalgia, and malaise, resembling those of a viral upper respiratory tract infection. Early in the course of the disease, chest radiographs show a widened mediastinum, which is evidence of hemorrhagic mediastinitis, and marked pleural effusions. After one to three days, the disease takes a fulminant course with dyspnea, strident cough, and chills, culminating in death.34,59 In Sverdlovsk, the mean time between the onset of symptoms and death was 3 days (range, 1 to 10). Although accompanying evidence of clinical signs of pneumonia in these cases is lacking, some of the autopsies from the Sverdlovsk outbreak showed a focus of necrotizing hemorrhagic pneumonitis, possibly at the portal of infection.58 Submucosal hemorrhages occurred in the trachea and bronchi, with hemorrhage and necrosis of peribronchial lymph nodes. Hemorrhagic mediastinal lymph nodes represent the primary lesion; however, gastrointestinal and leptomeningeal lesions are the result of hematogenous spread. </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">There may be wide individual variation in susceptibility to inhalational anthrax, as suggested by experimental studies in nonhuman primates and by the absence of persons younger than 24 years among the 66 deaths reported in the Sverdlovsk outbreak.2,51,57 </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Anthrax Meningitis</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Involvement of the meninges by B. anthracis is a rare complication of anthrax.65 The most common portal of entry is the skin, from which the organisms can spread to the central nervous system by hematogenous or lymphatic routes. Anthrax meningitis also occurs in cases of pulmonary and gastrointestinal anthrax.58,66 Anthrax meningitis is almost always fatal, with death occurring one to six days after the onset of illness, despite intensive antibiotic therapy. In the few cases in which patients have survived, antibiotic therapy was combined with the administration of antitoxin, prednisone, or both.65,67 In addition to common meningeal symptoms and nuchal rigidity, the patient has fever, fatigue, myalgia, headache, nausea, vomiting, and sometimes agitation, seizures, and delirium. The initial signs are followed by rapid neurologic degeneration and death. The pathological findings are consistent with a hemorrhagic meningitis, with extensive edema, inflammatory infiltrates, and numerous gram-positive bacilli in the leptomeninges.43,68 The cerebrospinal fluid is often bloody and contains many gram-positive bacilli.69 Gross examination at autopsy finds extensive hemorrhage of the leptomeninges, which gives them a dark red appearance described as "cardinal's cap."58 </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Diagnosis</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Differential Diagnosis</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Table 1 summarizes the differential diagnosis of anthrax. In cutaneous anthrax, the painless, blackened, necrotic eschar is limited to the late stages of the infection. The ulcerative eschar of cutaneous anthrax must be differentiated from other papular lesions that present with regional lymphadenopathy. If the lesion is purulent and the regional lymph nodes are palpable, staphylococcal lymphadenitis is the most likely cause, although cutaneous anthrax lesions can be superinfected with pyogenic bacteria.70 </div> <bR> <bR> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">View this table:</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">[in this window]</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">[in a new window]</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">   Table 1. Differential Diagnosis of Clinical Manifestations of Anthrax.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The initial symptoms of inhalational anthrax are nondescript or "flulike" and are similar to those of atypical pneumonia from other causes. The prognosis is improved if early treatment is implemented, so that a high level of suspicion is necessary if there is a chance of exposure to anthrax. The cardiopulmonary collapse associated with a history of radiographic evidence of mediastinal widening in the late stages of inhalational anthrax must be differentiated from cardiovascular collapse with noninfectious causes, such as dissecting or ruptured aortic aneurysm and the superior vena cava syndrome. Anthrax infection is unusual in that mediastinal changes can be detected early in the course of infection by chest radiography, although similar pictures can be seen in acute bacterial mediastinitis and fibrous mediastinitis due to Histoplasma capsulatum.71 Less specific findings include pleural effusions and radiographic evidence of pulmonary edema. Silicosis, siderosis, alveolar proteinosis, and sarcoidosis are often alternative causes of chronic mediastinitis in patients with the relevant occupational history and previous chest radiographs demonstrating long-standing mediastinal widening. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">When ingestion of contaminated meat is suspected, the symptoms of an acute abdomen should be considered as possible early signs of intestinal anthrax infection. Hemorrhagic meningitis caused by anthrax must be distinguished from subarachnoid hemorrhage by computed tomography without contrast. To distinguish hemorrhagic meningitis caused by B. anthracis from that caused by other bacteria, Gram's staining and culture of cerebrospinal fluid should be performed.68 In addition to the above indictors, the clinician should consider anthrax if there is a history of contact with materials that may be contaminated with spores, such as infected farm animals and imported hides, or of travel to places where anthrax is endemic. Because of the remote possibility of an anthrax aerosol attack, clinicians should be alert to any sudden deaths of previously healthy persons from undiagnosed disease and report them promptly to the Centers for Disease Control and Prevention and other appropriate public health officials. </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Bacteriologic Tests</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">B. anthracis is a nonmotile, gram-positive, aerobic rod 1.2 to 10 µm in length and 0.5 to 2.5 µm in width that is capable of forming central or terminal spores (Figure 3).72 It is part of the B. cereus group of bacilli, which consists of B. cereus, B. anthracis, B. thurin-giensis, and B. mycoides.73 The bacteria in this group tend to be dismissed by clinical microbiology laboratories as contaminants unless the physician specifically requests testing.73 Except for B. anthracis, all members of this group are resistant to penicillin because they produce chromosomally encoded beta-lactamases.74 B. anthracis is easy to differentiate from other members of the B. cereus group by observing the morphologic features of the colony on a blood-agar plate. Colonies of most B. anthracis isolates are nonhemolytic and are white to gray, often looking like ground glass.75 The unusually tenacious colonies are able to retain their shape when manipulated. When inoculated onto nutrient agar containing 0.7 percent bicarbonate and grown overnight at 37°C in the presence of 5 to 20 percent carbon dioxide, B. anthracis will form its characteristic poly-d-glutamic acid capsule.76 These colonies have a mucoid appearance, and the capsule can be demonstrated microscopically in a colony smear stained with McFadyean's polychrome methylene blue or India ink.75 Blood samples obtained from patients late in the course of infection and stained in the same manner will reveal large numbers of encapsulated bacilli. Bacilli can also be observed in and cultured from ascites fluid, pleural effusions, cerebrospinal fluid (in cases of meningitis),77 and fluid carefully expressed from the eschar, although expressing eschar fluid is not recommended because it can cause dissemination of the pathogen.78 </div> <bR> <bR> <bR> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">View larger version (82K):</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">[in this window]</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">[in a new window]</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">   Figure 3. Photomicrographs of Bacillus anthracis Vegetative Cells and Spores.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Panel A shows a Gram's stain of B. anthracis vegetative bacteria. The bacterial cells exhibit gram-positive staining (purple filaments) (x600). Panel B shows an electron photomicrograph of a B. anthracis spore (arrowhead) partially surrounded by the pseudopod of a cultured macrophage (x137,000). The bar represents 1 µm.</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Patients with systemic disease often die before positive blood cultures can be obtained, making early diagnosis and treatment crucial. If the samples are likely to be contaminated with other bacillus species, polymyxin–lysozyme–EDTA–thallous acetate agar is used as a selective medium for B. anthracis.79 The API 50 CH test strip (API Laboratory Products, Plainview, N.Y.) can be used in conjunction with the API 20E test strip to identify a number of bacillus species, including B. anthracis.80 Blood cultures in cases of systemic anthrax infection are almost always positive, because of the large numbers of bacterial cells in the circulation.1 Cultures of tissue from skin lesions, however, are not useful diagnostically, because the rate of positive cultures does not exceed 60 to 65 percent, probably owing to the use of antimicrobial therapy or the microbicidal activity of local antagonistic skin flora.81 There are reports of clinical isolates of B. anthracis that are resistant to penicillin.31,82 Because of the potential for drug-resistant strains, including deliberately modified strains, antibiotic-susceptibility testing should be performed on all isolates. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Serologic and Immunologic Tests</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The major immunogenic proteins of B. anthracis appear to be capsular antigens and the exotoxin components. Specific enzyme-linked immunosorbent assays (ELISAs) that show a quadrupling of the titer of antibodies against these components are diagnostic of past infection or vaccination. The most reliable indicators are the titers of antibody to protective antigen and to capsular components.73,83,84 In studies of the measurement of antibody titers by ELISA, the sensitivity of possible indicators was as follows: 72 percent for protective antigen, 95 to 100 percent for capsule antigens, 42 percent for lethal factor, and 26 percent for edema factor.85 Enzyme-linked immunoelectrotransfer blotting provided a higher specificity when used in conjunction with ELISA-based testing.85 Indirect microhemagglutination gives results similar to those obtained with ELISA but has certain drawbacks, including the short shelf life of antigen-sensitized red-cell preparations, the limited reproducibility of the test, and longer preparation times.86 </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Immunologic detection of the exotoxins in blood during systemic infection is possible with similar tests if antibodies to anthrax toxins are available, but those tests are unreliable for diagnosis. Thus, although these tests are of epidemiologic value, they have little diagnostic value in acute illness.83 During systemic infections, antibodies to toxin or capsular components cannot be detected until late in the course of the disease, often when it is too late to initiate treatment.73 In treated infections, no increase in the antitoxin antibody titer is seen. The anthraxin skin test, consisting of subdermal injection of a commercially produced chemical extract of an attenuated strain of B. anthracis, is available for the diagnosis of acute and previous cases of anthrax.81,87,88 In one study the skin test diagnosed 82 percent of cases one to three days after the onset of symptoms and 99 percent of cases by the end of the fourth week.81 The skin test may be suitable for both rapid diagnosis of acute cases and the retrospective analysis of anthrax infections. </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">New Molecular Diagnostic Methods</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">New diagnostic techniques have focused on the use of the polymerase chain reaction to amplify markers specific to B. anthracis or the B. cereus group. Two markers, vrrA89 and Ba813,90,91,92 have been the subject of extensive study. Other methods using the polymerase chain reaction to amplify specific virulence plasmid markers harbored by different anthrax strains may soon become available.56,93,94,95,96 These new rapid methods may become useful in the clinical setting, where early diagnosis is crucial. </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Prevention and Treatment</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Prophylaxis, Vaccination, and Decontamination</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Prophylaxis for asymptomatic patients with suspected exposure to anthrax spores can be achieved with a six-week course of doxycycline or ciprofloxacin. If the suspected dose of spores is high, a longer course of antibiotics is warranted. Extended treatment is needed for total pulmonary clearance of spores, which are not affected by the presence of antibiotics.63,97 </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The standard anthrax vaccine in the United States is approved by the Food and Drug Administration and is routinely administered to persons at risk for exposure to anthrax spores. The existing supplies are currently being used to immunize all military personnel. Designated "anthrax vaccine adsorbed" (AVA), it is an aluminum hydroxide–precipitated preparation of protective antigen from attenuated, nonencapsulated B. anthracis cultures of the Sterne strain.98,99 Two inoculations with AVA afforded substantial protection against inhalational anthrax in rhesus monkeys,100 and a limited trial of a similar vaccine in humans indicated that it afforded considerable protection against cutaneous anthrax.101 AVA is administered subcutaneously in a 0.5-ml dose that is repeated at 2 and 4 weeks and at 6, 12, and 18 months.102 Boosters are then given annually. For those receiving antibiotic prophylaxis for suspected exposure, AVA may be given concurrently. There is a need for vaccines with better protection and a simpler schedule. Vaccines now being tested include preparations of protective antigen subunits with different adjuvants, protective antigen purified from recombinant sources, and live vaccines based on anthrax strains with auxotrophic mutations.103,104,105,106,107,108,109,110,111,112,113 Live attenuated endospore-based vaccines were widely used in the Soviet Union for both humans and livestock and remain in use in the Russian Federation today.103 The ability of any vaccine to protect humans in the event of aerosol attack, as in biologic terrorism or warfare, cannot be tested directly and therefore must remain a concern.114 </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">A textile mill contaminated with anthrax spores was decontaminated with vaporized formaldehyde,115 and soil decontamination at Gruinard Island was achieved with formaldehyde in seawater.116 Although decontamination is desirable, the risk that resuspension of a deposited aerosol will lead to inhalational anthrax is much less than the risk due to a primary aerosol.117,118 Autoclaving and incineration are acceptable procedures for the decontamination of laboratory materials. </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Treatment</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">            Antibiotics</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Table 2 summarizes pharmacologic therapy for anthrax. Penicillin and doxycycline are used for the treatment of anthrax. Intravenous administration is recommended in cases of inhalational, gastrointestinal, and meningeal anthrax. Cutaneous anthrax with signs of systemic involvement, extensive edema, or lesions on the head and neck also requires intravenous therapy. Streptomycin had a synergistic effect with penicillin in experiments and may also be given for inhalational anthrax. Despite early and vigorous treatment, the prognosis of patients with inhalational, gastrointestinal, or meningeal anthrax remains poor. Antibiotic therapy should be continued for at least 14 days after symptoms abate.67,78 In cutaneous anthrax, treatment with oral penicillin renders lesions sterile after 24 hours, although they still progress to eschar formation. Chloramphenicol, erythromycin, tetracycline, or ciprofloxacin can be administered to patients who are allergic to penicillin. If resistance to penicillin and doxycycline is suspected and antibiotic-susceptibility data are not available, ciprofloxacin may be administered empirically. Doxycycline and tetracycline are not recommended for pregnant women or children, and the effects of ciprofloxacin in pregnant women have not been determined.4 </div> <bR> <bR> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">View this table:</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">[in this window]</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">[in a new window]</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">   Table 2. Pharmacologic Therapy for Bacillus anthracis Infection and Its Sequelae.</div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">For culturing cutaneous lesions, gentle sampling with a moist, sterile applicator is preferred. Excision of the eschar is contraindicated and might hasten systemic dissemination. Lesions should be covered with sterile dressings that are changed regularly. Soiled dressings should be autoclaved and properly disposed of. In cases of extensive edema, meningitis, or swelling in the head-and-neck region, corticosteroid therapy should be initiated.119,120 Supportive therapy should be initiated to prevent septic shock and fluid and electrolyte imbalance, and to maintain airway patency. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">            Potential New Treatments</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The current understanding that anthrax is a toxigenic condition suggests the potential of antitoxin therapy. The central importance of lethal toxin is supported by much research. Early experiments in which antibiotics were administered to animals at different stages of infection found a principle of "no return"; once the infection had reached a certain point, the animal was doomed, even after removal of the microbes. Test animals injected intravenously with purified lethal toxin died in a manner very similar to that of animals that died of the natural infection.3,15,19 Lethal-toxin–deficient strains are highly attenuated.121,122 Prior immunity (passive or active) to the lethal-toxin proteins protects animals from endospore challenge.63,123 Finally, toxin-affected macrophages produce the proinflammatory cytokines that mediate the shock and sudden death that occur in anthrax.3,15,19 Unfortunately, antitoxin preparations are not currently available in the United States. In addition, the recent discovery that lethal toxin acts as a zinc metalloprotease inside target cells and the identification of potential target substrates may provide new insights for use in designing drugs that directly inhibit the toxicity of lethal factor in vivo.14,17,18 </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Future Challenges</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Anthrax holds an important place in the development of modern medicine and has long been intertwined with human history. Anthrax is believed to have been one of the Egyptian plagues at the time of Moses, and cases were clearly recorded by the ancient Romans.124 The anthrax bacillus was the model first used in the development of Koch's postulates and is considered the first "germ" proved to cause human disease.125 Pasteur later generated a capsule-null anthrax strain that was the first vaccine made from live attenuated bacteria for use in humans.126 At the birth of cellular immunology, Metchnikoff used the anthrax bacillus to examine the ability of his newly discovered macrophages to kill microbes.127 Today, investigators are using B. anthracis and its toxins in an attempt to understand early events in the infectious process and the molecular basis of inflammation.3,15,19 </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Unfortunately, new issues have arisen beyond those related to scientific inquiry. No casualty-producing terrorist use of anthrax has occurred, and the Federal Bureau of Investigation has stated that it has "no intelligence that state sponsors of terrorism, international terrorist groups, or domestic terrorist groups are currently planning to use these deadly weapons in the United States."128 However, the incidence of hoaxes has greatly increased with recent publicity about anthrax, providing a challenge to law enforcement.129 Recent revelations regarding the development of anthrax weapons by the former Soviet Union and by Iraq, and of attempts to develop such weapons by the Aum Shinrikyo cult in Japan, make the potential use of B. anthracis in biologic terrorism a legitimate concern.4,129 New strains resistant to antibiotics or containing additional virulence factors could be misused with the intent of confounding treatment or prophylaxis.114,130 Whether our medical system would be able to provide appropriate prophylaxis and therapy in the event of a large-scale exposure to pathogenic endospores remains uncertain, even doubtful. It has now become relevant for physicians to refamiliarize themselves with clinical anthrax. </div> <bR> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Supported in part by grants (AI-08649 and AI-40644) and a Medical Scientist Training award from the National Institutes of Health, by a grant (IRG-158 K) from the American Cancer Society, and by Duke University Medical Center. </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">We are indebted to Arthur Friedlander, M.D., Julia Chosy, Tanya Dixon, John Ireland, Matthew Weiner, and Kenneth Alexander, M.D., Ph.D., for their reading and critical discussion of the manuscript. </div> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Source Information</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">From the Department of Microbiology, Duke University Medical Center, Durham, N.C. (T.C.D., P.C.H.); the Department of Molecular and Cellular Biology, Harvard University, Cambridge, Mass. (M.M.); the Department of Sociology, Boston College, Chestnut Hill, Mass. (J.G.); and the Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor (P.C.H.). </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Address reprint requests to Dr. Hanna at 1150 W Medical, 5641 MS II, Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48104, or at dixont@umich.edu.</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">References</div> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Hanna P. Anthrax pathogenesis and host response. 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Vaccine 1997;15:1846-1850.[Medline] </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">      </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Table of Contents  </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> PDF of this article  </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Related Letters to the Editor  </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Find Similar Articles in the Journal  </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">    </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Add to Personal Archive  </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Download to Citation Manager  </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Alert me when this article is cited  </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">    </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Related Articles in Medline  </div> <div> <IMG BORDER="0" SRC="Symb075c00b700b499006600.png" HEIGHT="12" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Articles in Medline by Author:  Dixon, T. 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