4. października 2001r. w Stanach Zjednoczonych zarejestrowano pierwszy przypadek wąglika wywołanego umyślnym zastosowaniem broni biologicznej.

Od tego dnia amerykańscy epidemiolodzy w miejsce dotychczasowych zaleceń wprowadzają nowe procedury postępowania. Nadal wiele pytań pozostaje bez odpowiedzi. 

• Jak szybko wykryć zagrożenie wąglikiem? Jak unieszkodliwić zarazki? 

Według ostatnich oficjalnych danych w USA zarejestrowano 15 przypadków wąglika (11 potwierdzonych i 4 podejrzenia) odpowiadających przyjętej definicji przypadku. U 7 osób wąglik wystąpił w postaci wziewnej, u 8 - skórnej. Spośród 7 osób z postacią płucną wąglika  - 5 pracowało na poczcie, 1 sortowała pocztę w biurze adresata.

Wiadomo o trzech listach zawierających przetrwalniki wąglika. 

Odnotowano zgony. 

• 5. października 2001r. zmarł 63-letni pracownik redakcji prasowej na Florydzie, u którego  2. października pojawiła się gorączka i zaburzenia psychiczne.
• 21. października zmarł 55-letni pracownik sortowni poczty przeznaczonej dla instytucji centralnych w Waszyngtonie, który zgłosił się do lekarza 18. października z utrzymujacymi się od dwóch dni bólami mięśni, narastająca nużliwością i gorączką do 39 st. C, odesłany do domu z rozpoznaniem "grypy", umarł trzy dni później w szpitalu, pomimo intensywnego leczenia. 
• 22. października  zmarł 47-letni pracownik tej samej sortowni, kóry w przeddzień zgonu zgłosił się do szpitala z nasilającymi się  od 5 dni takimi objawami, jak: nużliwość, nudności, wymioty, biegunka i omdlenia. U pacjenta stwierdzono podciśnienie ortostatyczne, prawidłową temperaturę ciała i  brak zmian w obrazie rentgenowskim klatki piersiowej. Po dożylnym nawodnieniu pacjent opuścił szpital. Wrócił po 26 godzinach po kolejnym omdleniu i z utrzymującymi się objawami żołądkowo-jelitowymi. Zmarł pomimo intensywnego leczenia.
• w szpitalu w Nowym Jorku zmarła w środę na płucną odmianę wąglika 61-letnia kobieta. Mieszkająca w dzielnicy Bronx imigrantka z Wietnamu, pracowała wszpitalu laryngologicznym na Manhattanie, w pokoju przylegającym do pomieszczenia, gdzie odbierano pocztę. Ani tam jednak, ani nigdzie indziej w tej klinice n ie stwierdzono żadnego śladu wąglika. Kobieta ta zachorowała w zeszły czwartek, z takimi objawami, jak bóle mięśni i trudności z oddychaniem, charakterystycznymi także dla grypy. Mimo podawania antybiotyków, jej stan stale się pogarszał i trzeba ją było podłączyć do respiratora. W środę rano pacjentka zmarła.

Każdy dzień przynosi nowe informacje. Narasta liczba rozpoznanych zachorowań, wysuwane są podejrzenia, co do większej liczby śmiercionośnych przesyłek pocztowych, już nie zagraniczne a wewnątrzamerykańskie mają być inspiracje bioterroryzmu.

Wśród epidemiologów narasta przekonanie, że mamy do czynienia z nową postacią starej broni biologicznej. Prace nad genetycznie zmodyfikowaną laseczką wąglika były intensywnie prowadzone w Związku Radzieckim.  Spośród dziesiątków tysięcy radzieckich uczonych zatrudnionych przy produkcji broni biologicznej postacią najbardziej znaną - również polskim epidemiologom - jest Ken Alibek, który po udanej ucieczce w 1992r. znalazł zatrudnienie w Stanach Zjednoczonych. Ostatnio kilkakrotnie oświadczył przed komisją Kongresu Stanów Zjednoczonych, że osoby obawiające się kontaktu z przesyłkami pocztowymi powinny prasować listy gorącym żelazkiem z parą wodną: wystarczy żelazko parowe i mokra ścierka do prasowania, aby zabić zarodniki wąglika. Poddawanie korespondencji działaniu gorącej pary wodnej w specjalnych urządzeniach ma udowodnioną skuteczność, również komercyjną. Cena może się wahać od 300 do 500 dolarów za aparat  do użytku domowego do 5 milionów dolarów za wielkie komory przeznaczone dla sortowni poczty. Naturalnie czas wymagany do zabicia zarodników spowalnia przepływ poczty. Pomimo to główny poczmistrz Stanów Zjednoczonych zapowiedział szybkie wprowadzenie technologii pozwalających na napromienianie i sanityzację przesyłek.

Odpowiednio spreparowane zarodniki wąglika mogą przeniknąć przez pory papierowej koperty (średnica 1-2 mikronów) i są tak lekkie, że wystarczy niewielki ruch powietrza, aby dostały się do dróg oddechowych. W biurze senatora Toma Daschle potwierdzono ekspozycję 20 osób w wyniku otwarcia jednej koperty. Zarazki mogą osadzać się na różnych przedmiotach, odzieży i skórze ludzi i zwierząt. Broń zaprojektowana do wdychania może prawdopodobnie wywołać także postać skórną wąglika. Zdarzyło się to w przypadku 7-miesięcznego niemowlęcia, które na swoje nieszczęście przebywało w newsroomie stacji ABC News w Nowym Jorku. Jednak badania środowiskowe przyniosły tam wynik negatywny.

Do 26. października 2001r. ponad dziesięciu tysiącom Amerykanów zalecono profilaktyczne leczenie antybiotykami. Okoliczności narażenia decydują o podjęciu tego rodzaju profilaktyki. Leczenie profilaktyczne powinien otrzymać każdy, kto uległ ekspozycji, bądź miał kontakt z przedmiotem lub środowiskiem, o których wiadomo, że są zanieczyszczone bakteriami wąglika lub są podejrzane o tego rodzaju zanieczyszczenie. Profilaktyczne leczenie przeciwbakteryjne należy podjąć niezależnie od wyników badań laboratoryjnych. 

Narażenie lub kontakt  a nie wyniki badań laboratoryjnych stanowią podstawę podjęcia leczenia. W celu wykrycia zarodników wąglika zakłada się hodowlę wymazów z nosa. Wymazy z nosa mogą niekiedy udokumentowac ekspozycję na bakterie wąglika, ale nie mogą jej wykluczyć. Dla oszacowania ryzyka wystąpienia postaci wziewnej wąglika może byc przydatna szybka ocena podejrzanego proszku, uwzględniająca wielkość cząsteczek i ich cechy. W przypadku podejrzenia lub potwierdzenia wąglika Ośrodki Zwalczania Chorób i Zapobiegania rekomendują leczenie intensywne i długotrwałe według założonego schematu. Obok cyprofloksacyny w leczeniu zakażenia niezmodyfikowanymi genetycznie laseczkami wąglika używa się także doksycyliny, penicyliny  i innych antybiotyków.

Podkreślam, że przyjmowanie antybiotyków bez kontroli lekarza pociąga za sobą wiele zagrożeń zdrowia. Najważniejsze z nich to: 
(a) działania uboczne i niepożądane wynikające  ze stanu pacjenta (rozpoznane już i  i jeszcze nierozpoznane choroby), zmieniających się cech zarazka, który ma być unieszkodliwiony i jakości  antybiotyku; 
(b) nieskuteczność antybiotyku i innych antybiotyków należących do tej samej grupy podczas kolejnej próby unieszkodliwienia tego samego lub innych zarazków i to nieraz w sytuacji bezpośredniego zagrożenia zdrowia pacjenta.

Zagrożeń zdrowia związanych z przyjmowaniem antybiotyku można uniknąć, stosując go wyłącznie według wskazań lekarza, który wypisze receptę dopiero po starannym zbadaniu pacjenta. Dotyczy to również cyprofloksacyny, która od dość dawna jest stosowana w np. jednodawkowym leczeniu rzeżączki, a wobec zagrożenia atakiem terrorystycznym jest masowo wykupywana w Stanach Zjednoczonych. Ustalenie dawki i udzielanie infomacji o działaniach ubocznych i niepożądanych leków należy do lekarza wypisującego receptę.

Kolejny raz przypominam o bezcennej wartości, jaką jest naturalna odporność człowieka na zakażenie. Nie wolno jej niszczyć stressem, alkoholem, tytoniem, innymi truciznami i niezdrowym trybem życia. O odporność trzeba dbać i ją wspomagać. Ruch na świeżym powietrzu jest tu bezkonkurencyjny.

Zanim kolejna epidemia przeziębień, schorzeń grypopodobnych i grypy nabierze nowego blasku w świetle nadchodzących zza Atlantyku zaleceń przeciwwąglikowych, warto w kluczowych punktach - choćby transportu poczty - postawić klatki z istotami bardzo już zasłużonymi dla ochrony zdrowia człowieka. Świnki morskie i myszy są bardzo wrażliwe na wąglik. I nie tylko na wąglik.

Zbigniew Hałat
lekarz specjalista epidemiolog
Serwer internetowy: www.halat.pl

Amerykańscy epidemiolodzy w dniu 2. listopada 2001r. określili procedurę postępowania   z osobą eksponowaną na wąglik lub zagrożoną z powodów zawodowych lub środowiskowych.

1. U osoby chorującej 2 - 5 dni następujące objawy uzasadniają podejrzenie płucnej postaci wąglika:

• gorączka z dreszczami lub bez
• poty, często zlewne
• zmęczenie, ogólne rozbicie
• kaszel, zwykle bez odpluwania, krótki oddech
• ucisk w klatce piersiowej, ból opłucnowy
• nudności, wymioty, biegunka, ból brzucha
• ból głowy, bóle mięśniowe
• ból gardła

2.2. Jeżeli powyższe objawy wystąpiły, należy wykonać następujące badania:

• leukocytoza
• prześwietlenie rtg klatki piersiowej 
• posiewy krwi
• gdy prześwietlenie rtg klatki piersiowej nie wykazuje zmian, 
• - należy rozważyć tomografię komputerową.
• należy rozważyć szybkie testy diagnostyczne w kierunku grypy
• należy powiadomić san-epid

3.2. Jeżeli leukocytoza, prześwietlenie rtg klatki piersiowej i tomografia komputerowa wykazują charakterystyczne zmiany lub przebieg choroby średnio-ciężki lub ciężki, należy rozpocząć leczenie przeciwbakteryjne.

3.2.1. Jeżeli wystąpi wysięk opłucnowy, należy pobrać płyn na rozmaz metodą Grama i posiew, PCR i blok komórkowy (uzyskany przez odwirowanie płynu opłucnowego) na badanie immunohistochemiczne.

3.2.2. Jeżeli wystąpią objawy oponowe lub zaburzenia psychiczne, należy wykonać  punkcję lędźwiową.

3.2.3. Inne badania diagnostyczne uwzględniają wykonanie badań serologicznych w CDC
 

1. działania uboczne i niepożądane wynikające 

• ze stanu pacjenta (rozpoznane już i  i jeszcze nierozpoznane choroby), 
• ze zmieniających się cech zarazka, który ma być unieszkodliwiony 
• jakości  antybiotyku

Dotyczy to również cyprofloksacyny, która od dość dawna jest stosowana w np. jednodawkowym leczeniu rzeżączki, a wobec zagrożenia atakiem terrorystycznym jest masowo wykupywana w Stanach Zjednoczonych, gdyż chroni nie tylko przed wąglikiem, lecz także przed tularemią i  dżumą. 

Ustalenie dawki i udzielanie infomacji o działaniach ubocznych i niepożądanych leków należy do lekarza wypisującego receptę. 

Z kolei służby odpowiedzialne za bezpieczeństwo ruchu drogowego i obsługę maszyn i urządzeń oraz inne prace wymagające koncentracji, bądź takie, jak praca na wysokości,  muszą wiedzieć, że po przyjęciu  cyprofloksacyny nie powinno się prowadzic samochodu i obsługiwać maszyn.
 

Objawy: po 12 do 36 godz. po zjedzeniu zanieczyszczonej żywności początek choroby: podwójne lub zmącone widzenie, niewyraźna wymowa, trudności połykania i postępujące osłabienie, które zaczyna się  od barków i schodzi w dół.

Przebieg zakażenia: ofiary, które spożyły niewielkie dawki mogą przeżyć, ale większe dawki mogą spowodować porażenie mięśni i zgon w ciągu 24 godzin, jeżeli pacjent nie ma dostępu do aparatury wspomagającej oddychanie.

Surowica: służba sanitarno-epidemiologiczna musi utrzymywać stały zapas surowicy w razie konieczności szybkiego zastosowania

Zagrożenie: botulizm jest wywoływany przez toksynę botulinową, która jest niezwykle silną i śmiercionośną trucizną już w małych ilościach - jednej miliardowej części grama. Według doniesień ekspertów japońska sekta bezskutecznie usiłowała przeprowadzić zamach z użyciem toksyny botulinowej. Toksyna może być użyta do skażenia wody i żywności, ale ponieważ szybko ulega zniszczeniu pod wpływem chloru, dostawy wody nie są zagrożone. Trucizna est bardzo niestabilna jako czynnik biologiczny, co sprawia trudności przy jej rozsiewaniu w otwartym środowisku. Do zakażenia botulizmem nie dochodzi w wyniku kontaktu z osobą zakażoną.

Objawy: po 1 - 6 dniach od czasu ekspozycji  początek choroby z wysoką gorączką, dreszczami, bólem głowy i trudnościami oddychania szybko osiągającymi ciężką formę, kaszel z krwią.

Przebieg zakażenia: zgon następuje w ciągu 2 - 4 dni.

Szczepionka: wykorzystywane dotychczas szczepienia przeciw przenoszonej przez pchły dżumie dymieniczej nie są skuteczne przeciw formie aerozolowej, która mogłaby być użyta w ataku terrorystycznym. Leczenie antybiotykiem podjęte w ciągu 24 godzin od pojawienia się pierwszych objawów może podnieść szanse przeżycia.

Zagrożenie: dżumę wywołują bakterie o bardzo wysokiej  zaraźliwości. Może być przenoszona na ludzi przez pchły, które karmiły się krwią zakażonego szczura. Szerzy się także przez kropelki obecne w powietrzu, kiedy ludzie zakażeni kaszlą. Obie formy mogą być leczone antybiotykami, ale odmiana szerząca się drogą oddechową rozwija się tak szybko, że najczęściej zawsze prowadzi do zgonu w ciągu kilku dni.

Objawy: około 12 godz. po ekspozycji zaczyna się wysoka gorączka, zmęczenie i bóle pleców, po czym po 2 -3 dniach na twarzy, kończynach górnych i dolnych pojawia się wysypka o charakterystycznej ewolucji zmian skórnych.

Przebieg zakażenia: aż 30% zakażonych może umrzeć, zazwyczaj w ciągu pierwszych dwóch tygodni choroby

Szczepionka: szczepień powszechnych zaniechano w 1972 r., ale nadal utrzymywane są specjalne zapasy szczepionki

Zagrożenie: Ospa jest bardzo zaraźliwa i mogłaby szerzyć się szybko wśród nieszczepionej ludności. Została wykorzeniona na całym świecie, ale istnieje obawa, że terroryści mogliby uwolnić nowy szczep. W 1999 Instytut Medycyny amerykańskiej National Academy of Science zalecił utrzymywać przy życiu zachowane w laboratoriach szczepy ospy prawdziwej w ramach sieci bezpieczeństwa na wypadek ponownego pojawienia się ognisk choroby. Stwierdzono, że rozsianie wirusa drogą powietrzną "jest uznawane za poważne zagrożenie bronią biologiczną".

Objawy: zwykle 3 - 5 dni - a nawet dwa tygodnie po ekspozycji - pojawiają się owrzodzenia, powiększone węzły chłonne, gorączka i zapalenie płuc

Przebieg zakażenia: w najcięższych postaciach prowadzi do zgonu w 35% nieleczonych przypadków w ciągu dni lub tygodni

Szczepionka: siły zbrojne są w posiadaniu szczepionki, ale i leczenie antybiotykami może być skuteczne, nawet jeśli są podane po upływie dni lub tygodni

Zagrożenie: tularemia lub gorączka zajęcza jest chorobą bakteryjną, której rezerwuarem są ssaki lub kleszcze, które mogą ją przenosić do krwi człowieka przez uszkodzenie skóry. Nawet bez leczenia przeżywa 95% osób zakażonych. Uwolnienie bakterii w formie aerozolu może jednak zwiększyć śmiertelność.

Objawy: do 6 dni od czasu ekspozycji początek choroby na wstępie  z gorączką, nużliwością, kaszlem i uciskiem w klatce piersiowej, potem ciężkie zaburzenia oddychania, poty, zasinienie powłok

Przebieg zakażenia: zgon następuje po 24- 36 godzinach do pojawienia się ciężkich objawów.

Szczepionka: Szczepionka musi być podana 18 miesięcy przed ekspozycją, aby można było oczekiwać jej pełnej skuteczności, choć jest nieco dowodów  jakiejś ochrony po pierwszych trzech dawkach (podanych w ciągu czterech
tygodni)

Zagrożenie: do zakażenia wąglikiem może dojść w wyniku kontaktu skóry człowieka z zakażonym zwierzęciem, zjedzenia zanieczyszczonego mięsa lub wprowadzenia do płuc z wdychanym powietrzem zarodników (spor) wąglika. Zakażenie w następstwie kontaktu z zakażonym zwierzęciem prowadzi do zgonu w 20% przypadków. Forma przetrwalnikowa prowadzi do śmierci w 90% przypadków. Zarodniki mogą przetrwać w ziemi lub wodzie wiele lat i łatwo je rozsiać w powietrzu przy użyciu pocisków, rakiet, artylerii, bomb lotniczych i rozpylaczy. Kiedy zarodniki dostaną się do płuc, bakterie wąglika zaczynają się namnażać i wytwarzać  toksynę, co prowadzi do zgonu.

Objawy: zależnie od wirusa (Ebola, Marburg lub inne) objawy takie jak wysoka gorączka, bóle mięśniowe, dreszcze i biegunka zaczynają się w ciągu kilku dni, potem występuje silny ból w klatce piersiowej, wstrząs i krwotok..

Przebieg zakażenia:  choroba nie zawsze kończy się zgonem, jednak gorączka  Ebola miała do 90% śmiertelności w niektórych ogniskach; zgon pojawia się po tygodniu od zakażenia.

Szczepionka:  nie ma szczepionek przeciwko gorączkom krwotocznym, z wyjątkiem żółtej gorączki i argentyńskiej gorączki  krwotocznej

Zagrożenie: wirusowa gorączka krwotoczna wywoływana jest przez rozmaite wirusy należące do czterech głównych rodzin - arena-, flavi-, bunya- i flaviwirusy. Na szczęście najbardziej śmiercionośne istnieją - jak się uważa - tylko w kilku laboratoriach na świecie. Dodatkowo wielu ekspertów przychyla się do opinii, że bariery techniczne czynią mniej prawdopodobną masową ich produkcję, a następnie rozprowadzanie w formie broni biologicznej. W 1995r. japońska sekta bezskutecznie usiłowała uzyskać z  Zairu wirus krwotocznej gorączki Ebola. Jak wąglik i botulizm, Ebola zagraża życiu tylko wtedy, kiedy dostanie się do płuc z wdychanym powietrzem.

1
INTERIM PHLS GUIDELINES FOR ACTION IN THE EVENT  OF A DELIBERATE RELEASE
Contents
(...)
Note: these are interim guidelines. Comments are welcome from healthcare, laboratory and public health professionals, and should be sent to rharling@phls.org.uk. Since these are interim guidelines, they may be subject to changes as comments are received, so please ensure that you have the latest issue and version: the most up to date is issue 2/version 2, available
through the PHLS website at www.phls.org.uk/facts/deliberate_releases.htm 

1 BACKGROUND
These guidelines are intended for healthcare, laboratory and public health professionals to guide clinical and public health action in the event of a deliberate release of anthrax.
1.1 Introduction
Anthrax is an acute infection caused by the Gram-positive, spore forming, bacteria Bacillus anthracis. Anthrax naturally infects many species of grazing mammals such as sheep, cattle and goats, which are infected through ingestion of soil contaminated by B. anthracis spores. There are three forms of human disease depending on how infection is acquired: cutaneous, inhalation and ingestion. In over 95% of cases the infection is cutaneous, acquired by inoculation of spores into small abrasions on the skin, usually during handling of untreated animal hides. 
1.1.1 Deliberate release of anthrax
The threat of a deliberate release of anthrax is of the release of large quantities of spores in an aerosol. This threat is considered serious because:
· The organism is relatively easy to cultivate from environmental sources.
· The inhalation form of disease has a high mortality rate.
Despite this, creation of an infective anthrax aerosol is not easy – particles need to be between 1 and 5mm in size and sufficient energy is required to disperse them.
1.2 Epidemiology
Anthrax is a zoonosis to which most mammals, especially grazing herbivores, are susceptible. Human infections usually result from contact with infected animals or animal products. Direct exposure to secretions from cutaneous anthrax lesions may
result in secondary cutaneous infection, but there have been no known cases of person-to-person transmission of inhalation disease.
1.2.1 Transmission
The spores of B. anthracis are extremely durable. Modes of transmission include:
· Cutaneous contact with spores, spore contaminated materials or infected skin lesions. Infection required an existing break in the skin.
· Inhalation of spores.
· Ingestion of contaminated meat.
1.2.2 Infectious dose
The ID50 for inhalation anthrax is estimated at 10,000 spores. (This is the infectious dose required to cause disease in 50% of those exposed by inhalation).
1.2.3 Incubation period
1 day to 8 weeks (mode 5 days), dependent on dose and exposure route.
· 1-7 days following cutaneous exposure.
· 1-6 days following inhalation exposure.
· 1-7 days following ingestion.?PHLS-CDSC
1.2.4 Period of communicability
· Transmission of anthrax infection from person to person is highly unlikely.
· Contact with skin lesions can result in subsequent cutaneous infection.
· Airborne transmission from person to person does not occur.
1.3 Clinical features
Human anthrax can occur in three forms: inhalation/pulmonary, cutaneous or gastrointestinal, depending on the route of exposure, and details of these diseases are given below. It can be expected that any malicious or deliberate release of
anthrax spores will involve aerosol exposure. Clinicians should be aware of the possibility of cases of inhalation anthrax, and any previously healthy patient with the following clinical presentations should be immediately reported to the Consultant in Communicable Disease Control and to the duty doctor at CDSC (020 8200 6868 - 24 hour service).
· A severe, unexplained febrile illness or febrile death.
· Severe sepsis not due to a predisposing illness, or respiratory failure with a widened mediastinum.
· Severe sepsis with Gram-positive rods or Bacillus species identified in the blood or cerebrospinal fluid and assessed not to be a contaminant.
1.3.1 Inhalation/pulmonary
· Non-specific prodrome of flu-like illness following inhalation of spores with fever, headache, myalgia and non-productive cough. Two to four days after initial symptoms, there is abrupt onset of respiratory failure and on chest X-ray a widened mediastinum is often present, suggestive of mediastinal lymphadenopathy and haemorrhagic mediastinitis. Note that a widened
mediastinum may also be apparent in cases of TB due mediastinal lymphadenopathy.
· Gram-positive bacilli seen in blood cultures, usually after 2-3 days of onset of illness.
· Treatment may be successful in the prodromal stage, but by the time respiratory or bacteraemic symptoms develop, treatment may not arrest the disease before a fatal outcome.
1.3.2 Cutaneous
· Local skin involvement after direct contact.
· Commonly seen on hands, forearms and head.
· Three days after exposure a raised, itchy, inflamed pimple appears followed by a papule that turns vesicular and then 2-6 days later a black eschar develops.
Extensive oedema accompanies the lesion.
· Responds to oral antibiotics.
· Rarely may progress to bacteraemia or meningitis without treatment.
1.3.3 Gastro-intestinal
· Rare.
· Characterised by severe abdominal pain, nausea and vomiting with watery or bloody diarrhoea.
· 2-3 days after onset bacteraemia may develop.
· Usually fatal if it progresses to bacteraemia.
1.4 Mortality
Systemic infection resulting from inhalation of the organism has a mortality rate approaching 100%, with death usually occurring within a few days after the onset of symptoms. Cutaneous anthrax, the most common form, is usually curable with antibiotics. The mortality rate among people with infection resulting from ingestion is variable, but may also approach 100%.
1.5 Organism survival
Anthrax endospores do not divide, have no detectable metabolism, and are resistant to drying, heat, UV light, gamma irradiation and many disinfectants. In some types of soil, anthrax spores can remain dormant for decades.
1.6 Antimicrobial susceptibilities
Most naturally occurring anthrax strains are sensitive to penicillin which historically has been the preferred therapy for the treatment of anthrax. There are no clinical studies of the treatment of inhalational anthrax in humans. Thus, antibiotic
regimens commonly recommended for first line treatment of sepsis have not been studied in this setting. Natural strains of B. anthracis are resistant to extended-spectrum cephalosporins.
In studies of small numbers of monkeys infected with susceptible strains of B. anthracis, oral doxycycline has proved efficacious. Doxcycline is therefore the preferred option from the tetracycline class of antibiotics because of its proven
efficacy in monkey studies and its ease of adminstration. Other members of this class of antibiotics are suitable alternatives.
Although treatment of anthrax infection with ciprofloxacin has not been studied in humans, animal models suggest excellent efficacy. In-vitro data suggest that other fluroquinolone antibiotics would have equivalent efficacy in treating anthrax
infection, although no animal data exist for fluoroquinolones other than ciprofloxacin. Pharmacokinetic studies of ciprofloxacin in humans have demonstrated excellent penetration into lung tissue following oral administration. Ciprofloxacin has the added advantage that it is also the first line prophylactic treatment for other potential agents that may be used in deliberate release scenarios such as plague and tularaemia.

2 CLINICAL PROCEDURES
2.1 Diagnosis and collection of samples
Despite its reputation, anthrax is not contagious, and humans are not highly susceptible to the disease. While theoretically it only takes one spore to initiate a cutaneous infection, B. anthracis is not invasive, requiring an existing lesion to penetrate the skin and commence infection. Use of standard Universal Precautions (gloves, gowns and hand washing) in the laboratory reduces the risk of cutaneous anthrax to zero in the simple procedures outlined below. Infectious doses in the pulmonary or intestinal forms are high, and these have to be delivered in the correct size of particle. It can be seen, therefore, that the simple laboratory isolation and identification tests described do not create higher risks of dangerous infection than other pathogens being handled in a routine containment level 3 clinical laboratory.
2.1.1 Precautions for sampling
The samples outlined below should be taken to confirm the diagnosis. These must be taken using Universal Precautions and with the utmost care to avoid inoculation injuries. The procedure for transporting samples to the laboratory are outlined in
section 3.6. The receiving laboratory should be telephoned to expect arrival.
2.1.2 Samples to be taken from acutely ill humans
· Blood for culture.
· Nasal swabs (laboratory diagnosis is easier if these are sent dry since this prevents growth of other organisms and facilitates detection of anthrax spores).
· Sputum samples and swabs from cutaneous lesions.
2.1.3 Post mortem specimens
Samples may be taken from dead humans to assist diagnosis, including:
· Blood from a vein (the blood is non-clotting at death in anthrax).
· Nasal swabs.
· Swabs of haemorrhagic exudate from orifices.
· Swabs or sample of other body fluids if appropriate.
However full post-mortems are discouraged if anthrax is suspected because of the risk of releasing anthrax spores present in body fluids, drips etc. If postmortem is carried out, swabs or samples of lung, spleen or lymph node should be sent (transport medium is not necessary, but it will not damage specimens).
2.1.4 Samples to be taken from the environment
Samples should be taken from any material (soil, dust, clothing, swabbing etc) present in the environmental area thought to have been exposed to the release of anthrax spores, or soiled by exudates from humans (or animals). Further advice on environmental sampling methods will be provided if a release is suspected.
2.1.5 Samples to be taken from others who have or may have been exposed 
Depending on the scale of a release, it may be possible to obtain nasal swabs from people present within and adjacent in the exposed area at the time of release. This will assist confirmation of the release and designation of an exposed zone.
2.1.6 Transport of samples
Strict procedures should be followed for the transport of samples of suspected anthrax, both from the clinical environment to the laboratory, and from local laboratories onto the reference laboratory. These are outlined in section 3.6.
2.2 Treatment
2.2.1 Inhalation and ingestion
Table 1: recommended treatment for inhalation and ingestion anthrax
(...)
2.2.2 Cutaneous
(..,)
2.3 Infection control practice
2.3.1 Decontamination of exposed persons
In the event of a known exposure to anthrax spores, the risk for re-aerosolization from the clothing of those exposed is extremely low. However even a low numbers of spores could potentially lead to cutaneous infection in attending healthcare
workers. In situations where the threat of exposure to B. anthracis spores exists, cleansing of skin and potentially contaminated fomites such as clothing, personal possessions or environmental surfaces should be considered in order to reduce the risk of the cutaneous form of the disease. Decontamination of persons exposed to anthrax may include:
· Removal of contaminated clothing and possessions – it should be stored in labelled double plastic bags until exposure to anthrax has been ruled out. 
· If anthrax is confirmed, all contaminated material must be incinerated or autoclaved.
· Minimal handling of clothing and fomites to avoid agitation.
· Instructing exposed persons to shower thoroughly with soap and water-appropriate facilities will be provided at the scene as necessary.
· Instructing attending personnel to wear appropriate barrier protection – Universal Precautions - when handling contaminated clothing and other fomites.
2.3.2 Isolation of patients
· Standard Universal Precautions should be used for the care of patients infected with B. anthracis – gloves, gowns and hand washing.
· Single room placement for anthrax patients is not necessary.
· Airborne transmission does not occur.
· Skin lesions may be infectious, but requires direct skin contact.
· Standard Universal Precautions should be maintained when patients are moved.
2.3.3 Cleaning, disinfection & waste disposal
Contaminated environmental surfaces should be cleaned with 0.5% hypochlorite solution (5,000ppm; equivalent to one part household bleach added to nine parts water).
2.3.4 Post-mortem
Post-mortem examinations are discouraged if anthrax is suspected. However, if they are undertaken, standard Universal Precautions should be observed with the use of appropriate personal protective clothing, including gloves, gowns and hand
washing. Instruments should be autoclaved. Cremation is the preferred method for disposal of the deceased. Embalming of
bodies should be strongly discouraged. 
2.4 Prophylactic treatment for persons exposed to anthrax spores
In the event of a known exposure to anthrax spores, antibiotic prophylaxis should be initiated as soon as possible – as described in Table 2.
Prophlyaxis should continue until B. anthracis exposure has been excluded. If exposure is confirmed, prophylaxis should continue for 60 days. During this period, no special precautions are required for exposed persons, however they should receive an anthrax information sheet and be instructed to seek medicalattention immediately in the event of any suspicions symptoms.
Table 2: Recommended prophylaxis after exposure to B. anthracis 
2.4.1 Immunisation
In certain circumstances, in addition to antimicrobial prophylaxis, post-exposure immunisation may also be indicated. This consists of 5 doses of vaccine at 0, 3 and 6 weeks, then at 6 months and 1 year after exposure. With vaccination, post-exposure antibiotic prophylaxis can be reduced to 4 weeks. Advice on the use of  vaccine must be obtained from PHLS-CDSC.
2.4.2 Contacts of cases
There is no need to provide antibiotic prophylaxis or immunisation to contacts of patients unless there is concern that they were also exposed to the initial release.
2.5 Environmental decontamination
The greatest risk to human health following a release of anthrax spores occurs during the period in which anthrax spores remain airborne, called primary aerosolisation. The duration and scale of the infectious risk depends on the duration for which spores remain airborne and the distance they travel before they fall to the ground. This depends on meteorological conditions and aerobiological properties of the dispersed aerosol. The aerosol is likely to be fully dispersed within hours to 1 day at most, well before the first symptomatic cases would be seen. In the event of a known release, an exposed zone will be defined according to the time and place of release in order to identify all persons exposed to primary aerosolisation. This is explained in section 4. The area surrounding the site of release will remain designated as an exposed zone until sufficient time has elapsed and there is no further risk of infection. Expert advice will be provided to determine the time after release for which spores are likely to remain airborne. Once they have settled, although they remain infectious for long periods, the risk to human health is much lower. Decontamination of small areas may be achieved with 0.5% hypochlorite solution (5,000ppm; equivalent to one part household bleach added to nine parts water).
2.6 Protection of frontline workers
This includes all emergency staff involved in management at the scene of a release, as well as those involved in treating patients with anthrax.
2.6.1 Protective clothing
Following an overt release of anthrax spores, the area affected by primary aerosolisation will depend on the time and place of release. This exposed zone (see section 4) presents a high risk of infection, and anyone entering it should wear full protective equipment such as Type 3 high efficacy air filter masks with Class A suits, conferring full biological protection. Healthcare workers will not normally be asked to enter this zone, however it is possible that they may be called to treat casualties, for example if an explosive device has accompanied the release of biological agent. In this case the full protective clothing should be worn. Exposed persons will normally be moved from the exposed zone, through decontamination, and into a place of safety (see section 4.3.1) for medical assessment and administration of prophylactic treatment. Those involved in decontamination, and others who have who have any contact with contaminated clothing and fomites should observe standard Universal  Precautions - gloves, gowns and hand washing. Emergency staff who attend exposed persons after decontamination has been completed do not need to take any special precautions. For healthcare workers involved in the management of hospitalised patients with all forms of anthrax, Universal Precautions provide sufficient protection, and mortuary staff should use similar barrier protection. More sophisticated countermeasures for airborne protection such as high-efficacy air filter masks airborne protection are not required.
2.6.2 Antibiotic prophylaxis and immunisation
Frontline workers entering the exposed zone should be offered antibiotic prophylaxis as in Table 2, and in addition, should be offered a course of vaccination at 0, 3 and 6 weeks then at 6 months and 1 year following exposure, subject to availability.
Prophylactic treatment may also be considered for frontline workers involved in other activities including:
· Decontamination of exposed persons.
· Handling exposed persons.
· Management of patients or disposal of bodies infected with anthrax.
Decisions about whom should receive prophylaxis should be taken on an individual basis according to duration and degree of potential exposure, and taking intoaccount the availability and side effects of prophylactic treatments.
2.7 Other Considerations – patient, visitor and public information
Information sheets have been prepared for distribution in the event of an incident.
3 LABORATORY PROCEDURES
3.1. Risk assessment
B. anthracis is a Hazard Group 3 pathogen, and should thus be covered by existing risk assessments for handling such organisms in diagnostic laboratories.
3.1.1 Receipt of samples
Samples should have been labelled as ‘High risk’ by the submitting staff, and should be handled according to local protocols for such samples. All laboratory procedures should be performed, by experienced MLSOs or scientists, in a containment level 3 facility using a Class 1 protective safety cabinet. Chain-of-evidence documentation should accompany specimens. In larger incidents, this would only be required for several of the initial cases.
3.2 Isolation and identification
Two smears should be made on microscope slides and fixed by immersion in absolute ethanol for 1 minute. Slide 1 should be stained with polychrome methylene blue (if available) or Giemsa stain as an alternative, and the typical capsulated short chains of “box-car” bacilli looked for under oil immersion. Their presence is highly suggestive of anthrax. If numerous bacilli in short chains are visible, dispatch the second slide to a reference laboratory for confirmation. The specimens should also be cultured on to blood agar for incubation at 37 o C in air/CO2. Antimicrobial susceptibility tests must be set up as soon as possible.
3.2.2 Culture
B. anthracis is a non-motile, Gram-positive, aerobic bacillus 1.2 to 10mm in length, capable of forming central and terminal spores. Cultures should be inoculated onto an agar slope in a bijoux bottle and incubated overnight. After incubation, the
typical white, non-haemolytic colonies, with bees-eye appearance (that is, oval, slightly granular but not dry, about 2mm diameter) and characteristically tacky on teasing with a loop, will be apparent in large numbers. These can be subcultured to a slope in a class 1 protective cabinet within a containment level 3 facility that can then be transmitted to the reference laboratory
for confirmation.
3.2.3 Antibiotic sensitivity
Organisms should be tested for sensitivity to antibiotics including ciprofloxacin, penicillin, doxycycline and gentamicin.
3.3 Confirmation
Clinical microbiology laboratories should take care not to regard all isolates of Bacillus species as contaminants, especially if isolated from sterile sites (blood, cerebrospinal fluid) and/or multiple cultures are positive from the same patient.
The PHLS recommends that all sterile site Bacillus isolates be further evaluated, and if non-motile or non-haemolytic (particularly if they form short chains), and/or if the clinical syndrome is suggestive of anthrax, the isolates should be immediately
referred to reference laboratory.
3.4 Waste disposal
In the laboratory, 0.5% hypochlorite (5,000ppm) disinfection is necessary for decontaminating surfaces that may have been exposed to B. anthracis spores. All other waste containers should be autoclaved.
3.5 Reference laboratory
All positive isolates and cultures should be sent to the reference laboratory for confirmation. In addition, samples may be sent directly to the reference laboratory if local laboratories lack the facilities for dealing with them. These and other specimens should then be sent to the reference laboratory taking care to observe the procedures outlined in section 3.6. The sender’s name and address should be clearly marked. The reference laboratory should be telephoned prior to sending to expect the sample. Samples should be forwarded urgently to:
Special Pathogens
CAMR
Porton Down, Salisbury
Wiltshire, SP4 0JG
Contact: Dr G Lloyd
Tel: (+44) 01980 612100 (24hours)
3.6 Transportation of samples with suspicion of B. anthracis
The following procedures should be adopted for the transport of all specimens, and also all cultures for confirmation. These apply within hospitals and laboratories as well as for specimens sent to the reference laboratory:
· Every effort should be made to avoid external contamination of specimen containers during specimen collection.
· The primary container (bijoux or similar) should be screwed tight, labelled and placed in an intact plastic bag.
· A ‘High Risk’ label should be affixed to both specimen and request form. The latter should include any other relevant information and include adequate clinical details to indicate level of suspicion.
· Under no circumstances should the request form be placed in the same bag as the specimen.
· The bag should be sealed, using tape or heat sealer. Pins, staples and metal clips should not be used. A separate bag should be used for each specimen.
· Each specimen must then be placed in a leak-proof secondary container with sufficient absorbent material to absorb all the contents should leakage occur.
· Each specimen must be packaged individually - ie. three specimens, three separate packages.
· The secondary container should be externally disinfected - eg. by wiping with 0.1% hypochlorite (1,000ppm).
3.6.1 Samples sent to the reference laboratory
· Secondary containers should be placed within a final outer tertiary packaging.
· This packaging must comply to the UN 602 standard packaging for the transport of infectious substances by air, road or rail.
· The package should be certified to this standard and carry the appropriate UN certification numbers on the tertiary packaging along with the following information:
1 BIOHAZARD – danger of infection symbol Class UN 6.2.
2 Instructions not to open if found.
3 Telephone number of a responsible person - eg. Consultant Microbiologist, Laboratory Manager.
· The container should be transported by an approved courier, without delay, directly to the reference laboratory.
3.6.2 Samples sent within hospitals and laboratories
· Secondary containers should be placed in a good quality box, which is well taped up and clearly labelled “Pathological Specimen – Open only in Laboratory”.
· Specimens should be transported by hand by a responsible person using the above packaging. Vacuum-tube systems should not be used for transportation of specimens within hospitals or laboratories.
· Extra care should be taken to ensure that laboratory records are kept to a high standard.
4 PUBLIC HEALTH PROCEDURES
4.1 Surveillance and detection of deliberate releases of anthrax A deliberate release may be overt with an announcement and/or confirmation by environmental sampling. However, it is also possible that a deliberate release may be covert and will not be identified until the first cases of disease arise. Anthrax is a rare disease. In the last 20 years there has been fewer than one case per year in the UK. These are mainly cutaneous and are due to handling hides imported from countries with endemic disease (and thus often associated with the leather industry).
Deliberate release should be considered in the event of:
· Single confirmed cases of inhalation anthrax.
· Single confimed cases of cutaneous anthrax arising in indiviuals who do not routinely have contact with animals or animal hides.
· Two or more suspected cases of anthrax that are linked in time and place, especially geographical related groups of illness following a wind direction pattern (analogous to legionnaire’s disease).
Close co-ordination with veterinary colleagues is essential: grazing animals (cows, sheep, goats) are far more susceptible to disease and have a shorter incubation period than humans. Confirmed and suspected cases of anthrax in animals may
provide an early warning system.
4.2 Case Definition
4.2.1 Suspected cases
Any previously healthy patient with the following clinical presentations should be immediately reported to the Consultant in Communicable Disease Control.
· A severe, unexplained febrile illness or febrile death.
· Severe sepsis not due to a predisposing illness, or respiratory failure with a widened mediastinum.
· Severe sepsis with Gram-positive rods or Bacillus species identified in the blood
or cerebrospinal fluid and assessed not to be a contaminant.
If anthrax is suspected, microbiological specimens should be sent to the reference laboratory, and consideration should be given to initiating empirical treatment pending results. Obviously the level of suspicion of anthrax depends on local circumstances at the time – in the event of a known or suspected deliberate release the threshold for making a diagnosis of anthrax should be lower. As discussed in section 3.3, clinical microbiology laboratories should also be alert to the possibility of anthrax. The PHLS recommends that all sterile site Bacillus isolates should be carefully evaluated, and if suspicious, and/or if the clinical syndrome is suggestive of anthrax, they should be immediately referred to reference laboratory.
4.2.2 Confirmed case
A case that clinically fits the criteria for suspected anthrax, and in addition, definitive positive results are obtained on one or more pathological specimens by the reference laboratory.
4.2.3 Definitive diagnosis in the reference laboratory
The definitive test for B. anthracis is polymerase chain reaction (PCR). This test can be applied to cultures sent from local laboratories, in which case results will be available in 3 hours from receipt of specimen. It can also be applied to isolates and
other clinical samples, but this will normally require overnight culture at the reference laboratory, so the result will take 24 hours.
4.3 Public Health Action
4.3.1 Procedure for handling exposed persons
Depending on the site and method of release, anthrax spores may be dispersed over a wide area. Expert advice will be provided to define an exposed zone in time and space. All individuals who have been present in the exposed zone need to
be identified. In the event of an overt release, some of them will still be at the scene when emergency services respond to the incident. This group will be decontaminated and then referred to health workers at a nearby place of safety for assessment and prophylaxis (this will be a clinical area just outside the exposed zone and within the cordon that will be established at the scene of the incident). Others will have left the scene before emergency services arrive and will be identified later when they approach GPs and A+E departments after details of the incident have been made public. Procedures need to ensure that these individuals
are appropriately decontaminated, receive prophylaxis, and have their details collected for follow up.
4.3.2 Post-exposure prophylaxis
There are 2 groups of individuals for which prophylaxis is indicated:
I Individuals who have been present in the exposed zone should be offered post-exposure prophylaxis as outlined in Table 2.
II Healthcare workers may require prophylaxis as described in section 2.6.2.
If suspected or confirmed cases of anthrax arise among persons who have been outside but in close proximity to the exposed zone in time or space, the defined parameters of the exposed zone should be reviewed with a view to extending post-exposure prophylaxis. Prophylaxis for other groups may be considered in the event of an incident. However, it is not advisable to give antibiotics to people who do not have a clear history of having been present at the time and site of release. It is inappropriate to provide antibiotics to large numbers of people who have not been exposed, but who are generally concerned or have non-specific mild illnesses.
4.3.3 Follow up of exposed persons
After an overt release, a basic set of personal details needs to be collected from all persons present in the exposed zone.
4.3.4 Case finding
If cases of anthrax arise and a covert release is suspected, health services should be contacted to determine whether other possible cases have presented.
4.3.5 Preventing secondary spread
As previously mentioned, person to person spread of anthrax is negligible, and therefore there is no specific treatment or advice is required for secondary contacts. There is no requirement for quarantine of infected patients. However those contaminated with Anthrax spores will need to be decontaminated as described in section 2.4.2.
4.4 Epidemiological investigation
If a case is strongly suspected or confirmed, the PHLS-CDSC should be notified immediately. If cases arise due to a covert release, or following an overt release but in people who have not been present in the exposed zone, it is important to
collect some epidemiological details in addition to a basic set of personal details. This is in order to define or redefine the exposed zone and aid identification of others at risk of infection. Details should be as thorough as possible, whilst
recognising that in the event of a large release with multiple exposed persons or cases, it may not be possible to collect comprehensive information from everyone.
The aim of epidemiological investigations may be:
· Following a covert release to assist definition and ongoing review of the temporal and spatial parameters of the exposed zone so that post exposure prophylaxis can be distributed appropriately.
· Following an overt release to guide review of the exposed zone if cases arise in persons who were not present within it.
4.4.1 Epidemiological sampling
Microbiological samples may be available from the environment, and depending on the scale of the release, it may be possible to take nasal swabs from people present in the exposed zone. These may provide further information to help guide ongoing administration of post exposure prophylaxis. This is particularly important in the event of a covert release, when the process of defining the exposed zone will involve continuous review according to emerging epidemiological information.

LIST OF NATIONAL SPECIALISTS
Laboratory diagnosis and treatment
Advice can be obtained from:
· Dr Nigel F Lightfoot
Group Director
Public Health Laboratory Services (North)
Directorate Office, E Floor, Milburn House
Dean Street
Newcastle upon Tyne
NE1 1LF
Tel: (+44) 0191 261 2577
Fax: (+44) 0191 261 2578
E-mail: grpnligh@north.phls.nhs.uk
and
· Dr Robert C Spencer
Deputy Director
Public Health Laboratory
Bristol Royal Infirmary, Level 8
Marlborough Street
Bristol
BS2 8HW
Tel: (+44) 0117 9282879
Fax: (+44) 0117 9299162
E-mail: robert.spencer@ubht.swest.nhs.uk
Out of hours contact details are held by the 24 hour CDSC on call duty doctor;
Tel: (+44) 020 8200 6868
Public Health
Contact details are held by the 24 hour CDSC on call duty doctor;
Tel: (+44) 020 8200 6868?REFERENCES
1. Dixon TC, Meselson M, Guillemin J & Hanna PC. (1999). Anthrax. N Engl J Med 341: 815-26.
2. Hanna P. (1998). Anthrax pathogenesis and host response. Curr Top Microbiol Immunol 225: 13-35.
3. Ibrahim KH, Brown G, Wright DH, & Rotschafer JC. (1999). Bacillus anthracis:medical issues of biologic warfare. Pharmacotherapy 19: 690-701.
4. Inglesby TV, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, Friedlander AM, Hauer J, McDade J, Osterholm MT, O’Toole T, Parker G, Perl TM, Russell PK & Tonat K. (1999). Anthrax as a biological weapon: medical and public health
management. Working Group on Civilian Biodefense. JAMA 281: 1735-45.
5. Little SF & Ivins BE. (1999). Molecular pathogenesis of Bacillus anthracis infection.Microbes Infect 1: 131-9.
6. (1999). Bioterrorism alleging use of anthrax and interim guidelines for management – United States 1998. MMWR 48: 69-74.
7. Shafazand S, Doyle R, Ruoss S, Weinacker A & Raffin TA. (1999). Inhalational anthrax: epidemiology, diagnosis and management. Chest 116: 1369-76.
8. Turnbull PC. (1999). Definitive identification of Bacillus anthracis – a review. J Appl Microbiol 87: 237-40.
 

The History and Extent of the Threat

Dr. Michael Osterholm offered opening remarks, as well as the first segment, to a widely attended morning symposium on the third day of the 39th ICAAC, addressing issues in bioterrorism.[1] He pointed out that the use of biologic agents as a weapon is not a new concept. Germany and Japan both had experience in that capacity in the World Wars of this century. In fact, in 1943 the US began research into the offensive uses of biologic agents. This program was discontinued in 1969 by the Nixon 
administration. The US was one of many nations to sign the biological weapon convention document declaring the use of biological warfare unacceptable. It is worthy to note that Iraq and the former Soviet Union, two nations known to have had extensive biological weapon manufacturing since that time, were also among the participants.

Society in general does not appear ready to acknowledge the use of biologic agents as methods of mass destruction. This is partly because they are not aware of significant biologic exposures in the past. It is generally not appreciated that these capabilities exist. Perhaps the very idea of this method of harming innocent people is so repugnant that it is often dismissed. This widespread belief has generally held true, but as the Irish Republican Army has been quoted to say, "You have to be 
lucky all of the time, we have to be lucky just once."

Osterholm described the coming of age of bioterrorism in an era where the technology to cultivate these agents in mass quantities has simultaneously matured with the methods to effectively disseminate them. These events have occurred at a time when intelligence agencies are inadequate to monitor the activities of a broad range of potential perpetrators, including rebels, state-sponsored organizations, and cultist groups with apocalyptic beliefs. Additionally, there appears to be no shortage of sources for agents to be used in bioterrorism, with 453 known repositories in 67 nations. Fifty-four of these sites holding 
anthrax and 18 with stores of plague will ship or sell these isolates with few or no questions asked.

Dr. Osterholm yielded the presentation of specific organisms to the speakers to follow, but introduced the likely methods of dissemination as aerosolization or ingestion. Large gathering places such as malls, office buildings, and airports, as well as big cities, would serve as logical targets. The question does not appear to be if, but when and how bad it will be.

Smallpox

Dr. John Bartlett filled in for Peter Jahrling of USAMRIID for a segment devoted to one of the likely potential bioterrorist agents, smallpox.[2] The use of this agent to intentionally cause human disease dates back to 1754 during the French and Indian War, when infected blankets were given to Native Americans as a "token of good fortune." The last case of smallpox occurred in 1977, but official viral stores remain at the CDC and at Vector in Novosibirsk, Siberia. However, it is suspected that 17 countries harbor stores of this virus. These facts led the World Health Organization to delay the disposal of their own smallpox isolates.

The natural history of human smallpox has been defined. Spread is from infected individuals with a rash by direct contact or aerosolization. Patients with smallpox who do not exhibit a rash are generally not infectious. On day 4, asymptomatic viremia occurs, and the first signs of fever appear on day 8. Days 12 to 14 are associated with a rise in degree of fever as well as severe aching pains and prostration. Some 2 to 3 days later, a papular rash develops over the face and spreads to 
the extremities, soon becoming vesicular. The rash typically evolves into pustular lesions and lasts about 2 weeks. Roughly 4 days later survivors experience a resolution of fever.

Although smallpox can be confused with chickenpox, several distinctions are known. Most physicians recognize the superficial crops of lesions with a truncal predominance, appearing in varying stages of evolution in a typical case of chickenpox. In contrast, smallpox infection produces deeper skin lesions on the face and extremities (including the palms and 
soles), which tend to evolve at the same pace. Additionally, under most circumstances, chickenpox has a benign course, while smallpox has a 30% mortality rate.[3]

Epidemiologic review describes an illness that moves in 12-14 day waves with a "disease multiplier" of 10 to 20. For example, 10 initial cases would become 100-200 after 12-14 days. Additional cases would likely appear during the next wave at days 24-28, with total cases ranging from 1000-4000.

There is no proven treatment, but there is interest in cidofovir as potential therapy. With the lack of effective therapies, decontamination is important after exposure. Standard disinfectants are effective for surfaces, and hot water and bleach are necessary for exposed clothing and linens.

Vaccination before exposure or within 2 to 3 days after exposure affords good protection against disease and may prevent mortality when given as late as 4 to 5 days after exposure. However, vaccine is in short supply when one considers the size of the population at risk. The CDC possesses only 6-7 million doses, and WHO 500,000 doses. Vaccine is awkward to 
administer, can be associated with uncommon but significant side effects such as encephalitis, and is contraindicated in pregnancy, immunodeficiency, and in those with eczematous or exfoliative skin disorders.

Most experts believe that anthrax and plague are among the likely agents for bioterrorism. Dr. Thomas Inglesby Jr, of Johns Hopkins University School of Public Health, gave an up-to-date review of these pathogens.[4]

Anthrax

As little as 100 kg of powdered Bacillus anthracis could cause 300,000 to 3 million deaths if released under the proper environmental circumstances into a densely populated region. The Iraqi government has admitted to producing as much as 8,000 liters of anthrax at their biologic weapon sites discovered during the Persian Gulf conflict.

Although mainly a disease of grazing animals, up to 2,000 cases of cutaneous anthrax occur worldwide in humans each year. Gastrointestinal disease is seen infrequently. There have been no cases of inhalational anthrax in the US in 20 years.

Patients exposed to inhalational anthrax typically experience fever, dyspnea, headache, and chest pain. Untreated, these symptoms progress to a septic-like syndrome with meningeal involvement in about 50% of cases. Inhalational disease does not cause bronchopneumonia, but the chest x-ray often reveals a widened mediastinum, indicative of associated hemorrhagic mediastinitis and lymphadenitis. Secondary spread does not occur.

Standard blood cultures are usually identified as Bacillus species at 6-24 hours, but these cultures may be disregarded as a contaminant. If further identification is pursued, the anthracis species can be elucidated. This gram-positive, nonmotile, nonflagellated, spore-forming bacillus takes on a bamboo-like appearance under light microscopy.

Decontamination procedures are instituted for those exposed. Initial treatment is IV ciprofloxacin until susceptibility testing is available because of concerns of engineered resistance to drugs like penicillin and doxycycline. A switch to oral therapy can be made at signs of improvement, with treatment carried out to 60 days.

Anthrax vaccine is mandated for all US military personnel but is not generally available to the public. For more information on anthrax, the interested reader can link to the CDC and FDA Web sites as well as the Anthrax Vaccine Immunization Program of the Department of Defense for the latest information.

Plague

There have been 390 cases of plague over the last 50 years in the US, most of which have followed an infected flea bite. The vast majority (84%) of these cases have been of the bubonic variety. Septicemic plague without the formation of buboes occurred in 13% of cases. Pneumonic plague has been the least common, accounting for only 2% of cases, but 
this variety would be the goal of a bioterrorist. Direct aerosolization of plague bacilli would be necessary to initiate this process, and person-to-person spread would continue to perpetuate the disease.

Symptoms begin 1-6 days after exposure, with fever, cough, and bloody or purulent sputum. Acrocyanosis of digits or the tip of the nose is a fairly distinctive feature, with other signs and symptoms similar to that of a septic syndrome. Chest x-ray reveals bilateral infiltrates or consolidation. Mortality is substantial without treatment.

Diagnosis can be made with PCR technology, although this is not widely available. Alternatively, Wright-Giemsa staining will demonstrate gram-negative bacilli with a safety-pin appearance.

First-line treatments consist of parenteral therapy with gentamicin or streptomycin, but oral doxycycline or fluoroquinolones may be used when mass casualties occur. Currently available vaccines for plague prevent only the bubonic form of the disease but do not prevent or even ameliorate pneumonic disease and therefore have no role in the management of bioterrorist outbreaks.

Hemorrhagic Fever Agents

Viral hemorrhagic fever viruses may also be used as bioterrorism agents.[5] Selected agents of the arenaviridae, bunyaviridae, and flaviviridae are potential candidates. These viruses induce fever, prostration, and diffuse vascular damage, often leading to thrombocytopenic hemorrhage. These hemorrhagic complications induce intense psychological discomfort in the observing population. Viral hemorrhagic fever patients require intensive medical care and substantial resources. Without proper isolation practices nosocomial spread is not uncommon.

All of the hemorrhagic fever viruses, with the exception of hantavirus, present with viremia and can be detected via culture. The presence of IgM antibodies is the more commonly used method of detection.
 

The Role of the Infectious Disease Community in Responding to Bioterrorism

The final segment of the symposium on bioterrorism was appropriately left to Dr. John Bartlett.[6] His focus was on the role of the infectious disease community and its interaction with public health infrastructure at the federal, state, and local levels when confronted with a potential bioterrorism event.

The federal government has recently allocated $258 million for planning and infrastructure to address issues related to bioterrorism. The CDC as well as state and local authorities will all play critical roles in preparation for and containment of a bioterrorist attack. However, Dr. Bartlett emphasized that the first responders will not be public safety workers (police, fire) as expected in chemical attacks, but rather medical personnel. These personnel will thus need to be trained to recognize early signs of infection with bioterrorism agents, initiate containment efforts, and alert local health officials.

In an effort to test the preparedness of one of the most progressive medical systems nationwide, Dr. Bartlett conducted a mock terrorist attack at Johns Hopkins. At 6 am one day earlier this year, Dr. Bartlett described a case of inhalational anthrax to the emergency department staff and inquired as to the fate of this fictitious patient. The diagnosis would probably be made as influenza, and the patient would be discharged. He then took a chest x-ray with a widened mediastinum to the 
radiology department and asked for a differential diagnosis. Although extensive, the list did not include inhalational anthrax. Next, he called the lab and asked what they would do if they discovered a blood culture that revealed Bacillus species. The reply was that it may be discarded as a contaminant, but physician request or a small cluster of positive cultures would prompt further identification and the correct diagnosis. When laboratory personnel were asked what next, they said they would call infection control. So Dr. Bartlett called infection control and asked their advice. They referred him to the state health 
department. He called the state health department and reached a recorded message to which he replied, "I am Dr. John Bartlett, Chief of Infectious Diseases at Johns Hopkins, and I have an urgent inquiry about bioterrorism." His call was returned 3 days later. It turned out that there was a system in place to initiate the proper cascade of events, but the phone number could not be found.

In summary, Dr. Bartlett successfully made the point that we as a medical community are not ready to handle a bioterrorist attack. Infectious disease physicians need to familiarize themselves with the presentation and management of potential agents and learn how to activate an appropriate public health response. Critically important are efforts to come together as a medical community with a strong voice against bioterrorism and work to prevent research leading to the development and deployment of these agents.

References

1. Osterholm MT. The threat of bioterrorism in the modern world. Program and abstracts from the 39th ICAAC; September 26-29, 1999; San Francisco, Calif. Symposium 135.B: New and Emerging Pathogens III: Bioterrorist Threats: What the Infectious Diseases Community Should Know (1347).
2. Jahrling P. Smallpox. Program and abstracts from the 39th ICAAC; September 26-29, 1999; San Francisco, Calif. Symposium 135.B: New and Emerging Pathogens III: Bioterrorist Threats: What the Infectious Diseases Community Should Know (1348).
3. Henderson DA. Smallpox: clinical and epidemiologic features. Emerg Infect Dis. 1999 Jul-Aug;5(4):537-9.
4. Inglesby TV. Anthrax and plague. Program and abstracts from the 39th ICAAC; September 26-29, 1999; San Francisco, Calif. Symposium 135.B: New and Emerging Pathogens III: Bioterrorist Threats: What the Infectious Diseases Community Should Know (1349).
5. Peters CJ. Viral hemorrhagic fevers. Program and abstracts from the 39th ICAAC; September 26-29, 1999; San Francisco, Calif. Symposium 135.B: New and Emerging Pathogens III: Bioterrorist Threats: What the Infectious Diseases Community Should Know (1350).
6. Bartlett JG. The role of the infectious diseases community in responding to bioterrorism. Program and abstracts from the 39th ICAAC; September 26-29, 1999; San Francisco, Calif. Symposium 135.B: New and Emerging Pathogens III: Bioterrorist Threats: What the Infectious Diseases Community Should Know (1351).