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BIOTERRORISM MEDICINE AAEM February 16 th , 2002

BIOTERRORISM MEDICINE AAEM February 16 th , 2002. Dr. William Deagle M.D. Special Problems with Bioterrorism and Public Health. Identifying a covert attack Specialized labs needed for some agents Risks to laboratory workers Communication between agencies Social and economic dysruption

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BIOTERRORISM MEDICINE AAEM February 16 th , 2002

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  1. BIOTERRORISM MEDICINEAAEM February 16th, 2002 Dr. William Deagle M.D. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  2. Special Problems with Bioterrorism and Public Health • Identifying a covert attack • Specialized labs needed for some agents • Risks to laboratory workers • Communication between agencies • Social and economic dysruption • Military and covert operations activation • Delays in flights, travel and transport of materials DR. WM DEAGLE MD,ABFP,CIME,CCFP

  3. Introduction • BIOTERRORISM ABCs • The primary weaponized organisms, clinical presentations, public health safety measures, and therapies. • For primary medical doctors and first responder medical providers, from a broader global medical enviromental perspective DR. WM DEAGLE MD,ABFP,CIME,CCFP

  4. Signals of Biological or Chemical Bioterrorism Event • 1] Large numbers of persons with a similar syndrome of presenting complaints and progression or illnesses • 2] Increase in unexplained deaths • 3] Higher mobidity or mortality with a common disease or syndrome or failure of such patients to respond to the usual therapies • 4] Single case of disease caused by an uncommon agent • 5] Illness that is unusual or atypical for a given population or age group DR. WM DEAGLE MD,ABFP,CIME,CCFP

  5. Agenda • Top three bioweapons • Anthrax (Bacillus anthraxis) • Smallpox (Smallpox) • Plague (Yersinia pestis) • Second line of attack • Tularemia (Francisella tularensis) • Botulism (Botulinum toxin) • Viral hemorrhagic fevers (Filoviruses and Arenaviruses) DR. WM DEAGLE MD,ABFP,CIME,CCFP

  6. Overview Primary doctor • Poor man’s WMD “Weapon of Mass Destruction” • Early recognition, cluster analysis, public health to CDC activation, mass causality logitistics and therpeutics Small pox Anthrax Plague Botulinum toxin Early identification Tularemia Filoviruses Text DR. WM DEAGLE MD,ABFP,CIME,CCFP

  7. Vocabulary • Main terms used in Bioweapon Defense • Reservoir – natural source of bioweapon organisms in the wild • Weaponization – modification of the toxin production, aerosol properties, and lethality via invasivness and persistance in the environment to increase illness or lethality rates as a weapon. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  8. VOCABULARY: • Cutaneous disease – skin localization of organism proliferation or local toxin absorption caused by a bioweapon induced skin disease. • Gastrointestinal disease – gastrointestinal toxicity and disease caused by proliferation of an organism or toxin production. • Inhalation disease – repiratory tract disease caused by the proliferation of an organism, toxin production or local airway spasm or mucous and inflammatory induced repiratory dysfunction caused by a bioweapon. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  9. VOCABULARY: • Symtom cluster analysis – The public health early reporting of symptom clusters in a geographic cohort population in real time to identify early bioweapon release and early disease identification. • Vaccination – Prophylactic induction of cellular and humoral immune production to protect against organism proliferation or toxin production with attenuated organism or fractions of dead organisms introduced to a human host in anticipation of possible bioterrorist attack. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  10. ANTHRAX • 5TH PLAGUE OF MOSES in EXODUS • Primary disease of herbivores worldwide • Soil reservoir – 90 plus years • Humans usually infected with contact with infected animals or contaminated animal products, e.g. “wool sorter’s disease” • No “person to person” transmission of inhalation anthrax • Weaponization: reverse spore charge to repell each other, change organism antibiotic resistance patterns, amplify toxin production • DNA analysis of anthrax subspecies DR. WM DEAGLE MD,ABFP,CIME,CCFP

  11. ANTHRAX: MICROBIOLOGY • Gram stain – positive • Endospores germinate inside macrophages • Vegetative bacteria are released from ruptures macrophages and multiply in lymphatic system • Blood concentration 10 to 7 or 8 power in blood • Septicemia, toxemia, cardiovascular failure and coma rapidly DR. WM DEAGLE MD,ABFP,CIME,CCFP

  12. Visual Images of Bacillus anthracis • Slide: Bacillus anthracis spore and veg form - gram stain • Vegetative and spore forms of B. anthracis as they appear on gram stain DR. WM DEAGLE MD,ABFP,CIME,CCFP

  13. Visual Images of Bacillus anthracis • Slide: Wound smear • Appearance of B. anthracis on a gram stain of a direct smear from a cutaneous lesion. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  14. ANTHRAX: TOXIN TYPES • MAJOR VIRULENCE PLASMIDS: • Both are required to have full anthrax lethality • #1 Plamid for Capsule pXO2 – inhibits phagocytosis • #2 Plasmid for Toxins pXO1: • 1] Protective Antigen – helps get anthrax organism inside the macrophage • 2] Edema Toxin – Calmodulin dependent adenylate cyclase causes increased cAMP causing explosive increase in edema and heart failure • 3] Lethal Toxin – Zinc metalloprotease increased cellular MAPK, stimulates TNF release, and interleukine 1B DR. WM DEAGLE MD,ABFP,CIME,CCFP

  15. ANTHRAX: LETHALITY MECHANISMS • Organism proliferation and spread via the lymph system primary • Secondary spread from gastrointestinal to respiratory tract or cutaneous to respiratory tract • Toxin production in hilar lymph nodes causes cardiovascular shock and encephalopathy with rapid death DR. WM DEAGLE MD,ABFP,CIME,CCFP

  16. ANTHRAX: TIMELINE OF CUTANEOUS DISEASE • 95 % OF CASES • Inoculation of spores under the skin • Incubation hours to seven days • Small papule progresses to ulcer surrounded by vesicles (24-48 hours) • Painless eschar with edema • Death rate 20 % if untreated and very rare if identified and treated with antibiotics within 48 hours DR. WM DEAGLE MD,ABFP,CIME,CCFP

  17. Cutaneous Anthrax: Timeline • Anthrax Lesion - 3rd day after onset.   • Note the central vesicle beneath which can be seen the early developing necrotic area. The vesicle is surrounded by edema and erythema extending irregularly on toward the anterior surface of the neck. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  18. Cutaneous Anthrax: Timeline • Anthrax Lesion - 4th day after onset. • The lesion has enlarged and a ring of vesicles surrounds the central area. The darkening color is the result of tissue necrosis. The central vesicle has ruptured. Erythema and edema have increased. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  19. Cutaneous Anthrax: Timeline • Anthrax Lesion - 7th day after onset. • Vesicles have disappeared. Central area now reveals depressed early black eschar with distinct edges. Surrounding edema and erythema have begun to recede.  DR. WM DEAGLE MD,ABFP,CIME,CCFP

  20. Cutaneous Anthrax: Timeline • Anthrax Lesion - 15th day after onset • Black, hard, leather slough represents area of necrosis and is beginning to separate from the surrounding tissue. The necrotic material was cut away and wet dressings were applied. Six weeks after the reported onset of the infection, only a smooth, pale pink, soft scar remained DR. WM DEAGLE MD,ABFP,CIME,CCFP

  21. ANTHRAX: GASTROINTESTINAL • Meat ingestion with spores or live organisms • Incubation up to seven days • Fever, enterocolitis with vomiting, bloody and mucoid diarrhea • Intestinal lesions on scope appearance of cutaneous anthrax lesion • Generalized toxemia progression with mortality 50 to 100 % despite appropriate treatment with antibiotics, electrolytes, and shock treatments DR. WM DEAGLE MD,ABFP,CIME,CCFP

  22. ANTHRAX: INHALATION • RARE HUMAN OCCUPATIONAL EXPOSURE CASES • Animal models – primate studies after WWII • Two human population exposures: • #1 Svedlorsk 1979 – wind plume distribution of death over three plus weeks • #2 USA 2001 – letters with Aimes, Iowa substrain weaponized opposite charged spores in mail ‘bombs’ DR. WM DEAGLE MD,ABFP,CIME,CCFP

  23. ANTHRAX: INHALED PRESn • Incubation 1 to 43 days • Initial symptoms 2 to 5 days • Terminal symtoms 1 to 2 days • Time from toxic systemic symtoms to near 100 % lethality 4 to 6 hours ONLY!! • Mortality – 85 to 100 % despite aggressive IV antibiotics • Cluster population symtom to Rx critical!!! DR. WM DEAGLE MD,ABFP,CIME,CCFP

  24. Anthrax References: • Svedlorsk – Meselson, et al, Science, 1994. • #1 Hemorrhagic mediastinitis • #2 Timeline of epidemic pattern • #3 Case counts in wind pattern downwind of bioweapons plant for anthrax • Microbiology – Borio, et al, JAMA, 200. • MMWR Nov 2, 2001 – date and work location of US Bioterroist attacks. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  25. Anthrax Case Reviews: • Bush, L.M. et al, Index case of fatal inhalation anthrax due to bioterrorism in the United States. NEJM, Nov 8th, 2001. • Jernigan, J.A. et al, Bioterrorism-related inhalation anthrax: the first 10 cases reported in the United States. Emer Infect Disease, Nov 20, 2001. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  26. Anthrax – Clinical Presentation • JAMA 2001; Vol 286: 2549, Mayer, “Report of two surviving patients” • JAMA 2001: Vol 286: 2554, Borio, et al, “ “Report of two deaths” • JAMA 2001; Vol 286: 2595, Lane, HC, Fauci, AS, “Bioterrorism on the home front.” DR. WM DEAGLE MD,ABFP,CIME,CCFP

  27. Anthrax – “FLU without Upper Respiratory Congestion and Tachycardia” • Fever > 37.8 degrees 7/10 cases • Tachycardia: HR > 100/min 8/10 cases • Hypotension: SBP< 110 mm Hg 1/10 cases • Lack of upper respiratory congestion • Collapse without prodrome • Rapid progression to toxic shock and death • Window of 4 to 6 hours to reverse course DR. WM DEAGLE MD,ABFP,CIME,CCFP

  28. Anthrax: Laboratory Testing • Normal WBC - common • Neutrophil relative elevation – common • Neutrophil band forms – less common • Liver enzyme elevation – almost always • Hypoxemia with high A-a gradient - common • Metabolic acidosis - minority • Elevated creatinine - minority DR. WM DEAGLE MD,ABFP,CIME,CCFP

  29. Anthrax – Chest Xray • Mediastinal widening – common • Pleural effusion – very common • TOMO FINDINGS or Spiral CT: • Mediastinal lymphadenopathy – very common • Pleural effusion – almost always • Infiltrates and consolidation - common DR. WM DEAGLE MD,ABFP,CIME,CCFP

  30. INHALATION ANTHRAX:DIAGNOSIS • GRAM STAIN and Culture: blood, CSF, pleural fluid, tissue fluids. • Tissue biopsy: Immunohistochemical studies. • PCR: DFA – State Lab and CDC labs. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  31. ANTHRAX - ANTIBIOTICS • MMWR OCTOBER 26TH, 2001: • ALL ISOLATES SENSITIVE TO: • Ciprofloxacin, doxycycline, chloramphenicol, clindamycin, tetracycline, rifampin, vancomycin, and intermediate sensitivity to ceftriaxone. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  32. Interim Guideline for Anthrax Evaluation and Care • History of exposure or occupational/environmental risk with 2 – 5 day illness of : • Symptoms: fever - with or without chills,sweats – often drenching, fatigue and malaise, cough – usually nonproductive, shortness of breath, chest discomfort, pleuritic pain, nausea, vomiting, diarrhea, abdominal pain, headache, myalgias, sore throat • Signs: Fever, Prostration and severe rapid onset weakness and disorientation. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  33. Interim Guideline for Anthrax Evaluation and Care • YES TO ???? • LAB: WBC – normal to elevated, neutrophils with bands, Blood Cultures 24 + hours --- see attached figures --- BLOOD, CSF, TISSUES. • CHEST X-RAY: Mediastinal widening, pleural effusion, pulmonary infiltrates. • CT or Spiral CT of Chest: If CXR Neg, CT is much more accurate with early diagnosis of toxin induced changes particularly spiral CT scan. • Rapid Diagnostic Testing for Influenza • NOTIFY CDC, LOCAL DEPT OF PUBLIC HEALTH DR. WM DEAGLE MD,ABFP,CIME,CCFP

  34. Interim Guideline for Anthrax Evaluation and Care • ILL PATIENT OR POSITIVE CT, CXR, OR WBC, GM STAIN BLOOD ETC. • Begin Antimicrobial therapy: MMWR 2001: Vol 50; 909-919. • Pleural effusion: Gm Stain, PCR, Cell Block for Immunocytochemistry. • Meningeal signs: CT scan of Head and Then LP for Gm Stain, PCR, and Immunocytochemistry. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  35. Anthrax Treatment • Ciproc 400 mg IV q12h (adults) and 10-15 mg / kg IV q12h ( children) • Doxycycline 100 mg IV q12h (adults) and adjusted as fraction of adult based on weight/ age for children. • REDUCTION OF TOXINS: • ADD: Rifampin for tissue penetration and Clindamycin to suppress ribosomal toxin manufacture. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  36. Anthrax Prophylaxis • Ciproc 500 mg BID in adults or 10-15 mg /kg in children. • Doxycycline 100 mg BID or age/weight for children as fraction. • Prophylaxis continued until exposure is excluded. If exposed to spores, continue for sixty days of antibiotics, or 4 weeks post-confirmation of exposure AND until three doses of vaccine are administered. • If PCN sensitive, switch to Amoxicillin • Other Fluoroquinolones: Levaquin, Tequin, Avelox, Etc. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  37. Adverse Reactions to Prophylaxis for Anthrax: • MMWR Nov 30th, 2001: • 8,424 Postal Employees, questionnaires 7-10 days. • 5, 819 questionairres completed • 3,863 initiated antimicrobial prophylaxis • 3,428 Rx: Ciprofloxacin therapy protocol DR. WM DEAGLE MD,ABFP,CIME,CCFP

  38. Ciproc Side Effects in Postal Workers Nov 30th, 2001. • 19% Severe nausea, vomiting, diarrhea, abdominal pain. • 14 % Dizziness, Light-headedness • 7 % Acid Reflux • 6 % Itching, rash or hives • 8 % Discontinued medication, no reason • 3 % Discontinued medication, adverse reaction. • 2% Medical attention due to anaphylaxis DR. WM DEAGLE MD,ABFP,CIME,CCFP

  39. Anthrax – Old Vaccine • Brachman 1962 – 50s Human Data: • 26 cases of Anthrax in 4 years NE USA • Imported Raw Goat Hair: Four Mills • RATE OF ANTRAX INFECTIONS: • High Risk Group vaccinated 3.1 % • High Risk Group unvaccinated 36 % • Low Risk Group vaccinated 0 % • Low Risk Group unvaccinated 10.0 % DR. WM DEAGLE MD,ABFP,CIME,CCFP

  40. Anthrax: US Licensed Bioport Vaccination • Culture Supernatant (PA) of attenuated non-encapsulated strain • Protective against cutaneous (human data) and possibly inhalation anthrax (animal data) • Injection at 0,2,and 4 weeks, then 6,12,18 months, yearly boosters • 3 dose schedule ( 0,2, and 4 weeks) may be effective • 83 % serological response after 3 doses; 100% after 5 doses • Limited Availability of Vaccine DR. WM DEAGLE MD,ABFP,CIME,CCFP

  41. Anthrax Reactions • Local Reactions – Common • Up to 30 % of mild to moderate local discomfort for up to 72 plus hours • < 2 % Severe local reactions, limiting use of arm for one to two days • Systemic Reactions - Uncommon DR. WM DEAGLE MD,ABFP,CIME,CCFP

  42. Bioport Controversy – Dr Meryl Nass MD, MPH • One human study 70 % effective • Anthrax vaccine causes longlasting illness in a significant proportion of military personnel that have been vaccinated in the Gulf War at a rate estimated from current multipracticioner incidences of 10-35 %: • Gulf War syndrome presentation – chronic fatigue, fibromyalgia, MCS mulitple chemical sensitivity, autoimmune illness, and neuropathies DR. WM DEAGLE MD,ABFP,CIME,CCFP

  43. Bioport Controversy – Dr Meryl Nass MD, MPH • All current vaccine is owned by the Department of Defense • FDA has repeated cited Bioport for violations at its only Michigan manufacturing plant – contamination and QA suspicious record changes • Vaccine testing 1970s FDA licence for cutaneous anthrax and not inhalation type • 1996 Bioport applied for Inhalation License extension • 1997 US Military embarks on massive 2.4 million active and reserve personnel program DR. WM DEAGLE MD,ABFP,CIME,CCFP

  44. Russian Live Anthrax Vaccine: • Vaccine 1994 Jun;12(8):727-30 Human live anthrax vaccine in the former USSR.Shlyakhov EN, Rubinstein E.Infectious Diseases Unit, Sheba Medical Centre, Sackler School of Medicine, Tel-Aviv University, Tel-Hashomer, Israel DR. WM DEAGLE MD,ABFP,CIME,CCFP

  45. Anthrax - New Vaccines: • Newer vaccines are being evaluated, such as a PA (protective antigen) toxoid vaccine and a PA-producing live vaccine. • In the former Soviet Union, in addition to the chemical vaccine, a live anthrax spore vaccine has been widely used for prophylaxis against anthrax in both humans and animals. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  46. Anthrax – Adjuvant Vaccines • Because none of the currently available vaccines is ideal, efforts at developing better agents are a major area of research. • Among the newer approaches for anthrax vaccine development for human use are • (1) combination of the PA with adjuvants derived from the BCG strain or killed cells of Bordetella pertussis and • (2) PA cloned into a Bacillus subtilis as a recombinant vaccine that does not contain the B. anthracis genome DR. WM DEAGLE MD,ABFP,CIME,CCFP

  47. Serological Anthrax Testing: • J Infect Dis 1989 Oct;160(4):706-10 Evaluation of serologic tests for diagnosis of anthrax after an outbreak of cutaneous anthrax in Paraguay.Harrison LH, Ezzell JW, Abshire TG, Kidd S, Kaufmann AF.Division of Bacterial Diseases, Centers for Disease Control, Atlanta, Georgia 30333. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  48. EITB and ELISA Testing • The outbreak was analyzed six weeks post-incidents by • (1) electrophoretic-immunotransblots (EITB) to detect serum antibodies to the protective antigen (PA) and lethal factor components of anthrax toxin. • (2) Serum was also tested by enzyme-linked immunosorbent assay (ELISA) for the presence of antibodies to poly-D-glutamic acid capsule. DR. WM DEAGLE MD,ABFP,CIME,CCFP

  49. Anthrax Suspect Bioterrorism • 1] Place the item on a flat surface and do not further handle it. Do not clean up any spilled material. • 2] Evacuate the immediate vicinity, close the room and keep people away from the item. • 3] Thoroughly wash hands with soap and water • 4] Contact local law enforcement or the FBI and CDC • 5] List all persons who physically handled or were near the package: provide the list to authorities DR. WM DEAGLE MD,ABFP,CIME,CCFP

  50. SMALLPOX: CLINICAL PRESENTATIONS • Incubation for 7 to 17 days prodrome • Acute onset of fever, malaise, headache, vomiting, occaisional delirium • Transient erythematous rash – ONLY INFECTIVE TO OTHERS NOW • Exanthem: From Outside to Center • Starts at face, hands, forearms and spreads to lower extremities than to trunk over 7 days • Synchronous progression: macules>vesicles>pustules>scabs • Lesions on palms and soles • Mortality up to 30 % for unvaccinated DR. WM DEAGLE MD,ABFP,CIME,CCFP

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