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Published on March 24, 2008

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Slide1:  Bioterrorism The Basics for General Practitioners Bioterrorism:  Bioterrorism The use, or threatened use, of a micro-organism or the product of a micro-organism in order to generate fear, morbidity or mortality in a population. Bioterrorism Agents:  Bioterrorism Agents Category A Diseases Anthrax (Bacillus anthracis) Smallpox (Variola virus) Plague (Yersinia pestis) Tularemia (Francisella tularensis) Botulism (botulinum toxin) Viral Hemorrhagic Fever Delivery Mechanisms:  Delivery Mechanisms Aerosol route Easiest to disperse Highest number of people exposed Most infectious Undetectable to humans Food / Waterborne less likely Larger volumes required More technically difficult Roles of Clinicians:  Roles of Clinicians General Concepts High level of suspicion Hoofbeats could be a zebra Unusual epidemiologic trends Case clustering Severe, fulminant disease in otherwise healthy Unusual for the region Similar disease in animals Roles of Clinicians:  Roles of Clinicians For specific Bioterrorism (BT) diseases Recognize typical BT disease syndromes Perform appropriate diagnostic testing Initiate appropriate treatment/prophylaxis Report suspected cases to proper authorities 1) Local health department 2) Hospital epidemiologist 3) Infectious Disease consultants Anthrax:  Anthrax Bacillus anthracis History:  History Sporadic disease in 20th century U.S. Experience as biological weapon U.S., 2001 Most letter-associated 22 cases (18 confirmed), 5 deaths Sverdlovsk, Russia, 1979 Accidental release from weapons facility ≥77 cases, 66 deaths Epidemiology:  Epidemiology Forms of disease Inhalational (<5% cases; 45-89% mortality) Cutaneous (95%; <1-20% mortality) Gastrointestinal (<5%; >50% mortality) Risk Factors Exposure to infected animals Exposure to aerosolized spores Microbiology:  Microbiology Bacillus anthracis Aerobic, large Gram positive bacillus Non-motile, non-hemolytic Potential mislabeling as contaminant Forms hardy spores Triggered by harsh environment Inert but infectious 1m size Slide11:  Jernigan, et al. EID. 2001;7:933-944. Figure is not shown because the copyright permission granted to the Centers for the Study of Bioterrorism and Emerging Infections does not include usage on our website Slide12:  Dixon, et al. NEJM. 1999;341:815-26. Figure is not shown because the copyright permission granted to the Centers for the Study of Bioterrorism and Emerging Infections does not include usage on our website Slide13:  Dixon, et al. NEJM. 1999;341:815-26. Figure is not shown because the copyright permission granted to the Centers for the Study of Bioterrorism and Emerging Infections does not include usage on our website Clinical Features - Inhalational:  Clinical Features - Inhalational Incubation Range 2-43, median 4-7 days Prodrome “flu-like” - fever, malaise, dry cough Nausea, vomiting, diarrhea Lack of nasal symptoms Fulminant Respiratory failure, shock, toxemia Slide15:  Inglesby, et al. JAMA. 1999;281:1735-45 Figure is not shown because the copyright permission granted to the Centers for the Study of Bioterrorism and Emerging Infections does not include usage on our website Clinical Features – Inhalational:  Clinical Features – Inhalational Differential Diagnosis Influenza, viral URI’s Pneumonia Community-acquired Atypical Pneumonic tularemia Pneumonic plague Mediastinitis Thoracic aortic aneurysm Bacterial meningitis Expect if anthrax Rapid diagnostics – Abnormal CXR No nasal symptoms Usually no sputum May be no infiltrate No prior surgery Fever Gram+ rods in CSF Clinical Features - Cutaneous:  Clinical Features - Cutaneous Most common areas of exposure Hands/arms Neck/head Incubation period 3-5 days (maximum 12 d.) Mild constitutional symptoms Systemic disease rare Lymphangitis/lymphadenopathy Sepsis, multiorgan failure, death Clinical Features - Cutaneous :  Clinical Features - Cutaneous Progression of painless lesions Papule/macule – pruritic Vesicle/bulla – clear or serosanguinous Ulcer – nonpitting, gelatinous edema Eschar – black, depressed, rarely scars 24-48 hrs days Slide19:  Photo courtesy of the Tropical Medicine Institute, UPCH Figure is not shown because the copyright permission granted to the Centers for the Study of Bioterrorism and Emerging Infections does not include usage on our website Clinical Features - GI:  Clinical Features - GI Oropharyngeal Oral/esophageal ulcer, regional adenopathy Edema/stridor, sore throat, fever, sepsis Intestinal Early - nausea, vomiting, malaise Late - hematochezia, acute abdomen, ascites Differential diagnosis Gastroenteritis (early) Any source of acute abdomen, peritonitis (late) Diagnosis:  Diagnosis High index of suspicion necessary Early diagnosis difficult Gold Standard - culture blood, fluids Prior to antibiotics Confirmation by reference labs PCR, special stains, serology, etc Nasal swabs not a diagnostic tool Treatment:  Treatment Hospitalization IV antibiotics Empiric until sensitivities known Intensive supportive care Electrolyte and acid-base imbalances Mechanical ventilation Hemodynamic support Steroids Consider for severe disease Treatment:  Treatment Empiric therapy for inhalational (Adults) Ciprofloxacin 400 mg IV q12° OR Doxycycline 100 mg IV q12° AND One or two other antibiotics - clindamycin - penicillin - vancomycin - chloramphenicol - rifampin - imipenem Avoid macrolides, cephalosporins, sulfa Treatment:  Treatment Empiric therapy for inhalational (Children) Ciprofloxacin 10-15 mg/kg/d IV q12° (max 1 g/d) OR Doxycycline 2.2 mg/kg IV q12° (adult dose >8yo/45 kg) AND One or two antibiotics (same as adult) Weigh risks (arthropathy, dental enamel) Treatment:  Treatment Empiric therapy for cutaneous Same as inhalational regimen if: Systemic disease Extensive edema Head/neck lesions Localized cutaneous Ciprofloxacin 500mg po bid OR Doxycycline 100mg po bid Empiric therapy for GI Same as inhalational Treatment:  Treatment Antibiotic therapy – all forms Adjust per sensitivities Duration 60 days - delayed spore germination Follow closely after cessation Switch to oral Clinical improvement, able to tolerate po 1 or 2 drugs including cipro or doxy initially Children can complete course with amoxicillin No role for vaccine in treatment Post-Exposure Prophylaxis:  Post-Exposure Prophylaxis Indications Exposure to anthrax spores Not for contacts of cases Oral antibiotics Ciprofloxacin 500 mg po bid OR Doxycycline 100 mg po bid Duration 60-100 days +/- Vaccination Vaccination:  Vaccination Inactivated, cell-free vaccine Effective >95% animals vs. inhalational Protective for humans vs. cutaneous Well-tolerated Uncommon adverse effects No reported deaths Limited supply Infection Control:  Infection Control Person-to-person transmission None for inhalational Rarely reported for cutaneous Patient handling Standard precautions Gloves for draining lesions Laboratory safety BSL-2 for clinical specimens BSL-3 for environmental or large volume Smallpox:  Smallpox Variola Virus History:  History Ancient scourge – many millions killed Global eradication in 1977 Bioweapon potential Prior use in French-Indian War Produced by USSR Stocks still exist Epidemiology:  Epidemiology No animal reservoir/vector Mortality 25-30% Transmission via droplets/aerosol Person-to-person transmission Secondary attack rate 25-40% Up to 3-20 contacts infected Hi risk of nosocomial spread Microbiology:  Microbiology Variola virus Orthopoxviridae family Variola strains Variola major – high mortality Variola minor – low mortality, 20th Century Vaccinia Current smallpox “vaccine” Other pox viruses (cowpox, monkeypox) Pathogenesis:  Pathogenesis Virus contacts respiratory/oral mucosa Carried to nodes Viremia Organ seeding WBCs infected Dermal invasion Vesicle Sepsis Clinical Features:  Clinical Features Stages of disease Incubation Asymptomatic 12-14 days (range 7-17) Prodromal Nonspecific febrile prostrating flu-like illness 3-5 days Eruptive Characteristic rash – location, grouping, depth Marker of infectiousness Slide36:  Courtesy of National Archives Slide37:  Courtesy of National Archives Slide38:  Courtesy of World Health Organization Clinical Features:  Clinical Features Differential Diagnosis Chickenpox (varicella) Vesicles Shallow Asynchronous development Distribution of rash Centripetal Spares palms/soles Diagnosis:  Diagnosis Clinical Traditional confirmation Electron microscopy Culture Newer rapid tests Reference labs (e.g. CDC) PCR, RFLP Treatment:  Treatment No effective antivirals Supportive care Fluid balance Electrolytes Hemodynamic support Antibiotics for secondary infections Isolation Post-Exposure Prophylaxis:  Post-Exposure Prophylaxis Vaccine Reduces incidence 2-3 fold Decreases mortality by ~50% Vaccinia immune globulin (VIG) 3 fold decrease in incidence and mortality Passive immunity for 2 weeks Cidofovir – antiviral agent Effective vs other poxviruses in animals Vaccination:  Vaccination Vaccinia virus Stock ~15million doses >20 years old, still viable Efficacy 10 fold reduction secondary attack rate Substantial protection for 3-10 years Multiple vaccinations boost duration Vaccination:  Vaccination Adverse Effects 3/100,000 vaccinees Death 1/million vaccinees Highest risk Primary vaccinees Infants Vaccination:  Vaccination Serious complications Encephalitis Vaccinia gangrenosum/necrosum Eczema vaccinatum Mild complications Generalized vaccinia Autoinoculation VIG can treat/prevent Slide46:  Fenner F., D. A. Henderson, et al. Smallpox and its Eradication. Geneva: WHO; 1988. Original photo by C. H. Kempe. Infection Control:  Infection Control Isolation of Cases Contact precautions Gloves, gowns Airborne precautions Negative pressure HEPA filtered room, N95 masks Home isolation an option Avoids nosocomial spread Assign immune persons for care Infection Control:  Infection Control Management of Case Contacts Rash = Infectious, fever precedes rash Contact identification Exposure to case patient after fever onset Contact with secretions or face-to-face <3 meters All patients and staff in hospital with a case Immediate vaccination Observation (not isolation) 17 day fever watch – isolate if >38°C Quarantine may be necessary Plague:  Plague Yersinia pestis History:  History 3 Pandemics Justinian - 6th century Africa/Asia Black Death – 14th century Europe Worldwide – 19th/20th century Potential for use as bioweapon Unit 731 Manchuria Former USSR production Epidemiology:  Epidemiology Distribution Global – ~1700 cases/yr Southwestern U.S. – 5-10 cases/yr Routes of transmission Flea bites Animal contact Inhalation – animals, people, BT aerosol Epidemiology:  Epidemiology Forms of Disease Pneumonic (2-12% of cases) Inhalation (1°) or hematogenous (2°) Mortality 57% (>90% if treatment delayed) Most likely route for bioterrorism Bubonic (84%) Flea bite or animal handling Mortality <5% (40-60% untreated) Septicemic (13%) Mortality 30-50% (>90% untreated) Microbiology:  Microbiology Enterobacteriaceae family, Yersinia genus Y.pestis, Y.enterocolitica, Y.pseudotuberculosis Aerobic Gram negative (cocco)bacillus Intracellular Bipolar staining (special stains) Highly virulent F1 antiphagocytic capsule LPS endotoxin Slide54:  CDC. Available at http://www.ohd.hr.state.or.us/phl/bt/plague/levelaprocedures.pdf. Accessed June 21, 2002. Pathogenesis:  Pathogenesis Primary pneumonic plague Organisms inhaled Lobular lobar pneumonia Pulmonary necrosis Bacteremia Multiorgan seeding, failure Sepsis Clinical Features:  Clinical Features Primary pneumonic plague Incubation 1-4 days (range 1-6) Initial symptoms Influenza-like syndrome (F/C/HA/myalgias) N/V/D, abdominal pain common 2nd day Severe pneumonia – cough, hemoptysis, SOB Multi-organ disease, sepsis Skin manifestations – purpura, acral gangrene Differential Diagnosis – any severe pneumonia Slide57:  Inglesby, et al. JAMA. 2000;283:2281-2290 Figure is not shown because the copyright permission granted to the Centers for the Study of Bioterrorism and Emerging Infections does not include usage on our website Clinical Features:  Clinical Features Bubonic Plague Constitutional symptoms Lymphadenopathy “bubo” May drain Septicemic Plague Same flu-like illness progressing to sepsis No discernible adenopathy Diagnosis:  Diagnosis High index of suspicion necessary No readily available rapid tests Samples - blood, sputum, CSF, bubo fluid Preliminary – bipolar staining bacilli Confirmation Culture – requires special biochemicals Serology - retrospective Rapid tests (PCR, DFA, etc) at reference labs Treatment:  Treatment Parenteral antibiotics Aminoglycosides – 1st choice Streptomycin 1 g IM bid (adults) Gentamicin 5 mg/kg IV q24° Tetracyclines Doxycycline 100 mg IV q12° Fluoroquinolones Ciprofloxacin 400 mg IV q12° (adults) Chloramphenicol – for meningitis Treatment:  Treatment Ineffective antibiotics ß-lactams (penicillins, cephalosporins) Rifampin Aztreonam Macrolides Switch to oral Duration 10-14 days or at least 3 days afebrile Post-Exposure Prophylaxis:  Post-Exposure Prophylaxis Oral Antibiotics Doxycycline 100 mg po bid Ciprofloxacin 500 mg po bid Duration 7 days Who should receive PEP? Exposed to initial aerosol release Asymptomatic contact of pneumonic case Household, Hospital Within two meters Vaccination:  Vaccination No available vaccine in U.S. since 1999 Previous vaccine Killed virulent strain Effective versus bubonic only Minor adverse effects Infection Control:  Infection Control Pneumonic Plague Respiratory (droplet) isolation Surgical mask when within 3 feet Isolate until treated 48 hours Must have clinical improvement Bubonic Plague Contact isolation if draining buboes Specimens – BSL-2 (BSL-3 for hi-risk) Tularemia:  Tularemia Francisella tularensis History:  History Discovered early 20th century Tulare county, California “deerfly” fever Bioweapon potential Incapacitating Former US and USSR production Prior use Unit 731, Manchuria Epidemiology:  Epidemiology Distribution Moderate climates – U.S., Europe, Russia, Japan 125 annual U.S. cases – mostly Midwest Zoonosis Small mammals (rabbits) Transmission Skin contact - e.g. infected animal Arthropod bite - ticks Aerosolization - BT attack; lawn mowers Mortality <2% overall, 30-60% untreated pneumonic Epidemiology:  Epidemiology Forms of disease Pneumonic (<5% of cases) Expected in aerosol release Ulceroglandular (45-85%) Glandular (5-25%) Oculoglandular (<5%) Oropharyngeal (<5%) Typhoidal (<5-15%) Microbiology:  Microbiology Pleomorphic Gram negative coccobacillus Usually not visible in clinical specimens Small (0.2 m), aerobic Non-motile, non-sporulating Fastidious Slow growth (2-3+ days) Requires cysteine-enriched media 2 major strains (A and B) A predominates in U.S., higher mortality Pathogenesis:  Pathogenesis Inoculation virulent organisms Local infection at site Lung – bronchiolitis, pneumonitis, pleuritis Migrate to regional lymph nodes Hematogenously seed multiple organs Suppurative immune response Clinical Features:  Clinical Features All forms of disease Incubation 2-5 days (range 1-21) Acute onset Initial flu-like illness Fevers, chills, sweats, headache Lower back myalgias Pulmonary symptoms Cough, dyspnea, chest pain (40%) Pulse/temperature dissociation (40%) Clinical Features:  Clinical Features Pneumonic form Symptoms Nonproductive cough, +/- hemoptysis Dyspnea, pleuritic pain Chest radiograph Infiltrates – patchy, bilateral Effusions common Ulceroglandular form Ulcer – painful maculopapule, pustule, ulcer Slide73:  CDC/Emory University/Dr. Sellers. PHIL1344 Diagnosis:  Diagnosis High index of suspicion No readily available rapid tests Gram stain unhelpful Gold Standards Serology (retrospective) Culture (insensitive, hazardous, slow) Rapid presumptive tests DFA, IFA, PCR, IHC at reference labs Treatment:  Treatment Supportive care Parenteral antibiotics ASAP Aminoglycosides Streptomycin 1 g IM q12° Gentamicin Once-daily or traditional dosing Tetracyclines – higher relapse rate Doxycycline 100 mg IV q12° Tetracycline - oral Treatment:  Treatment Parenteral antibiotics Others Chloramphenicol – for meningitis Ciprofloxacin Ineffective agents ß-lactams, macrolides Duration of therapy 10 (aminoglycosides) – 21 (tetracyclines) days Switch to oral therapy when clinically improved Post-Exposure Prophylaxis:  Post-Exposure Prophylaxis Who should receive PEP? Suspected very recent exposure (<3 days) Not contacts of cases Antibiotics Oral doxycycline or ciprofloxacin Duration - 14 days Fever watch without antibiotics Suspected exposure in last 3-14 days Vaccination:  Vaccination Live, attenuated vaccine Commercially available For researchers No proven efficacy versus pneumonic Minimal adverse effects Infection Control:  Infection Control No documented person-person spread Standard precautions Laboratory specimens Routine handling for clinical specimens Alert microbiology lab if tularemia suspected Pure culture hazardous to lab personnel Requires BSL-2 handling with safety cabinet Botulism:  Botulism Botulinim toxin History:  History Neurologic disease from botulinum toxin Most lethal substance known History as bioweapon Japanese in WWII (Unit 731) Former US and USSR programs Iraqi deployed weapons Japanese cult in early 1990’s Epidemiology:  Epidemiology Found worldwide U.S. incidence ~100 cases annually (1/4 foodborne) Mechanisms of intoxication No person-to-person transmission Toxin ingestion (foodborne) Toxin generated from wound infection (wound) Toxin from intestinal colonization (infant, intestinal) Toxin inhalation (aerosol release) Mortality <10% Microbiology:  Microbiology Clostridium botulinum Large, anaerobic Gram positive bacillus Spore-forming Rarely infects humans Produces potent neurotoxin 7 types (A-G) Types A,E,B most common in U.S. Same general mechanism Slide84:  Arnon S, et al. JAMA. 2001;285:1059-70. Figure is not shown because the copyright permission granted to the Centers for the Study of Bioterrorism and Emerging Infections does not include usage on our website Clinical Features:  Clinical Features Incubation 12-72 hours Probably faster if inhalational exposure Classic syndrome Acute symmetric cranial nerve palsies Blurry vision, ptosis, dysphasia Descending flaccid paralysis Complete skeletal muscle paralysis Respiratory (ventilatory) failure Autonomic – urinary retention, orthostasis Afebrile, normal mentation Clinical Features:  Clinical Features Differential Diagnosis Myasthenia Gravis – anticholinesterase response Guillaine-Barre Syndrome - ascending Stroke – asymmetric, abnormal brain imaging Tick paralysis – ascending, presence of tick Poliomyelitis – asymmetric, preceding viral illness Other features Foodborne – nausea, diarrhea, dry mouth Infant - constipation Diagnosis:  Diagnosis High index of suspicion necessary No readily available rapid confirmatory tests Clinical diagnosis Laboratory confirmation Specimens – blood, stool At reference labs Mouse bioassay ELISA Treatment:  Treatment Supportive care Mechanical ventilation, nutritional support Prevention of secondary infections Avoid aminoglycosides, clindamycin Passive immunization (antitoxin) Halts paralysis, doesn’t reverse Must be given ASAP Equine antitoxin (Types A, B and E toxins) Serum sickness (9%), anaphylaxis (2%) Heptavalent antitoxin (Types A-G) Investigational, less hypersensitivity Post-Exposure Prophylaxis:  Post-Exposure Prophylaxis Antitoxin not recommended High incidence hypersensitivity Limited supplies Clinical monitoring Extreme vigilance for symptoms At least 72 hours Antitoxin immediately for any symptoms Vaccination:  Vaccination Botulinum toxoid No role for post-exposure prophylaxis Immunity develops over months Excellent efficacy Not tested versus aerosol exposure Few adverse effects Infection Control:  Infection Control No person-to-person transmission Patient handling Standard precautions Clinical specimens Standard precautions Viral Hemorrhagic Fevers:  Viral Hemorrhagic Fevers History:  History Variety of viral illnesses Similar syndrome with fevers and bleeding No known use as bioweapon Great potential for fear High mortality/morbidity Attention in media, entertainment Epidemiology:  Epidemiology Multiple RNA viruses, similar syndrome Filoviruses Ebola, Marburg Arenaviruses Junin [Argentinian HF], Machupo [Bolivian HF], Guanarito [Venezuelan HF], Lassa Flaviviruses Dengue [Dengue HF], Yellow Fever Bunyaviruses Hantaviruses [HF with Renal Syndrome], Congo-Crimean HF, Rift Valley Fever Epidemiology:  Epidemiology Transmission variable Endemic (sporadic or epidemic) Arthropod bites Contact with infected animals Person-to-person Blood, body fluids Filoviruses, CCHF, probably arenaviruses Respiratory route Uncommon All but dengue infectious as aerosol Mortality up to 90% Slide96:  Atlanta, Georgia: Electron Micrograph: Ebola virus causing African Hemorrhagic Fever. (Courtesy of the National Archives, 82-424) Pathogenesis:  Pathogenesis Entry Mucous membrane, needlestick Inhaled Viremia and spread to liver, spleen, lungs Mucosal shedding preceded by fever Incubation period 2 days-3 weeks Vascular endothelium disruption Loss of integrity of vascular endothelium Edema Coagualation system defects Hemorrhage, fibrin deposition Clinical Features:  Clinical Features Early symptoms - Fever, myalgias, malaise Severity - mild to fulminant Hallmarks Disrupted vascular permeability Edema, shock in severe cases Bleeding diathesis Mucous membrane hemorrhage, petechiae Thrombocytopenia, leukopenia, hepatitis DDX – malaria, typhoid, rickettsia, DIC Slide99:  Textbook of Military Medicine. Courtesy of Robert Swanepoel, PhD, DTVM, MRCVS, National Institute for Communicable Diseases, Sandringham, South Africa. Figure is not shown because the copyright permission granted to the Centers for the Study of Bioterrorism and Emerging Infections does not include usage on our website Diagnosis:  Diagnosis High index of suspicion No readily available rapid specific test Presumptive Clinical diagnosis in outbreak setting Confirmation – only at reference labs Serology Retrospective Culture from blood Requires BSL-4 lab PCR, etc Treatment:  Treatment Supportive therapy Volume, electrolyte, hemodynamic support Treatment of hemorrhage Minimize sedation Ribavirin Useful for some (CCHF, Lassa) No useful for others (filo-,flavivirus HF’s) Post-Exposure Prophylaxis:  Post-Exposure Prophylaxis Close monitoring for all Oral ribavirin Investigational CCHF Lassa fever No role for vaccination Immunity takes too long to develop Vaccination:  Vaccination Vaccines available Yellow Fever Effective for travelers to endemic areas Safe Rare adverse effects Others in various stages of development Infection Control:  Infection Control All patients strict isolation Respiratory droplet precautions Surgical mask Contact (barrier) precautions Including face shield or goggles Those with the highest potential of spread (severe cough, hemorrhage, diarrhea) Airborne precautions Negative pressure room HEPA filtered respirator Other Resources:  Other Resources Web sites www.bioterrorism.slu.edu (SLU-CSBEI) www.bt.cdc.gov (CDC) www.hopkins-biodefense.org/ (JH-CCB) www.apic.org (APIC) www.usamriid.army.mil (USAMRIID)

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