Anthrax.

Anthrax

Saint Louis Unversity School of Public Health
Anthrax: History Caused by Bacillus anthracis Human zoonotic disease Spores found in soil worldwide Primarily disease of herbivorous animals Sheep, goats, cattle Many large documented epizootics Occasional human disease Epidemics have occurred but uncommon Rare in developed world Saint Louis Unversity School of Public Health

Anthrax: Bioweapon Potential
Many countries have weaponized anthrax Former bioweapon programs U.S.S.R.,U.S.,U.K., and Japan Recent bioweapon programs Iraq Attempted uses as bioterrorism agent WW I: Germans inoculated Allied livestock WW II: Alleged Japanese use on prisoners Saint Louis Unversity School of Public Health

Features of anthrax suitable as BT agent Fairly easy to obtain, produce and store Spores easily dispersed as aerosol Moderately infectious High mortality for inhalational (86-100%) Saint Louis Unversity School of Public Health

Aerosol method of delivery Most likely method expected in BT attack Would cause primarily inhalational disease Spores reside on particles of 1-5 μm size Optimal size for deposition into alveoli Form of disease with highest mortality Would infect the largest number of people Saint Louis Unversity School of Public Health

Dispersed as powder Frequent letter hoaxes since 1997 Recent letter deliveries Highest risk is for cutaneous Inhalational theoretically possible Particle size Likelihood of aerosolization GI theoretically possible Spores > hands > eating without handwashing Saint Louis Unversity School of Public Health

Sverdlovsk, Russia 1979 Accidental release from anthrax drying plant 79 human cases All downwind of plant 68 deaths Some infected with multiples strains Saint Louis Unversity School of Public Health

Estimated effects of inhalational anthrax 100 kg spores released over city size of Washington DC 130,000 – 3 million deaths depending on weather conditions Economic impact $26.2 billion/100,000 exposed people Saint Louis Unversity School of Public Health

Anthrax: Epidemiology
Three forms of natural disease Inhalational Rare (<5%) Most likely encountered in bioterrorism event Cutaneous Most common (95%) Direct contact of spores on skin Gastrointestinal Rare (<5%), never reported in U.S. Ingestion Saint Louis Unversity School of Public Health

All ages and genders affected Occurs worldwide Endemic areas - Africa, Asia True incidence not known World 20, ,000 in 1958 U.S. 235 total reported cases 18 cases inhalational since 1900, last one 1976 Until 2001, last previous case cutaneous 1992 Saint Louis Unversity School of Public Health

Mortality Inhalational % (despite treatment) Era of crude intensive supportive care Cutaneous <5% (treated) – 20% (untreated) GI approaches 100% Saint Louis Unversity School of Public Health

Incubation Period Time from exposure to symptoms Very variable for inhalational 2-43 days reported Theoretically may be up to 100 days Delayed germination of spores Saint Louis Unversity School of Public Health

Human cases – historical risk factors Agricultural Exposure to livestock Occupational Exposure to wool and hides Woolsorter’s disease = inhalational anthrax Rarely laboratory-acquired Saint Louis Unversity School of Public Health

Transmission No human-to-human Naturally occurring cases Skin exposure Ingestion Airborne Bioterrorism Aerosol (likely) Small volume powder (possible) Foodborne (unlikely) Saint Louis Unversity School of Public Health

Transmission Inhalational Handling hides/skins of infected animals Microbiology laboratory Intentional aerosol release Small volume powdered form In letters, packages, etc Questionable risk, probably small Saint Louis Unversity School of Public Health

Transmission Cutaneous Handling hides/skins of infected animals Bites from arthropods (very rare) Handling powdered form in letters, etc. Intentional aerosol release May see some cutaneous if large-scale Saint Louis Unversity School of Public Health

Transmission Gastrointestinal Ingestion of meat from infected animal Ingestion of intentionally contaminated food Not likely in large scale Spores not as viable in large volumes of water Ingestion from powder-contaminated hands Inhalational of spores on particles >5 m Land in oropharynx Saint Louis Unversity School of Public Health

Anthrax: Microbiology
Bacillus anthracis Aerobic, Gram positive rod Long (1-10μm), thin ( μm) Forms inert spores when exposed to O2 Infectious form, hardy Approx 1μm in size Vegetative bacillus state in vivo Result of spore germination Non-infectious, fragile Saint Louis Unversity School of Public Health

Colony characteristics Large (4-5mm) Non-hemolytic Opaque white, gray Retain shape when manipulated (“egg white”) Forms capsule at 37º C, 5-20% CO2 Saint Louis Unversity School of Public Health

Classification Same family: B. cereus, B. thuringiensis Differentiation from other Bacillus species Non-motile Non β-hemolytic on blood agar Does not ferment salicin Note: Gram positive rods are usually labeled as “contaminants” by micro labs Saint Louis Unversity School of Public Health

Environmental Survival Spores are hardy Resistant to drying, boiling <10 minutes Survive for years in soil Still viable for decades in perma-frost Favorable soil factors for spore viability High moisture Organic content Alkaline pH High calcium concentration Saint Louis Unversity School of Public Health

Microbiology Virulence Factors All necessary for full virulence Two plasmids Capsule (plasmid pXO2) Antiphagocytic 3 Exotoxin components (plasmid pXO1) Protective Antigen Edema Factor Lethal Factor Saint Louis Unversity School of Public Health

Protective Antigen Binds Edema Factor to form Edema Toxin Facilitates entry of Edema Toxin into cells Edema Factor Massive edema by increasing intracellular cAMP Also inhibits neutrophil function Lethal Factor Stimulates macrophage release of TNF-α, IL-1β Initiates cascade of events leading to sepsis Saint Louis Unversity School of Public Health

Anthrax: Pathogenesis
Disease requires entry of spores into body Exposure does not always cause disease Inoculation dose Route of entry Host immune status May depend on pathogen strain characteristics Saint Louis Unversity School of Public Health

Forms of natural disease Inhalational Cutaneous Gastrointestinal Determined by route of entry Disease occurs wherever spores germinate Saint Louis Unversity School of Public Health

Inhalational Spores on particles 1-5 m Inhaled and deposited into alveoli Estimated LD50 = 2500 – 55,000 spores Dose required for lethal infection in 50% exposed Contained in imperceptibly small volume Saint Louis Unversity School of Public Health

Inhalational Phagocytosed by alveolar macrophages Migration to mediastinal/hilar lymph nodes Germination into vegetative bacilli Triggered by nutrient-rich environment May be delayed up to 60 days Factors not completely understood Dose, host factors likely play a role Antibiotic exposure may contribute Delayed germination after antibiotic suppression Saint Louis Unversity School of Public Health

Inhalational Vegetative bacillus is the virulent phase Active toxin production Hemorrhagic necrotizing mediastinitis Hallmark of inhalational anthrax Manifests as widened mediastinum on CXR Does NOT cause pneumonia Followed by high-grade bacteremia Seeding of multiple organs, including meninges Saint Louis Unversity School of Public Health

Inhalational Toxin production Has usually begun by time of early symptoms Stimulates cascade of inflammatory mediators Sepsis Multiorgan failure DIC Eventual cause of death Symptoms mark critical mass of bacterial burden Usually irreversible by this time Clearance of bacteria unhelpful as toxin-mediated Early research on antitoxin promising Saint Louis Unversity School of Public Health

Cutaneous Spores in contact with skin Entry through visible cuts or micro-trauma Germination in skin Disease begins following germination Toxin production Local edema, erythema, necrosis, lymphocytic infiltrate No abscess or suppurative lesions Eventual eschar formation Saint Louis Unversity School of Public Health

Cutaneous Systemic disease Can occur, especially if untreated Spores/bacteria carried to regional lymph nodes Lymphangitis/lymphadenitis Same syndrome as inhalational Sepsis, multi-organ failure Saint Louis Unversity School of Public Health

Gastrointestinal Spores contact mucosa Oropharynx Ingestion Aerosolized particles >5 m Intestinal mucosa – terminal ileum, cecum Larger number of spores required for disease Incubation period 2-5 days Saint Louis Unversity School of Public Health

Gastrointestinal Spores migrate to lymphatics Submucosal, mucosal lymphatic tissue Mesenteric nodes Germination to vegetative bacilli Toxin production Massive mucosal edema Mucosal ulcers, necrosis Death from perforation or systemic disease Saint Louis Unversity School of Public Health

Anthrax: Clinical Features
Symptoms depend on form of disease Inhalational Cutaneous Gastrointestinal Saint Louis Unversity School of Public Health

Inhalational Asymptomatic incubation period Duration 2-43 days, ~10 days in Sverdlovsk Prodromal phase Correlates with germination, toxin production Nonspecific flu-like symptoms Fever, malaise, myalgias Dyspnea, nonproductive cough, mild chest discomfort Duration several hours to ~3 days Can have transient resolution before next phase Saint Louis Unversity School of Public Health

Inhalational Fulminant Phase Correlates with high-grade bacteremia/toxemia Critically Ill Fever, diaphoresis Respiratory distress/failure, cyanosis Septic shock, multi-organ failure, DIC 50% develop hemorrhagic meningitis Headache, meningismus, delirium, coma May be most prominent finding Usually progresses to death in <36 hrs Mean time from symptom onset to death ~3 days Saint Louis Unversity School of Public Health

Laboratory Findings Gram positive bacilli in direct blood smear Electrolyte imbalances common Radiographic Findings Widened mediastinum Minimal or no infiltrates Can appear during prodrome phase Saint Louis Unversity School of Public Health

Cutaneous Most common areas of exposure Hands/arms Neck/head Incubation period 3-5 days typical 12 days maximum Saint Louis Unversity School of Public Health

Cutaneous – progression of painless lesions Papule – pruritic Vesicle/bulla Ulcer – contains organisms, sig. edema Eschar – black, rarely scars 24-36 hrs days Saint Louis Unversity School of Public Health

Cutaneous Systemic disease may develop Lymphangitis and lymphadenopathy If untreated, can progress to sepsis, death Saint Louis Unversity School of Public Health

Gastrointestinal Oropharyngeal Oral or esophageal ulcer Regional lymphadenopathy Edema, ascites Sepsis Abdominal Early symptoms - nausea, vomiting, malaise Late - hematochezia, acute abdomen, ascites Saint Louis Unversity School of Public Health

Anthrax: Diagnosis Early diagnosis is difficult Non specific symptoms Initially mild No readily available rapid specific tests Saint Louis Unversity School of Public Health

Anthrax: Diagnosis Presumptive diagnosis History of possible exposure Typical signs & symptoms Rapidly progressing nonspecific illness Widened mediastinum on CXR Large Gram+ bacilli from specimens Can be seen on Gram stain if hi-grade bacteremia Appropriate colonial morphology Necrotizing mediastinitis, meningitis at autopsy Saint Louis Unversity School of Public Health

Anthrax: Diagnosis Definitive diagnosis Direct culture on standard blood agar Gold standard, widely available Alert lab to work up Gram + bacilli if found 6-24 hours to grow Sensitivity depends on severity, prior antibiotic Blood, fluid from skin lesions, pleural fluid, CSF, ascites Sputum unlikely to be helpful (not a pneumonia) Very high specificity if non-motile, non-hemolytic Requires biochemical tests for >99% confirmation Available at Reference laboratories Saint Louis Unversity School of Public Health

Anthrax: Diagnosis Definitive diagnosis Rapid confirmatory tests Role is to confirm if cultures are negative Currently available only at CDC Polymerase Chain Reaction (PCR) Hi sensitivity and specificity Detects DNA Viable bacteria/spores not required Immunohistochemical stains Most clinical specimens can be used Saint Louis Unversity School of Public Health

Anthrax: Diagnosis Other diagnostic tests Anthraxin skin test Chemical extract of nonpathogenic B. anthracis Subdermal injection 82% sensitivity for cases within 3 days symptoms 99% sensitivity 4 weeks after symptom onset Not much experience with use in U.S. – not used Saint Louis Unversity School of Public Health

Anthrax: Diagnosis Testing for exposure Nasal swabs Can detect spores prior to illness Currently used only as epidemiologic tool Decision for PEP based on exposure risk May be useful for antibiotic sensitivity in exposed Culture on standard media Swabs of nares and facial skin Serologies May be useful from epidemiologic standpoint Investigational – only available at CDC Saint Louis Unversity School of Public Health

Anthrax: Diagnosis Environmental samples Suspicious powders Must be sent to reference laboratories as part of epidemiologic/criminal investigation Assessed using cultures, stains, PCR Air sampling First responders Handheld immunoassays Not validated Useful for detecting massive contamination Saint Louis Unversity School of Public Health

Anthrax: Diagnosis Test Availability Time Sens Spec Culture Most labs 1-3 days Mod High Biochemical Large labs Hours N/A Skin test None 1-2 days ? PCR Reference ELISA Saint Louis Unversity School of Public Health

Anthrax: Differential Diagnosis
Inhalational Influenza Pneumonia Community-acquired Atypical Pneumonic tularemia Pneumonic plague Mediastinitis Bacterial meningitis Thoracic aortic aneurysm Expect if anthrax Flu rapid diagnostic – More severe in young pts No infiltrate No prior surgery Bloody CSF with GPBs Fever Saint Louis Unversity School of Public Health

Cutaneous Spider bite Ecthyma gangrenosum Pyoderma gangrenosum Ulceroglandular tularemia Mycobacterial ulcer Cellulitis Expect if anthrax fever no response to 3º cephalosporins painless, black eschar +/- lymphadenopathy usually sig. local edema Saint Louis Unversity School of Public Health

Gastrointestinal Gastroenteritis Typhoid Peritonitis Perforated ulcer Bowel obstruction Expect if anthrax Critically ill Acute abdomen Bloody diarrhea Fever Saint Louis Unversity School of Public Health

Impact of suspected BT during flu season Early disease mimics influenza Affects same population Increased role for rapid flu tests Possible development of ER protocols In settings of high suspicion for BT release Observation until flu test results obtained Caveats Possible addition of influenza to aerosol release False positives/negatives Must still use clinical judgement Saint Louis Unversity School of Public Health

Anthrax: Treatment Immediately treat presumptive cases Prior to confirmation Rapid antibiotics may improve survival Differentiate between cases and exposed Cases Potentially exposed with any signs/symptoms Exposed Potentially exposed but asymptomatic Provide Post-Exposure Prophylaxis Saint Louis Unversity School of Public Health

Anthrax: Treatment Hospitalization IV antibiotics Empiric until sensitivities are known Intensive supportive care Electrolyte and acid-base imbalances Mechanical ventilation Hemodynamic support Saint Louis Unversity School of Public Health

Anthrax: Treatment Antibiotic selection Naturally occurring strains Rare penicillin resistance, but inducible β-lactamase Penicillins, aminoglycosides, tetracyclines, erythromycin, chloramphenicol have been effective Ciprofloxacin very effective in vitro, animal studies Other fluoroquinolones probably effective Engineered strains Known penicillin, tetracycline resistance Highly resistant strains = mortality of untreated Saint Louis Unversity School of Public Health

Anthrax: Treatment Empiric Therapy Until susceptibility patterns known Adults Ciprofloxacin 400 mg IV q12° OR Doxycycline 100mg IV q12° AND (for inhalational) One or two other antibiotics Saint Louis Unversity School of Public Health

Anthrax: Treatment Other antibiotic considerations Other fluoroquinolones possibly equivalent High dose penicillin for 2nd empiric agent 50% present with meningitis Clindamycin for severe disease May reduce toxin production Chloramphenicol for known meningitis Penetrates blood brain barrier Saint Louis Unversity School of Public Health

Anthrax: Treatment Empiric Therapy Children Ciprofloxacin mg/kg/d IV q12°, max 1 g/d OR Doxycycline 2.2 mg/kg IV q12° (adult dosage if >8 years and >45 kg) Add one or two antibiotics for inhalational Weigh risks (arthropathy, dental enamel) Saint Louis Unversity School of Public Health

Anthrax: Treatment Empiric therapy Pregnant women Same as other adults Weigh small risks (fetal arthropathy) vs benefit Immunosuppressed Saint Louis Unversity School of Public Health

Anthrax: Treatment Alternative antibiotics If susceptible, or cipro/doxy not possible Penicillin, amoxicillin Gentamicin, streptomycin Erythromycin, chloramphenicol Ineffective antibiotics Trimethoprim/Sulfamethoxazole Third generation cephalosporins Saint Louis Unversity School of Public Health

Anthrax: Treatment Susceptibility testing should be done Narrow antibiotic if possible Must be cautious Multiple strains with engineered resistance to different antibiotics may be co-infecting Watch for clinical response after switching antibiotic Saint Louis Unversity School of Public Health

Anthrax: Treatment Antibiotic therapy Duration 60 days Risk of delayed spore germination Vaccine availability Could reduce to days therapy Stop antibiotics after 3rd vaccine dose Switch to oral Clinical improvement Patient able to tolerate oral medications Saint Louis Unversity School of Public Health

Anthrax: Treatment Other therapies Passive immunization Anthrax immunoglobulin from horse serum Risk of serum sickness Antitoxin Mutated Protective Antigen Blocks cell entry of toxin Still immunogenic, could be an alternative vaccine Animal models promising Saint Louis Unversity School of Public Health

Anthrax: Postexposure Prophylaxis
Who should receive PEP? Anyone exposed to anthrax Not for contacts of cases, unless also exposed Empiric antibiotic therapy Vaccination Saint Louis Unversity School of Public Health

Avoid unnecessary antibiotic usage Potential shortages of those who need them Potential adverse effects Hypersensitivity Neurological side effects, especially elderly Bone/cartilage disease in children Oral contraceptive failure Future antibiotic resistance Individual’s own flora Community resistance patterns Saint Louis Unversity School of Public Health

Antibiotic therapy Treat ASAP Prompt therapy can improve survival Continue for 60 days 30-45 days if vaccine administered Saint Louis Unversity School of Public Health

Antibiotic agents Same regimen as active treatment Substituting oral equivalent for IV Ciprofloxacin 500 mg po bid empirically Alternatives Doxycycline 100 mg po bid Amoxicillin 500 mg po tid Saint Louis Unversity School of Public Health

Antibiotic agents Children Same dose adjustments as treatment Weigh benefits vs. risks Recommended switch if PCN-susceptible Amoxicillin 80 mg/kg/day, max 500 mg tid Saint Louis Unversity School of Public Health

Anthrax: Prevention Vaccine Anthrax Vaccine Absorbed (AVA) Supply Limited, controlled by CDC Production problems Single producer – Bioport, Michigan Failed FDA standards None produced since 1998 Saint Louis Unversity School of Public Health

Anthrax: Prevention Vaccine Inactivated, cell-free filtrate Purified with Al(OH)3 Protective Antigen Immunogenic component Necessary but not sufficient Saint Louis Unversity School of Public Health

Anthrax: Prevention Vaccine Administration Dose schedule 0, 2 & 4 wks; 6, 12 & 18 months initial series Annual booster 0.5 ml SQ Saint Louis Unversity School of Public Health

Anthrax: Prevention Vaccine – Effective and Safe Efficacy >95% protection vs. aerosol in animal models >90% vs. cutaneous in humans Older vaccine that was less immunogenic Protection vs inhalational but too few cases to confirm Saint Louis Unversity School of Public Health

Anthrax: Prevention Vaccine Adverse Effects >1.6 million doses given to military by 4/2000 No deaths <10% moderate/severe local reactions Erythema, edema <1% systemic reactions Fever, malaise Saint Louis Unversity School of Public Health

Anthrax: Infection Control
No person to person transmission Standard Precautions Laboratory safety Biosafety Level (BSL) 2 Precautions Saint Louis Unversity School of Public Health

Anthrax: Decontamination
Highest risk of infection at initial release Duration of aerosol viability Several hours to one day under optimal conditions Covert aerosol long dispersed by recognition 1st case Risk of secondary aerosolization is low Heavily contaminated small areas May benefit from decontamination Decontamination may not be feasible for large areas Saint Louis Unversity School of Public Health

Skin, clothing Thorough washing with soap and water Avoid bleach on skin Instruments for invasive procedures Utilize sporicidal agent Sporicidal agents Sodium or calcium hypochlorite (bleach) Saint Louis Unversity School of Public Health

Suspicious letters/packages Do not open or shake Place in plastic bag or leak-proof container If visibly contaminated or container unavailable Gently cover – paper, clothing, box, trash can Leave room/area, isolate room from others Thoroughly wash hands with soap and water Report to local security / law enforcement List all persons in vicinity Saint Louis Unversity School of Public Health

Opened envelope with suspicious substance Gently cover, avoid all contact Leave room and isolate from others Thoroughly wash hands with soap and water Notify local security / law enforcement Carefully remove outer clothing, put in plastic Shower with soap and water List all persons in area Saint Louis Unversity School of Public Health

Anthrax: Outbreak Investigations 2001
Case definitions Confirmed case Clinically compatible syndrome +culture or 2 +non-culture diagnostics Presumptive case 1 +non-culture diagnostic or confirmed exposure Exposures Confirmed exposure May be aided by nasal swab cultures, serology Asymptomatic Saint Louis Unversity School of Public Health

Florida (Palm Beach) 1st U.S. case since 1976 reported 10/4/01 1st ever cases of intentional infection Inhalational Index Case 63yo man presented with fever and altered MS Preceding flu-like symptoms Reported by astute clinician Noticed GPB’s in CSF on 10/2 Lab confirmation by State and CDC on 10/4 Rapid deterioration, died on 10/5 Saint Louis Unversity School of Public Health

Florida Case #2 73yo man Admitted 10/1 for pneumonia Nasal swab culture + on 10/5 PCR+ on pleural fluid, serology + Responding to antibiotics, still in hospital Saint Louis Unversity School of Public Health

Florida Exposed Anyone at worksite for >1 hour since 8/1 1/1075 nasal swabs +, all given PEP Confirmed powder exposure from mail Saint Louis Unversity School of Public Health

New York City - cutaneous cases Case #1 – 38 yo woman, NBC employee Handled suspicious letter with powder marked 9/18 9/25 developed raised skin lesion on chest Progressive erythema, edema over 3 days 9/29 malaise and HA, lesion painless 10/1 5cm oval, raised border, satellite vesicles Left cervical lymphadenopathy Black eschar over next few days Saint Louis Unversity School of Public Health

Outbreak Investigations 2001
New York City – cutaneous cases Case#1 Vesicle fluid –cx and Gram stain Eschar biopsy +immuno-histochemical stain Powder in letter confirmed anthrax spores Improving on oral ciprofloxacin Saint Louis Unversity School of Public Health

New York City – cutaneous cases Case #2 – 7 month old son of ABC worker Visited worksite on 9/28 9/29 large weeping skin lesion left arm Nontender, massive edema Progressed to ulcerative with black eschar Initial Dx- spider bite Complicated by hemolytic anemia, thrombocytopenia 10/12 anthrax considered 10/2 blood PCR+, 10/13 skin bx IHC stain+ No source identified, improving with ciprofloxacin Saint Louis Unversity School of Public Health

New York City Exposures by nasal/facial swab cx’s Police officer transporting the NBC sample 2 lab techs processing NBC sample Saint Louis Unversity School of Public Health

Washington, D.C. Letter sent to Senator Daschle Originated from Trenton, NJ 28 Senate staff confirmed exposure Evacuation of Senate then House Saint Louis Unversity School of Public Health

Trenton, New Jersey 2 confirmed inhalational cases Postal workers in distribution center Others with symptoms, results pending 2 suspicious deaths Probable inhalational anthrax Saint Louis Unversity School of Public Health

As of 10/22/01 FL NY NJ DC Inhalational 2 4 Cutaneous 1 Total Cases Exposure 6 3 ? 29 Deaths (all inhalational) Saint Louis Unversity School of Public Health

Anthrax Essential Pearls
Rapidly fatal flu-like illness in previous healthy Widened mediastinum on Chest X-ray Painless black skin ulcer Non-motile gram positive bacilli in specimens Diagnosis primarily by routine culture No person-to-person transmission Rx prior to prodrome essential for survival Empiric therapy - ciprofloxacin Saint Louis Unversity School of Public Health

Anthrax Essential Pearls
Single inhalational case is an emergency Contact Local Health Departments ASAP Saint Louis Unversity School of Public Health

Viral Hemorrhagic Fever

Hemorrhagic Fever Viruses
Families Responsible for VHF: Arenaviridae Bunyaviridae Filoviridae Flaviviridae Centers for Disease Control and Prevention

Arenaviruses Argentine Hemorrhagic Fever Bolivian Hemorrhagic Fever Sabia Associated Hemorrhagic Fever Lassa Fever Centers for Disease Control and Prevention

Bunyaviruses Crimean-Congo Hemorrhagic Fever Rift Valley Fever Hantavirus Pulmonary Syndrome Hemorrhagic Fever Centers for Disease Control and Prevention

Filoviruses Ebola Hemorrhagic Fever Marburg Hemorrhagic Fever Centers for Disease Control and Prevention

Flaviviruses Tick-borne Encephalitis Kyasanur Forest Disease Omsk Hemorrhagic Fever Centers for Disease Control and Prevention

Viral Hemorrhagic Fevers
Contagious --- Moderate Infective dose particles Incubation period days Duration of illness days Mortality ---variable Persistence of organism --- unstable Non-endemic in U.S. No vaccine Bullet 1: contagious 1.Person to person transmission of Lassa, Ebola, Marburg and CCHF occurs through DIRECT CONTACT WITH VHF-INFECTED MATERIAL 2. Via INFECTIOUS BODY FLUIDS: blood, urine, vomitus, pus, stool, semen, saliva. 3.THE VIRUS IS PRESENT IN THE PATIENT’S BODY FLUIDS And is transmitted through unprotected contact with infectious body fluids!! (ref: Infection Control for VHF, in the African Health Care Setting, p 3,4,120) Bullet 2: Extremely small infective dose Bullet 5: Mortality: Ebola approaches 90%; Marburg 25%, Lassa 5-10% Bullet 7, 8: Again, not endemic in US… and there’s no vaccine available. Information for speaker: see Table 7 of handouts for vaccine questions or whether immunity is conferred by natural exposure. Centers for Disease Control and Prevention

Centers for Disease Control and Prevention
VHF Specimens Diagnosis is clinical, not laboratory No specimen accepted without prior consultation The diagnosis is clinical….the role of the laboratory will be to package/ship the specimen Centers for Disease Control and Prevention

Handling VHF Specimens
Sample for serology ml ship on dry ice Tissue for immunohistochemistry formalin-fixed or paraffin block ship at room temperature Tissue for PCR/virus isolation ante-mortem, post-mortem; ship on dry ice Ship serum cold or on dry ice in a plastic tube CDC must be notified…. via state health lab. Specimen of choice: Serum….2 red tops. Last bullet…”cold” means 4 degrees, like in cold-pack Tests that can be performed on serum: 1. Antigen-capture ELISA 2. IgG ELISA 3. PCR for virus 4. Virus isolation Centers for Disease Control and Prevention

Pneumonic Plague

Pneumonic Plague Yersinia pestis Flea bite in natural conditions
Gram-negative coccobacillus Flea bite in natural conditions Easily transmitted direct contact person-person High mortality Pneumonic form most deadly Dr. Alexandre Yersin in Front of the National Quarantine Station, Shanghai Station, This was the laboratory building in Shanghai, China where in 1936 Dr. Yersin first isolated and described in detail, Pasteurella pestis, the old term used for Yersinia pestis.

Plague Epidemiology U.S. averages 13 cases/yr (10 in 1998) 30% of cases are in Native Americans in the Southwest. 15% case fatality rate Most cases occur in summer Highlight: Bullet #1: cases/yr Bullet #2: Disease of native Americans in SW Centers for Disease Control and Prevention

Plague Epidemiology Bubonic Septicemic Pneumonic
Painful adenopathy (bubo) groin or axillae Septicemic Septicemia w/o adenopathy Pneumonic Severe Respiratory Symptoms (Yersinia aerosol transmission-bioterroism threat) Bubonic plague has a characteristic lymphadenitis, affecting sometimes the neck,axilla or groin (infrequently)

Plague Epidemiology Pneumonic Plague CAP-like Respiratory symptoms
Sudden Onset Severe headache Abdominal pain Adenopathy

Plague Differential Diagnosis
Pneumonic Plague Cavitation Multilobar consolidation Highly variable CXR May have alveolar infiltrates May have massive consolidation

(Yersinia) Schoenlein-Henoch Disease-bacterial vasculitis
Plague is an infectious disease of animals and humans caused by a bacterium Yersinia pestis. People usually get plague from being bitten by a rodent flea that is carrying the plague bacterium or by handling an infected animal. Prairie dogs have been known to have yersinia infected fleas. Septic shock and organ failure are likely when the disease becomes systemic.

Safety pin Appearance Y. pestis
A presumptive diagnosis can be made using a microscope which shows gram-negative cocco-bacillus with safety-pin bipolar staining from smears taken from lymph node aspirate, sputum, or CSF fluid.

Yersinia pestis Technical Hints
Small gram-negative, poorly staining rods from blood, lymph node aspirate, or respiratory specimens Safety pin appearance in Gram, Wright, Giemsa, or Wayson stain Summary slide for pestis Review each bullet Refer to Level B lab Centers for Disease Control and Prevention

Plague Treatment Streptomycin, Gentamycin Effectiveness Time of initiation Access to advanced supportive care Dose of inhaled bacilli Centers for Disease Control and Prevention

Plague Alternative Treatments-& Prophylaxis of Close Contacts
Adults, Children, Pregnant Women Doxycycline, Ciprofloxacin Mass Casualty Setting Alternative Above or Tetracycline

Plague Infection Control
Facemasks for close patient contact Avoid unnecessary close contact until on antibiotics 48 hours Biosafety level-2 labs for simple cultures No need for environmental decontamination of areas exposed to plague aerosol. Droplet precautions for persons exposed to pneumonic plague, and standard precautions for persons exposed to bubonic plague. Centers for Disease Control and Prevention

Tularemia

Tularemia Francisella tularensis
Flu-Like Illnesses, atypical pneumonias Inhalation route 10-50 microbes -> Infection & Disease No Human-to-Human transmission Isolation not necessary Tularemia is also known as rabbit or deer fly fever. It is a zoonotic disease which humans can acquire from contact with infected animals or bites from infected mosquitoes, ticks, and deerflies. Other methods for acquisition of tularemia include inhalation of contaminated dust and ingestion of contaminated water and food.

Tularemia Plague-like disease in rodents (California) Deer-fly fever (Utah) Glandular tick fever (Idaho and Montana) Market men’s disease (Washington, DC) Rabbit fever (Central States) O’Hara’s disease (Japan) 1914: Vail described the first human case, the ocular form 1914: Wherry and Lamb implicated the tick as a vector 1921: Francis described the septic form in humans, along with implicating the deerfly as another vector. The Genus was eventually named in his honor Then in 1924, O’hara in Japan reported a milder form of the disease, which we now know as the Type B. It differs from the more virulent form found in North America by a number obscure biochemical reactions: type A ferments glycerol and sucrose and is citrulline ureidase positive…..while type B is negative for these tests O’hara is also given credit for performing the first human transmission studies by placing heart blood of an infected rabbit onto the skin of his……..WIFE. She developed a self-limiting case of ulceroglandular tularemia. He also isolated the organism from one of her lymph nodes. In Arkansas, this disease is affectionately referred to as “BUBBA AND SPOT DISEASE” That’s where Bubba goes hunting; shoots a rabbit. Spot gets the rabbit. Then, Bubba gets tularemia. Centers for Disease Control and Prevention

Tularemia Contagious --- no Infective dose organisms Incubation period days (average=3-5 days) Duration of illness --- ~2 weeks Mortality --- treated : low untreated: moderate Persistence of organism ---months in moist soil Vaccine efficacy --- good, ~80% BULLET #1: it is not transmissible from man to man, but can be acquired in lab. Third most commonly reported lab-acquired bacterial infection (Brucella is leading lab-assoc bacterial infection) BULLET #2: very low infective dose… organisms. LAST BULLET: vaccine has partial protection. Some individuals demonstrate protection (80%), while multiple episodes have occurred among others that have been vaccinated. A PARADOX: Tularemia and brucellosis are not infectious from man to man…but can be acquired in the lab; whereas, pneumonic plague is readily acquired via man to man….but it is not infectious in the lab. Centers for Disease Control and Prevention

Tularemia Clinical Features
Targets kidney, liver, lungs,lymph, spleen Spread bloodstream/lymph Organs-PMNs and focal suppurative necrosis

Alternate Sites-Tularemia
Aerosol bioterrorism attack: lower respiratory infection, eyes, pharynx, skin Broken skin-->ulcerative form GI involvement if ingested

Tularemia Influenza Chills, coryza, cough, fever, headache, malaise, myalgia, sore throat Relative bradycardia ie, pulse-temperature dissociation Variable severity Same No dissociation Most symptoms similar

Lab Tularemia Influenza
WBC normal or high UA= sterile pyuria 5-15% have elevated LFTs Culture pharynx, sputum or gastric aspirates high yield for Francisella tularensis WBC may be normal, No pyuria No LFT elevation

CXR Tularemia 25-50% abnormal CXR inhalation tularemia
Peri-vascular infiltrates early May resemble symptoms and CXR of Anthrax, plague or Q-fever

Tularemia Differs from Similar Bio Weapons
Plague Anthrax Q Fever Rapid progression Symmetrical mediastinal widening Clinically same as tularemia Copious sputum Hemoptysis Absence of broncho-pneumonia Lab testing differentiates

Tularemia: Gram Negative Coccobacilli
Most likely Acinetobacter Actinobacillus H. aphrophilus Bordetella spp. Pasturella spp. Least likely DF-3 Brucella spp. Francisella spp. This a just a “garden-variety” list of various gram-negative coccobacilli that may be encountered in a clinical laboratory…..they are not in any particular order of frequency… Below is background info for the speaker Acinetobacter….oxidase negative; inert/oxidizer Actinobacillus….oxidase positive (weak); glucose fermenter Haemophilus…..oxidase positive (weak or variable); glucose fermenter Bordetella……..oxidase positive; inert Pasteurella……..ozidase positive (weak); glucose fermenter DF3……………oxidase negative; glucose fermenter Brucella…………oxidase positive; glucose oxidizer Francisella………oxidase negative; ….requires cysteine-base

Francisella tularensis Technical Hints
If you see: Tiny, gram-negative coccobacilli from blood, lymph node aspirate, or respiratory specimens Blood isolates that grow slowly on chocolate agar but poorly on blood agar Robust growth in BCYE; requires cysteine Review each bullet…. BOTTOMLINE: REFER Whenever, ‘TECHNICAL HINTS” appears….that means we are coming to the end of that given topic….So, if you’d like to ask any questions at this time, I’ll do my best to answer them. Centers for Disease Control and Prevention

Tularemia Treatment Streptomycin & Gentamycin Alternatives:
Doxycycline, Ciprofloxacin

Tularemia: Mass Casualty RX
Exposed Persons Only Their contacts not at high risk Streptomycin or Gentamycin, or Ciprofloxacin, Doxycycline CDC has stockpiles, ventilators and emergency equipment

Botulism

Botulism Clostridium botulinum Most Potent Neurotoxin
169 USA cases in 2001 Foodborne or in wounds, usually IVDU

FOODBORNE BOTULISM Infective dose: g/kg Incubation period: hours Dry mouth, double vision, droopy eyelids, dilated pupils Progressive descending bilateral muscle weakness & paralysis Respiratory failure and death Mortality 5-10%, up to 25% The infective dose is 1 nanogram, and if my calculations are correct a little over 20grams of purified bot-tox if administered to the entire population of the USA (250 million)….1/2 would die Centers for Disease Control and Prevention

FOODBORNE BOTULISM Among 309 persons with clinically diagnosed botulism reported to CDC from 1975 to 1988: Stool cultures for C. botulinum: 51% + Serum botulinum toxin testing: 37% + Stool botulinum toxin testing: 23% + Overall, at least one of the above tests was positive for 65% of all patients Overall sensitivity is only 65%. Notice, that the sensitive of detecting botulinum toxin in serum is only 37% Centers for Disease Control and Prevention

Botulism Transmission
Home Canned foods, baked potatoes in aluminum foil, cheese, fish Wound botulism-spores germinate in open wounds Individual cases of botulism have been confused with GBS (Guillain-Barre Syndrome) ascending paralysis with partial or complete bulbar palsies, MG (Myasthenia Gravis) episodic weakness or paralysis of voluntary musculature with preservation of pupillary reflexes, Eaton-Lambert Syndrome – fluctuating weakness relieved with rest with sparing of cranial nerves, or Tick Paralysis - progressive ascending paralysis with bulbar involvement.

Botulism Features Symmetric descending paralysis
Motor and autonomic nerves Cranial nerves first affected Death rate 5%, respiratory failure Recovery takes months Botulism works by irreversibly binding to the presynaptic neuromuscular junction and preventing the release of acetylcholine there and at cholinergic autonomic sites.

Botulism Incubation 2 hours to 8 days (dose related)
Heat inactivates (>85°C for 5 minutes) Lab testing –Call Public Health Lab Should be suspected if multiple persons simultaneously present with similar symptoms – need to get good history of each persons’ past activities Physical exam may show an alert and oriented patient without fever, postural hypotension, dry mucuous membranes and complaint of dry mouth, possible difficulty in speaking and swallowing, absent gag reflex, pupils may be dialated and fixed. Drooping of eye lids and extra-ocular muscle palsies may be present, varying degrees of skeletal muscle weakness may be present, and respiratory problems may present very quickly in some cases.

Botulism Symptoms Alert mental status
Fatigue, dizziness, dysarthria, facial palsy Vision blurred, double, ptosis Dysphagia, dry mouth Dyspnea Constipation Weakness, progressive A descending paralysis (head-to-toe) and bulbar palsies become the characteristic symptoms. A bulbar palsy is a cranial neuropathy that produces a loss of function in the nerves that originate from the brain stem.

Botulism Differential Diagnosis
Notable symmetrical weakness Absence of sensory nerve damage Descending flaccid paralysis Prominent cranial nerve palsies

Botulism Confused with:
Myasthenia Gravis Tick Paralysis Organophosphate intoxication CNS infections More likely than, but confused with polyradiculoneuropathy: Guillain-Barre´ or Miller-Fisher syndrome

BOTULISM Diagnosis of botulism is made clinically Health care providers suspecting botulism should contact their State Health Department Centers for Disease Control and Prevention

Botulism Treatment Antibiotics not useful Equine Antitoxin risky
Neurologic support No neuromuscular blockade drugs Ventilatory support Respiratory failure secondary to paralysis of respiratory muscles is the most serious complication and generally the cause of death. Tracheostomy, ET tube, and ventilator support have decreased the rate of deaths due to botulism. Recovery can be slow and take from weeks to months.

Botulism Biosafety Alert
Botulism toxins are extremely poisonous Minute quantities acquired by ingestion, inhalation, or by absorption can cause death All materials suspected of containing toxin must be handled with CAUTION! Centers for Disease Control and Prevention

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