Robert J Leggiadro MD Villanova University Cohen Childrens Medical Center of NY Donald and Barbara Zucker School of Medicine at HofstraNorthwell ACHA Annual Meeting ID: 776683
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Slide1
Biological Threat Agents 101
Robert J. Leggiadro, MD
Villanova University
Cohen Children’s Medical Center of NY
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
ACHA Annual Meeting
Washington, DC
May 30, 2018
Slide2Disclosures
Dr. Leggiadro was a full-time employee of Pfizer and Merck
Slide3Learning Objectives
Know the epidemiology, including contagiousness and ease of dissemination, of the more credible biological threat agents.
Identify clinical features of the more credible biological threat agents, including recognition of unusual clinical syndromes or increases above seasonal levels in the incidence of common syndromes or deaths from infectious agents.
Understand management, including reporting, treatment and prevention, of the more credible biological threat agents.
Slide4Clinical and Epidemiological Clues to a BTA Attack
Abrupt onset\Large number of cases “Point-source” outbreak
Occurrence of non-endemic disease
Disease occurring “out of season”
Unusual clinical presentations
No obvious epi risk factors
Slide5Critical Biological Agents
Bacteria
Anthrax
Plague
Tularemia
Viruses
Smallpox
Viral hemorrhagic fever
Toxins
Botulinum toxin
Anthrax
Bacillus anthracis
, a bacterial zoonosis
Anthrakis, from the Greek word for coal
Cutaneous, inhalational, GI and injectional
clinical forms
Cutaneous most common 2
0
animal contact
No human-human transmission
Slide7Sverdlovsk
Incident at a military microbiology facility
Former Soviet Union, 1979
Grim warning of biologic weapons dangers
Accidental release anthrax spores
At least 79 cases, including 68 deaths
Largest reported inhalational outbreak, occurred within 4 km zone downwind
Slide8Investigation of Bioterrorism-related Anthrax and Interim Guidelines for Clinical Evaluation of Persons with Possible Anthrax CDC. MMWR 2001; 50: 94-8.
Slide9Investigation of Bioterrorism-related Anthrax and Interim Guidelines for Clinical Evaluation of Persons with Possible Anthrax CDC MMWR 2001; 50: 94-8.
Slide10Anthrax Mediastinal Widening
Jernigan JA et al. Emerg Infect Dis 2001; 7:933-44.
Slide11Anthrax Pneumonia
Jernigan JA et al. Emerg Infect Dis 2001; 7:933-44.
Slide12Anthrax Meningitis
Gram stain of cerebrospinal fluid showing B. anthracis. Jernigan JA et al. Emerg Infect Dis 2001; 7:933-44.
Slide13Inhalational Anthrax Management
Ciprofloxacin
and
1 additional antibiotic
e.g. linezolid
or
clindamycin
Cipro, meropenem and linezolid if meningitis has not been ruled out
Slide14Anthrax
Raxibacumab humanized monoclonal antibody directed against protective antigen, a component of the anthrax toxin.
Approved for use together with antibiotics to treat anthrax with systemic illness.
Anthrax Immune Globulin (AIG) CDC IND
Either AIG or raxibacumab antitoxin is indicated in cases of systemic anthrax.
Slide15Inhalational AnthraxPost-exposure ProphylaxisAntibiotics
Ciprofloxacin
Doxycycline
Amoxicillin
Vaccination
Anthrax vaccine adsorbed (AVA)
Inactivated, cell-free product, 3 doses
Slide16Cutaneous Anthrax
Blisters or small bumps may itchSwelling can occur around sorePainless ulcer with black center later (eschar) Face, neck, arms, handswww.cdc.gov/anthrax
Slide17Smallpox
First used as biological weapon over 200 years ago
British troops infected Native Americans
through contaminated blankets
Slide18Smallpox
Responsible for more deaths than any other infectious disease.
18th century Europe; 400,000 deaths/yr, including peasants and monarchs alike.
20th century alone; 1/2 billion deaths.
1949; last case in U.S. (Texas)
Routine immunization in U.S. ended in 1972
Target date for destruction
of known virus stock deferred
Slide19Smallpox:Potential Significance
WHO declared eradication in 1980
Known viral stocks in only 2 labs: U.S. and Russia
? Clandestine stockpiles of virus
Increasing number of
susceptibles
Stable virus, aerosol infectivity,
human-human transmission, high mortality
Diagnosis of Smallpox
Requires astute diagnostician to distinguish from varicella or erythema multiforme
Tissue culture, variola-specific PCR assay and serologic tests will be performed at CDC reference laboratory
Slide21Smallpox
Lesions on each area at same stage of development; deeply embedded; concentrated on face, extremities.Henderson DA. Emerg Infect Dis 1999; 5: 537-9.
Slide22Chickenpox
Series of crops; superficial; trunk. Henderson DA. Emerg Infect Dis 1999; 5: 537-9.
Slide23Smallpox:Medical Management
Even one confirmed case is an international public health emergency with immediate reporting to public health authorities
Strict isolation with both respiratory and wound isolation
No proven effective antiviral therapy
Slide24New York City Residents Line Up for Vaccinations During a Smallpox Vaccination Campaign, 1947. CDC. MMWR 2003; 52: 933-6.
Slide25Smallpox:Preventive Measures
Vaccination
: vaccinia live virus vaccine
- Protection decreases with time
- Contraindicated if pregnant or
immunosuppressed
All contacts should be STRICTLY quarantined for 16 -17 d post-exposure
Slide26Smallpox Vaccines
Do not contain variola virus
Made from related vaccinia virus
FDA licensed new smallpox vaccine, grown in lab cell culture, ACAM2000 in 2007, which replaced previously licensed vaccine Dryvax
Two additional smallpox vaccines in the Strategic National Stockpile are: WetVax and Imvamune
Slide27Smallpox Vaccines
WetVax liquid formulation live vaccinia virus similar to lyophilized vaccine, Dryvax
ACAM2000 and WetVax by scarification (percutaneous, bifurcated needle)
Imvamune 3
rd
-generation, non-replicating smallpox vaccine for healthy persons AND persons with immunocompromising or pre-existing conditions, e.g., atopic dermatitis (subcutaneous injection)
Slide28Dermatologic Vaccinia Reactions
Progressive vaccinia:
Necrosis in the area of vaccinia
Eczema
vaccinatum
:
Local or generalized spread of vaccinia virus in eczema
Generalized vaccinia:
Skin lesions remote from the vaccination site
Adalja AA et al. N
Engl
J Med 2015; 372: 954-62
Slide29Household Transmission of Vaccinia Virus from Contact with a Military Smallpox Vaccinee—IL and IN, 2007 CDC. MMWR 2007; 56: 478-81
Slide30Smallpox Vaccination and Adverse Reactions CDC. MMWR 2003; 52(RR04): 1-28
Slide31Ring Around the Rosie: Plague Reference
Ring around the rosie (rosy rash of plague)
A pocket full of posies (herbs to ward off smell of the dead)
Ashes! ashes! (cremation and burning victims’ houses)
We all fall down (die)
Slide32Plague
Zoonotic illness (
Yersinia pestis
)
First used as biological weapon
in the 14th century
Tatar force attacking Caffa (Ukraine)
Catapulted bodies of plague victims
into the city
Slide33Plague
Primarily disease of rodents
Transmission to humans: flea bites, direct contact infected body fluids or tissues, or inhalation respiratory droplets (human-human transmission)
1-17 average # cases reported in the U.S. between 2001-2012; median # , 3
Arizona, California, Colorado, New Mexico
Bubonic, septicemic, pneumonic
clinical forms
Slide34Epidemiology of Human Plague in the U.S.
Multiple rodents contribute to the current ecology of plague in the U.S., including:
Ground squirrels
Prairie dogs
Wood rats
Chipmunks
Deer mice
Voles
16
Slide35Reported Cases of Human Plague— United States, 1970--2016
www.cdc.gov/plague
Slide36Human Plague Cases and Deaths United States, 2000-2016
www.cdc.gov/plague
Slide37Reported Plague Cases by Country, 2010-2015
www.cdc.gov/plague
Slide38Plague: Potential Significance
Could be delivered as aerosol
during a biological attack
Has been studied as potential
weapon by both Japan (WWII)
and United States (1950s)
Slide39Pneumonic Plague: Clinical Features
Incubation period of 2-3 days
Initial symptoms are nonspecific:
fever, chills, headache, cough
Later progresses to respiratory
failure and shock
Human-to-human transmission
Slide40Diagnosis of Plague
Gram\Wright-Giemsa\Wayson stain:
- Gram negative coccobacillus
- Bipolar “safety-pin” staining
Pinpoint, grayish, slightly mucoid
colonies after 24 hours on culture
Confirmatory testing at CDC’s
reference laboratory (DFA, PCR)
Slide41Plague Management
Streptomycin, gentamicin
Doxycycline, ciprofloxacin
Post-exposure Prophylaxis
Doxycycline, ciprofloxacin
Pre-exposure Prophylaxis
Killed, whole-cell vaccine no longer available
Droplet precautions for pneumonic plague
Slide42Tularemia
Infection with
Francisella tularensis
Zoonosis
Infectious dose is very low
No human-human transmission
Several forms reflect portal of entry: ulceroglandular, glandular, pneumonia, oropharyngeal, oculoglandular, typhoidal and gastrointestinal
Slide43Tularemia
U.S., 2001-2010
1,208 cases (mean, 126 cases/yr; range, 90-154)
Cases were reported from 47 states
MO, AR, OK, MA, SD, KS; 59% cases
77% cases occurred May through September
Peak arthropod activity/outdoor human activity
Most common males, young and old
Slide44Tularemia
Transmission
Arthropod bites (Summer)
Animal contact (Winter)
Aerosolization (Lawn mowing)
Contaminated water (Europe)
Slide45Reported cases of tularemia—United States, 2001-2010
Tularemia—United States, 2001-2010. CDC. MMWR 2013; 62: 963-6.
Slide46Average incidence of tularemia, by age group and sex—United States, 2001-2010
Tularemia—United States, 2001-2010. CDC. MMWR 2013; 62: 963-6.
Slide47Geographic distribution of reported tularemia cases—CO, NE, SD, and WY, January-September, 2015
Pedati C, et al. Increase in Human Cases of Tularemia—CO, NE, SD, and WY, June-September, 2015. CDC. MMWR 2015; 64:1317-8.
Slide48Tularemia, U.S.- September, 2015
About 125 cases reported annually over the past 20 years
As of 9/30/15, 100 cases reported from CO (43), NE (21), SD (20), and WY (16)
Substantial increase in annual mean # of cases reported in each state during 2004-2014
Slide49Tularemia, U.S.-- 9/30/15
Possible reported exposure routes:
Animal contact n=51
Environmental aerosolizing activities n=49
Arthropod bites n=34
41 patients reported 2 or more exposures
Slide50Tularemia, U.S.--9/30/15
Cause for the increases in 4 states unclear
Possible explanations include:
Increased rainfall promoting vegetation
Pathogen survival
Increased rodent and rabbit populations
Slide51Tularemia
Diagnosis
Serology, Culture, DFA, PCR
Treatment
Aminoglycosides
Ciprofloxacin, doxycycline
Slide52TularemiaBioterrorist Event
Inhalation of aerosol likely route
Pneumonic or typhoidal most likely
clinical manifestations
Postexposure
Doxycycline, ciprofloxacin
Pre-exposure
Live-attenuated vaccine no longer available in the U.S.
Slide53Botulism:Potential Significance
Clostridium botulinum
toxin is one of the most potent compounds known
Clinical forms include infantile, wound, GI, iatrogenic, and inhalational (rare)
Can be aerosolized or used to
sabotage food/water supplies
No human-human transmission
Slide54Botulism:Clinical Features
Estimated toxic dose = .0001
u
g/kg
Incubation period for inhalational
botulism varies from 24-36 hours
Syndrome is the same whether
toxin is ingested or inhaled: afebrile; symmetric, descending paralysis, clear sensorium with bulbar palsies; diplopia, dysarthria, dysphonia, dysphagia
Slide55Diagnosis of Botulism
Clinical presentation may be
confused with Guillain – Barre
or myasthenia gravis
Toxin assay on sera, stool
or “suspect” food
Eight known toxin types: A through H; A (West), B (East), E (Canada, Alaska); E is found almost exclusively in seafood; G does not cause natural human disease
Slide56Botulism:Medical Management
Intensive supportive care
(often for weeks or months)
Equine-derived Heptavalent (A-G) Botulinum Antitoxin (BAT)
Licensed by FDA 2013 and
available exclusively through CDC
No vaccine
Features Suggesting Deliberate Botulinum Toxin Release
Outbreak of acute flaccid paralysis with prominent bulbar palsies
Outbreak with unusual botulinum toxin type (C,D,F, or G, or E not from aquatic food)
Outbreak with common geographic factor, but without common dietary exposure (suggestive of aerosol attack)
Multiple simultaneous outbreaks without common source
Slide58Viral Hemorrhagic Fever
Arenaviruses
New World
Argentine, Bolivian, Brazilian, Venezuelan
Old World
Lassa Fever
Bunyaviruses
HFRS (Old World Hantavirus)
HPS (New World Hantavirus)
Crimean-Congo HF
Rift Valley Fever
Slide59Viral Hemorrhagic Fever
Filoviruses
Marburg
Ebola
Flaviviruses
Dengue
Yellow Fever
Slide60Viral Hemorrhagic Fever
Geographic Distribution
Ebola, Marburg Africa
Lassa (Old World Arenavirus) West Africa
New World Arenavirus Americas
Yellow Fever Africa, Americas
Dengue Africa, Americas, Asia
Hantavirus Americas, Asia
Rift Valley Fever Africa, Middle East
Crimean-Congo HF Africa,Balkans,ME,Asia
Slide61Viral Hemorrhagic Fever
Vectors
Rodent: Arenavirus, Hantavirus
Tick: Crimean-Congo HF
Mosquito: Rift Valley Fever
Yellow Fever, Dengue
Fruit Bat: Ebola
Marburg
Viral Hemorrhagic Fever
Clinical Features
Symptoms vary among viruses
Fever, myalgia, prostration
Petechiae, hemorrhage, shock
Neurologic, pulmonary, hepatic involvement
Mortality
Highest in Filoviruses
Slide63Ricin
Ricin toxin extracted from beans of the castor plant; byproduct of castor oil
Found in paints, varnishes, oils
Inhibits protein synthesis
Inhalation, ingestion, injection
CDC Category B threat agent
1978 assassination Bulgarian exile
Slide64References
CDC. Investigation of bioterrorism-related anthrax and interim guidelines for clinical evaluation of persons with possible anthrax.
MMWR
2001; 50: 94-8.
Jernigan JA, et al. Bioterrorism-related inhalational anthrax: The first 10 cases reported in the United States.
Emerg Infect Dis
2001; 7: 933-44.
www.cdc.gov/anthrax
Henderson DA. Smallpox: Clinical and epidemiologic features.
Emerg Infect Dis
1999; 5:537-9.
CDC. Cardiac deaths after a mass smallpox vaccination campaign-New York City, 1947. MMWR 2003; 52: 933-6.
Adalja AA, Toner E, Inglesby TV. Clinical management of potential bioterrorism conditions.
N Engl J Med
2015; 372: 954-62
Slide65References
CDC. Household transmission of vaccinia virus from contact with a military smallpox vaccinee--IL and IN, 2007.
MMWR
2007; 56: 478-81
CDC. Smallpox vaccination and adverse reactions.
MMWR
2003; 52 (RR04): 1-28.
www.cdc.gov/plague
CDC. Tularemia—United States, 2001-2010.
MMWR
2013; 62: 963-6.
Pedati C, et al. Increase in human cases of tularemia—CO, NE, SD, and WY, January-September 2015.
MMWR
2015; 64: 1317-8.
Slide66Self Assessment
Anthrax, plague, and tularemia are all zoonoses. True or False
Known stocks of smallpox virus currently exist in only two labs, one in the United States and one in Russia. True or False
Bodies of plague victims were catapulted into the city during the siege of Caffa in the 14
th
century. True or False
Diagnosis of tularemia pneumonia in an urban setting without a travel history would warrant evaluation of a possible intentional release. True or False
Vaccines are available for anthrax and smallpox. True or False
Slide67Self Assessment
Declared eradicated worldwide in 1980, the report of a single case of smallpox would represent an International Public Health Emergency. True or False
Plague is endemic in the Southwest U.S. True or False
The intentional release of anthrax through contaminated U.S. mail in the Fall of 2001 was an act of bioterrorism. True or False
Antimicrobial therapy is available for anthrax, plague, and tularemia. True or False
Antitoxin therapy is available for botulism through the CDC. True or False
All answers are True