Management of Potential Exposure to Biological Agents: Anthrax, Tularemia, and Plague

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Management of Potential Exposure to Biological
AgentsAnthrax, Tularemia, and Plague

• LTC Michael J. Roy, MD, MPH
• Dir., Div. of Military Internal Medicine
• Uniformed Services University

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Case Scenario

• 38 y.o. woman, White House press secretary
• Attended Redskins game 3 days ago
• Travel to Far East in past 2 weeks
• Fever, headache, fatigue, dry cough, sore throat
• Exam? Tests?
• Differential Diagnosis? Empiric Rx?

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Findings

• No skin lesions
• Enlarged cervical lymph nodes
• Slight pharyngeal exudate
• WBC 13,000
• Chemistries unremarkable

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Biological Warfare Agents

• Anthrax (Bacillus anthracis)
• Inhalational
• Direct skin contact
• Ingestion
• Tularemia (Francisella tularensis)
• Ulceroglandular
• Typhoidal

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Bacillus anthracis

• Gram-positive rod
• Transformation to spores
• Protects vs. heat/cold, drying, radiation
• May survive for decades
• Highly infectious
• germinate in macrophage
• Carried to regional lymph nodes
• Produce toxinsgtgttissue necrosis edema

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(No Transcript)
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Easily transmissible
but not person-to-person
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NEJM, Sep 9, 1999
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Cutaneous Anthrax Presentation

• Exposed areas prior cuts or abrasions most
  commonly involved
• Initial 1-2 cm pruritic red papule or macule _at_
  1-6 days (max 12 days)gtgt
• ulceration by the next daygtgt
• 1-3 mm vesicles filled w/ bacteriagtgt
• Painless black eschar, falls off 1-2 wks

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Cutaneous Anthrax
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Cutaneous Anthrax
JAMA, May 12, 1999
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Eschar with edema
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Course of cutaneous anthrax
NEJM, Sep 9, 1999
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Cutaneous Anthrax Presentation

• Spores germinate in tissue
• Produce toxin, leading to local edema
• Antibiotics dont affect eschar course, but do
  prevent systemic disease
• Mortality up to 20 w/o antibiotics
• Mortality rare w/ antibiotics

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Cutaneous Anthrax Infant
NEJM Nov 29, 2001
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Inhalational Anthrax

• Spores enter alveoli
• Ingested by macrophages
• Lysis
• Destruction

NEJM, Sep 9, 1999
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Inhalational Anthrax

• Surviving spores go to mediastinal lymph nodes
• Germination in days to months
• Replicating bacteria release toxins
• Hemorrhage, edema, necrosis
• Mediastinal widening

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Anthrax Classic CXR findings
JAMA, Nov 28, 2001
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Anthrax mediastinal widening
NEJM Nov 29, 2001
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Anthrax Fatal Progression
JAMA, Nov 28, 2001
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Anthrax CXR Gram Stain
JAMA, Nov 28, 2001
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Anthrax CXR Chest CT
JAMA, Nov 28, 2001
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Anthrax CXR Chest CT
JAMA, Nov 28, 2001
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Inhalational Anthrax Symptoms

• 1st Phase (hours to days)
• Fever, myalgias, fatigue, /- cough, HA, dyspnea,
  chest pain, abdominal pain
• Transient improvement for some
• 2nd Phase (abrupt onset, rapid course)
• Fever, dyspnea, diaphoresis, shock
• Cyanosis, hypotension, death (hours)

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Anthrax vs. influenza
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Hemorrhagic meningitis
Complicates 50 of inhalational anthrax
cases almost always fatal
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Lab Changes with Anthrax

• Elevated WBC /- thrombocytopenia
• Severe hypoglycemia
• Hyperkalemia
• Hypocalcemia
• Respiratory alkalosis, terminal acidosis
• Late positive blood gram stain, culture
• Sputum gram stain usually negative

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Diagnosis of Anthrax

• PCR or ELISA at national reference labs
• Contact local Dept of Health or CDC
• Clinical pathognomonic signs such as mediastinal
  widening occur too late to save patient
• Treat based on suspicion first, diagnose later

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Anthrax Mortality Rates

• Estimated 80-90 with inhalation
• Antibiotics highly effective if started prior to
  symptoms, may also work if started in 1st phase,
  but mortality close to 100 even if started in
  2nd phase
• Estimated 10-20 for cutaneous form without
  treatment, less than 1 with antibiotic treatment

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Rx for Inhalational Anthrax

• 60 day course, IV, then oral when stable
• Cipro 400 mg IV q 12 hours
• Doxycycline 100 mg IV q 12 hours
• PCN 4 million U IV q 4 hrs if sensitive
• In vitro evidence for ofloxacin 400 mg IV q 12
  hrs levofloxacin 500 mg IV qd
• Alternatives gentamicin, erythromycin,
  chloramphenicol, tetracycline

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Anthrax treatment in children

• Cipro 10-15 mg/kg IV q 12 hours
• PCN 50,000 U/kg IV q 6 hours
• Doxycycline 2.2 mg/kg IV q 12 hrs
• If gt8 and gt45 kg, use adult dosing

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Post-exposure prophylaxis

• 60 day course unless vaccine available
• Cipro 500 mg po q 12 hours
• If susceptible strain
• Amoxicillin 500 mg po q 8 hours
• Doxycycline 100 mg po q 12 hours
• In vitro evidence for ofloxacin (400 BID) and
  levofloxacin (500 qd)

acceptable in pregnancy immunocompromised
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Prophylaxis for children

• Cipro 10-15 mg/kg po BID
• Do not exceed 500 mg BID
• If susceptible strain
• Amoxicillin 40 mg/kg po q 8 hours
• Adult dose if gt 20 kg
• Doxycycline 100 mg po q 12 hours
• Adult dose if gt 8 yrs and gt 45 kg

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After possible exposure

• Immediately wash hands w/soap, water
• Isolate area with suspicious item(s)
• Remove clothing or other belongings in contact
  with suspicious item, and place in plastic bags
• Contact law enforcement agents
• Shower with soap and water
• Person-to-person transmission unlikely

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Gastrointestinal anthrax

• Ingestion of large of anthrax spores
• Spores germinate in GI tract
• Toxins destroy mesenteric lymph nodes
• Mesenteric hemorrhages, bowel infarcts
• Unlikely to occur with bioterrorism

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GI anthrax clinical picture

• Fever, nausea, vomiting, abdominal pain, bloody
  diarrhea
• Progression to acute abdomen
• Sometimes accompanied by ascites, may be severe,
  with rapid onset
• High mortality

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Anthrax Enteritis on CT
JAMA, Nov 28, 2001
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Anthrax vaccine

• Cell-free filtrate from attenuated strain
• Contains no whole bacteria, dead or alive
• Licensed by the FDA in 1970
• Safely and routinely administered to at-risk wool
  mill workers, veterinarians, laboratory workers,
  livestock handlers, military
• Manufactured by BioPort

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Vaccine side effects

• 30 of men, 60 of women have local tenderness,
  erythema, edema, a/o pruritis for up to 2-3 days
• 5-35 have myalgias, Has, nausea, fever, chills,
  malaise for up to 2-3 days
• 1/200,000 hospitalized, incl. lt1/100K w/ allergic
  reactions

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Anthrax vaccine efficacy

• Aerosol anthrax challenge after two doses
• All 25 monkeys challenged _at_ 8-38 weeks survived
• 18/20 monkeys challenged _at_ 10-20 weeks survived
• 9 of 10 monkeys challenged 2 years later survived
  
• Aerosol anthrax challenge after one dose
• All 10 monkeys challenged 6 weeks later
• survived

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US Military Anthrax ImmunizationProcedures
Plus annual booster
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Francisella tularensis

• Aerobic gram-neg. coccobacillus
• Non spore former
• Lasts weeks in
• moist soil, hay
• Culture on cysteine
• heart blood agar
• opalescent

JAMA June 6, 2001
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Tularemia infection

• Can enter through breaks in skin, mucous
  membranes, GI tract, lungs
• Multiplies within macrophages
• Spreads to regional lymph nodes, may
  disseminate throughout body
• Clinical findings vary by site of infection,
  dose, and virulence

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Ulceroglandular form

• Most common with animal or arthropod contact
• Lesions on skin, mucous membranes, or
  conjunctivae (0.4 to 3 cm, with raised edges)
  papulegtgtpustulegtgtulcer within a few days
• Tender, fluctuant adenopathy gt 1 cm
• _at_ 3-6 days, fever w/pulse-temp dissoc, chills,
  HA, cough, /- myalgias

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Tularemia skin lesion
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Tularemia ulcer
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Oropharyngeal tularemia

• Most common with contaminated food or water
  ingestion, can occur with aerosol exposure
• Severe sore throat
• Exudative pharyngitis or tonsillitis /- ulcers,
  fever
• Prominent cervical adenopathy

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Tularemia adenopathy
JAMA June 6, 2001
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Pulmonary involvement

• Common occurs 3-5 days post-aerosol exposure, or
  via hematogenous spread
• Bronchopneumonia in one or more lobes some with
  hilar adenopathy a/o pleural effusions
• Pharyngitis often associated
• Can progress to resp. failure death

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Tularemia CXR findings
JAMA June 6, 2001
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Typhoidal tularemia

• Ulcers adenopathy absent
• Fever, chest pain, cough, abd pain, other
  nonspecific symptoms
• Most have pneumonia, associated w/ greater
  mortality than ulceroglandular
• Pericarditis, enteritis, appendicitis,
  peritonitis, meningitis, E. nodosum may be
  associated

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Lab Findings w/ Tularemia

• Mild elevation of WBC w/normal diff
• Microscopic pyuria
• Mildly elevated transaminases, LDH, and alkaline
  phosphatase
• Sometimes causes rhabdo, w/ incr CPK
• CSF some have mildly abnormal glucose, protein,
  or cell count

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Diagnosis of tularemia

• Staining or DFA of sputum, exudates, or biopsies
• Later confirmation by serology
• Culture is difficult

JAMA June 6, 2001
Gram Stains Anthrax Plague
Tularemia
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Tularemia Mortality Rates

• Historically, up to 5-15 w/o treatment, now 1-
  2 with appropriate treatment
• Up to 30-60 for untreated pneumonic or other
  severe disease
• Approximately 35 for typhoidal form
• Approximately 4 for ulceroglandular form

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Treatment of tularemia

• Streptomycin 1g IM BID X 10 days
• Gentamicin 5 mg/kg IM or IV qd X 10d
• Alternatives
• Cipro 400 mg IV BID X 10 days
• Doxycycline 100 mg IV BID X 2-3 wks
• Chloramphenicol 15 mg/kg IV QID X 2-3 weeks

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Tularemia Rx in Children

• Streptomycin 15 mg/kg IM BID
• Gentamicin 2.5 mg/kg IM or IV TID
• Alternatives
• Doxycycline 2.2 mg/kg IV BID
• Adult dose if gt 8 and gt 45 kg
• Chloramphenicol 15 mg/kg IV QID
• Cipro 15 mg/kg IV BID

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Post-exposure prophylaxis

• Treat for 14 days, or wait for flu-like symptoms,
  then treat 14 days
• Doxycycline 100 mg po BID, or
• Cipro 500 mg po BID
• Children
• Doxycycline 2.2 mg/kg po BID, or
• Cipro 15 mg/kg po BID

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Tularemia vaccine

• Live, attenuatedused for lab workers being
  reviewed by FDA
• Reduced inhalation infection in lab workers from
  5.7/1000 person-yrs to 0.27 ulceroglandular not
  decreased, but milder
• Not recommended for post-exposure

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Plague (Yersinia pestis)

• Nonmotile, non-spore forming GNR
• Wright-Giemsa bipolar staining
• Flea bite can
• deposit thousands
• of organisms into
• skin

JAMA, May 3, 2000
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Plague natural pathogenesis

• Spread to regional lymph nodes
• Characteristic buboes
• Rapid multiplication
• Destruction necrosis of LNs
• Bacteremiagtgtsepsisgtgtendotoxemia
• DIC, coma, and death ensue

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Plague progression
Cervical bubo
Sepsis leads to Petechiae ecchymoses
Gangrene of Digits (black death)
JAMA, May 3, 2000
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Pneumonic plague

• Secondary in 10-25, via hematogenous spread
  after flea bite
• Bronchopenumonia, chest pain, dyspnea, cough,
  hemoptysis
• Primary inhalational exposure
• Most likely with bioterrorism
• Also can occur with exposure to infected animal
  or individual with pneumonic form

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Pneumonic plague CXR
Consolidation, Bilateral Infiltrates common
JAMA, May 3, 2000
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Plague bioterrorism

• Symptoms in 1-6 days (avg 2-4)
• Fever, dyspnea, cough /- hemoptysis
• May have nausea, vomiting, abdominal pain
  diarrhea
• Progression to septic shock
• Leukocytosis, toxic granulation, coagulopathy,
  transaminitis, azotemia

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Diagnosing Plague

• GNRs on gram stain of sputum or blood
• Bipolar Wright or Giemsa staining
• Cultures _at_ 24-48 hours or more
• Few labs able to do PCR, AG detection, or IgM EIA

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Treatment for Plague

• Preferred
• Streptomycin 1g IM BID
• Gentamicin 5 mg/kg IM or IV qd
• Alternatives
• Doxycycline 100 mg IV BID
• Cipro 400 mg IV BID
• Chloramphenicol 25 mg/kg IV QID

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Treating Plague in Children

• Preferred
• Streptomycin 15 mg/kg IM BID
• Gentamicin 2.5 mg/kg IM or IV TID
• Alternatives
• Doxycycline 2.2 mg/kg IV BID
• Cipro 15 mg/kg IV BID
• Chloramphenicol 25 mg/kg IV QID

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Prophylaxis for Plague

• Doxycycline 100 mg po BID, or
• Cipro 500 mg po BID
• Children
• Doxycycline 2.2 mg/kg po BID, or
• Cipro 15 mg/kg po BID

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Case Scenario revisited

• Most likely diagnosis?
• Confirmatory
• tests?
• Best treatment?
• Coverage of
• other possibilities?

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Conclusions

• Treat promptly if anthrax in differential
• Antibiotic treatment for anthrax covers plague
  and tularemia as well
• Empiric treatment for possible exposure more
  important for anthrax than tularemia