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Author: Susan Hadley, M.D.
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1. General Introduction

While advances in identification, culture techniques, diagnosis and treatment have led to remarkable improvements in the consequences of infectious diseases worldwide in the past quarter century, newly identified pathogens continue to emerge and affect mankind. Recent examples include Legionella species, hemorrhagic fever viruses (Ebola and others), Hantavirus, and HIV. The past several years have proved extremely rich in old pathogens (anthrax, smallpox) and pathogens in new populations (West Nile Virus, coronavirus, monkeypox virus) creating important public health challenges.

In addition, antimicrobial resistance is developing at a rapid pace and contributing to the re-emergence of some major infectious disease challenges such as multi-drug resistant tuberculosis, penicillin resistant Streptococcus pneumoniae and community acquired- or vancomycin resistant- Staphylococcus aureus.

1.1. Objective

The objective of this lecture is to briefly review the microbiology, epidemiology and pathology of 5 emerging pathogens.

2. Factors contributing to the emergence of infections include:

(adapted from Table 54.4, Schaechter (1998). Mechanisms of microbial disease. Third Edition. Baltimore, MD: Williams and Wilkins)

2.1. Change in the ecological niche or global environment

  • Lyme disease in the wake of reforestation
  • Hantavirus in the wake of weather changes

2.2. Human behaviors

  • AIDS epidemic in the wake of sexual behaviors and IV drug users

2.3. International travel/trade

  • Cholera spread to South America
  • Malaria in returning traveler
  • West Nile Virus in Northern Hemisphere
  • SARS

2.4. Technology applied to industry

  • Enterohemmorhagic E. coli in mass food processing
  • Viral transmissions with medical use of blood and tissues
  • Toxic shock and tampon use

2.5. Microbial adaptation

  • Antibiotic resistance

2.6. Relaxation of public health controls

  • Multi-drug resistant tuberculosis

3. Four definitions of Emerging Infections

These pathogens reflect the four definitions of the verb “to emerge” found in Webster’s dictionary:

3.1. To become manifest: Agents of biological warfare

  1. Variola virus (smallpox)
  2. Bacillus anthracis (anthrax)

3.2. To rise from an obscure or inferior position or condition: Epizootic infections, transcontinental spread

  1. West Nile Virus
  2. (Monkeypox virus)

3.3. To rise from or as if from an enveloping fluid; to come out into view: new variant of common virus

  1. Coronavirus (SARS)

3.4. To come into being through evolution: evolution of resistance genes

  1. Glycopeptide intermediate Staphylococcus aureus
  2. Multi-drug resistant tuberculosis

Do not memorize everything in this syllabus, but use it as a reference. Pay attention to the key concepts and how the emerging infections emphasize these concepts.

4. Agents of Biological Warfare

4.1. Key Concepts:

Characteristics of ideal biological warfare agents

4.2. Environmental survival:

spores of Anthrax viable at extremes of environmental stresses; spore size ideal for inhalation into lower respiratory tract; body temperature allows for germination and release of toxin

4.3. Widely spread before detected:

smallpox long incubation period

4.4. High fatality rate:

inhalational anthrax and toxin mediated cell death


Viral hemorrhagic fevers

5. Definition of bioterrorism:

Bioterrrorism is the intentional or threatened use of viruses, bacteria, fungi, or toxins from living organisms to produce death or disease in humans, animals, or plants

6. Characteristics of ideal biological warfare agents

  1. high morbidity and mortality
  2. easy to produce
  3. efficiently disseminated and/or able to spread from person to person
  4. stable in aerosol form
  5. highly infective

7. Classification of agents of biological warfare

7.1. Category A

  • Easily disseminated or transmitted person to person
  • High mortality
  • Potential to cause public panic and disruption
  • Require special action for preparedness
    Organism Syndrome
    Bacteria: B. anthracis Anthrax
    Yersinia pestis Plague
    Franciscella tularensis Tularemia
    Clostridium botulinum toxin Botulism
    Viruses: Variola major Smallpox
    Hemorrhagic fever viruses:
    Marburg, Ebola

7.2. Category B

  • Moderately easy to disseminate
  • Moderate morbidity; low mortality
  • Require specific diagnostic tests and enhanced disease surveillance
    Organism Syndrome
    Bacteria: Coxiella burnetti Q fever
    Brucella species Brucellosis
    Burkholder mallei Glanders
    Staphylococcus enterotoxin B
    Food- or waterborne pathogens
    Salmonella
    Shigella dysenteriae
    E. coli 0157:H7
    Vibrio cholerae
    Viruses: Venezuelan encephalomyelitis; Eastern and Western Equine
    Encephalomyelitis
    Toxin: Ricin (from castor beans)

8. Requirements for a public health response to a biological terrorism event

  1. conduct surveillance
  2. investigate disease clusters
  3. test a hypothesis regarding disease transmission
  4. evaluate control strategies

9. Descriptions of Organisms

9.1. Bacillus anthracis

A gram positive spore forming rod

  • spores are resistant to a wide variety of environmental changes and may survive in soil for years -first disease to fulfill Koch’s postulates
  • first bacterial disease for which a vaccine available (1881)
  • toxin production mediates cell death allowing access of organisms to the circulation
    • antiphagocytic capsule is produced by organism as well as 3 virulence factors
      • EF: edema factor
      • LF: lethal factor
      • PA: protective antigen
    • Toxins are formed when EF + PA combine (edema toxin) or LF + PA combine (lethal toxin)

9.1.1. Pathogenesis:

Introduction of spore (skin, mucous membrane, lung)
germination of spores and extracellular replication
capsule and toxin production

9.1.1.1. 3 disease states

  1. gastrointestinal (rare)
    • ingestion of undercooked, contaminated meat
    • fever, abdominal pain, diarrhea (may be bloody)
  2. cutaneous
    • most common form of endemic anthrax
    • contracted by close contact of abraded skin with products
    • derived from infected herbivores (sheep, cattle, goats)
  3. inhalational (the form of biological terrorism)
    • spores deposited in alveoli (2-6 µ) and ingested by pulmonary macrophages and carried to tracheobronchial or mediastinal lymph nodes where they germinate (1-6d) and toxin production occurs resulting in necrosis of the lymphatic tissue causing release of large numbers of B. anthracis which gain access into the circulation resulting in overwhelming bacteremia and death
    • 1-6 d hemorrhagic mediastinitis
      • CXR HALLMARK: widened mediastinum from hemorrhaged lymph nodes
      • Subsequent bacteremia, pneumonia +/- meningitis and DEATH in 3-5 days

9.1.2. Diagnosis

  • culture from blood, although this occurs late in fatal disease process

9.1.3. Management

  • antibiotics, supportive care
    • Ciprofloxacin
    • Doxycycline
  • prophylaxis for other possibly exposed individuals
    • Ciprofloxacin or doxycycline for 60 days
    • Immunization (3 doses required at 0, 2, and 4 weeks)

9.2. Smallpox (Variola major)

A unique DNA virus for which humans are its only reservoir.

9.2.1. Mode of transmission:

person to person spread by air droplets/aerosols

9.2.2. Pathogenesis:

Inahalation of air droplet
mucosal replication and viremia
dissemination to organs and skin
INCUBATION PHASE (7-17 [12] DAYS)
2ND viremia
TOXEMIC PHASE
rash (3-4d), high fevers, myalgias
head arms + hands legs and trunk
HIGHLY INFECTIOUS VIRAL SHEDDING LESIONS

How to distinguish from chickenpox:

  • Smallpox lesions develop at the same pace and are uniform in appearance and deep in skin
  • Chickenpox lesions are more superficial, develop in crops over several days and are at varying stages from vesicle to scab to crust at any given time
  • Smallpox lesions are “top heavy” – head, arms, legs, then trunk Chickenpox lesions most dense on the trunk

9.2.3. Treatment:

isolation, supportive care

9.2.4. Prevention:

vaccination before exposure or within 2 to 3 days of exposure
Vaccinia live virus

  • Complications:
    • Accidental infection
    • Generalized vaccinia
    • Eczema vaccinatum
    • Postvaccinal encephalopathy
    • Progressive vaccinia
    • Myocarditis

10. Epizootic infections

10.1. West Nile Encephalitis

  • Key Concepts:
    • Spread to humans from vertebrate host via bridge vector (mosquito able to bite both humans and birds, in case of WNV) that has transmitted virus as a result of globalization across continents
    • Rapidly expanding geographic distribution
    • Advanced age is greatest risk factor for severe neurologic disease

10.1.1. Virology:

RNA flavivirus

10.1.2. Transmission cycle:

West Nile Virus

Adapted from: Petersen et al. West Niile Virus: A Primer for the Clinician. Annals of Internal Medicine 2002;137:E173-E179

10.1.3. Clinical features:

Symptom % Symptom %
Fever 90 Myalgia 32
Fatigue 63 Photophobia 32
Δ Mental Status 58 Abnormal reflexes 32
Headache 58 Meningismus (stiff neck) 32
Weakness 42 Abdominal pain 21
Nausea 42 Motor weakness 16
Vomiting 42 Seizures 16

The majority of infections are asymptomatic. Fever, neurologic and gastrointestinal symptoms are most common. The neurologic effects are most severe in the elderly; cases of acute flaccid paralysis/polio-like syndrome have been reported.

A high index of suspicion for WNV in setting of older adults with onset of unexplained encephalitis or meningitis in late summer or early fall should be maintained.

10.1.4. Diagnosis:

10.1.4.1. CSF examination:

pleocytosis with lymphocytic predominance; elevated protein

10.1.4.2. Serologic examination:

the most efficient diagnosis is detection of IgM antibody to WNV in serum or CSF by ELISA – this test is available through local or state health departments. All cases should be reported to the CDC.

10.1.5. Treatment and Prevention:

  • Treatment is supportive.
    • No controlled studies demonstrating benefits of antiviral agents. Promising vaccine candidates in development. One is based on a licensed yellow fever vaccine that contains 2 WNV genes and is currently in human trials. Another uses an attenuated dengue virus with WNV genes inserted.
  • Prevention:
    • States dead bird/mosquito pool surveillance
    • Mosquito control:
      • DEET, drainage of standing water
    • Vaccine:
      • experimental, available only for horses

11. New Variant of Common Virus

To Come Out Into View: SEVERE ACUTE RESPIRATORY SYNDROME (SARS)

11.1. Key Concepts:

  • Newly recognized transmissible respiratory illness characterized by fever then rapidly progressive respiratory compromise
  • Case fatality rate 3 to 4% worldwide; higher in those with advanced age or comorbidities
  • Probable viral etiology (SARS coronavirus) that may have jumped species from masked palm civets, raccoon dogs and badgers
  • Transmission most likely through direct contact and air droplets suspended in air; airborne route of infection emphasizes the importance of strict infection control practices to limit the spread of infection

Severe respiratory illness outbreak first reported in November 2002 in China, then worldwide spread. The contagiousness of the illness suggested an infectious etiology. Incubation period appeared to be 2-16 days with a median of 6 days. Without knowledge of the etiologic agent, cases were defined by clinical, epidemiologic and laboratory criteria and classified as probable, suspect or excluded cases. A novel corona like virus with 50 – 60% homology with human coronaviruses was isolated from respiratory specimens and subsequently isolated from other non-human mammalian species. The importance of infection control practices to limit the spread of infection was emphasized by the recurrence of the outbreak in Toronto, CA when unsuspected cases incubated in hospitals after relaxation of infection control precautions.

11.2. CDC Case Criteria: 3 categories for case classification

Clinical Epidemiologic Laboratory
Asymptomatic or mild respiratory illness Travel within 10 days of symptom onset to area with current or previously documented or suspected SARS OR Confirmed
• Diction of Ab to SARS-CoV in specimens during acute illness or >21 d after illness onset OR
• Detection of SARS-CoV RNA by RT-PCR confirmed by 2nd PCR assay using 2nd specimen aliquot and different primers OR
• Isolation of SARS-CoV
Moderate Respiratory illness Close contact within 10 days of symptom onset with person with known or suspected SARS Negative
• T>100.4°F • Absence of Ab to SARS-CoV >21 d after illness onset
• One or more of cough, SOB, difficulty breathing, hypoxia
Severe Respiratory Illness Undetermined
Findings above AND • Laboratory testing not performed or incomplete
• Radiographic evidence of pneumonitis
• Respiratory distress syndrome
• Autopsy findings of pneumonia or ARDS without cause

11.3. CDC Case Definition: Classification

11.3.1. Probable Case

  • Meets clinical criteria for severe respiratory illness of unknown cause, epidemiologic criteria; lab criteria confirmed, negative or undetermined

11.3.2. Suspect Case

  • Meets clinical criteria for moderate respiratory illness of unknown cause and epidemiologic criteria; lab criteria confirmed, negative or undetermined

11.3.3. Exclusion Case

  • Alternative diagnosis established
  • Case reported based on contact with index case subsequently excluded as SARS, provided other epidemiologic exposure criteria absent

11.3.4. Diagnosis:

  • Clinical
  • DNA microarray “SARS chip” to rapidly identify SARS sequence variants is in development
  • SARS PCR

Question for 2005 and beyond is where will this re-emerge and how will we recognize it??

11.4. Some useful, but not pathognomonic features:

11.4.1. Clinical Features

  • Fever, rigors or chills, myalgias, cough and headache in >50% (fever = Hallmark in 100%); GI symptoms have occurred in 6-26% and may mislead diagnosis

11.4.2. Laboratory Features

  • Lymphopenia and elevated LDH more common

11.4.3. Radiographic Features

  • Diffuse or patchy interstitial infiltrates

11.4.4. Infection Control Measures

  • Avoid admission to hospital of less severe cases
  • Isolation of cases in negative pressure rooms
  • Personal protective equipment appropriate for standard, contact AND airborne precautions mandatory (hand hygiene, gown, gloves, and N95 respirators) in addition, eye protection recommended for all healthcare workers

11.4.5. Treatment

  • Supportive care
  • 2 candidate vaccines based on SARS-CoV spike protein in development; intranasal vaccine promising in monkeys.
    • For further reading see:
      • Bukreyev A, Lamirande EW, Buchholz UJ, et al. Mucosal immunization of African green monkeys (Cercopithecus aethiops) with an attenuated parainfluenza virus expressing the SARS coronavirus spike protein for the prevention of SARS. Lancet 2004;363:2122-7.
      • Bisht H, Robers A, Vogel L, et al. Severe acute respiratory syndrome corona virus spike portein expressed by attenuated vaccinia virus protectively immunizes mice. Proc Natl Acad Sci USA 2004;101:6641-6.
      • Yang Z, Kong WP, Huang Y, et al. A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice. Nature 2004;428:561-4
  • role for passive immunization with intravenous immunoglobulin under investigation
    • For further reading see:
      • Subbararo K, McAuliffe J, Vogel L et al. Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus in the respiratory tract of mice. J Virology 2004;78:3572-7.

12. The re-challenge of Staphylococcus aureus

Community acquired Methicillin Resistant S. aureus (CA-MRSA)

12.1. Key Concepts:

  • Novel strains of MRSA infecting healthy children and adults
  • Strains differ from major clones of hospital acquired (HA) MRSA by:
    • Composition of gene cassette coding for resistance
      • CA-MRSA strains often only resistant to ß-lactams and usually remain susceptible to tetracyclines, clindamycin, and trimethroprim-sulfamethoxazole
    • Carriage of plasmids encoding resistance
    • Virulence factors (Panton-Valentine leukocidin (PVL) toxin)
      • Likely accounts for major syndrome of skin and soft tissue infections associated with these strains
  • As clinician, MUST consider Methicillin Resistance even in the healthy adult with implications for appropriate choice of empiric antibiotics. For further reading, see below

13. Evolution of Resistance Genes

Vancomycin (Glycopeptide) Intermediate Staphylococcus aureus (VISA)

13.1. Key Concepts:

  • Increased use of vancomycin in past 20 years is the likely cause of the development of S. aureus clinical isolates that demonstrate vancomycin resistance clinically and microbiologically
    • MRSA infections on rise requiring vancomycin therapy
  • The mechanism of VISA is unknown but thought related to altered cell wall
    • Upregulation of cell wall synthesis
      • Disorganized and thickened cell walls may block the action of vancomycin
  • Patients at risk are those with:
    • Significant vancomycin exposure (MRSA infections)
    • Hemo- or peritoneal dialysis
  • High mortality associated with infection
  • Control measures needed
    • Antibiotic use
    • Strict infection control when patient diagnosed with GISA

14. Ancillary Material

14.1. Readings

14.1.1. Required

  • Schaechter M, Engleberg NC, Eisenstein BI, Medoff G.Mechanisms of Microbial Disease. Third Edition; Williams and Wilkins, 1998,Chapter 54 Addressing Emerging Infectious Diseases pages491-498.

14.1.2. Suggested

  • Petersen et al. West Niile Virus: A Primer for theClinician. Annals of Internal Medicine 2002;137:E173-E179.
  • SARS - http://www.cdc.gov/mmwr
  • Booth CM et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA 2003;289:2801-2809
  • Srinivasan A et al. Vancomycin resistance in Staphylococci. Clinical Microbiology Reviews 2002;15:430-438.
  • Deresinski S. Methicillin-Resistant Staphylococcus aureus: an evolutionary, epidemiologic, and therapeutic odyssey. Clin Infect Dis 2005;40:562-73.
  • Centers for Disease Control and Prevention. Methicillin-resistant Staphylococcus aureus among competitive sports participants—Colorado, Indiana, Pennsylvania, and Los Angeles County, 2000–2003. MMWR Morb Mortal Wkly Rep 2003; 52:793–5.
  • Centers for Disease Control and Prevention. Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus— Minnesota and North Dakota, 1997–1999. MMWR Morb Mortal Wkly Rep 1999; 48:707–10.
  • Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care–associated methicillin-resistant Staphylococcus aureus infection. JAMA 2003; 290:2976–84.
  • Zinderman CE. Community-acquired methicillin-resistant Staphylococcus aureus among military recruits. Emerg Infect Dis 2004; 10: 941–4.