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» 首頁 » Pathophysiology of Infectious Diseases » 課堂講稿
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Author: Susan Hadley, M.D.
| Color Key |
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Important key words or phrases. |
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Important concepts or main ideas.
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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
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
- Variola virus (smallpox)
-
Bacillus anthracis (anthrax)
3.2. To rise from an obscure or inferior position or
condition: Epizootic infections, transcontinental spread
- West Nile Virus
- (Monkeypox virus)
3.3. To rise from or as if from an enveloping fluid; to come
out into view: new variant of common virus
- Coronavirus (SARS)
3.4. To come into being through evolution: evolution of
resistance genes
- Glycopeptide intermediate Staphylococcus
aureus
- 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
- high morbidity and mortality
- easy to produce
-
efficiently disseminated and/or able to spread from
person to person
- stable in aerosol form
- 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
- conduct surveillance
- investigate disease clusters
- test a hypothesis regarding disease
transmission
- 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) |
|
��� |
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germination of spores and extracellular replication |
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��� |
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capsule and toxin production |
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9.1.1.1. 3 disease states
-
gastrointestinal (rare)
- ingestion of undercooked, contaminated
meat
- fever, abdominal pain, diarrhea (may be
bloody)
-
cutaneous
- most common form of endemic anthrax
- contracted by close contact of abraded skin with
products
- derived from infected herbivores (sheep, cattle,
goats)
-
inhalational (the form of biological
terrorism)
- spores deposited in alveoli (2-6 繕) 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:
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 |
|
��
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簞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
��-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.
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