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Lessons Learn from SARS
The Etiology ,Pathology and
Clinical Features of SARS
Nantong Medical College
The Department of Pathology
Chen Li
Introduction
SARS is a condition of unknown cause
that has recently been recognized in
patients in Asia , North America , and
Europe . This report summarizes the
initial epidemiologic findings ,
pathologic description , clinical and
diagnostic findings.
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An outbreak of atypical pneumonia, referred
to as severe acute respiratory syndrome
(SARS) and first identified in Guangdong
Province, China, has spread to several cities
and countries. The severity of this disease is
such that the mortality rate appear to be
3 to 6%. A number of laboratories
worldwide have undertaken the identification
of the causative agent.
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Medical personnel , physicians ,nurses
and hospital workers are among those
commonly infected . Sadly,Dr. Carlo
Urbani,the 46-year-old WHO
physician and infectious disease
specialist whose work defined
SARS(Ferbruany 28),and died on
March 29 of SARS .
The WHO issued a global alert SARS
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The first time on march 12
The second time on march 15
The third time on march 27
The international society are taking actions to SARS.
The virus has been identified to be coronavirus by
the cooperation of laboratories all over the world.
The target has been aimed, and the actions are
undertaken. This is a battle without fire.
1. Etiology
On march 24 ,scientists at the CDC in USA and
in Hong Kong announced that a new
coronavirus had been isolated from patients
with SARS.
This coronavirus(COV) has been named publicly by
the WHO and member laboratories as “SARS virus”.
This is a novel virus that is not closelt related
to any of the known clusters of coronaviruses.
SARS virus
completely new coronavirus
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The National Microbiology Laboratory in Canada obtained
the Tor2 isolated from a patient in Toronto, and
succeeded in growing a coronavirus-like agent in African
Green Monkey Kidney (Vero E6) cells.
This virus was purified and its RNA genome extracted and
sent to the British Columbia Centre for Disease Control in
Vancouver for genome sequencing by the Genome
Sciences Centre at the BC Cancer Agency.
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The coronaviruses are members of a family of enveloped
viruses that replicated in the cytoplasm of animal
host cells. They are distinguished by the presence of a
single-stranded plus sense RNA genome approximately 30
kb in length that has a 5’ cap structure and 3’ polyA tract.
Upon infection of a host cell, the 5’ most open reading
frame (ORF) of the viral genome is translated into a large
polyprotein that is cleaved by viral-encoded proteases to
release several nonstructural proteins including an RNAdependent RNA polymerase (Rep) and ATPase helicase
(Hel). These proteins in turn are responsible for replicating
the viral genome as well as generating nested transcripts
that are used in the synthesis of the viral proteins. The
mechanism by which these subgenomic mRNAs are
made is not fully understood.
SARS virus
completely new coronavirus
SARS virus structure
S(spite protein)
M(membrane protein)
E(small membrane protein)
HE(hemagglutinin eaterase)
N(nucleocapsid protein)
RNA genome
Some small nonstructure ORFs
SARS virus in EM
60-220nm
The SARS genomic sequence has been deposited into
Genbank (Accession AY274119.3 , Apr. 18 03, Canada)
The nucleotide position ,associated ORF and
putative transcription regulatory sequences(TRSs).
The feature of the Tor2 genome sequence (Canada)
The SARS genomic sequence has been deposited
into Genbank (Accession AY278554, Apr.18 03, USA)
Make a comparison beteen tow SARS genomic sequence
Canada
29736nt
USA
29727nt
GenBankAY278554
attachment
engulfenment
lost envelope
early protein
synthesis
nucleotide
synthesis
later protein
synthesis
encapisula
assemble
release
Human coronaviruses surivival time
229E---6 days in suspension
3 hours after drying on surfaces
OC43---<1hour after drying on surfaces
SARS virus---4-5 days on drying plastic film
5 days in excrements
10 days in urine
15 days in blood
Extinct Cov
High tempreture 56c 90min or 75c 30min
Ultraviolet 30 min
Other disinfectants handling effectively
Comparison of previously 3 groups CoV
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Phylogenetic analysis of the predicted viral proteins
indicates that the virus does not closely resemble any
of the three previously known groups of CoVs
Cov are divided into
three serotypes,
The SARS virus is
the fouth ?
The purpose of studying genome sequence
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The genome sequence will aid in the
diagnosis of SARS virus infection in humans
and potential animal hosts (using PCR and
immunological tests), in the development of
antivirals (including neutralizing antibodies),
and in the identification of putative epitopes
for vaccine development.
About metapneumovirus
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In addition, a novel coronavirus was isolated from
vero cell cultures of SARS patiens and
metapneumovirus was also identified . Futher studies
are currently being completed to help determine
whether the human metapneumovirus and novel
coronavirus, either alone or in combination ,are the
cause of SARS or whether other thus far undetected
pathogens are possibly responsible .The possibility
that coinfection of either virus with another
agent may be responsible for SARS cannot be
excluded.
Conclusion
1. SARS virus(coronavirus), a single-stranded plus
sense RNA.
2. SARS virus are stable but a few variforms
3. SARS virus has long period survival
4. The genome sequencing of the virus has been
finished
5. Different from previously found coronaviruses.
6. The largest enveloped virus is difficult to be
cultured in vitro.
7. May be the animals sources?----fruit fox
2. Pathology
Severe exudate and
tansudate inflammation
congestion,edema and
formation of hyline
membrane
highly reactive blood vessels (Cap)
Capillary highly
dilatation and
congestion
RBC transudation
Virus inclusion
syncytial giant cells pneumonia
Scanty interstitial
inflammatory-cell infiltrates
Multinucleated syncytial giant cells and abundant
foamy macrophages,no conspicuous viral inclusions
in lung of SARS patient
Special staining for virus
Diffuse alveolar
damage with
proliferation of
Alveolar epithelial
typeⅡ
Virus inclusion
(Macchiavell
staining )
Immunohistochemical staining of SARSassociated Cov-infected cells
Immunoalkline phosphatase with napthol-fast red substrate
and hematoxylin counterstain (FAF X250)
The immuno-fluorescent staining for virus
Lung solidification
diffuse alveolar damage and no
infection evidence
Intraalveolar and interstitial mononuclar cells
suggesting a possible viral cause were also noted ,
but no viral inclusion were seen .
Lesions in other organs
Multifocal
hemorrhage
and necrosis
Proliferation of
histocytes in
the surrounding
tissue
phagocytosis of
histocytes
Conclusion
1. Diffuse alveolar damage
2. Severe exudate and tansudate but no infection
evidence in lung
3. Proliferation of Alveolar epithelial typeⅡ
4. Syncytial giant cells pneumonia
5. Hyline membrane formation
6. Lung solidification
7. The main cause of death is the progressing
respiratory failure caused by lung damaging,
which also have relationships with immunopathological change of the patients.
3. Clinical Features
1. Epidemiology (contact and influential area)
2. Symptoms and signs (fever, dry cough ,myolgia ,
diarrhea and the number of viruses in sputum is
>100M/ml)
3. Laboratory tests: WBC↓,LC ↓ (CD4+ ↓,CD8+↓)
4. X-ray: patches and confluent air-space opacification
5. No effective to antibiotics，partially effective to
hormone.
X-ray appearance
X-ray appearance
SARS has spread rapidly becouse
during the incubation period , which
appears to be between 1 day and 11
days.With a median of about 5 days,
patients can transmit the disorder to
others.
The statistical data of WHO
appear the mortabity rate :
age
<24 year-old
mortabity rate
<1%
25-44year-old
6%
45-64 year-old
15%
>65 year-old
>50%
Review X-ray appearance of
15 SARS cases
Case 1 : 29 year old symptomatic female with
normal radiographic appearance
Case 2: A 31-year-old health-care worker presented with
2-day history of fever, chills and myalgia
Figure 1 - CXR at the
time of diagnosis
showed ill-defined
air space
opacification in right
lower zone
Figure 2 - CXR after 3 days
showed partial resoulation
of consolidative changes in
right lower zone. There is a
new finding of ill-defined air
space opacification in left
lower zone
Figure 3 - CXR after
another 4 days showed
progressive resolution
of the changes in both
lower zones
Case 3: A 34-year-old presented with 3-day history of
fever, chills and malaise
Figure 1 - CXR (7
days after admission)
showed ill-defined air
space opacification in
periphery of right
lower zone
Figure 2 - CXR (2 days
later) showed progression
of air space opacification
in right lower zone and a
new finding of similar
changes in left mid and
lower zones after initial
treatment
Figure 3 - CXR (after
another 4 days)
showed marked
resolution of the
consolidative
changes in both
lungs after treatment
Case 4: A 34-year-old health care worker presented
with fever, chills and myalgia for 2 days
Figure 1 - CXR
showed ill-defined
air-space opacity in
periphery of left
upper and mid
zones
Figure 2 - CXR (after 5
days) showed
progressive air-space
opacities in both
lungs
Figure 3 - CXR (after
another 7 days) showed
resolution of
radiographic changes
after successful
treatment
Case 5: 52-year-old symptomatic female from Virginia
15 MARCH 2003
(On presentation to
A&E)
19 MARCH 2003
20 MARCH 2003
Case 6: 24-year-old Filipino nursing aid from nursing
home with one week history of fever,
dry cough and myalgia
Day 1 - CXR showed
subtle left lower
zone air-space
infiltrates
Day 5 - CXR showed left
lower zone
consolidation became
more obvious
Day 7 - Patient
became hypoxic &
required subsequent
intubation. CXR
showed bilateral
widespread air-space
infiltrates
Case 7: 30-year-old worker with one week history of
fever, dry cough and myalgia
Fig 1: (day 3 after
onset of symptoms)
Fig 2: (day 4 after
onset of symptoms)
Ill-defined air-space
opacification in
right lower zone
Confluent air-space
opacification in left
lower zone
Fig 3: (day 5 after
onset of symptoms)
Air-space
opacification in the
periphery of middle
lobe abutting the
superior aspect of the
horizontal fissure
Case 8: A 38-year-old doctor presented
with fever, chills and myalgia for 2 days
Fig1: (day 2 after
onset of symptoms)
Middle lobe air-space
opacity obscuring part
of right heart border
Fig 2: (day 3 after
onset of symptoms)
Ill-defined opacity
in left lower zone
Fig 3: (day 4 after onset
of symptoms)
Bilateral lower zones airspace opacities in paracardiac areas after
successful treatment.
Case 9: 26 year old symptomatic male
Fig 1: (day 4 after
onset of symptoms)
Fig 2: (day 5 after
onset of symptoms)
Fig 3: (day 6 after
onset of symptoms)
Peripheral segmental
air-space opacification
in right upper lobe
Patchy peripheral
opacities involving
both lower lobes
Multi-focal ill-defined
air-space opacities in
both lower and right
upper zones
Case 10: 23 year old symptomatic female
Fig 1: (day 4 after
onset of symptoms)
Fig 2: (day 5 after
onset of symptoms)
Fig 3: (day 7 after
onset of symptoms)
Peripheral patchy
opacification in right
upper and left lower
zones
Patchy air-space
opacification in both
mid and lower zones
Multi-focal diffuse
air-space opacities in
both lungs
Case 11: 57 year old symptomatic retire worker
Fig 1: (day 5 after onset of
symptoms)
Fig 2: (day 6 after onset of
symptoms)
Multi-focal confluent areas
of air-space opacities in
both lungs
Diffuse and widespread
consolidative changes in
both lungs (patient is
intubated)
Case 12: 46 year old symptomatic man
An obvious area of
air-space shadowing
on the left side
A follow-up chest
radiograph showed
progression of the
disease , with mulotiple,
bilateral ateas of
involvement.
A subsequent chest
radiograph shows
improvement of
bilateral lung
opacities after
therapy.
Case 13-15:children’s SARS
2-year-old boy
presented with febrile
convulsion and
cough. CXR on
admission showed
air-space opacities in
left mid and lower
zones
6-year-old girl
presented with fever,
running nose and
cough. CXR on
admission showed
focal air-space
consolidation in left
upper zone
5-year-old girl
presented with fever
for 4 days. CXR
showed air-space
opacity in left lower
zone
Conclusion
1. Respiratory difficult (>30times/min)
2. Hypoxmia
3. Abnormal chest radiographs show air-space
consolidation in either unilateral multifocal or
Bilateral involvement, which progressing more than
50% within 48 hours
4. Shock
5. Chest X-ray features separated from clinical features.
6. The diagnosis must dependent on clinical features
The results of research on SARS may
give some hints to the clinical therapy
1. The main pathological change of severe SARS is the
exudate and transudate inflammation with hyline
membrane formation, which suggests the proper time
and large dose of hormone therapy is helpful to
ease the ARDS.
2. Considering the possibility of correlative infections,
the correlative therapy should be conducted in
clinics.
3. The damage immuno-organs suggests the applying of
immuno-enhancing and regulating agents is
helpful.
4. Antibody treatment and proteose
It is becoming quite clear that
SARS is an infectious disease.
Although progress has been
extraordinarily rapid because of
unprecedented worldwide
scientific cooperation , there is
still a lot to be learned.
Emerging global microbial threats
Lessons learn from SARS
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Importance of strong national and international
collaborations and partnerships
Enhancing global infectious disease surveillance
Rebuilding domestic public health capacity
Developing optimal diagnostic tests
Effective therapy need for new antimicrobial drugs
Educating and training multidisciplinary workforce
Vaccine approaches, development and production