clinical diagnosis & management of sars...diagnosis of sars who criteria (revised 1 may 2003)...
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Clinical Diagnosis & ManagementClinical Diagnosis & Managementof SARSof SARS
Joseph SUNG MD, PhDDepartment of Medicine & Therapeutics
Prince of Wales HospitalThe Chinese University of Hong KongHospital Authority of Hong Kong SAR
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Diagnosis of SARSDiagnosis of SARS
WHO criteria (revised 1 May 2003)High fever (>38°C) ANDCough or breathing difficulty ANDOne or more of the following exposures during the 10 days prior to onset of symptoms: - close contact with a person who is a suspect or probable
case of SARS; - history of travel to an area with recent local transmission
of SARS - residing in an area with recent local transmission of
SARS
www.who.int/csr/sars/casedefinition/en
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138 patients20 doctors34 nurses15 allied health16 medical students
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Common Symptoms of SARSCommon Symptoms of SARS
0
10
20
30
40
50
60
70
80
90
100Fe
ver
Chi
lls &
Rig
or
Mya
lgia
Cou
gh
Hea
dach
e
Diz
zine
ss
Sput
um
Sore
thro
at
Run
ning
nose
Nau
sea
&Vo
miti
ng
Dia
rrhe
a
% o
f pat
ient
s
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Chest RadiographsChest Radiographs
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CT ThoraxCT Thorax
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DiarrheaDiarrhea
73%
27%
DiarrheaNo Diarrhea
Amoy GardenN=75
38%
62%
Prince of Wales HospitalN=138
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Features of DiarrheaFeatures of Diarrhea
Large volume
Watery
No blood
No mucus
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Diarrhea is associated with FeverDiarrhea is associated with Fever
Peiris et al. Lancet 2003N=75
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0.217 (8.2)8 (15.1)Death
<0.00110 (11.8)26 (49.0)ICU care
0.0047 (8.2)14 (26.4)Ventilatory support
0.0720.0 ± 11.624.0 ± 14.6Hospital stay (Day)
0.19 (10.6)11 (20.8)Comorbidity
0.1337.8 ± 16.642.1 ± 16.5Mean age in years ± SD
0.2937 (43.5)28 (52.8)Male sex
pNo diarrhea (%)Diarrhea (%)
Diarrhea affects clinical outcomeDiarrhea affects clinical outcome
PWH cohort
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ColonColon
A. lipofusin-laden macrphage
B. Dilated ER & viral particle at microvilli
C. Vesicles containingviral particles
D. Viral particles on the luminal surface of villi
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Terminal IleumTerminal Ileum
E. Normal mucosa, sub-mucosa and muscle layer
F. No inflammation
G. Viral particles on villi
H. Cytoplasmic vesicleswith viral particles
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LymphopeniaLymphopenia
0 1 2 3 4 5 6 7 80
250
500
750
0.0024
0.0227
*
*
Day of Admission
CD
4 ce
ll nu
mbe
r(c
ells
/ul)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 160
250
500
750
Day of Admission
CD
8 c
ell n
umbe
r(c
ells
/ul)
0.0171
0 1 2 3 4 5 6 7 8 9 101112131415160
1
2
3
4
5
Day of Admission
CD
4/C
D8
ratio
0 1 2 3 4 5 6 7 8 9 101112131415160
250
500
750
Day of Admission
B c
ell n
umbe
r(c
ells
/ul)
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Prolonged APTTProlonged APTT
0.0
10.0
20.0
30.0
40.0
50.0
60.0
Day 1 Day 3 Day 5 Day 7 Day 10 Day 14 Day 17 Day 21 Week 4 Week 5Day of illness
Perc
enta
ge o
f pat
ient
s
Wong et al. BMJ 2003
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ThrombocytopeniaThrombocytopenia
010
2030
405060
7080
90100
Day 1 Day 3 Day 5 Day 7 Day 10 Day 14 Day 17 Day 21 Week 4 Week 5Day of illness
Perc
enta
ge o
f pat
ient
s
500-1000<500
Wong et al. BMJ 2003
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Lymph node, Spleen & Bone MarrowLymph node, Spleen & Bone Marrow
Wong et al. BMJ 2003
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Hong Kong SARS RegistryHong Kong SARS Registry
1. Survival Analysis
• Subject – 1,700+ SARS cases in e-SARS Registry
2. Retrospective Statistical Analysis
• Subject – 1,315 SARS discharged cases with information captured into SARS Clinical Data Collection
• Method – Univariate and Multivariate analyses (such as Logistic Regression, Discriminant Analysis)
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Survival Analysis
SexAge
Comorbidity
Cohort
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85.0
87.0
89.0
91.0
93.0
95.0
97.0
99.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Day from symptom onset
discharged death
% Mean SaO2(lowest)
0
200
400
600
800
1000
1200
1400
1600
1800
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Day from symptom onset
discharged death
IU/L Mean absolute LDH readings
0
2
4
6
8
10
12
14
16
18
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Day from symptom onset
discharged death
10^9/L Mean Neutrophil readings
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Day from symptom onset
discharged death
10^9/L Mean Lymphocyte readings
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Nicholls, Yuen, Peiris, et al. Lancet 2003 May
Peiris, Yuen, et al. Lancet2003 Apr
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SARS: a triSARS: a tri--phasicphasic diseasediseaseMa
x. da
ily bo
dy te
mper
ature
(o C)
Days after onset of disease
Viral replicativephase
Immune hyperactive phase
Pulmonary-destruction phase
36
37
38
39
40
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
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ProtocolProtocol Fever & ChillsSuspected SARS
IV CefotaximeIV Levofloxacin
IV Methyl-prednisolone 0.5 g/dayFor 3 consecutive days
Oral Ribavirin 3.6g per dayOral Prednisolone 1mg/kg/day
IV Ribavirin 1.2g per dayIV hydrocortisone 100mg q6h
De-saturation
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ProtocolProtocol IV Methyl-prednisolone 0.5 g/dayFor 2 consecutive days
Fever persistRadiograph show sign of deterioration
3rd or 4th Pulse Steroid
Convalescent serum therapy
Plasma exchange
Fail
to m
aint
ain
oxyg
en s
atur
atio
n: IC
U?
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Response to RxResponse to Rx
12 (11.2)113 (81.9)138 (100)No response
45 (42.1)9 (6.5)0 (0)Partial response
50 (46.7)16 (11.6)0 (0)Sustained response
IV Methyl-prednisolone+
(%)N=107
Ribavirin + Corticosteroid#
(%)N=138
Board-spectrumAntimicrobial*
(%)N=138
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Ribavirin 200µg/ml 100µg/ml 50µg/ml 25µg/ml 12.5µg/ml 6.25µg/ml
Lopinavir10µg/ml 5µg/ml 2.5µg/ml 1.25µg/ml 625ng/ml 3.125ng/ml
Control: 100 PFU, CO2, 48 h,SARS-assocaiated coronavirus(HKU-39849 isolate) added.
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Study Subjects- SARS Patients Admitted before May 2003 -
Ribavirin+ Ever Pulse MP+ Ever Intubation
Ribavirin+ Ever Pulse MP
RibavirinMatched cohort(4-D match)
K as Late rescue (n = 33)
K as Early rescue(n = 33)
K as Initial Rx (n = 34)
Cases*CBA
Dx made -ribavirin/ steroid
Pulse MP if CXR/ SaO2↓
Intubationif pulse MP fails
Timing of treatment
* All cases have Ribavirin
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1.0NS
27.9%(standardised)
27.3%De-saturation rate(min SaO2<=90%)
0.003
0.03
0.04
P-value
85.2%(standardised)
63.6%De-saturation rate(min SaO2<=95%)
12.6%(standardised)
0%Intubation rate
10.4%(standardised)
0%Death rate by Day 30
Control_A(n = 690)
Case_A(n = 34)
KaletraKaletra as Initial Rxas Initial Rx
By
D21
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KaletraKaletra as early rescue therapyas early rescue therapy(with pulse MP)(with pulse MP)
89.4%(standardised)
35.4%(standardised)
19.5%(standardised)
8.8%(standardised)
Control_B(n = 431)
0.0454.5%De-saturation rate(min SaO2<=90%)
0.56NS
93.9%De-saturation rate(min SaO2<=95%)
0.0020%Intubation rate
0.34NS
3.0%Death rate by D30
P-valueCase_B(n =33)
By
D21
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KaletraKaletra as late rescueas late rescueafter after intubationintubation
42.9%(standardised)
Control_C(n = 77)
0.0321.2%Death rate by Day 30
P-valueCase_C(n = 33)
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SummarySummary
SARS has both pulmonary & extra-pulmonary manifestationsAge, gender, comorbidity, LDH, neutrophil & lymphocyte count affects mortalitySARS is a tri-phasic diseaseAntiviral & immuno-suppressant may be beneficialRCT for antiviral therapy is needed