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

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

138 patients20 doctors34 nurses15 allied health16 medical students

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

Chest RadiographsChest Radiographs

CT ThoraxCT Thorax

DiarrheaDiarrhea

73%

27%

DiarrheaNo Diarrhea

Amoy GardenN=75

38%

62%

Prince of Wales HospitalN=138

Features of DiarrheaFeatures of Diarrhea

Large volume

Watery

No blood

No mucus

Diarrhea is associated with FeverDiarrhea is associated with Fever

Peiris et al. Lancet 2003N=75

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

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

Terminal IleumTerminal Ileum

E. Normal mucosa, sub-mucosa and muscle layer

F. No inflammation

G. Viral particles on villi

H. Cytoplasmic vesicleswith viral particles

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)

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

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

Lymph node, Spleen & Bone MarrowLymph node, Spleen & Bone Marrow

Wong et al. BMJ 2003

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)

Survival Analysis

SexAge

Comorbidity

Cohort

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

Nicholls, Yuen, Peiris, et al. Lancet 2003 May

Peiris, Yuen, et al. Lancet2003 Apr

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

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

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?

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

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.

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

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

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

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)

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