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A Journey in Dengue Research and Case Management
Lucy Lum
Johore Scientific Meeting
5 Oct 2015
Why did I choose Dengue?
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Puan Sri Datin Dr. Rebecca GeorgeProfessor Dato’ Lam Sai Kit
Dengue Encephalitis: A True Entity?
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Cincinnati, 1994: Scott Halstead M.D., Am Soc of Trop Med & Hyg
Dengue Encephalitis: A True Entity?L. C. S. Lum, S. K. Lam, Y. S. Choy, R. George, and F. Harun
Am J Trop Med Hyg, 1996; 54:256-9
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Six children presenting on the second or third day of illness with dengue encephalitis.
All were confirmed dengue infections. Dengue 3 virus was isolated from the CSF of four cases and in one case, dengue 2 by PCR in both the CSF and blood, 6th case dengue IgM in the CSF and blood.
Since the onset of encephalitis appears early in the viremic phase, we postulate that the virus crosses the blood-brain barrier and directly invades the brain causing encephalitis. This study provides strong evidence that dengue 2 and 3 viruses have neurovirulent properties and behave similarly to other members of the Flaviviridae.
The greatest enemy of knowledge is not ignorance,
it is the illusion of knowledge (which closes our hearts to
further learning).
– Stephen Hawking
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Professor Suchitra Nimmanitya
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Long nights and days saving lives
10-year retrospective review of114 patients with severe dengue infections,
22 patients (20%) severe bleeding
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Risk factors for hemorrhage in severe dengue infections
Lucy Chai See Lum, MBBS, MRCP, EDIC, Adrian Yu Teik Goh,
MBBS, MMed, MRCP, Patrick Wai Keong Chan, MBBS, MMed,
MRCP, Abdel-Latif Mohd El-Amin, MBBS, MPH, MPH (Epid)
and Sai Kit Lam, MSc, PhD, FRCPath, FRCP, FASc
J Pediatr 2002;140:629-31
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Clinical and laboratory data and outcome of severe hemorrhage in dengue shock syndrome
J Pediatr 2002;140:629-31
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Multivariate logistic regression analysis of clinical and laboratoryfeatures of severe hemorrhage in dengue shock syndrome
J Pediatr 2002;140:629-31
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Plasma leakage precedes severe bleeding;
Even in severe bleeding in ill patients with prolonged shock,hematocrit will not decrease to low levels
Plasma leakage
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Time/ hours
Baseline HCT
Plasma leakage precedes severe bleeding;
Even in severe bleeding in patients with severe shock,hematocrit will not decrease to low levels
Time lines (Hours) of Plasma Leakage & Bleeding in Severe Dengue
TreatmentIV crystalloids +
colloids
IV crystalloids ,
colloids & Blood
Compensated shock Hypotensive shock
Bleeding
A B
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J Pediatr 2003;143:682-4 14
Preventive transfusion in dengue shock syndrome –
is it necessary?
Lucy Chai See Lum, MBBS, MRCP, EDIC,
Abdel-Latif Mohd El-Amin, MBBS, MPH, MPH (Epid),
Adrian Yu Teik Goh, MBBS, MMed, MRCP,
Patrick Wai Keong Chan, MBBS, MMed, MRCP,
and Sai Kit Lam, MSc, PhD, FRCPath, FRCP, FASc
Development of pulmonary edema & days of hospitalization were higher in the group that received
platelet/plasma transfusion!
Changing Epidemiology of Dengue in Malaysia
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Global Dengue Risk
17Simmons CP, et al. Dengue. N Engl J Med 2012;366:1423-32
highest risk
1997 WHO Dengue Case Classification
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Dengue virus infection
Asymptomatic Symptomatic
Undifferentiated Fever
Dengue fever(DF)
DHF(with plasma leakage)
DHF non-shock
Dengue shock
syndrome (DSS)
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• 2002: Prospective study of adult and pediatric dengue patients to see how physicians classify the disease over 3 month period.
• 520 adults and 191 paediatric subjects• Thrombocytopenia and plasma leakage present in 9% and 19% of
adults and paediatric subjects respectively.• 93% and 47% of these patients were given discharge diagnosis of
Dengue Fever instead of Dengue Hemorrhagic Fever.
Review of 37 papers, published in English.
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Venezuela
Antwerp,Belgium
Philippines
Heidelberg,Germany
Vietnam
Malaysia
Thailand
TDR/WHO,Geneva
Europe
Latin America
Asia
Cuba
Liverpool,UK
Nicaragua
Brazil
TDR branch of WHO – DENCO Partners
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Method
• Prospective hospital based multicentre study – local centres of excellence
• Children & adults, clinically suspected dengue
• Recruited < 7 days of illness and
• Daily follow-up with a detailed CRF
– Hct and platelets done at least daily
– Other tests (liver & renal function) at least twice during acute illness
– Radiological evidence of plasma leakage within 24h of defervescence
– WHO trained monitors
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Study population
N cases (%)
Continent
SE Asia
L America
1501 (86.6)
233 (13.4)
Age group
<15 years
≥ 15 years
1062 (61.2)
672 (38.8)
Day of illness at enrollment
<= 2
3
4
5
6
77 (4.4)
294 (17.0)
598 (34.5)
562 (32.4)
203 (11.7)
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0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
DSS
DHF
DF
not classifiable
Current WHO classification applied to DENCO patients (N=1734)
More than 40% of the patients could not be classified without using population haematocrit dataDHF
DSS
DF
Unclassifiable
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Current WHO classification including population reference data for Hct (N=1734)
770
306
193
555
611 710
160 163
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
internal Hct baseline only plus external Hct baseline
DSS
DHF
DF
not classified
After including population reference data 18% still remain un-classifiable
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Intermediate Tool: grading severity by
interventions
• Nursing care level
• Fluid Therapy
• Blood products
• Other interventions
Category 1 Standard
Category 2 Intermediate
Category 3 Major
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Classification by current WHO system& by intervention category (N=1734)
414392
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277
420
13
0
1
162
0
50
100
150
200
250
300
350
400
450
DF (N=861) DHF (N=710) DSS (N=163)
Category 1 (Standard) Category 2 (Intermediate) Category 3 (Major)
(6%)
(46%)
(39%)
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Suggested indicators for severe dengue- one or more of the following
• Severe plasma leakage
– Clinical shock
– Any evidence of fluid accumulation with respiratory distress
• Severe bleeding as evaluated by clinician
• Severe organ involvement
– Severe liver involvement with AST or ALT >= 1000
– Impaired consciousness with GCS < 15 or BCS < 5• (Death caused by dengue)
Sensitivity = 96%Specificity = 97%
• 1. Severe plasma leakage
• 2. Severe haemorrhage
• 3. Severe organ impairment
Without Withwarning signs
Dengue case classification (2009)
Dengue Severe dengue
WHO. Dengue Guidelines for Diagnosis, Treatment, Prevention and Control,
New edition, 2009. WHO Geneva (TDR 2009)
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Figure 1a. Children Figure 1b. Adults
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20
Days from beginning of symptoms
Qu
ali
ty o
f li
fe (
%)
Children hospitalized with leakage (n=44)Children hospitalized without leakeage (n=3)Children ambulatory (n=8)
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20
Days from beginning of symptoms
Qu
ali
ty o
f li
fe (
%)
Adults hospitalized with leakage (n=49)Adults hospitalized without leakeage (n=26)Adults ambulatory (n=75)
• 1,695 patients in 2005
• Average illness 11.9 days and 11.0 days of ambulatory and hospitalised patients, respectively
• 5.6 school days lost
• 9.9 work days lost per dengue episode
• Cost of ambulatory patient I$514 and I$1,394 for hospitalisedpatients
• Annual average of ~570,000 cases reported, I$587 million
• Underreporting - $1.8 billion, excluding surveillance and vector control.
• Substantial costs on both health sector and overall economy
Dengue Bulletin 2012
Prospective cohort studyEnrolment less than 72 hours of fever
Between 2007 to 2000, enrolled 238 febrile patients
International Research Consortium on Dengue RiskAssessment, Management, and Surveillance
IDAMS study sites in Klang Valley
Site number
Site Dates Ministry
51 *University Malaya Medical Center, KL
Apr 12 MoHE
52 Pantai HC Sep 12 to Nov 12 MoH
*Hosp Tengku AmpuanRahimah
July 13 to May 15 MoH
Anika HC Jun 13 MoH
53 Kelana Jaya HC Sep 12 to Jun 13 MoH
Hosp Sg Buloh Apr 14 to Jun 15 MoH
54 Shah Alam HC Jul 12 to May 15 MoH
Botanic HC Jun 13 MoH
55 *Hosp Ampang Apr 12 MoH
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* Admitting hospitals
Map of Klang Valley (part of) – IDAMS Study sites
Between HTAR and UMMC: Federal Highway ~35 km
Kelana Jaya HCShah Alam HC
Botanik and Anika HC
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Ampang Hosp
Pantai
Monthly enrolment (Apr 12 to Aug 15)
0
10
20
30
40
50
60
70
Ap
r 2
01
2M
ayJu
ne
July
Au
gSe
pO
ctN
ov
Dec
Jan
-13
Feb
Mar
Ap
rM
ayJu
ne
July
Au
gSe
pO
ctN
ov
Dec
Jan
-14
Feb
Mar
Ap
rM
ayJu
ne
July
Au
gSe
pO
ctN
ov
Dec
Jan
-15
Feb
Mar
Ap
rM
ayJu
ne
July
Au
g
Enrolled patients, n= 929
Enrolled patients
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FIRST STEP: CHANGE YOUR PROGRAMMING
• “It is our programming that sets up our beliefs, and the chain reaction begins. In logical progression, what we believe determines our attitudes, affects our feelings, directs our behavior, and determines our success or failure:
• 1. Programming creates beliefs.2. Beliefs create attitudes.3. Attitudes create feelings.4. Feelings determine actions.5. Actions create results.
• That’s how the brain works. If you want to manage yourself in a better way, and change your results, you can do so at any time you choose. Start with the first step. Change your programming.”
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SOLOMON ISLANDS
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SOLOMON ISLANDS
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