27-Oct-18

INFORMASI UMUM
• Presentasi ini disampaikan pada kegiatan 1ST ASMP-ID
• Hari / Tanggal : Sabtu - Minggu / 27-28 Oktober 2018
• Tempat : Hotel Novotel Tangerang
• Narasumber : Prof. Lucy C.S. Lum, MD, Paed

• Semua isi dan materi presentasi adalah hak cipta dari narasumber,
digunakan untuk kalangan terbatas dalam kepentingan edukasi
kesehatan di bidang terkait.

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Curriculum Vitae
• Prof. Dr. Lucy Lum Chai See
– Department Of Paediatrics / Faculty Of Medicine

• ACADEMIC QUALIFICATION
– MRCP(UK)(1987), ROYAL COLLEGE OF PHYSICIANS, UNITED KINGDOM
– MBBS(UM)(1981), UNIVERSITY OF MALAYA (UM)

• PROFESSIONAL
– BABY-FRIENDLY HOSPITAL INITIATIVE, UNIVERSITY HOSPITAL, Founding Member, 1998, (University)
– Editorial Board, Journal Paediatric Critical Care Medicine, Editorial Board Member, 2001 to 2014, (International)
– WHO/TDR Steering Committee, Member, 2005 to 2005, (International)
– WHO/TDR Steering Committee, Member, 2006 to 2006, (International)
– Pediatric Infectious Disease Journal, Reviewer, 2007, (International)
– Intensive Care Medicine, Reviewer, 2007 to 2014, (International)
– WHO/TDR Steering Committee, Member, 2007 to 2007, (International)

• BOOKS AUTHOR :
– Clinical Manifestations of Dengue, 1997
– Clinical Management and delivery of services, 2009
– Handbook for Clinical Management of Dengue, 2012

• PAPERS & RESEARCH :

– Cohorting Dengue Patients Improves the Quality of Care and Clinical Outcome, 2015
– Dengue death with evidence of hemophagocytic syndrome and dengue virus infection in the bone marrow, 2015
– Clinical evaluation of dengue and identification of risk factors for severe disease: protocol for a multicentre study in 8 countries, 2015

Dengue Case Classification 2009

Professor Lucy C S Lum
University of Malaya

Infectious and Tropical Disease Working Disease

Indonesian Pediatric Society
27 Oct 2018
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Lecture contents

• Dynamic course of clinical dengue

• The sources of evidence for the WHO 2009

dengue case classification

Natural History of DENV Infections

Infection Incidence
~ 5% / year

Asymptomatic Symptomatic
75% 25%

Dengue fever Severe dengue

95-99% 1-5%

Survive Die
Adapted from Vaccine 2004; 22: 1275-1280 95-99.5% 0.5 - 5%

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Clinical course of dengue

Viraemia:
headache, nausea, myalgia,
body ache and rash Critical
Phase
Incubation period Febrile Phase Recovery Phase

Days
0 1 2 3 4 6 8 10
After the incubation period, the illness begins abruptly.
It is characterized by 3 phases:

Febrile phase – commences at symptom onset

Critical phase – commences around time of defervescence*, PLASMA LEAKAGE

* Defined as when body temperature drops to less than 38°C and remains below this level.

Recovery phase – commences when plasma leakage resolves

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Dynamic phases of dengue

Viremic phase Immunological phase

(3-5 days) (from 3 to 7th day onwards)

It is Difficult to predict course of dengue …

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WHO 1997 Dengue Case Classification

Dengue virus infection

Asymptomatic Symptomatic

DHF
Undifferentiated Dengue fever (with plasma leakage)
Fever (DF)

DHF I & II DHF III & IV or

non-shock Dengue
Criteria for DHF (ALL 4 must be present):
shock
1. Fever syndrome (DSS)
2. Thrombocytopenia <100,000/dL
3. Bleeding – Tourniquet test
4. PLASMA LEAKAGE
• Raised HCT > 20% above baseline
• Pleural effusion, ascites, shock

(but the name is Hemorrhagic!)

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(1) difficulties in applying the criteria for DHF/DSS, esp

in ADULTS

(2) the tourniquet test has a low sensitivity for

distinguishing between DHF and DF; and
Lancet Inf Dis 2006; 6: 297-302
(3) most DHF criteria had a large variability in frequency
of occurrence.

Lancet 2006; 368: 170-173

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Why the need for classification?

Wide range of disease manifestation – DYNAMIC clinical phases

• Clinical
Is it for disease recognition?
Triage
Management strategies
Audit – case fatality rates

• Epidemiology/Surveillance

• Burden of disease
Budget allocation/cost-effectiveness

• Research
Pathogenesis
Clinical trials – vaccines, anti-viral agents, therapeutic agents

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Clinical Perspectives

• Classification should be useful for triage

• Should guide clinical management

– Retrospective classification

• Should capture severe cases accurately

– Plasma leakage ± bleeding the main determinants

• Easy to use, understood by physicians in different levels of care

– primary health care levels in rural areas – stethoscope, BP sets
and iv fluids.

• Not for recognition of disease!!

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TDR branch of WHO – DENCO Partners, 2006

Liverpool, Heidelberg, TDR/WHO,

UK Germany Geneva Philippines

Cuba
Antwerp,
Nicaragua Belgium
Vietnam

Thailand
Brazil
Venezuela

Malaysia

Europe
Latin America
Asia

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Intermediate Tool: grading severity by interventions

Category 1 Category 2 Category 3

Standard Protocol Intermediate Protocol Major intervention
Nursing  Level 1 and no  Level 2 or 3 and no
care* intervention intervention

Fluid  None  IV fluids (any) for  Shock resuscitation, or IV fluids (any) for
therapy maintenance or rehydration rehydration with nursing care level 3

Blood  None  Platelets, fresh frozen  Platelets, fresh frozen plasma or

products plasma or cryoprecipitate** cryoprecipitate with nursing care level 3
with nursing care level 1 or 2  Whole blood, packed red cells, or any
combination of blood products
Other  None  Oxygen therapy  Oxygen therapy with nursing care level 3
interventions  Diuretics without other  Respiratory support
specific intervention  Inotropic support
 Specific treatment for liver, renal or other
organ failure
*Nursing care levels, individualised according to local practice:-
1 - in- or out-patient, free to walk around, standard observation protocol – e.g. 6 hourly
2 - hospitalised, more stringent observation protocol – e.g. 2-4 hourly
3 - bed rest, ICU level observation protocol – e.g. hourly
** At some sites certain blood products were given in response to abnormal laboratory findings rather than for clinical reasons. We
classified such interventions in the moderate category. 14

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Evidence for the development:

The DenCo study

Applying the DF/DHF/DSS criteria strictly:

55/230 (24%) of patients with shock did not fulfil all criteria for DHF
The DCC (DF,/DHF/DSS) is not correlated with disease severity.
Not intended to guide medical therapy, case management 15

Suggested indicators for severe dengue

- one or more of the following
• Severe plasma leakage
Sensitivity = 96%
– Clinical shock Specificity = 97%
– 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)

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Classification into uncomplicated and moderate

disease – an example
• 3 or more present
– Clinical
• Clinical evidence of fluid accumulation
• Evidence of mucosal bleeding Sensitivity = 77%
• Liver enlarged Specificity = 57%
• Skin flush or rash
• Abdominal pain or tenderness
• Tourniquet test positive
– Laboratory
• WBC <= 2.0
• Percentage haematocrit increase >= 20
• Platelet count <= 50

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Binary classification
DENGUE SEVERE DENGUE

• Severe plasma
leakage
Watch for • Severe
Warning Signs bleeding
• Severe organ
impairment

The development of the 2009 WHO DCC

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9

Dengue case classification by severity
DENGUE ± Warning Signs
With
Without
WARNING
SIGNS
Warning Signs*
• Abdominal pain or tenderness
• Persistent vomiting
• Clinical fluid accumulation
• Mucosal bleed
• Lethargy; restlessness
• Liver enlargement >2cm
• Laboratory: Increase in HCT
concurrent with rapid decrease
in platelet count
* Requiring strict observation and medical intervention
Dengue is one disease entity with different clinical presentations
and often with unpredictable clinical evolution and outcome
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SEVERE DENGUE
1.Severe plasma leakage
2.Severe haemorrhage
3.Severe organ impairment
1. Severe plasma leakage leading to
• Shock (DSS)
• Fluid accumulation with
respiratory distress
2. Severe bleeding
as evaluated by clinician
3. Severe organ involvement
 Liver: AST or ALT>=1000
 CNS: Impaired consciousness
 Heart and other organs
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Using the 2009 WHO

case classification in
practice:

An algorithm for
clinical mangement
(needs local
adaptation)

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Evidence for the development:

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The steps for the development of the WHO 2009 dengue case classification
Numerous publications describing - Numerous reports of the difficulties using
1
the difficulties using DF/DHF/DSS DF/DHF/DSS: epidemiology has changed
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A systematic review of the issue
9 Bandyopadhyay - High level evidence/confirmation
S et al., TMIH 2006, Volume 11 no 8 pp 1238–1255 of the above
0
´s DF/DHF/DSS national application study - Large differences of DHF case definitions
Santamaria R et al, International Health (2009) 1, 133—140 between countries; application difficult
-
2 The DenCo study (dengue & control ) - Clear evidence for classifying into
0
Alexander N et al, TMIH, Volume 16 no 8 pp 936–948 August 2011 ”dengue and severe dengue” (D/SD)
- Dengue is just ¨one disease entity with different
1 Four expert consensus meetings clinical presentations and often with unpredictable
La Habana and Kuala Lumpur 2007/09
6 clinical evolution and outcome¨
A global expert consensus meeting - Further design: 1) dengue with or without
Geneva 2008 warning signs and 2) severe dengue
Dengue guidelines validation studies - Analysis showing user-friendliness and
Barniol J et al, BMC Infectious Diseases 2011, 11:106 acceptance of dengue/severe dengue

Revising dengue case classification - Final analysis, revision of chain of

Horstick O et al, Pathogens and Global Health, August 2012 evidence and recommendations

A systematic review of the use -Clear evidence for the use confirmed in
Horstick O et al, AJTMH September 2014 91(3, 621 634 studies in mostly clinical settings

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Evidence used for the development

of the 2009 WHO dengue case classification:
The analysis has shown that the revised dengue case classification is better
able to

– Standardise clinical management

– Raise awareness about unnecessary interventions

– Match patient categories with specific treatment instructions

– Make the key messages of patient management understandable for all

health care staff
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12 studies, 4 prospective

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Studies analysing sensitivity/specificity

of dengue/severe dengue

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Sensitivity/specificity
of dengue/severe dengue vs DF/DHF:

12 studies, 4 prospective: When determining severe dengue

2009 DCC 1997 DCC

• Sensitivity: 59-98% • 25-90%

• Specificity 41-99% • 25%-100%

Easy to apply
BUT for non-severe dengue – risk of monitoring increased case numbers

The THREE SEVERE DENGUE criteria are useful research endpoints,

Epidemiological purposes.

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Dengue/Severe Dengue Model

(1) Describe disease progression of dynamic nature,
(2) Defines disease severity and allows evaluating progression of cases,
(3) Describes all forms of severe dengue,
(4) Allows pathophysiological research
(5)Warning signs help identify early cases at risk of shock (children and
adults)
(6) Helps treat individual dengue cases and reorganization of health-
care services for outbreak management,
(7) Currently no update of ICD10 to include new classification of
dengue (D/SD);

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The expert consensus meeting in PAHO

Conclusion: The expert panel recommends to

1) update ICD10,
2) include D/SD in country epidemiological reports,
3) implement studies improving sensitivity/specificity of the
4) dengue case definition.

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ICD 11 update

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Comparing the WHO 2009 and 1997 DCCs

WHO 2009 DCC WHO 1997 DCC

Development Series of studies, both quantitative and Expert consensus

qualitative
Validation Tested in many different countries No validation process

Focus Towards severity of disease and early No relation to severity

detection of severe cases (especially DHF)
Usefulness Especially for clinical management, but
also for improved surveillance
Strength Inclusion of all severe clinical pictures of
dengue
Helpful for clinical management without
laboratory facilities
ICD ICD 11 Previous ICDs

Outlook Further studies soon available on warning

signs and case definitions
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Conclusion: Issues around the 2009 WHO DCC

- The dengue case definition (dengue yes or no) is based on the case
definition of the 1997 WHO DCC – modified through expert opinion – for the
better or for worse?
Question: Modifications with more quantifiable evidence (IDAMS)?

- Warning signs partly based on the DENCO study, partly on expert opinion,
- Question: Modifications perhaps best with more quantifiable evidence
(IDAMS)?

- Global use remains an issue, implications on quality of surveillance data, but

more countries are now following the model, this will probably speed up with
the ICD11
Question: A process for global use of 2009 WHO DCC should be initiated?

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THANK YOU FOR YOUR

ATTENTION!

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