Brian Eka Rachman, dr., Sp.

PD,
FINASIM

19 Mei 2024
 EPIDEMIOLOGY
Dengue virus infections: 390 million dengue virus infections per year
(95% credible interval 284–528 million)

Despite a risk of infection existing in 129 countries  70% of the actual

burden is in Asia

The number of dengue cases reported to WHO increased over 15 fold

over the last two decades
• 2000 = 505,430 cases
• 2010 = 2,400,138 cases
• 2015 = 3,312,040 cases
• 2019 = 5,210,032 cases

Deaths from 2000 to 2015 increased from 960 to more than 4032.

Waggoner, J.J., et al., Viremia and Clinical Presentation in Nicaraguan Patients Infected With Zika Virus, Chikungunya Virus, and Dengue Virus. Clinical Infectious Diseases, 2016. 63(12): p. 1584-1590.
Bhatt, S., et al., The global distribution and burden of dengue. Nature, 2013. 496(7446): p. 504–507.
Brady, O.J., et al., Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLOS Neglected Tropical Diseases, 2012. 6(8): p. e1760.
 DISTRIBUTION OF DENGUE

Kularatne SA, Dalugama C. Dengue infection: Global importance, immunopathology and management. Clin Med (Lond). 2022 Jan;22(1):9-13. doi: 10.7861/clinmed.2021-0791.
PMID: 35078789; PMCID: PMC8813012.
 HIGHLY DENGUE ENDEMIC ASEAN COUNTRIES
AS REPORTED TO WHO 2004 - 2010
Brunei 372

Singapore

Lao PDR

Myanmar 15225

Cambodia 18967

Malaysia 42368

Philippines 54639

Thailand 60205

Vietnam 91321

Indonesia 129435
0 20000 40000 60000 80000 100000 120000 140000
Average Number of Cases

Source: WHO Global Strategy for Dengue Prevention and Control, 2012
 CFR OF DENGUE IN ASEAN COUNTRIES:
2009/2010
Vietnam 0.04

Singapore 0.11

Thailand 0.12
SEARO & WPRO COUNTRIES

Lao PDR 0.2

Malaysia 0.29

Cambodia 0.3

Philippines 0.59

Brunei 0.67

Myanmar 0.93

Indonesia 0.95
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
CFR
INCIDENCE RATE AND CASE FATALITY RATE
IN INDONESIA

Kementerian Kesehatan RI. 2023. Laporan Tahunan 2022 Demam Berdarah Dengue
 DENGUE VIRUS
• An arbovirus (arthropod-borne virus)
• Genus: Flavivirus
• Family: Flaviviridae
• Serotypes: DENV-1, DENV-2, DENV-3 and DENV-4
• Recovery: immunity against that serotype.
• Cross-immunity to the other serotypes: partial, and temporary.
• Subsequent infections (secondary infection): other serotypes 
Severe dengue
 VECTOR

Aedes mosquitoes. Courtesy of Centers for Disease Control and Prevention,

National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of
Vector-Borne Diseases (DVBD). (a) Aedes aegypti mosquito. (b) Aedes
albopictus mosquito
LIFE CYCLE OF AEDES MOSQUITO

Source: https://www.cdc.gov/dengue/training/cme/ccm/page47319.html
TRANSMISSION CYCLE
 Immuno-pathogenesis

Capillary leakage and

PATHOPHYSIOL shock
OGY
Coagulopathy in dengue
LIFECYCLE OF DENGUE VIRUS IN A
MAMMALIAN CELL
 Primary Infection Secondary Infection
Dengue Virus (DV)
Cross-reactive Ab
M
Tn B CELL
NK Neutralizing Ab
T CELL B CELL
B CELL
EC

Monocyte Non-neutralizing Ab
PLASMA
CELL Tn TM
Platelet DC

TM

Susceptible: TM
DF DHF HLA-B*15,
(↑↑) IL-1ra, IL-18, B*51,B*78
(↑) IP-10, MCP-1,
Eotaxin, MIP-1, MCP-1, (DF);B*13,
(↑↑) MIP-1
IP-10, ICAM-1 B*53 (DHF)
(↓↓) IFN-, IL-4, IL-5, IL- Protective: T cell target- DV
DV Neutralizing Antibody (↓) IL-12, IL-13, G-CSF 12, FGF-Basic, G-CSF, HLA-B*35 Epitopes:
PDGF, VEGF (DF);HLA- NS2B, NS3, NS4A,
A*03, NS4B, NS5
B*18(DHF)

C3a, C5a Eotaxin,ICAM-1,VEGF

Endothelial Cell

Vascular Permeability
Vascular Leakage

95% of DHF occurs with secondary DV infection

PROPOSED MODEL
FOR THE
PATHOGENESIS OF
DF, DHF, AND DSS
 CAUSES OF BLEEDING IN DF/DHF

Abnormal coagulogram Decrease fibrinogen level

Thrombocytopenia Increase level of fibrinogen

degradation product (FDP)
Platelet dysfunction
Increase level of D-Dimer
Prothombin complex deficiency
secondary to Liver involvement
Consumptive coagulopathy (activation
Endothelial injury of mononuclear phagocytes)

DIC and Prolong aPTT Sequestration of platelets

CAUSES OF THROMBOCYTOPENIA

Destruction of Disseminated Bone marrow Peripheral

platelet Intravascular suppression in early sequestration of
(antiplatelet Coagulation (DIC) stage platelets
antibodies)
 CLINICAL MANIFESTATIONS OF DF/ DHF

Dengue virus
infection

Asymptomatic Symptomatic

Undifferentiated Dengue Expanded dengue

Dengue fever haemorrhage fever Syndrome/Isolated
Fever (viral
(DF) (DHF) (with plasma organopathy (unusual
syndrome) leakage) manifestation)

DHF with shock

Without With unusual
DHF non-shock Dengue shock
haemorrhage haemorrhage
syndrome (DSS)
 EXPANDED DENGUE SYNDROME
(EDS)

System Unusual or atypical manifestations

CNS involvement Encephalopathy, encephalitis, febrile seizures, I/C bleed
G. I. involvement Acute Hepatitis/fulminant hepatic failure, cholecystitis, cholangitis acute
pancreatitis
Renal involvement Acute renal failure, haemolytic uremic syndrome, acute tubular necrosis
Cardiac involvement Cardiac arrhythmia, cardiomyopathy, myocarditis, pericardial effusion
Respiratory Pulmonary oedema, ARDS, pulmonary haemorrhage. pleural effusion
Eye Conjunctival bleed, macular haemorrhage, visual impairment, optic neuritis
 CASE DEFINITION
Probable DF/DHF
A case compatible with clinical description of dengue fever during outbreak
OR
Non-ELISA based NS1 antigen/IgM positive

Confirmed dengue fever

A case compatible with the clinical description of dengue fever with at least one of the following:

• Isolation of the dengue virus (virus culture + VE) from serum, plasma, leucocytes
• Demonstration of IgM antibody titre by ELISA positive in single serum sample
• Demonstration of dengue virus antigen in serum sample by NS1-ELISA
• IgG seroconversion in paired sera after 2 weeks with four fold increase of IgG titre
• Detection of viral nucleic acid by polymerase chain reaction (PCR)

19
 CLINICAL CRITERIA FOR DF /
DHF/DSS
Clinical Features of DF:
An acute febrile illness of 2-7 days duration with two or more of the following manifestations: headache, retro-orbital pain, myalgia,
arthralgia, rash, haemorrhagic manifestations

Dengue Haemorrhagic Fever (DHF):

a. A case with clinical criteria of dengue fever
Plus
b. Haemorrhagic tendencies evidenced by one or more of the following
1.Positive tourniquet test
2.Petechiae, ecchymoses or purpura
3.Bleeding from mucosa, gastrointestinal tract, injection sites or other sites
Plus
c. Thrombocytopenia (<100.000 cells per cumm)
Plus
d. Evidence of plasma leakage due to increased vascular permeability, manifested by one or more of the following:
4.A rise in average haematocrit for age and sex  20%
5.A more than 20% drop in haematocrit following volume replacement treatment compared to baseline
6.Signs of plasma leakage (pleural effusion, ascites, hypoproteinemia)

Dengue Shock Syndrome (DSS):

All the above criteria for DHF with evidence of circulatory failure manifested by rapid and weak pulse and narrow pulse pressure ( 20%
mmHg) or hypotension for age, cold and clammy skin and restlessness
 Febrile
phase

NATURAL Critical
COURSE OF phase
DENGUE
INFECTION
Convalescen
t phase
NATURAL COURSE OF DENGUE
INFECTION
 GRADING OF DF/DHF
DF/
DHF Grade Sign and Symptoms Laboratory
DF Fever with two of the following: • Leucopenia (wbc ≤5000 cells/mm3)
• Headache • Thrombocytopenia (Platelet count < 150.000
• Retro-orbital pain cells/mm3)
• Myalgia • No evidence of plasma loss
• Arthralgia / bone pain
• Rash
• Haemorrhagic manifestations
• No evidence of plasma leakage
DHF I Fever and haemorrhagic manifestation (positive Thrombocytopenia <100.000 cells/mm3; HCT rise 
tourniquet test) and evidence of plasma leakage 20%)
DHF II As in Grade I plus spontaneous bleeding Thrombocytopenia <100.000 cells/mm3; HCT rise 
20%)
DHF# III As in Grade I or II plus circulatory failure (weak pulse, Thrombocytopenia <100.000 cells/mm3; HCT rise 
narrow pulse pressure ( 20 mmHg), hypotension, 20%)
restlessness)
DHF# IV As in Grade III plus profound shock with Thrombocytopenia <100.000 cells/mm3; HCT rise 
undetectable BP and pulse 20%)

Source: http://www.who.int/csr/resources/publications/dengue/Denguepublication/en/
#
: DHF III and IV are DSS
LABORATORY DIAGNOSIS
ELISA-based NS1 antigen tests

IgM-capture enzyme-linked immunosorbent assay (MAC-ELISA)

Isolation of dengue virus

Polymerase chain reaction (PCR)

IgG-ELISA

Serological tests

RDTs
 TYPES OF DIAGNOSTIC TEST FOR DENGUE
INFECTION
Technique Recommended time, specificity, and sensitivity

IgM detection 4 days after onset of symptoms and up to 3 months in primary dengue
3 days after onset of symptoms and sometimes hindered by large-scale IgG production in secondary dengue
(Sensitivity, 61.5-100%; specificity, 52-100%)
Antibody IgG detection 10 days after onset of symptoms in primary dengue
detection 3 days after onset of symptoms in secondary dengue
(Sensitivity, 46.4-99%; specificity, 80-100%)
Rapid IgM 5 days after onset of symptoms and up to 2 months
detection (strips) (Sensitivity, 20.5-97.7%; specificity, 76.6-96.6%)
NS1 and IgM As this is a combo test, useful in early stage of infection (day 3 onwards) and up to sero-conversion period (up to 2 weeks onwards)
Antigen combo kit (Sensitivity, 89.9-92.9%; specificity, 75-100%)
/antibody
combined NS1 and IgM/IgG As this is a combo test, useful in early stage of infection (day 3 onwards) and up to sero-conversion period (up to 2 weeks onwards). In the
detection combo kit event of both NS1 and IgM are non-reactive and IgG is reactive, case can be interpreted as secondary dengue
(Sensitivity, 93%; specificity, 100%)
Virus isolation 1-5 days of onset of symptoms in primary dengue and 1-4 days after onset of symptoms in secondary dengue
(cell culture) (Sensitivity, 40.5%; specificity, 100%)
Virus isolation Same as above
(mosquitoes) (Sensitivity, 71.5-84.2%; specificity, 100%)
Viral Viral RNA RT-PCR Same as above
detection (conventional) (Sensitivity, 48.4-100%; specificity, 100%)
Viral RNA RT-PCR Same as above
(real time) (Sensitivity, 58.9-100%; specificity, 100%)
Viral antigen 1-7 days of onset of symptoms in primary dengue and 1-5 days after onset of symptoms in secondary dengue
(NS1) (Sensitivity, 54.2-93.4%; specificity, 92.5-100%)
Abbreviations: IgM immunoglobulin M, IgG immunoglobulin G, NS1 non-structural protein 1, RNA ribonucleic acid, RT-PCR reverse transcriptase polymerase chain reaction
 RECOMMENDATION OF TYPE OF DENGUE TEST BASED ON THE
CLINICAL HISTORY OF PATIENTS AND INTERPRETATION OF
THEIR RESULTS

Clinical history (test) Results Interpretations

Positive Acute dengue infection

Fever < 5 days (dengue NS1 or
RCT) Negative DVI still cannot rule out. Repeat for dengue IgM after day 5 of
fever
Positive Suggestive of recent dengue infection

Fever > 5 days (dengue IgM)
Fever > 5 days and dengue
IgM and/or NS1 was negative
(dengue IgG)
Abbreviations: IgM immunoglobulin M, IgG immunoglobulin G, NS1 non-structural protein 1, RCT rapid combo test, DVI dengue
Intermediate Repeat
Negative The result does not rule out dengue infection. Repeat sample
for dengue IgM after day 7 of fever or dengue IgG test
Elevate IgG levels are seen in acute or past infection. A titer of
Positive
1:2560 is consistent with acute secondary infection
Intermediate Repeat if clinically indicated
The absence of elevated IgG is presumptive evidence that the
Negative patient does not have secondary dengue infection
viral infection
 DIFFERENTIAL DIAGNOSIS
Chikungunya virus (this has often been mistaken for dengue
Arboviruses in South-East Asia

Other viral Measles; rubella and other viral exanthems; Epstein Barr
disease virus (EBV); enteroviruses; influenza; hepatitis A; Hantavirus

Bacterial Meningococcaemia, leptospirosis, typhoid, melioidosis,

diseases rickettsial disease, scarlet fever

Parasitic Malaria
diseases
 Symptom DHF (%) Chikungunya fever (%)
Injected pharynx 98.9 90.3
Vomiting 57.9 59.4
Constipation 53.3 40.0
Abdominal pain 50.0 31.6
Headache 44.6 68.4
Generalized lymphadenopathy 40.5 30.8
Conjunctival injection 32.8a 55.6a
Cough 21.5 23.3
Restlessness 21.5 33.3
Rhinitis 12.8 6.5
Maculopapular rash 12.1a 59.6a
Myalgia/arthralgia 12.0a 40.0a
Enanthema 8.3 11.1
Abnormal reflex 6.7 0.0
Diarrhoea 6.4 15.6
Palpable spleen (in infants of <6 months) 6.3 3.1
Coma 3.0 0.0

Source: Nimmannitya S., et al., American Journal of Tropical Medicine and Hygiene, 1969, 18:954-971.
a
Statistically significant difference
 CRITERIA
FOR ADMISSION
OF A PATIENT
 GROUP A
OUTPATIENT
MANAGEMENT
GROUP B
WARNING
SIGNS
SUGGESTED DENGUE CLASSIFICATION AND
LEVEL OF SEVERITY
Source: World Health Organization. Dengue Guidelines for Diagnosis, Treatment, Prevention and Control - New Edition 2009. WHO: Geneva; 2009
 GROUP C
COMPENSATED
SHOCK
 GROUP C
HYPOTENSIVE
SHOCK
HEMODYNAMIC ASSESSMENT
 CRITERIA FOR DISCHARGE OF
PATIENTS

• No fever for at least 24 hours

• Normal blood pressure

• Adequate urine output

• No respiratory distress

• Persistent platelet count >50,000/cu.mm

 VAKSINASI DENGUE

• Vaksin diberikan pada orang dewasa usia 19-45 tahun.

• Vaksin Dengue diindikasikan untuk pencegahan penyakit dengue yang
disebabkan oleh serotipe virus dengue apapun pada individu usia 6-45
tahun.
• Vaksin diberikan dalam 2 dosis masing-masing 0,5ml pada bulan ke-0
dan bulan ke-3.
• Vaksin ini dikontraindikasikan pada ibu hamil dan menyusui dan
kelompok dengan imunodefisiensi seperti HIV dengan bukti adanya
gangguan imun, imunodefisiensi bawaan atau yang didapat seperti
penggunaan steroid dosis tinggi dan kemoterapi.
• Pilih jenis vaksin yang direkomendasikan/diizinkan BPOM untuk usia 19-
45 tahun.
 ANALYSES FROM THE LONG-TERM
SAFETY FOLLOW-UP

• Overall population level benefit of vaccination remains favorable, but the vaccine
performs differently in seropositive versus seronegative individuals.
• Vaccine efficacy (VE) against virologically confirmed symptomatic dengue was high
among inferred baseline seropositive participants ≥9 years of age: 76% (95%CI:
63.9, to 84.0), but much lower among baseline seronegative participants: 38.8%
(95%CI: –0.9 to 62.9%) in the first 25 months after the first dose of vaccine.
• There is an increased risk of hospitalized and severe dengue in seronegative
individuals starting about 30 months after the first dose.
• In areas of 70% dengue seroprevalence, over a 5-year follow-up, for every 4
severe cases prevented in seropositive, there would be one excess severe case in
seronegative per 1,000 vaccinees; for every 13 hospitalizations prevented in
seropositive vaccinees, there would be 1 excess hospitalization in seronegative
vaccinees per 1,000 vaccinees.
https://www.who.int/news-room/questions-and-answers/item/dengue-vaccines
 EFIKASI VAKSIN DENGUE

• Studi klinis menunjukkan bahwa vaksin Dengue CYD-TDV memiliki

tingkat efikasi sekitar 66% dalam mencegah kasus Dengue berat dan
sekitar 60% dalam mencegah kasus Dengue secara keseluruhan
(Hadinegoro et al., 2015).
• Penelitian menunjukkan bahwa efikasi vaksin Dengue dapat bervariasi
tergantung pada prevalensi dan jenis virus Dengue di suatu wilayah
(Capeding et al., 2014).
• Data uji klinis menunjukkan bahwa vaksin Dengue dapat memiliki
efikasi yang lebih baik pada kelompok umur tertentu, seperti anak-
anak usia di atas 9 tahun (Villar et al., 2015).
•Hadinegoro, S. R., et al. (2015). Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. New England Journal of Medicine, 373(13), 1195–1206.
•Capeding, M. R., et al. (2014). Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. The
Lancet, 384(9951), 1358–1365.
•Villar, L., et al. (2015). Efficacy of a Tetravalent Dengue Vaccine in Children in Latin America. New England Journal of Medicine, 372(2), 113–123.
 EFIKASI VAKSIN DENGUE (2)

• Studi jangka panjang menunjukkan bahwa vaksin Dengue dapat

memberikan perlindungan yang signifikan selama beberapa tahun
setelah vaksinasi, meskipun tingkat perlindungan dapat menurun
seiring waktu
• Analisis data menunjukkan bahwa vaksin Dengue dapat mengurangi
risiko hospitalisasi akibat penyakit Dengue, dengan efikasi sekitar
80% dalam mengurangi kasus-kasus parah yang memerlukan
perawatan medis

Sabchareon, A., et al. (2014). Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue
vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. The Lancet, 384(9951), 1358–1365.
THANK YOU