Dengue

Clinical Manifestations
and Epidemiology

Rizka Humardewayanti
 I
Virus, Vector and Transmission
 Dengue Virus
• Causes dengue and dengue hemorrhagic fever
• Is an arbovirus
• Transmitted by mosquitoes
• Composed of single-stranded RNA
• Has 4 serotypes (DEN-1, 2, 3, 4)
 Dengue Viruses
• Each serotype provides specific lifetime
immunity, and short-term cross-immunity
• All serotypes can cause severe and fatal disease
• Genetic variation within serotypes
• Some genetic variants within each serotype
appear to be more virulent or have greater
epidemic potential
Transmission of Dengue Virus
by Aedes aegypti

Mosquito feeds / Mosquito refeeds /

acquires virus transmits virus

Extrinsic Intrinsic
incubation incubation
period period
Viremia Viremia
0 5 8 12 16 20 24 28
DAYS
Illness Illness
Human #1 Human #2
 Replication and Transmission
of Dengue Virus (Part 1)
1. Virus transmitted 1
to human in mosquito
saliva
2
2. Virus replicates 4
in target organs
3. Virus infects white
3
blood cells and
lymphatic tissues

4. Virus released and

circulates in blood
 Replication and Transmission
of Dengue Virus (Part 2)

5. Second mosquito 6
ingests virus with blood

6. Virus replicates
in mosquito midgut 7
and other organs,
infects salivary
glands 5
7. Virus replicates
in salivary glands
Aedes aegypti Mosquito
 Aedes aegypti
• Dengue transmitted by infected female
mosquito
• Primarily a daytime feeder
• Lives around human habitation
• Lays eggs and produces larvae preferentially in
artificial containers
 II
EPIDEMIOLOGY
 Distribusi infeksi Dengue

Infestasi Aedes aegypti

Area Aedes aegypti dan epidemik dengue
 III
Clinical Manifestations of
Dengue and Dengue
Hemorrhagic Fever
Dengue Clinical Syndromes

• Undifferentiated fever
• Classic dengue fever
• Dengue hemorrhagic fever
• Dengue shock syndrome
 Undifferentiated Fever
• May be the most common manifestation of
dengue
• Prospective study found that 87% of students
infected were either asymptomatic or only mildly
symptomatic
• Other prospective studies including all age-
groups also demonstrate silent transmission

DS Burke, et al. A prospective study of dengue infections

in Bangkok. Am J Trop Med Hyg 1988; 38:172-80.
 Clinical Characteristics
of Dengue Fever
• Fever
• Headache
• Muscle and joint pain
• Nausea/vomiting
• Rash
• Hemorrhagic manifestations
 Hemorrhagic Manifestations
of Dengue
• Skin hemorrhages: petechiae,
purpura, ecchymoses
• Gingival bleeding
• Nasal bleeding
• Gastro-intestinal bleeding:
hematemesis, melena, hematochezia
• Hematuria
• Increased menstrual flow
Ptekiae
 Tourniquet Test
• Inflate blood
pressure cuff to a
point midway
between systolic and
diastolic pressure for
5 minutes
• Positive test: 20 or
more petechiae per 1
inch2 (6.25 cm2)

Pan American Health Organization: Dengue and Dengue Hemorrhagic Fever:

Guidelines for Prevention and Control. PAHO: Washington, D.C., 1994: 12.
 Clinical Case Definition for
Dengue Hemorrhagic Fever
4 Necessary Criteria:
• Fever, or recent history of acute fever
• Hemorrhagic manifestations
• Low platelet count (100,000/mm3 or less)
• Objective evidence of “leaky capillaries:”
– elevated hematocrit (20% or more over baseline)
– low albumin
– pleural or other effusions
Pleural Effusion Index

PEI = A/B x 100

B
A
Vaughn DW, Green S, Kalayanarooj S, et al. Dengue in the early febrile
phase: viremia and antibody responses. J Infect Dis 1997; 176:322-30.
Clinical Case Definition for Dengue
Shock Syndrome
• 4 criteria for DHF
• Evidence of circulatory failure manifested
indirectly by all of the following:
– Rapid and weak pulse
– Narrow pulse pressure ( 20 mm Hg) OR
hypotension for age
– Cold, clammy skin and altered mental status
• Frank shock is direct evidence of circulatory
failure
 Four Grades of DHF
• Grade 1
– Fever and nonspecific constitutional symptoms
– Positive tourniquet test is only hemorrhagic manifestation
• Grade 2
– Grade 1 manifestations + spontaneous bleeding
• Grade 3
– Signs of circulatory failure (rapid/weak pulse, narrow pulse
pressure, hypotension, cold/clammy skin)
• Grade 4
– Profound shock (undetectable pulse and BP)
 Danger Signs in
Dengue Hemorrhagic Fever

• Abdominal pain - intense and sustained

• Persistent vomiting
• Abrupt change from fever to
hypothermia, with sweating and
prostration
• Restlessness or somnolence

Martínez Torres E. Salud Pública Mex 37 (supl):29-44, 1995.

 Unusual Presentations
of Severe Dengue Fever

• Encephalopathy
• Hepatic damage
• Cardiomyopathy
• Severe gastrointestinal hemorrhage
 Signs and Symptoms of
Encephalitis/Encephalopathy
Associated with Acute Dengue Infection

• Decreased level of consciousness: lethargy,

confusion, coma
• Seizures
• Nuchal rigidity
• Paresis
 IV
Disease Pathogenesis
 Risk Factors Reported for DHF
• Virus strain
• Pre-existing anti-dengue antibody
– previous infection
– maternal antibodies in infants
• Host genetics
• Age
 Risk Factors for DHF
(continued)
• Higher risk in secondary infections
• Higher risk in locations with two or more
serotypes circulating simultaneously at high
levels (hyperendemic transmission)
 Increased Probability of DHF
Hyperendemicity

Increased circulation Increased probability

of viruses of secondary infection

Increased probability of Increased probability of

occurrence of virulent strains immune enhancement

Increased probability of DHF

Gubler & Trent, 1994
Hypothesis on Pathogenesis
of DHF (Part 1)
• Persons who have experienced a dengue
infection develop serum antibodies that
can neutralize the dengue virus of that
same (homologous) serotype
Homologous Antibodies Form
Non-infectious Complexes

Dengue 1 virus
Neutralizing antibody to Dengue 1 virus
Non-neutralizing
antibody
Complex formed by neutralizing antibody
and virus
Hypothesis on Pathogenesis
of DHF (Part 2)
• In a subsequent infection, the pre-
existing heterologous antibodies form
complexes with the new infecting virus
serotype, but do not neutralize the new
virus
Heterologous Antibodies Form
Infectious Complexes

Dengue 2 virus
Non-neutralizing antibody to Dengue 1
virus
Complex formed by non-neutralizing
antibody and virus
 Hypothesis on Pathogenesis
of DHF (Part 3)
• Antibody-dependent enhancement is the
process in which certain strains of dengue
virus, complexed with non-neutralizing
antibodies, can enter a greater proportion of
cells of the mononuclear lineage, thus
increasing virus production
Heterologous Complexes Enter More
Monocytes, Where Virus Replicates

Dengue 2 virus

Non-neutralizing antibody
Complex formed by non-
neutralizing antibody and
Dengue 2 virus
 Hypothesis on Pathogenesis
of DHF (Part 4)
• Infected monocytes release vasoactive
mediators, resulting in increased vascular
permeability and hemorrhagic manifestations
that characterize DHF and DSS
 Viral Risk Factors
for DHF Pathogenesis
• Virus strain (genotype)
– Epidemic potential: viremia level,
infectivity
• Virus serotype
– DHF risk is greatest for DEN-2, followed
by DEN-3, DEN-4 and DEN-1
 Infeksi Dengue
(heterolog)

Gangguan lekosit Gangguan endotel Gangguan trombosit

monosit makrofag

Pelepasan PF3, Sekuestrasi Degranulasi

Aktivasi limfosit PF4, BRG, TXA2 SRE

Trombosit < Disfungsi

Sel B Sel NK Sel T PG 2
Trombosit

IFN Ɣ Permeabilitas Aktivasi

Virus >
kapiler > pembekuan
TNF
IL-1
Ab+Ag >> Permeabilitas
kapiler >>
Aktivasi komplemen
Permeabilitas DIC Perdarahan
Anafilatoksin kapiler >>>
C3a, C5a Konsumsi faktor2
pembekuan

Syok DIC Perdarahan

Syok DIC Perdarahan

Kematian
 Patogenesis Renjatan pada DBD

Infeksi Dengue heterolog sekunder

Replikasi virus Respon antibodi

Kompleks antibodi virus

Agregasi trombosit Aktivasi koagulasi Aktivasi komplemen

Plasmin 
Gangguan Pelepasan PF III F. Hageman teraktivasi
fungsi trombosit anafilatoksin

Pelepasan trombosit oleh RES

Koagulopati konsumtif Sistem kinin
trombositopenia Permeabilitas vaskuler >
Clotting factor < kinin

FDP
SYOK
Perdarahan eksesif
Sindroma kebocoran kapiler
 V

DIAGNOSIS AND
LABORATORIUM
WHO guidelines for the diagnosis of dengue haemorrhagic fever (DHF)
and dengue shock syndrome (DSS).
 Demam Dengue
• Dengue Fever adalah demam akut (2-7 hari) dengan dua atau
lebih gejala berikut :
– Nyeri kepala
– Nyeri retro-orbital
– myalgia/arthralgia
– Ruam makulopapular
– Manifestasi perdarahan (petechiae dan RL positif) dan,
– leukopenia.
• Biasanya tidak menyebabkan kematian/sembuh tanpa
gejala sisa
 Kriteria DHF (WHO, 1997)
• Demam/riw. Demam akut 2-7 hr (bifasik)
• Kecenderungan perdarahan :
– RL (+)
– Ptekiae, ekimosis atau purpura
– Perdarahan mukosa, gastrointestinal, atau tempat lain
– Hematemesis/melena
• Trombositopenia (<100.000)
• Bukti plasma leakage karena penurunan permeabilitas vaskuler :
– Peningkatan Hmt > 20% di atas rata2
– Penurunan Hmt setelah penggantian cairan > 20%
– Tanda2 plasma leakage seperti efusi pleura, ascites, dan
hipoproteinemia
 Kriteria DSS (WHO, 1997)
• Semua kriteria DHF (4)
• Bukti gagal sirkulasi yang secara tidak
langsung ditandai oleh:
– Nadi cepat dan lemah
– Tekanan nadi melebar (< 20 mmHg)
– Hipotensi
– Acral dingin dan gangguan status mental
 Laboratory Tests
in Dengue Fever
• Clinical laboratory tests
– CBC--WBC, platelets, hematocrit
– Albumin
– Liver function tests
– Urine--check for microscopic hematuria
• Dengue-specific tests
– Virus isolation
– Serology
 Temperature, Virus Positivity and Anti-
Dengue IgM , by Fever Day
Temperature (degrees Celsius)

100

Dengue IgM (EIA units)

300
39.5
Percent Virus Positive

80
39.0 225
38.5 60
150
38.0 40
37.5 20 75

37.0
0 0
-4 -3 -2 -1 0 1 2 3 4 5 6
Fever Day
Mean Max. Temperature Virus Dengue IgM
Adapted from Figure 1 in Vaughn et al.,
J Infect Dis, 1997; 176:322-30.
 Interpretasi antibodi Dengue HI

Respon antibodi Interval spesimen Titer Interpretasi

1-2 konvalesen
Naik > 4x > 7 hari < 1 : 1280 Infeksi flavivirus akut, primer
Naik > 4x Spesimen > 1 : 1280 Infeksi flavivirus akut, sekunder
sewaktu
Naik > 4x < 7 hari < 1 : 1280 Infeksi flavivirus akut, primer
atau sekunder
Tidak berubah Spsimen sewaktu > 1 : 1280 Infeksi flavivirus akut, sekunder
Tidak berubah > 7 hari < 1 : 1280 Bukan dengue
Tidak berubah < 7 hari < 1 : 1280 Tidak terinterpretasi
Tidak Spesimen tunggal < 1 : 1280 Tidak terinterpretasi
diketahui
 VI
Treatment
 Outpatient Triage
• No hemorrhagic manifestations and patient is
well-hydrated: home treatment
• Hemorrhagic manifestations or hydration
borderline: outpatient observation center or
hospitalization
• Warning signs (even without profound shock) or
DSS: hospitalize
 Patient Follow-Up
• Patients treated at home
– Instruction regarding danger signs
– Consider repeat clinical evaluation
• Patients with bleeding manifestations
– Serial hematocrits and platelets at least daily until
temperature normal for 1 to 2 days
• All patients
– If blood sample taken in first 5 days after onset,
need convalescent sample between days 6 - 30
– All hospitalized patients need samples on
admission and at discharge or death
Treatment of Dengue Fever
(Part 1)
• Fluids
• Rest
• Antipyretics (avoid aspirin and non-
steroidal anti-inflammatory drugs)
• Monitor blood pressure, hematocrit,
platelet count, level of consciousness
 Mosquito Barriers
• Only needed until fever subsides, to prevent
Aedes aegypti mosquitoes from biting patients and
acquiring virus
• Keep patient in screened sickroom or under a
mosquito net
 Treatment of Dengue Fever
(Part 2)
• Continue monitoring after defervescence
• If any doubt, provide intravenous fluids, guided by
serial hematocrits, blood pressure, and urine output
• The volume of fluid needed is similar to the treatment
of diarrhea with mild to moderate isotonic dehydration
(5%-8% deficit)
 Fluid for Moderate Dehydration
(Intravenous)

weight in lbs ml/lb/day weight in kgs ml/kg/day

< 15 100 <7 220

16 - 25 75 7 - 11 165

26 - 40 60 12 - 18 132

41 - 88 40 19 - 40 88
Adapted from Guidelines for Treatment of Dengue Fever/
Dengue Haemorrhagic Fever in Small Hospitals, WHO, 1999.
 Rehydrating Patients Over 40
kg
• Volume required for rehydration is twice the
recommended maintenance requirement
• Formula for calculating maintenance volume:
1500 + 20 x (weight in kg - 20)
• For example, maintenance volume for 55 kg
patient is: 1500 + 20 x (55-20) = 2200 ml
• For this patient, the rehydration volume would
be 2 x 2200, or 4400 ml

Pan American Health Organization: Dengue and Dengue

Hemorrhagic Fever: Guidelines for Prevention and Control.
PAHO: Washington, D.C., 1994: 67.
Treatment of Dengue Fever
(Part 3)

• Avoid invasive procedures when possible

• Unknown if the use of steroids, intravenous
immune globulin, or platelet transfusions to
shorten the duration or decrease the severity
of thrombocytopenia is effective
• Patients in shock may require treatment in an
intensive care unit
Penatalaksanaan Demam Dengue (WHO, 1999)
Penatalaksanaan DBD der I/II (WHO, 1999)
Penatalaksanaan DBD der I/II
(WHO, 1999)
Penatalaksanaan DBD der III/IV (WHO, 1999)
Penatalaksanaan DBD der III/IV (WHO, 1999)
Penatalaksanaan DBD der III/IV (WHO, 1999)
Penatalaksanaan DBD der III/IV
(WHO, 1999)
 Indications for Hospital
Discharge

• Absence of fever for 24 hours (without anti-

fever therapy) and return of appetite
• Visible improvement in clinical picture
• Stable hematocrit
• 3 days after recovery from shock
• Platelets  50,000/mm3
• No respiratory distress from pleural
effusions/ascites

Pan American Health Organization: Dengue and Dengue

Hemorrhagic Fever: Guidelines for Prevention and Control.
PAHO: Washington, D.C., 1994: 69.