Dengue

Fever
Plan of presentation

• Epidemiology
• Diagnosis
– Clinical features
– Laboratory findings
• Management
HOW BIG IS THE
PROBLEM ?
Epidemiology

• Over 2.5 billion people - over 40% of the world’s

population - are at risk
• WHO currently estimates 50-100 million dengue
infections each year
– http://www.who.int/mediacentre/factsheets/fs117/en/index.html
World Distribution of Dengue

(Source: www.cdc.gov)
• The number of reported dengue fever (DF) and dengue
haemorrhagic fever (DHF) cases in Malaysia shows an
increasing trend from year to year.
• The highest incidence rate is among the working and
school-going age groups of 15 years and above.
 EPIDEMIOLOGY OF DENGUE IN MALAYSIA

2013 2014

CASES
43346 108698

INCREASED BY
151%
MORTALITY
92 215
INCREASED BY
134%
Introduction
• Dengue infection is caused by dengue virus which is a
arthropod-borne viral diseases – flavivirus.

• Transmitted by Aedes aegypti and Aedes albopictus.

• There are four distinct serotypes, DEN-1, 2, 3 and 4.

• Each episode of infection induces a life-long

protective immunity to the homologous serotype

• However, it confers only partial and transient

protection against subsequent infection by the other
three serotypes.
• Humans are the main amplifying host of the virus. Dengue
virus circulating in the blood of viremic humans is ingested
by female mosquitoes during feeding.

• The virus then infects the mosquito mid-gut and

subsequently spreads systemically over a period of 8-12
days.

• After this extrinsic incubation period, the virus can be

transmitted to other humans during subsequent probing or
feeding.

• Thereafter the mosquito remains infective for the rest of its

life.
Serotypes of dengue in Malaysia

• DENV1, DENV2 and DENV3 were identified in

Negeri Sembilan, multiple entries of DENV2 and
DENV4 in Sarawak while DENV4 dominated the
populated regions of Kuala Lumpur and
Selangor.
Pathogenesis

• Virus transmitted into humans by bite of infected

female Aedes mosquitoes
• Virus infects immature dendritic cells
• Infected dendritic cells migrate into lymph nodes
• Virus multiplies in macrophages of lymph nodes,
liver, spleen and blood monocytes
• Occurrence of viremia
• Activation of humoral & cellular immune response,
release of inflammatory cytokines resulting in
fever
Dendritic cells

• DCs are professional antigen-

presenting cells located in the skin, mucosa and
lymphoid tissues.
• Their main function is to process antigens and
present them to T cells to promote immunity to
foreign antigens and tolerance to self antigens.
• They also secrete cytokines to regulate immune
responses.
• They act as messengers between the innate and
the adaptive immune systems.
 Pathophysiology of plasma leakage

• Increased vascular permeability is the primary

pathophysiological abnormality in DHF/ DSS.
• Increased vascular permeability leads to plasma
leakage and results in hypovolaemia or shock
• Hypovolaemia leads to reflex tachycardia and
generalised vasoconstriction due to increased
sympathetic output
• If the hypovolaemia is not corrected promptly, the
patient progresses to a refractory shock state.
Pathophysiology of
“Severe Dengue”

• Secondary infection is associated with

increased risk of developing DHF due to the
antibody-dependent enhancement
• The sub-neutralising concentration of the cross-
reacting antibody from the previous infection may
opsonise the virus
• Enhanced uptake and replication in the
macrophage or mononuclear cells
• The level of T-cell activation is also enhanced
• Profound T-cell activation with cell death during
acute dengue infection may suppress or delay
viral elimination
• Leading to the higher viral loads and increased
immunopathology found in patients with DHF.
Eventually, an immune response is triggered in the body of the patient

Release of cytokines from

macrophages (IL-1, TNF, IF-γ) Formation of antibodies (Antigen –
Antibody complex is formed)
Stimulate anterior
hypothalamus (increased Deposit in the
Deposit in vascular
prostaglandin synthesis) joints
endothelium
Increased thermoregulatory
set point Vasodilatation of Trigger
blood vessels inflammatory
response
FEVER
Increased cerebral
Increased metabolic rate
fluid flow ARTHRALGIA

Increased
Increased tissue activity &
intracranial
Protein breakdown
pressure
(accumulate) HEADACHE
Lactic acid accumulation MYALGIA
HOW TO
DIAGNOSE ?
Clinical Presentations / Findings

• The incubation period for dengue infection is 4-7

(3-14 days)

• It may be asymptomatic or may result in a spectrum of

illness ranging from undifferentiated mild febrile
illness to severe disease, with or without plasma
leakage and organ impairment.

• Symptomatic dengue infection is a systemic and

dynamic disease with clinical, haematological and
serological profiles changing as the disease progress.
Clinical Presentations / Findings

• Non-specific – sore throat; injected conjunctiva

and pharynx

• Sudden onset of high fever with facial flushing,

erythema, generalized body aches, myalgia,
arthralgia and headache
 Tourniquet test

• The tourniquet test may be

helpful in the early febrile
phase (less than three days)
in differentiating dengue
from other febrile illnesses.
Limitations of tourniquet test

• The sensitivity of the test varies widely from as

low as 0% to 57%, depending on the phase of
illness the test was done and how often the test
was repeated, if negative.

• In addition 5-21% of patients with dengue like

illness had positive tourniquet test but
subsequently have negative dengue serology
RASH OF
RECOVERY
Laboratory findings

• Leucopaenia followed by progressive

thrombocytopaenia is suggestive of dengue
infection.
Laboratory findings
IgM

• Most widely used serological test.

• Antibody titre is significantly higher in primary
infections, compared to secondary infections.
• Once the IgM is detectable, it rises quickly and
peaks at about 2 weeks after the onset of
symptoms, and it wanes to undetectable levels
by 60 days. However in some patients, it may
persist for more than 90 days.
Laboratory findings

IgG

• In primary and secondary dengue infection,

dengue IgG was detected in 100% of patients
after day 7 of onset of fever. Therefore dengue
IgG is recommended if dengue IgM is still
negative after day 7 with the negative IgG in the
initial test sample.
Laboratory findings

Non-structural Protein 1 (NS1) Antigen

• Secretion of the NS1 protein is a hallmark of

flavivirus infecting cells and can be found in
dengue infection as well as in yellow fever and
West Nile virus infection.

• This antigen is present in high concentrations in

the serum of dengue infected patients during
the early phase of the disease.
• The detection rate is much better in serum of
primary infection (75%- 97.3%) when compared
to the serum of secondary infection (60% - 70%).

• The sensitivity of NS1 antigen detection drops

from day 4-5 of illness onwards and usually
becomes undetectable in the convalescence
phase
Laboratory findings

• A rising HCT accompanying progressive

thrombocytopaenia is suggestive of DHF.
• In the absence of a baseline HCT level, a HCT
value of >40% in female adults and >46% in male
adults should raise the suspicion of plasma
leakage.
• The frequency and degree of elevation of the
liver enzymes are higher with DHF compared to
DF.
• Close Monitoring
• Fluid Administration
MANAGEMENT
Management – Outpatient
suspected or confirmed without warning signs

• Oral intake / Antipyretic

• Assess for
– mental state
– hydration status
– haemodynamic status
• tachypnoea / acidotic breathing/ pleural
effusion
• Check for abdominal tenderness/ hepatomegaly/
ascites
Dengue Monitoring Record (OPD)
Patient’s name ------------------------------------------ IC no. --------------------------
Address -------------------------------- Date of onset of fever ----------

Date / Temp BP Pulse HCT WCC Platelet Clinic Next

Time Co mmHg minute % X103/L X103/L Tel no appoin
Criteria for admission

• Abdominal pain or tenderness

• Persistent vomiting / inability to tolerate oral
fluids
• Reduced urine output
• Clinical fluid accumulation (pleural effusion,
ascites)
• Mucosal bleed / Bleeding manifestations
• Restlessness or lethargy / Seizures
• Tender enlarged liver
• Dehydration
• Shock
• Any organ failure
Special Situations
• Patients with co-morbidity
• Elderly
• Pregnancy
• Social factors that limit follow-up
Laboratory Criteria
• Rising HCT accompanied by decreasing platelet
count
Management – Inpatient

Close monitoring

• Clinical
– Signs of circulatory failure
– Narrow pulse pressure

• Laboratory
– Thrombocytopenia
– Hematocrit
Narrow pulse pressure

• A narrowing pulse pressure is an indicator of

impending shock

• In children a pulse pressure of ≤20 mmHg

indicates shock

• In adults, the pulse pressure of ≤ 20 mmHg may

indicate a more severe shock.
Thrombocytopenia

• In the early febrile phase platelet count is

usually within normal range but it will decrease
rapidly as the disease progresses to the late
febrile phase or at defervescence and it may
continue to remain low for the first few days of
recovery.
• There is a significant negative correlation
between disease severity and platelet count
and it is not predictive of bleeding.
Hematocrit

• Changes in the haematocrit are a useful guide to

treatment. However, changes must be
interpreted in parallel with the:
– haemodynamic status
– clinical response to fluid therapy
– acid-base balance
Hematocrit

• A rising or persistently high haematocrit

together with unstable vital signs (particularly
narrowing of the pulse pressure) indicates active plasma
leakage and the need for a further bolus of fluid
replacement.
Hematocrit

• A decrease in haematocrit together with

unstable vital signs indicates major
haemorrhage and the need for urgent blood
transfusion.
• A decrease in haematocrit together with stable
haemodynamic status indicates haemodilution
and/or reabsorption of extravasated fluids, so
intravenous fluids must be discontinued
immediately to avoid pulmonary oedema.
PREVENTION
Prevention

• Control of vector
– Involvement of community
– Insecticide sprays
– Genetically modified mosquitos
• Vaccination
COMBI

• COMBI stands for COMmunication

for Behaviourial Impact.

• The program is founded by the World Health

Organization (WHO) and implemented by the Ministry
of Health (MOH)

• COMBI is a dynamic approach that uses social

mobilization and communication strategies to
influence behaviour change in individuals, families
and the community towards a healthy behaviour.
COMBI - Goal

• To mobilize various sectors of the community to

address the issue of dengue in the community.
• Creating a shared responsibility in the
community.
• Influence and strengthen decision / behaviour /
social norms in the community.
COMBI - Target group
COMBI is a project-oriented approach from
community to community. The target groups for
the implementation of this project is based on the
following situations:

• Repeated outbreaks
• Uncontrolled outbreak
• Outbreak localities
• Localities that have a high Entomology Index
• Voluntary localities to set up projects COMBI
Thank you
• Dendritic cells are a type of antigen-
presenting cell (APC) that form an important role in
the adaptive immune system. The main function
of dendritic cells is to present antigens and
the cells are therefore sometimes referred to as
“professional” APCs.
• In addition, only the dendritic cells have the capacity
to induce a primary immune response in the
inactive or resting naïve T lymphocytes. To do this,
the dendritic cells capture the antigens from
invading bodies, which they process and then
present on their cell surface and presented, along
with the necessary accessory or co-stimulation
molecules.
• Dendritic cells also contribute to the function of B
cells and help maintain their immune memory.
Dendritic producing cytokines and other factors that
promote B cell activation and differentiation. After
an initial antibody response has occurred due to an
invading body, dendritic cells found in the germinal
centre of lymph nodes seem to contribute to B cell
memory by forming numerous antibody-antigen
complexes. This is to provide a long lasting source
of antigen that the B cells can take up themselves
and present to T cells.
• Antibody opsonization is the process by which a
pathogen is marked for ingestion and eliminated by
a phagocyte. Opson in ancient Greece referred to
the delicious side-dish of any meal, versus the sitos,
or the staple of the meal.
 EPIDEMIOLOGY OF DENGUE IN MALAYSIA BASED ON
WEEK 19 (2015)

January to 25th April January to 25th April

2014 2015

CASES 28814 38517

INCREASED BY
151%
MORTALITY 66 120

INCREASED BY
134%