Dengue Fever

Guangzhou 8th people’s hospital Guan Jialong

dr_guan@163.com

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 Definition
★ Dengue fever has another name
breakbone fever.
★ Dengue fever is a disease caused by a
virus that is transmitted by mosquito.
. ★ It is an acute, viral infection causing
fever, headache, severe joint and muscle
pain, hemorrhagic manifestations,
enlarged lymph node ,rash and
leukopenia.

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 Etiology
Dengue virus is a single stranded RNA
virus , a member of the flaviviridae family.

This is three-dimensional
structure of dengue virus.

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 Etiology

• There are four serotypes of dengue virus

(DEN-1, DEN-2, DEN-3 and DEN-4).
• DEN-2 is frequently associated with a severe
form of dengue fever .
• Cross-immunity
among the four serotypes;
among dengue virus and other flaviviruses.

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Genome and structural proteins

The virus has a genome of about 11,000 bases that for three structural proteins ,C, prM,
E ;seven nonstructural proteins, NS1 ,NS2a, NS2b, NS3 ,NS4a, NS4b, NS5 and short non-
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coding regions on both the 5ˋ and 3ˊ ends.
 Etiology

Physical and chemical properties

• Dengue virus is not tolerant of heat , acid and
ultraviolet ray.
• Inactivated at 60 ℃ for 30 min or 100℃ for 2
min.
• Survive in minus 20 ℃ for 5 years and minus
70℃ over 8 years.

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 Epidemiology
★The first reported dengue fever occurred in 1779-1780 in
Asia, Africa, and North America.
★During the 19th century, dengue was considered a sporadic
disease, but in the past 50 years, its incidence has increased.
★ More than 100 countries (Maps 1) have endemic dengue
transmission and more than 2.5 billion people (roughly 40%
of the world's population)are at risk of infection (Maps 1) .

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 Map 1. Global Distribution of Dengue

Dengue is endemic throughout the tropics and subtropics and is a leading

cause of febrile illness among travelers returning from the Caribbean,
South America, and South and Southeast Asia.
 Epidemiology
★ In china, the first epidemic of dengue fever is in
Xiamen city in 1873.

★The first case of dengue fever is in 1978

in Foshan.
★ A total of 45,171 dengue cases have been reported
in south China's Guangdong province since May
2014

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 Epidemiology
• Sources of infection:
Patients and people who have subclinical infection.

• Routes of transmission:
Arthropod-transmitted ,the two main species of
mosquito, Aedes aegypti and Aedes albopictus.

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 Epidemiology

• A rarely route of transmission?

• Susceptible people:
All of the people are susceptible. The disease
appears to most frequently affect adult, but
dengue infect children in chief in endemic
areas.

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 Epidemiology

• People get dengue fever after the bite of an

infected Aedes mosquito.

• Mosquitoes become infected when they bite

infected humans, and later transmit infection
to other people they bite.

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 Aedes mosquito

A.albopictus A.aegypti
The virus spreads through the mosquito's body over a period of eight to
twelve days.
The mosquito will remain infected with the virus for its entire life
The peak biting periods are early in the morning and in the evening
 Epidemiology
Endemic features

• High incidence in rainy season

• Guangdong: between May and October
Hainan: between March and October

• Rainfall, temperature, and other weather factors affect the

vectors.

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 Pathogenesis

• It is not well known.

• Dengue virus enter the body after the biting of
Aedes mosquito.
• Form Viremia stage for two times : dengue
virus replicates in the capillary endothelial cell
and mononuclear phagocyte system for two
times, then is released to the blood.

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 Pathogenesis

• Form circulating dengue antigen-antibody

complexes, activate complement, and release
of vasoactive inflammatory mediators.
• Increased vascular permeability, bleeding and
thrombocytopenia.

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 Pathogenesis
• The anti-body is not neutralizing,does allow enhanced
antibody-mediated macrophage uptake and leads to a
macrophage activation state.
• Macrophage excretes inflammatory mediators and the
mediators result in vascular leak.
• When the vascular leak is severe, it will cause shock.
• DSS(dengue shock syndrome):DHF is accompanied by
shock.
• It is characterized by capillary leakage.

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 Pathogenesis
• Dengue hemorrhagic fever is a severe form of
dengue fever .
• The attack rate is highest in children .
• It is believed to be the result of two or more
sequential infections with different dengue
serotypes.

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 Pathogenesis

• The mechanism is not very clear.

• Severe dengue usually occurs during a second
dengue infection.
• When infected for a second time with a different
serotype, a more severe infection may occur.
• This is due to a phenomenon referred to as
antibody dependent enhancement.

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 Clinical Manifestations

• The incubation period is 3-14 days(average 4-7

days) following the mosquito bite.
• It has a wide clinical spectrum that includes: 
Asymptomatic or mild infections
severe manifestations
non-severe manifestations
• It is often misdiagnosed at the beginning of illness.

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 Clinical Manifestations

• Two clinical forms are recognized.

Uncomplicated(classic) dengue fever
Severe Dengue
(Dengue hemorrhagic fever and Dengue
shock syndrome)

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Clinical Manifestations
 Classic Dengue Fever

• Fever: acute onset of high fever (40℃), the

fever subsides after 3-4 days, the temperature
returns to normal for a couple of days, and
then fever returns.

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41.0

40.0 体 温 （℃）

39.0

38.0

37.0

36.0
0 1 2 3 4 5 6 7 8 9

时间（天）
35.0

Saddleback Temperature Curve of Dengue Fever

 Classic Dengue Fever

• This biphasic or saddleback pattern is

considered characteristic.
• The fever is often accompanied by
headache, facial flushing, retro-bulbar
pain, conjunctival congestion and severe
joint and muscle pain.

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28
 Classic Dengue Fever
• Rash ： The rash is transient and multiform.
(maculo-papular, scarlatiniform,petechiae and so on).It
appears on the limbs and then spreads to involve the
trunk. It often occurs on the 3rd day of the course of
disease .
• Haemorrhagic manifestation :uncommon, petechiae,
gastrointestinal bleeding, epistaxis, gingival bleeding and
so on.

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with islands of skin sparing
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Large area of ecchymosis
Pleural and peritoneal effusion
Multiple hemorrhagic foci in the left
parietal lobe and temporal lobe were
seen in MRI
 Classic Dengue Fever

• Lymphadenopathy and hepatomegaly may

also occur.

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 Physical examination

• Blood pressure
• Tourniquet test
• The evidence of haemorrhagic manifestation
• Evidence of plasma leakage

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 Complication

• Acute intravascular hemolysis(the most

common) especially in G-6PD (glucose-6-
phosphate dehydrogenase)deficiency patients.
• Myocarditis
• Toxic hepatitis

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 Laboratory Findings

• Total White Blood Cells Count:

leukopenia often with lymphopenia
• Thrombocytopenia
up to 50% of dengue fever cases.
• liver enzymes increase

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 Laboratory Findings
• Isolation of dengue virus by tissue culture .
• Detection of dengue virus genomic sequences in
serum or cerebrospinal fluid samples by
polymerase chain reaction (PCR).
•  Detection of antigens
The NS1 glycoprotein is produced by all
flaviviruses and is secreted from mammalian cells.
The detection of NS1 to make an early diagnosis of
dengue virus infection.

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 Laboratory Findings
• Dengue specific IgM and IgG ELISA is widely
used, as it is relatively inexpensive, has good
sensitivity, and it is quick and simple to perform.
• A fourfold rise or greater in antibody titer is
diagnostic.
• IgM/IgG ratio
greater than 1.2: primary dengue infectoin
less than 1.2: secondary dengue infection)

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 Diagnosis

• Epidemiology:a history of exposure in an

endemic area .
• Clinical manifestations:
• Laboratory findings

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 Differential diagnosis
• Influenza: Different seasons, there can be no upper respiratory symptoms,
no facial flushing, rashes, bleeding, often with lymphocytosis, no
thrombocytopenia. throat swab or gargle to isolate virus.
• Hantavirus hemorrhagic fever of renal syndrome: rat contact, "three
reds" and "three pains", early renal damage, white blood cell count
increased, hemorrhagic fever specific IgM antibody positive in the early
stage .
• Measles: Different seasons, catarrh symptoms, Koplik's spots seen inside
the mouth, rash starts on the back of the ears and spreads to the head and
neck before spreading to cover most of the body,often causing itching, no
reduction of platelet count, early specific IgM antibody.
• Drug eruption: typical drug rash history, Most drug-induced cutaneous
reactions are mild and disappear when the offending drug is withdrawn.

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 Prognosis

Classic dengue fever is often self-limited.

★

★ The mortality rate is about 0.3/1000.

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 Severe dengue
• Severe dengue is defined by one or more
of the following:
(i) plasma leakage that may lead to shock
(dengue shock) and/or fluid accumulation,
with or without respiratory distress
(ii) severe bleeding
(iii) severe organ impairment.

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 Severe dengue

• As dengue vascular permeability progresses,

hypovolaemia worsens and results in shock.
• It usually takes place around defervescence,
usually on day 4 or 5 (range days 3–7) of
illness, preceded by the warning signs.

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 Severe dengue

• During the initial stage of shock, the

compensatory mechanism which maintains a
normal systolic blood pressure also produces
tachycardia and peripheral vasoconstriction  
• Uniquely, the diastolic pressure rises towards
the systolic pressure and the pulse pressure
narrows as the peripheral vascular resistance
increases. 
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 Severe dengue

• Patients in dengue shock often remain conscious

and lucid.
• The inexperienced physician may measure a
normal systolic pressure and misjudge the critical
state of the patient.
•  Finally, there is decompensation and both
pressures disappear abruptly.

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Haemodynamic assessment: continuum of haemodynamic changes.

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 Severe dengue

Shock:
• the pulse pressure (i.e. the difference between the
systolic and diastolic pressures) is ≤ 20 mm Hg in
children or
• he/she has signs of poor capillary perfusion (cold
extremities, delayed capillary refill, or rapid pulse
rate). 

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 Severe dengue

• In adults, the pulse pressure of ≤ 20 mm Hg

may indicate a more severe shock.
• Hypotension is usually associated with
prolonged shock which is often complicated
by major bleeding.

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 Severe dengue
• Severe dengue should be considered if the
patient is from an area of dengue risk,
presenting with fever of 2–7 days plus any of
the following features:

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1)There is evidence of plasma leakage, such as:
–high or progressively rising haematocrit;
–pleural effusions or ascites;
–circulatory compromise or shock (tachycardia, cold
and clammy extremities, capillary refill time greater
than three seconds, weak or undetectable pulse, narrow
pulse pressure or, in late shock, unrecordable blood
pressure).

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2)There is significant bleeding.
3)There is an altered level of consciousness (lethargy
or restlessness, coma, convulsions).
4)There is severe gastrointestinal involvement
(persistent vomiting, increasing or intense abdominal
pain, jaundice).
5)There is severe organ impairment (acute liver
failure, acute renal failure, encephalopathy or
encephalitis, cardiomyopathy) 58
 Management decisions

• Depending on the clinical manifestations

and other circumstances, patients may
sent home (group A)
referred for in-hospital management (group
B)
required emergency treatment and urgent
referral (group C)
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 Treatment according to groups A–C

Group A – patients who may be sent home

These are patients who are able to tolerate
adequate volumes of oral fluids and pass urine
at least once every six hours, and do not have
any of the warning signs, particularly when
fever subsides.

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What should be done?
•Adequate bed rest
•Adequate fluid intake (>5 glasses for average-sized a
dults or accordingly in children)
–Milk, fruit juice (caution with diabetes patient) and i
sotonic electrolyte solution (ORS) and barley/rice wat
er.
–Plain water alone may cause electrolyte imbalance.
•Take paracetamol (not more than 4 grams per day f
or adults and accordingly in children)
•Tepid sponging
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If any of following is observed, take the patient immediately
to the nearest hospital.
These are warning signs for danger:
•Bleeding:
–red spots or patches on the skin
–bleeding from nose or gums
–vomiting blood
–black-coloured stools
–heavy menstruation/vaginal bleeding
•Frequent vomiting
•Severe abdominal pain
•Drowsiness, mental confusion or seizures
•Pale, cold or clammy hands and feet
•Difficulty in breathing 62
Laboratory results monitoring
1st Visit

Date

Haematocrit

White cell
count

Platelet
count
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 Group B – patients who should be
referred for in-hospital management

These include patients with warning signs,

those with co-existing conditions that may make
dengue or its management more complicated (such
as pregnancy, infancy, old age, obesity, diabetes
mellitus, renal failure, chronic haemolytic diseases ),
and those with certain social circumstances (such as
living alone, or living far from a health facility
without reliable means of transport).

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(1)Obtain a reference haematocrit before
fluid therapy. Give only isotonic solutions
such as 0.9% saline, Ringer's lactate, or
Hartmann's solution.
Start with 5–7 ml/kg/hour for 1–2 hours, then
reduce to 3–5 ml/kg/hr for 2–4 hours, and
then reduce to 2–3 ml/kg/hr or less according
to the clinical response  65
(2)Reassess the clinical status and repeat the
haematocrit.
If the haematocrit remains the same or rises only
minimally, continue with the same rate (2–3
ml/kg/hr) for another 2–4 hours.
If the vital signs are worsening and haematocrit
is rising rapidly, increase the rate to 5–10
ml/kg/hour for 1–2 hours.
Reassess the clinical status, repeat the
haematocrit and review fluid infusion rates
accordingly.
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(3)Reduce intravenous fluids gradually when
the rate of plasma leakage decreases towards
the end of the critical phase ( good perfusion
and urine output of about 0.5 ml/kg/hr.).

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(4)Patients with warning signs should be
monitored by health care providers until
the period of risk is over.
A detailed fluid balance should be
maintained.
Parameters that should be monitored
include vital signs and peripheral
perfusion 1–4 hourly until the patient is
out of the critical phase.

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Group C – patients who require
emergency treatment and urgent referral
when they have severe dengue
• Patients require emergency treatment and urgent referral
when they are in the critical phase of disease, i.e. when they
have:
• –severe plasma leakage leading to dengue shock and/or fluid
accumulation with respiratory distress;
• –severe haemorrhage;
• –severe organ impairment (hepatic damage, renal
impairment, cardiomyopathy, encephalopathy or
encephalitis).

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 Recommendations for treatment

• There are no specific antiviral drugs for

dengue; however, maintaining proper
fluid balance is important.
• Treatment depends on the different stage
of disease and patient's physical condition
 The principle of rehydration
• The smallest amount of fluid required to achieve is
recommended.
• Intravenous hydration, if required, is typically only
needed for one or two days.
• The goal of fluid rehydration is to maintain the normal
vital signs,normal hematocrit and urine volume.
 Recommendations for treatment
• If there is obvious bleeding tendency or bleeding, invasive
therapy should be avoided.
• NSAIDs such as ibuprofen and aspirin are avoided as they
might aggravate the risk of bleeding.
• Blood transfusion is initiated early in people presenting with
unstable vital signs in the face of a decreasing hematocrit
• There is not enough evidence to use corticosteroids except for
encephalitis
• If there is no secondary infection,Antibiotics are not necessary
Recommendations for treatment

• During the recovery phase intravenous fluids are

discontinued to prevent a state of fluid overload
• If fluid overload occurs and vital signs are stable,
stopping further fluid is needed
• If a person is outside of the critical phase, a loop
diuretic such as furosemide may be used to eliminate
excess fluid from the circulation
 Prognosis

• The mortality with severe dengue ranges from

1 to 26%.
• Most deaths occur in children ， elder and
patients with chronic systemic diseases.
• Infants under a year of age are especially at
risk of dying from DHF.

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 Prevention
• Breteau Index
• Clean up mosquitoes breeding place
 Prevention

• No vaccines for dengue viruses are yet

available!
• Dengue patients should be protected from
mosquitoes.
• Effective control or eradication of the aedes
vectors.

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 Making a new mosquito

• To modify mosquito by transgenic technology.

• These genes allow the mosquito to produce su
bstances that block viruses and parasites from
reproducing -- so it cannot pass on the disease
to humans and animals.

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 Making a new mosquito

A breakthrough was made by Su

n Yat-sen University in January
2014 by Professor Xi .He
invented embryos injected with t
he Wolbachia to control mosqui
to vector. This study released the
male wolbachia mosquito in Nan
sha, Guangzhou, in the spring of
2015.
 Analyze case I

Female, 22-year-old, she was hospitalized

for “fever of unknown origin”. She presented
with a week history of fever, the temperature
was 39℃,with painful muscles and joints. She
presented with two days history of rash. The
patient said she had a travel in Thailand
recently. In the past she was in good health.

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 Analyze case
Physical examination: T:39℃, Bp: 120/70
mmHg, Flushing of the face, there were a few pink
macular lesions over her upper body. The lymph
nodes on armpit and groin were enlarged. Her neck
was soft, both of lungs were clear. The heart rate was
normal. The abdomen was flat and soft, there was no
tenderness and rebound tenderness. The liver and the
spleen couldn’t be palpable, no percussion pain on
renal region, shifting dullness negative.

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 Analyze case
Laboratory findings:
the blood routine showed white blood cell ：
2.6 ×109/L,platelet :79×109/L, liver function
and renal function tests were normal. The
chest x-ray was normal.
Question:
1.What is the diagnosis? 2.What should we do to
make a definite diagnosis?

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 Analyze case II
• Female, 66 -year- old, live in Fangcun
District,Guangzhou
• Severe fatigue for 3 days, Decrease of urine volume
and drowsiness for 1 day. Shock and renal failure
were admitted to ICU in Fangcun branch of
Guangdong Province Traditional Medical Hospital. 1
day later, turn to our hospital because of the
aggravation of the disease.
 Analyze case

• Signs: 38.6℃,R 40 HR/min,HR 140/min,shallow

coma,Conjunctival severe edema,deep
jaundice,extensive ecchymosis,respiratory sounds
were weakened,fine moist rales can be heard
unconsciousness,respiratory support
 Analyze case
• Laboratory examination: WBC 9.2 x 109/L, PLT 12 x
109/L; TBill 212umol/L, ALB 27g/L, AST 1830U/L, Cr
387umol/L, creatinine clearance 15%, BNP and troponin
positive;
• Nucleic acid of dengue virus positive : serotype 1
• CT: A small amount of ascites, large amounts of
hydronephrosis in the right kidney, and lithiasis of double
kidneny.
• Underlying diseases: diabetes, hypertension, coronary heart
disease, lithiasis of double kidneny.
Question:
1.What is the diagnosis?
2.What is the basis for the diagnosis of the
disease?
 Analyze case
• Diagnosis: severe dengue fever (DSS, MOF, DIC)
• Case characteristics: elderly woman, with underlying diseases,
shock, disorder of consciousness, acute liver failure, heart failure,
respiratory failure, and severe bleeding.
• Treatment: countershock, cardiac, diuretic, gave CRRT and
artificial liver treatment; invasive ventilation support; albumin,
gamma globulin, treatment of secondary pulmonary infection.
• The outcome : mind turned clear, kidney function recovered,
heart and liver function got better, and discharged from ICU.
 Video for dengue
• http://newyork.cbslocal.com/2013/11/20/new-york-states-first-
known-dengue-virus-infection-found-on-long-island/(New
York State’s First Known Dengue Fever Infection Found On
Long Island)
• http://www.hhmi.org/biointeractive/dengue-virus-life-cycle
• http://www.ndm.ox.ac.uk/kerstin-luhn-dengue-infection

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One more thing
• Vaccine
• Dengvaxia
• antibody-dependent enhancement(ADE)
• Anti-dengue day
• 2011 U.S. medical thriller-disaster film
directed by Steven Soderbergh.
• The plot of Contagion documents the
spread of a virus transmitted by fomites,
attempts by medical researchers and
public health officials to identify and
contain the disease, the loss of social
order in a pandemic, and finally the
introduction of a vaccine to halt its
spread.
• accurately portraying the "successes and
frustrations" of science