Dengue Dengue The DangerThe DangerA Sudden Seizure by a A Sudden Seizure by a

Demon…Demon…Group no. 20 , 3rd year

I.Ya. Horbachevsky Ternopil State Medical University.

INTRODUCTIONINTRODUCTION Dengue is caused by 4 flavivirus serotypes Dengue is caused by 4 flavivirus serotypes

(DEN1-4). The incidence of dengue fever (DEN1-4). The incidence of dengue fever (DF) & dengue hemorrhagic fever (DHF) has (DF) & dengue hemorrhagic fever (DHF) has increased 30 fold globally in the last 4 decades increased 30 fold globally in the last 4 decades and more than half the world’s population is and more than half the world’s population is now threatened with it’s infection. According now threatened with it’s infection. According to WHO 100 million attacks of DF, 2,50,000 to WHO 100 million attacks of DF, 2,50,000 DHF occurDHF occur annually with 25,000 unfortunate annually with 25,000 unfortunate deaths.deaths.

Epidemiological evidences show that Epidemiological evidences show that DHF & DSS (dengue shock DHF & DSS (dengue shock syndrome) occur more frequently on syndrome) occur more frequently on re-infection with a second serotype. re-infection with a second serotype.

EpidemiologyEpidemiology EpidemiologyEpidemiology Since the 18Since the 18thth. Century, dengue has . Century, dengue has

caused repeated epidemics worldwide. caused repeated epidemics worldwide. H.Graham in 1903 implicated Aedes H.Graham in 1903 implicated Aedes aegypti as the vector for the disease and aegypti as the vector for the disease and the virus was isolated in 1944 by Albert the virus was isolated in 1944 by Albert Sabin. DHF gained nosologic status in Sabin. DHF gained nosologic status in 1954 and subsequently became endemic 1954 and subsequently became endemic in many areas of tropical world. Dengue in many areas of tropical world. Dengue now affects >100 countries all over the now affects >100 countries all over the world except Europe.world except Europe.

Some important dataSome important data

In India, the first recorded In India, the first recorded outbreak was in 1812. outbreak was in 1812.

60 outbreaks have been reported 60 outbreaks have been reported during the period 1956 to 2001. during the period 1956 to 2001.

10252 cases and 423 deaths in the 10252 cases and 423 deaths in the

year 1996 in Delhi.year 1996 in Delhi.

India, 2006: 12750 cases, 217 deathsIndia, 2006: 12750 cases, 217 deaths

Dengue cases reported in india Dengue cases reported in india in september 2006in september 2006

886713

424324314306

22679

0 200 400 600 800 1000

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guj ar at

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west bengal

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Number of cases reported.

STATES

Dengue victim

A child with dengue A child with dengue hemorrhagic fever hemorrhagic fever or dengue shock or dengue shock syndrome may syndrome may present severely present severely hypotensive with hypotensive with disseminated disseminated intravascular intravascular coagulation (DIC)coagulation (DIC)

EtiologyEtiology A)A) Causative agent:Causative agent: 4 dengue viruses within the genus flavivirus 4 dengue viruses within the genus flavivirus

are found in India.are found in India. Dengue virions are small particles with Dengue virions are small particles with

lipoprotein envelope containing E proteins and lipoprotein envelope containing E proteins and nucleocapsid of single stranded RNA genome.nucleocapsid of single stranded RNA genome.

There is a close antigenic similarity among the There is a close antigenic similarity among the 4 serotypes but cross protection in human is 4 serotypes but cross protection in human is at best partial and transient. at best partial and transient.

DEN-2 is more virulent than other 3 serotypes.DEN-2 is more virulent than other 3 serotypes.

conceivable."

Immature Dengue Virus

Mature Dengue Virus

A TEM micrograph showing dengue virusA TEM micrograph showing dengue virus

Virus classificationVirus classification Group:Group IV Group:Group IV

((+)ssRNA)((+)ssRNA) Family:Family:FlaviviridaeFlaviviridae Genus:Genus:FlavivirusFlavivirus Species:Species:Dengue Dengue

virusvirus

B) Transmission:B) Transmission:1.1. Reservoir of infection is both man & Reservoir of infection is both man &

mosquito. mosquito. 2.2. The transmission cycle is “Man-Mosquito-The transmission cycle is “Man-Mosquito-

Man”.Man”.

3.3. Aedes aegypti is the principal vector, other Aedes aegypti is the principal vector, other less important vectors being Aedes less important vectors being Aedes albopictus, Aedes polynesiensis and several albopictus, Aedes polynesiensis and several species of Aedes scutellaris complex.species of Aedes scutellaris complex.

Incubation periodIncubation period

3-14 days with mosquitoes 3-14 days with mosquitoes remaining infected for life. The remaining infected for life. The outbreaks coincide with the outbreaks coincide with the monsoon.monsoon.

A MOSQUITO LARVA

Female Aedes Albopictus

Female Aedes Aegypti (Tiger Mosquito)

PathogenesisPathogenesis After the bite by an infected mosquito, After the bite by an infected mosquito,

the virus replicates in the regional the virus replicates in the regional lymph nodes of the affected individual lymph nodes of the affected individual and is disseminated via the lymph and and is disseminated via the lymph and blood to the other tissues.DHF & DSS blood to the other tissues.DHF & DSS are characterised by abnormally are characterised by abnormally increased capillary permeability and increased capillary permeability and disordered haemostasis. The DHF/DSS disordered haemostasis. The DHF/DSS are primarily seen in the are primarily seen in the young(<12yrs.) & mostly in secondary young(<12yrs.) & mostly in secondary infection. infection.

PathologyPathology

The pathologic findings include:The pathologic findings include:Depression of all haemopoietic cells Depression of all haemopoietic cells

including megakaryocytes in bone marrow.including megakaryocytes in bone marrow.Active proliferation and lymphocytolysis in Active proliferation and lymphocytolysis in

germinal centers in lymph nodes & spleen.germinal centers in lymph nodes & spleen.Focal mid-zonal necrosis and fatty changes Focal mid-zonal necrosis and fatty changes

in liver. in liver. Occasionally glomerulonephritis ( immune- Occasionally glomerulonephritis ( immune-

complex deposition).complex deposition).

Dengue virus infection

Asymptomatic symptomatic ↓

Dengue hemorrhagic fever (plasma leakage) ↓

Undifferentiated fever (viral syndrome)

Dengue fever syndrome ↓

No shock DSS

Without hemorrhage With unusual hemorrhage

Dengue fever DHF

Clinical spectrum of Dengue fever

Clinical featuresClinical featuresA)A) Classic Dengue (“Break-bone fever”)Classic Dengue (“Break-bone fever”) Abrupt onset of fever ĉ chill, headache, retro-Abrupt onset of fever ĉ chill, headache, retro-

orbital pain & low backache. The fever is orbital pain & low backache. The fever is typically high and occasionally followed by typically high and occasionally followed by remission lasting for a few hours to 2 days, remission lasting for a few hours to 2 days, comes again following appearance of rash comes again following appearance of rash (saddle-back fever) & lasts for 5-7 days.(saddle-back fever) & lasts for 5-7 days.

Transient generalized erythematous flush like Transient generalized erythematous flush like or typical morbilliform rash appears on trunk or typical morbilliform rash appears on trunk spreading to face & extremities sparing palms spreading to face & extremities sparing palms &soles. It may be accompanied by itching.&soles. It may be accompanied by itching.

Generalised myalgia, arthralgia.Generalised myalgia, arthralgia.

Constitutional symptoms like anorexia, Constitutional symptoms like anorexia, nausea, vomiting may be present.nausea, vomiting may be present.

Relative bradycardia, generalized Relative bradycardia, generalized lymphadenopathy.lymphadenopathy.

Convalescence may be accompanied by Convalescence may be accompanied by asthenia & bradycardia.asthenia & bradycardia.

Morbilliform rash of Dengue (A,B)

Clinical feature (contd.)Clinical feature (contd.)

B) Dengue haemorrhagic fever (DHF):B) Dengue haemorrhagic fever (DHF):The critical stage is reached after 2-7 The critical stage is reached after 2-7

days when fever subsides & circulatory days when fever subsides & circulatory disturbances start appearing as -disturbances start appearing as -

•Ascites.Ascites.•Petechiae, purpura, echymoses.Petechiae, purpura, echymoses.•Epistaxis, gum bleeding, GI haemorrhage etc.Epistaxis, gum bleeding, GI haemorrhage etc.•Generalized abdominal pain with tenderness Generalized abdominal pain with tenderness over right costal margin.over right costal margin.•Hepatomegaly.Hepatomegaly.

C) Dengue shock syndrome (DSS)C) Dengue shock syndrome (DSS) Some patients of DHF manifest signs of Some patients of DHF manifest signs of

restlessness, abdominal pain and shock (rapid restlessness, abdominal pain and shock (rapid weak pulse, cold clammy extremities, weak pulse, cold clammy extremities, diaphoresis, circumoral cyanosis, irritability or diaphoresis, circumoral cyanosis, irritability or drowsiness). These cases, known as DSS, are drowsiness). These cases, known as DSS, are characterised by severe hypotension or characterised by severe hypotension or undetectable BP & pulse.undetectable BP & pulse.

The duration of shock is very short & the The duration of shock is very short & the patient may die ĉ in 12-24 hrs.patient may die ĉ in 12-24 hrs.

Clinical feature (contd.)Clinical feature (contd.)

petechia

..Investigation....Investigation.. A) A) Virus isolationVirus isolation From blood during febrile phase.From blood during febrile phase.

Newer diagnostic techniques:Newer diagnostic techniques:1.1. RT-PCR (Reverse transcriptase RT-PCR (Reverse transcriptase

polymerase chain reaction). Very polymerase chain reaction). Very sensitive & specific for detection of viral sensitive & specific for detection of viral RNA.RNA.

2.2. Hybridization probe- identification of Hybridization probe- identification of viral nucleic acids.viral nucleic acids.

3.3. Immuno-cytochemical methods- for Immuno-cytochemical methods- for detecting Dengue virus antigen.detecting Dengue virus antigen.

B) SerologyB) Serology Hemagglutination inhibition assays:-Hemagglutination inhibition assays:- It is It is

the WHO recommended reference test the WHO recommended reference test for dengue virus infection. for dengue virus infection. Disadvantages of these tests are Disadvantages of these tests are

1.1. Time consumingTime consuming

2.2. Cannot identify specific serotypesCannot identify specific serotypes

3.3. Cross-reaction with other related Cross-reaction with other related flaviviruses. flaviviruses.

Interpretation of Interpretation of hemagglutination inhibition testhemagglutination inhibition test

S1S1 (1 (1stst.sample .sample taken on taken on adm.)adm.)

S2S2 (2(2ndnd.sample .sample taken after taken after 10-14 days)10-14 days)

InterpretationInterpretation

<1:20<1:20 <1:1280<1:1280 Primary Primary DengueDengue

>1:20>1:20 >1:1280>1:1280 Secondary Secondary DengueDengue

>1:1280>1:1280 ------ Presumptive Presumptive e/oe/o

Secondary Secondary DengueDengue

Commercial Dengue blot Commercial Dengue blot assay:assay:

It is a rapid diagnostic test, It is a rapid diagnostic test, which is as sensitive as which is as sensitive as haemagglutination inhibition haemagglutination inhibition assay in diagnosing a secondary assay in diagnosing a secondary dengue infection but not so in dengue infection but not so in case of primary infection. case of primary infection.

The IgM antibody– Capture ELISA (MAC-The IgM antibody– Capture ELISA (MAC-ELISA) is specially useful in diagnosis of ELISA) is specially useful in diagnosis of recent infection. recent infection.

IgG ELISA has results and interpretation IgG ELISA has results and interpretation same as haemagglutination inhibition same as haemagglutination inhibition assay.assay.

ELISAELISA

GUAIAC TESTGUAIAC TEST Signs of early Signs of early

coagulopathy may be coagulopathy may be as subtle as a guaiac as subtle as a guaiac test positive for occult test positive for occult blood in the stool. blood in the stool. This test should be This test should be performed on all performed on all patients in whom patients in whom dengue virus dengue virus infection is infection is suspected. suspected.

Other associated Other associated lab. Findingslab. Findings

WBC count- May be normal but WBC count- May be normal but leucopenia is common. Neutropenia leucopenia is common. Neutropenia occurs towards end of febrile phase. occurs towards end of febrile phase. Relative lymphocytosis ĉ >15% atypical Relative lymphocytosis ĉ >15% atypical lymphocytes is common in DHF/DSS.lymphocytes is common in DHF/DSS.

Thrombocytopenia Thrombocytopenia Rising haematocrit Rising haematocrit Hypoproteinaemia/ mild albuminuriaHypoproteinaemia/ mild albuminuria

..Treatment....Treatment..A) Classical DengueA) Classical Dengue Treatment of dengue fever is symptomatic only. Treatment of dengue fever is symptomatic only.

Bed rest, sponging, Paracetamol,oral Bed rest, sponging, Paracetamol,oral rehydration, which is most important from day1. rehydration, which is most important from day1.

B) Dengue haemorrhagic fever (grade I & II)B) Dengue haemorrhagic fever (grade I & II)

The patient should be hospitalized. The patient should be hospitalized.

Management of fever is same as classic dengueManagement of fever is same as classic dengue

Fluid replacement is through IV line.Fluid replacement is through IV line.

PrognosisPrognosis

The case fatality rate varies greatly The case fatality rate varies greatly on the condition of the patient at on the condition of the patient at admission and the quality of admission and the quality of available treatment. However, most available treatment. However, most DHF/DSS patients respond well to DHF/DSS patients respond well to supportive therapy, and overall supportive therapy, and overall mortality in an experienced center is mortality in an experienced center is as low as 1%.as low as 1%.

Measures to control outbreaksMeasures to control outbreaks

Initiate vector control measures (eg. Initiate vector control measures (eg. Residual spraying).Residual spraying).

Ensure community participation.Ensure community participation.Assess facilities for case management of Assess facilities for case management of

patients with haemorrhagic shock.patients with haemorrhagic shock.Alert health personnel to report Alert health personnel to report

increase /clustering of cases.increase /clustering of cases.Measures for prevention of mosquito bites Measures for prevention of mosquito bites

to be conveyed to general population:to be conveyed to general population:

Measures (contd.)Measures (contd.)1.1. Wear clothes that cover full arms & legsWear clothes that cover full arms & legs2.2. Mandatory use of mosquito nets/repellantsMandatory use of mosquito nets/repellants3.3. Keep patients protected from mosquito bite Keep patients protected from mosquito bite

in acute phasein acute phase Elimination of mosquito breeding places:Elimination of mosquito breeding places:1.1. Empty water tanks once a weekEmpty water tanks once a week2.2. Cover & seal septic tanks and soak away Cover & seal septic tanks and soak away

pits.pits.3.3. Regular removal of rubbishRegular removal of rubbish4.4. Change water of coolers & other stagnant Change water of coolers & other stagnant

domestic water sources etc.domestic water sources etc.

Mosquito breeding groundsMosquito breeding grounds

Eradication of mosquito breeding Eradication of mosquito breeding grounds by spraying of insecticidesgrounds by spraying of insecticides

..Immunisation....Immunisation..

Tetravalent vaccines are in Tetravalent vaccines are in advanced stage (phase III) of advanced stage (phase III) of development in Thailand and development in Thailand and are expected to be available are expected to be available in near future (within 5-in near future (within 5-10yrs).10yrs).

..Conclusion....Conclusion..

Though Dengue fever is usually a self-Though Dengue fever is usually a self-limiting disease, lack of proper limiting disease, lack of proper monitoring and adequate volume monitoring and adequate volume replacement may lead to fatal replacement may lead to fatal outcome.outcome.

In view of emerging outbreaks of In view of emerging outbreaks of dengue fever in various states of India, dengue fever in various states of India, it becomes imperative for primary care it becomes imperative for primary care physicians to have an updated physicians to have an updated knowledge of its early diagnosis and knowledge of its early diagnosis and recent management guidelines.recent management guidelines.

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