Dr.T.V.Rao MD 1

DENGUE FEVERDr.T.V.Rao MD

Dr.T.V.Rao MD 2

Arboviruses• The Arbovirus are also called as Arthropod borne viruses, represent an ecological grounding of viruses with complex transmission cycles involving Arthropods

• These viruses have diverse physical and chemical properties and are classified in several virus families.

• Dengue infection is caused by Arbovirus

Man-Arthropod-Man Cycle

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History - Dengue • This disease was first described 1780, and the

virus was isolated by Sabin 1944. Dengue virus infection is the most common arthropod-borne disease worldwide with an increasing incidence in the tropical regions of Asia, Africa, and Central and South America. There are four serotypes of the virus. All are transmitted by mosquitoes, which are not affected by the disease, although an infected mosquito may infect others (not via man).

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Over view of Dengue

• With more than one-third of the world’s population living in areas at risk for transmission, dengue infection is a leading cause of illness and death in the tropics and subtropics. As many as 100 million people are infected yearly. Dengue is caused by any one of four related viruses transmitted by mosquitoes

Dengue • Dengue  is the biggest Arbovirus problem in the world today  with

over 2 million cases per year. Dengue is found in SE Asia, Africa and the Caribbean and S America.

• Flavivirus, 4 serotypes, transmitted by Aedes mosquitoes which reside in water-filled containers.

• Human infections arise from a human-mosquitoe-human cycle

• Classically, dengue presents with a high fever, lymphadenopathy, myalgia, bone and joint pains, headache, and a Maculopapular rash.

• Severe cases may present with hemorrhagic fever and shock with a mortality of 5-10%. (Dengue hemorrhagic fever or Dengue shock syndrome.)

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Current Trends• In the 1980s, DHF began a second expansion

into Asia when Sri Lanka, India, and the Maldives Islands had their first major DHF epidemics; Pakistan first reported an epidemic of dengue fever in 1994. The epidemics in Sri Lanka and India were associated with multiple dengue virus serotypes, but DEN-3 was predominant and was genetically distinct from DEN-3 viruses previously isolated from infected persons in those countries.

Distribution of Dengue

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Genome of dengue virus

• The genome of dengue virus consists of seven non-structured protein and three structural proteins.

Non-structural proteins- NS1, NS2a, NS2b, NS3, NS4a, NS4b and NS5• Structural proteins-envelope protein E,

membrane protein M and capsid protein C

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Dengue Infection and Implications

• Dengue virus (DENV) infects 50 million (WHO) to 100 million (NIH) people annually. Forty per cent of the world’s population, predominately in the tropics and sub-tropics, is at risk for contracting dengue virus. DENV infection can cause dengue fever, dengue haemorrhagic fever, dengue shock syndrome, and death.

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Why Recurrent Infection is Dangerous

• The person who has been previously infected with dengue is more prone to its severe form. This happens as the antibodies meant for the old strain now start interfering in response of immune to the current restrain, thus facilitating dengue virus entry to the body.

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Dengue Mosquito transmitted Viral Infection

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What causes Dengue• Dengue (DF) and dengue haemorrhagic

fever (DHF) are caused by one of four closely related, but antigenic ally distinct, virus serotypes (DEN-1, DEN-2, DEN-3, and DEN-4), of the genus Flavivirus. Infection with one of these serotypes provides immunity to only that serotype for life,

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Aedes aegypti – Vector

• Aedes aegypti, a domestic, day-biting mosquito that prefers to feed on humans, is the most common Aedes species. Infections produce a spectrum of clinical illness ranging from a nonspecific viral syndrome to severe and fatal haemorrhagic disease. Other species of Aedes can also transmit.

Dengue Virus – A Flavivirus• Flavivirus are spherical and

40- 60 mm in diameter. Genome – Positive sense,

single sense RNA,11kb in size

Genome – RNA infectious Enveloped virus Three structural

polypeptides two are glycosylated

Replication in cytoplasm

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How Mosquitos spread the infection

• The disease starts during the rainy season, when vector Mosquito Aedes aegypti is abundant

• The Aedes breeds in the tropical or semitropical climates in water holding receptacles or in plants close to human dwellings

• A female Aedes acquires the infection feeding upon a viremic human.

• After a period of 8 – 14 days mosquitoes are infective and remain infective for life. ( 1- 3 ) months.

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Dengue - Endemics• Persons living in a dengue-endemic area

can have more than one dengue infection during their lifetime. DF and DHF are primarily diseases of tropical and sub tropical areas, and the four different dengue serotypes are maintained in a cycle that involves humans and the Aedes mosquito.

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Pathogenesis

• Presence of existing Dengue antibody, associated with fresh viral infection with new serotype complexes and forms within few days of the second dengue infection.• Non neutralizing enhancing antibodies

promote infection of higher number of Mononuclear cells.

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Immunology Dengue

• Four serotypes exist distinguished by Molecular basis and Nt tests• Infection confers life long immunity • But cross protection between serotypes is

of short duration.• Reinfection with different serotype after

primary attack is more dangerous causes Dengue hemorrhagic fever.

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Clinical Manifestations

• Any or few of the following events can occur.

• Fever,• Severe head ache• Muscle and joint pains• Nausea, vomiting,• Eye pain

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How Dengue Infection starts and manifests

• Incubation period 4 – 7 days ( 3 – 14 days)• Fever may start with, Malise,chills,head ache• Soon leads to severe back ache, joint pains, muscular pain,

pain in the eye ball.• Temperature may persist for 3 -5 days.• On some occasions once again raises in about 5 – 8 days

( Saddle back fever )• Myalgia may be severe with deep bone pain ( Break bone fever ) characteristic of the Disease

On majority of the occasions a self limited condition,Subside on its own

Death is a rare event.

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Dengue with Rashes

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Dengue Hemorrhagic Fever• DHF was first recognized in the 1950s during the

dengue epidemics in the Philippines and Thailand. By 1970 nine countries had experienced epidemic DHF and now, the number has increased more than fourfold and continues to rise. Today emerging DHF cases are causing increased dengue epidemics in the Americas, and in Asia, where all four dengue viruses are endemic, DHF has become a leading cause of hospitalization and death among children in several countries. ( WHO )

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Dengue Hemorrhagic Fever• Common in children.• In children passively acquired contributed by

the maternal antibodies transferred to the fetus.• In other ( Adults ) the presence of antibodies

due to previous infection with different serotype• Initially presents like classical Dengue infection• But patients condition abruptly worsens, an

important cause of morbidity and mortality in Dengue

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Symptoms of Dengue Hemorrhagic Fever

• The severe form of dengue typically starts like the mild form but gets a lot worse after a couple of days. Along with the symptoms above, dengue hemorrhagic fever may also cause:

• – Drastically reduced blood cells, making blood clotting difficult– Significantly damaged lymph and blood vessels– Mouth and nose bleeding– Bleeding underneath the skin that typically looks like bruises– Death

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Basic Understanding of Dengue Hemorrhagic Fever

• Dengue Hemorrhagic Fever is a probable case of dengue and

• hemorrhagic tendency evidenced by one or more of the following:

• Ø Positive tourniquet test• Ø Petechial, ecchymosis or purpura• Ø Bleeding from mucosa (mostly epistaxis or bleeding

from• gums), injection sites or other sites• Ø Haematemesis or melena

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Dengue hemorrhagic fever

• Dengue hemorrhagic fever (fever, abdominal pain, vomiting, bleeding) is a potentially lethal complication, affecting mainly children. Early clinical diagnosis and careful clinical management by experienced physicians and nurses increase survival of patients.

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How to do a Tourniquet test• The tourniquet test is performed

by inflating a blood pressure cuff to a point mid-way between the systolic and diastolic pressures for five minutes. A test is considered positive when 10 or more petechiae per 2.5 cm2 (1 inch) are observed. In DHF, the test usually gives a definite positive result (i.e. >20 petechiae). The test may be negative or mildly positive during the phase of profound shock.

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What Happens in Dengue Hemorrhagic Fever

• Thrombocytopenia (platelets 100,000/cu.mm or less) and Ø Evidence of plasma leakage due to increased capillary permeability manifested by one or more of the following:

• – A >20% rise in hematocrit for age and sex• – A >20% drop in hematocrit following treatment

with• fluids as compared to baseline• – Signs of plasma leakage (pleural effusion, ascites or• hypoproteinaemia).

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Risk factor for DHF• Important risk

factors for DHF include the strain of the infecting virus, as well as the age, and especially the prior dengue infection history of the patient

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Dengue Hemorrhagic Syndrome

• Chateresied by shock and hemoconcentration

• Contributed by circumstantial evidence suggests secondary infection with Dengue type 2 following type 1 infection in the past.

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Dengue hemorraghigic Syndrome

• DHS is caused due to release of, 1 Release of cytokines 2 Vasoactive mediators. 3 Procoagulants

Manifest with disseminated intravascular coagulation

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Risk of Hemorrhagic Fever• The risk of hemorrhagic fever syndrome is about

0.2% during the first attack• The second attack with different serotype increases

the risk to ten fold• The fatality rate with dengue hemorrhagic fever can

reach 15% but proper medical care and symptomatic management can reduce mortality to less than 1%

• On few occasions patients condition abruptly worsens into Dengue shock syndrome, a more severe form of disease characterized by shock and hemoconcentration.

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DiagnosisIn resource rich establishments

1 Reverse transcriptase polymerase chain reaction methods help rapid identification

2 Isolation of virus is difficult 3 The current favored approach is inoculation

of mosquito cell line with patient serum coupled with nucleic acid assay to identify a recovered virus.

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Dengue Serology• The serology is limited with cross reactivity of

IgG antibodies to heterologous Flavivirus antigens

• Most commonly used methods are Viral protein specific capture IgM or IgG by

ELISA IgM antibodies develop within few days of

illness Neutralizing anti Haemagglutination inhibiting antibodies

appear within a week after onset of Dengue fever

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Importance of paired sample testing in Serology

• Testing one sample for serum and reporting a negative test is fallacious• Analysis of paired acute and

convalescent sera to show significant rise in antibody titer is the most reliable evidence of an active dengue infection.

Newer Diagnostic MethodsRT - PCR

• RT PCR is a highly sensitive tool in Diagnosis, with established high sensitivity in Diagnosis in Puzzles

• Developing world lacks resources to implement and utilize the Scientific advances

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Caring Dengue patients (WHO)• All dengue patients must be carefully observed for

complications for at least 2 days after recovery from fever. This is because life threatening complications often occur during this phase. Patients and households should be informed that severe abdominal pain, passage of black stools, bleeding into the skin or from the nose or gums, sweating, and cold skin are danger signs.

• If any of these signs is noticed, the patient should be taken to the hospital.. The patient who does not have any evidence of complications and who has been afebrile for 2-3 days does not need further observation.

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Treatment • No Anti viral therapy

available• Symptomatic management

in Majority of cases• Dengue Hemorrhagic fever

to be treated with suitable fluid replacement

• No Vaccine available, difficult in view of four serotypes.

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Control of Dengue

• Control of Mosquito breeding places.• Anti mosquito measures • Use of Insecticides. • Screened windows and doors can

reduce exposure to vectors.

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WHO guidelines for Control of Dengue• Activities to control transmission should target Ae. aegypti

(the main vector) in the habitats of its immature and adult stages in the household and immediate vicinity, as well as other settings where human–vector contact occurs (e.g. schools, hospitals and workplaces), unless there is sound evidence that Ae. albopictus or other mosquito species are the local vectors of dengue. Ae. aegypti proliferates in many purposely-filled household containers such as those used for domestic water storage and for decorative plants, as well as in a multiplicity of rain-filled habitats – including used tyres, discarded food and beverage containers, blocked gutters and buildings under construction. Typically, these mosquitoes do not fly far, the majority remaining within 100 metres of where they emerged. They feed almost entirely on humans, mainly during daylight hours, and both indoors and outdoors

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Epidemiology - Dengue

• Dengue virus are distributed world wide in tropical regions.

• Where the Aedes vectors exist, are endemic areas

• Changing and increasing incidences are associated with rapid urban population growth, over crowding and lax mosquito control measures

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Dengue a Reemerging Infection

• Dengue in 2005 identified as the most important mosquito borne viral disease

• An estimated 50 million or more cases occur annually worldwide

• 400,000 cases of dengue hemorrhagic fever.

• Asian counties report major cases of childhood deaths

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Dengue NET• Epidemiological and laboratory-based surveillance is

required to monitor and guide dengue/DHF prevention and control programmes regardless of whether these are based on mosquito control or possible vaccination if an effective and safe vaccine becomes available. However, though there are standard case definitions for dengue and dengue haemorrhagic fever (DHF), the reporting of dengue/DHF is not standardized. Epidemiological and laboratory data are often collected by different institutions and reported in different formats, and are therefore difficult to collate.

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Dengue Net • WHO has created Dengue Net as a central

data management system to collect and analyse standardized epidemiological and virological data in a timely manner, and to present epidemiological trends, as soon as new data are entered and to provide both historical and real-time data. DengueNet currently houses data from 1995-2001.

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