Dengue

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DENGUE FEVER

• By Manar .M. Rashad
• Student of doctor degree in tropical medicine
• University of Alexandria

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History

• The first record of a case of probable dengue
  fever is in a Chinese medical encyclopedia from
  the Jin Dynasty (265420 AD) which referred to a
  water poison associated with flying insects. 
• The first recognized Dengue epidemics occurred
  almost simultaneously in Asia, Africa, and North
  America in the 1780s, shortly after the
  identification and naming of the disease in 1779.
  

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• The first confirmed case report
  dates from 1789 and was by Benjamin Rush, who
  coined the term "breakbone fever" because of the
  symptoms of myalgia and arthralgia

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• The origins of the word dengue are not clear, but
  one theory is that it is derived from the Swahili
  phrase "Ka-dinga pepo", meaning "cramp-like
  seizure caused by an evil spirit"
• Dengue fever is the most common arthropod borne
  viral disease.
• Dengue fever is one of the most important
  emerging disease of the tropical and sub tropical
  regions, affecting urban and pre urban areas

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Global burden of DENGUE

• During the 19th century, dengue was considered a
  sporadic disease that caused epidemics at long
  intervals,
•  Today, dengue ranks as the most important
  mosquito-borne viral disease in the world. In the
  last 50 years, incidence has increased 30-fold.

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• An estimated 2.5 billion people live in over 100
  endemic countries and areas where dengue viruses
  can be transmitted
• Up to 50 million infections occur annually with
  500 000 cases of dengue haemorrhagic fever and
  22,000 deaths mainly among children.

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Dengue virus

• a mosquito-borne flavivirus.
• DENV is a positive single stranded RNA virus of
  the family Flaviviridae, genus Flavivirus.

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• DENV causes a wide range of diseases in humans,
  from a self limited Dengue Fever (DF) 
• to a life-threatening syndrome called Dengue
  Hemorrhagic Fever (DHF) or Dengue Shock Syndrome
  (DSS).
• There are four antigenically different serotypes
  of the virus (although there is report of 2013
  that a fifth serotype has been found)
• DENV-1 DENV-2 DENV-3 DENV-4

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• Infection induces long-life protection against
  the infecting serotype, but it gives only a short
  time protective cross immunity against the other
  types.
• The first infection cause mostly minor disease,
  but secondary infections has been reported to
  cause severe diseases (DHF or DSS) in both
  children and adults. This fenomenon is
  called Antibody-Dependent Enhancement.

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Vector Aedes aegypti
Life cycle8-10 days
Adult
Larva
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• It can be identified by the white bands or scale
  patterns on its legs and thorax
• Mosquitoes fly an average of 400 metres.
• It has daytime activity
• Lives around human habitation
• Lays eggs and produces larvae preferentially in
  artificial containers

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Diseases transmitted by aedes aegypti
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Geographical distribution of the vector
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Challenge in controlling vector

• There is a very important adaptation of dengue
  vectors that makes controlling their populations
  a difficult task. Their eggs can withstand
  desiccation for several months, which means that
  even if all larvae, pupae, and adults were
  eliminated at some point in time, repopulation
  will occur as soon as the eggs in the containers
  are flooded with water. Unfortunately, there is
  no effective way to control the eggs in
  containers..

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Transmission

• The viruses are passed on to humans through the
  bites of an infective female Aedes mosquito it
  injects the dengue virus into the skin.
• The virus infects nearby skin cells called
  keratinocytes, the most common cell type in the
  skin.
• The dengue virus also infects and replicates
  inside a specialized immune cell located in the
  skin, a type of dendritic cell called a
  Langerhans cell.

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• Once the Langerhans cells are infected with the
  dengue virus, they travel from the infection site
  in the skin to the lymph nodes.
•  The infected Langerhans cells display dengue
  viral antigens on their surface, which activates
  the innate immune response by alerting two types
  of white blood cells, called monocytes and
  macrophages, to fight the virus. 

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• . As the infected monocytes and macrophages
  travel through the lymphatic system, the dengue
  virus spreads throughout the body.
• During its journey, the dengue virus infects more
  cells, including those in the lymph nodes and
  bone marrow, macrophages in both the spleen and
  liver, and monocytes in the blood.
• The spread and increase of the virus results
  in viremia, a condition in which there is a high
  level of dengue virus in the blood stream.

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Pathogenesis of Dengue
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• The microvascular leak occurs at a time when the
  viral load is in steep decline and is associated
  with a more intense immune response.
• Disruption in the endothelial glycocalyx layer
  has been implicated, through immune-mediated
  mechanisms by the virus or the NS1 antigen
  adhering to the endothelial layer.

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• The NS1 antigen is a glycoprotein secreted from
  dengue-infected cells and is required for viral
  replication.
• Studies have shown that NS1 can selectively bind
  to heparin sulphate in the glycocalyx layer of
  microvascular endothelial cells. Thus
  facilitating immune complex formation and
  antibody-dependent complement activation causing
  the endothelial damage and microvascular leakage.

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DENGUE fever is a Systemic disease
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Clinical course of Dengue
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• In November 2009, World Health Organization (WHO)
  issued a new guideline that classifies
  symptomatic cases as dengue or severe dengue.
• Dengue is defined by a combination of 2 clinical
  findings in a febrile person who traveled to or
  lives in a dengue-endemic area.
• Clinical findings include nausea, vomiting,
  rash, aches and pains, a positive tourniquet
  test, leukopenia.
• the following warning signs abdominal pain or
  tenderness, persistent vomiting, clinical fluid
  accumulation, mucosal bleeding, lethargy,
  restlessness, and liver enlargement. The presence
  of a warning sign may predict severe dengue in a
  patient.

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• Severe dengue is classified as dengue with any of
  the following symptoms
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• severe plasma leakage leading to shock or fluid
  accumulation with respiratory distress
• severe bleeding
• severe organ impairment such as elevated
  transaminases 1,000 IU/L, impaired
  consciousness, or cardiovascular compromise.

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Clinical Case Definition for Dengue Shock
Syndrome(DSS)

• 4 criteria for DHF
• Evidence of circulatory failure manifested
  indirectly by all of the following
• Rapid and weak pulse
• Narrow pulse pressure (lt 20 mm Hg) ORhypotension
  for age
• Cold, clammy skin and altered mental status
• Frank shock is direct evidence of circulatory
  failure

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Scenario of shock
Hours
Hours
Hours
Minutes
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Hemorrhagic Manifestations of Dengue

• Skin hemorrhagespetechiae, purpura, ecchymoses
• Gingival bleeding
• Nasal bleeding
• Gastrointestinal bleeding Hematemesis,
  melena, hematochezia
• Hematuria
• Increased menstrual flow

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Signs and Symptoms of Encephalitis/Encephalopathy
Associated with Acute Dengue Infection

• Decreased level of consciousness lethargy,
  confusion, coma
• Seizures
• Nuchal rigidity
• Paresis

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DIAGNOSIS/ LAB WORK

• ISOLATION OF DENGUE VIRUS
• INCREASED IgM OR IgG ANTIBODIES TITRES
• DENQUE ANTIGEN DETECTION (NS1) BY
  IMMUNOHISTOCHEMISTRY,IMMUNOFLUROSCENCE,ELISA
• PCR(detection of viral RNA)

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Test Interpretation
DNGV PCR RT- PCR can be detected in the blood (serum) from patients for approximately the first 5 days of symptoms. A positive PCR result is a definite proof of current infection and it usually confirms the infecting serotype as well.
DNG-IgM MAC- ELISA IgM detection is not useful for dengue serotype determination due to cross-reactivity of the antibody .
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Test Interpretation
DNG-IgG ELISA detection of a past dengue infection Samples with a negative IgG in the acute phase and a positive IgG in the convalescent phase of the infection are primary dengue infections. Samples with a positive IgG in the acute phase and a 4 fold rise in IgG titer in the convalescent phase (with at least a 7 day interval between the two samples) is a secondary dengue infection.
NS1 ELISA Tool for the diagnosis of acute dengue infections  As early as 1 day post onset of symptoms (DPO), and up to 18 DPO.
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CBC/COAGULATION PROFILE

• CBC
• Leukopenia
• Thrombocytopenia lt100.000 (warning sign)
• Increased haematocritgt 20 haemoconcentration(
  warning sign), it should be measured every 24
  hours

• COAGULATION PROFILE
• Prolonged PT
• Prolonged PTT
• Increased FDP
• Decreased fibrinogen

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Clinical course of Dengue
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Primary infection vs Secondary infection
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Management

• The initial management of dengue cases involves
  classification into appropriate severity grades
  with early recognition of potential complications
  and warning signs.
• Early detection of any circulatory compromise
  and judicious fluid resuscitation is the mainstay
  of treatment for severe dengue, with delays being
  associated with worse outcomes.

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• Antipyretics may be needed to control the high
  fever.
• Aspirin and other non-steroidal
  anti-inflammatory agents should not be used, to
  avoid gastric irritation and GI bleeding, and
  because of the link with Reye syndrome.
• Oral rehydration solution is recommended to
  replace losses from vomiting and high fevers.
• .

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• Fluid therapy
• The minimum amount of intravenous fluid should be
  given to ensure adequate perfusion, clinicians
  should be guided by vital signs, haematocrit and
  average urine output of 0.5 mL/kg per hour.
• Isotonic fluids should be given for the duration
  of the critical period only (usually 2448
  hours), as there is a significant risk of fluid
  overload if intravenous fluids are continued into
  the recovery phase.

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• Colloids may be given in
• Hypotensive shock
• After gt20-30 ml/ kg/ day crystalloids given
• Haematocrit does not decrease after crystalloids
  administration in shock state

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Hct Haemodynamic state (vital signs-UOP-cap refill-skin signs) Interpretation Judicious action
High or Rising persistently Unstable Active plasma leakage Further fluid replacement
High or Rising persistently Stable No more extravasated fluid Continue to monitor HCT closely (Expected to decrease 24 hours later)
Decrease Unstable Massive haemorrhage Urgent transfusion
Decrease Stable Haemodilution dt reabsorption of extravasated fluid Reducing IV fluids in stepwise manner or discontinue to prevent pulmonary oedema
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Dengue in Egypt

• On 27 October 2015, the National IHR Focal Point
  of Egypt notified WHO of an outbreak of Dengue
  fever in a village in the Dayrout District of
  Assiut Governorate.
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• Patients developed fever, headache, general body
  aches and abdominal pain with occasional vomiting
  and/or diarrhea but experienced no further
  complications or fatalities.

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• Several samples including oropharyngeal swabs,
  blood and serum samples were collected.
• A total of 28 out of the 118 serum samples were
  positive for Dengue virus type I by ELISA and PCR
  at the Central Public Health Laboratories.

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• For further confirmation, samples were sent to
  the Naval Medical Research Unit Three (NAMRU-3)
  laboratory and tested positive for Dengue virus
  type I by ELISA and PCR.
• They have been responding to the given medical
  care. Some of the cases come from the same
  household.

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Era of Dengue vaccine(upcoming!)

• The growing global epidemic of dengue is of
  mounting concern, and a safe and effective
  vaccine is urgently needed.
• WHO expects vaccines to be an integrated part of
  the Global dengue prevention and control strategy
  (2012-2020).

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• The first dengue vaccine, Dengvaxia (CYD-TDV) by
  Sanofi Pasteur, was first registered in Mexico in
  December, 2015.
• CYD-TDV is a live recombinant tetravalent dengue
  vaccine that has been evaluated as a 3-dose
  series on a 0/6/12 month schedule in Phase III
  clinical studies.
• It has been registered for use in individuals
  9-45 years of age living in endemic areas

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Thank you

• Thank you

Thank you