Pathophysiology and Clinical Presentation

Introduction
Dengue fever is the fastest emerging arboviral infection spread by the Aedes
The global incidence has grown dramatically over the past decade

Key facts
2.5 billion people in tropical and subtropical countries are at risk of dengue infection An estimated 50 million dengue infections occur annually An estimated 500 000 people with DHF require hospitalisation Dengue infection is endemic in over 100 countries. South East Asia and Western Pacific regions are the most affected

Dengue virus
The dengue virus is a single stranded RNA Belongs to the genus Flavivirus and family Flaviviridae 4 serologically distinct serotypes DENV: 1 to 4 Dengue infection provides life long immunity to only that serotype Transient protection to other serotypes

Vectors and host

The two principal vectors of dengue are the Aedes aegypti and Aedes albopictus The virus is maintained by the vector transovarially via the eggs Both monkeys and humans are the amplifying host

Pathophysiology

Evidence of plasma leakage

The hallmark of DHF is increased vascular permeability resulting in plasma leakage
The unique feature of the plasma leakage is
Selective leakage into the pleural and peritoneal space Period of leakage: 24 48 hours

Evidence of plasma leakage

The evidence of plasma leakage includes
hemoconcentration pleural effusion ascites hypovolemia and shock

Bleeding tendency
Vasculopathy
Increase capillary fragility as indicated by a positive tourniquet test Seen usually early in the febrile phase

Thrombocytopenia and platelet dysfuction

Due to decreased platelet production and increase peripheral destruction

Bleeding tendency
Coagulopathy
There is a variable but no significant reduction in a number of coagulation factors: prothrombin, factors V, VII, VIII, IX and X Low levels of protein C, protein S and prothrombin were also seen in DSS

These coagulation abnormalities are well compensated in the majority of patients without circulatory shock.

Clinical presentation

Manifestations of the dengue syndrome

Incubation period: 4 - 10 days Spectrum of illness:
Dengue virus Infection Asymptomatic Undifferentiated fever Symptomatic Dengue Fever Dengue Hemorrhagic Fever (plasma leakage)

No hemorrhage

Unusual hemorrhage

DHF 1& 2

DHF 3&4 DSS

Clinical course of dengue infection

Febrile Phase

Lasts for 2 7 days Clinical features are indistinguishable between DF and DHF

Critical Phase

Happens often after the 3rd day of fever Clinical presentation depends on the presence and degree of plasma leakage Lasts for about 24-48 hours

Recovery Phase

In DHF patients plasma leakage stops and is followed by reabsorption of extravascular fluid

Febrile phase
Sudden onset of high grade fever, may be biphasic, lasting for 2 -7 days Flushed face Headache and retro-orbital pain Severe myalgia and arthralgia: Breakbone fever Rash

Skin manifestations
Facial flush in first 24 to 48 hours Petechiae with positive Hess test Erythematous maculopapular rash : Isles of white in a sea of red

Hemorrhagic manifestations
Gum bleeding and epistaxis Menorrhagia GIT hemaorrhage Massive bleeding is rare in dengue fever

Dengue fever with hemorrhagic manifestations must be differentiated from DHF

Clinical Lab findings Clinical lab findings

Leucopenia with decreasing neutrophils throughout the febrile phase Thrombocytopenia: < 100 000 cells/mm3 Mild rise in hct ( ~ 10%) may be seen as a consequence of dehydration

Clinical Lab findings Clinical lab findings

Liver enzymes: ALT/AST may be elevated Coagulation profile: APTT may be prolonged

Clinical course of dengue infection

Febrile Phase

Lasts for 2 7 days Clinical features are indistinguishable between DF and DHF

Critical Phase

Happens often after the 3rd day of fever Clinical presentation depends on the presence and degree of plasma leakage Lasts for about 24-48 hours

Recovery Phase

In DHF patients plasma leakage stops and is followed by reabsorption of extravascular fluid

Risk factors for DHF

Secondary infection
Due to antibody-dependent enhancement

Viral virulence Viral load Host genetic background

High risk patients

Infants and the elderly Obesity Pregnant women Peptic ulcer disease Chronic diseases: DM, Hypertension, IHD, asthma, liver cirrhosis

Critical phase
Usually occurs on days 3 7 Drop in temperture Plasma leakage, if occurs usually lasts for 24 to 48 hours Progressive leucopenia with thrombocytopenia precedes plasma leakage

Critical Phase
During this phase

Minimal or no plasma leakage occurs

Patient feels better as the temperature subsides

Critical volume of plasma leakage occurs

Patient develops DHF Varying degrees of circulatory disturbances occur depending on the degree of plasma leakage

Warning signs
Lethargy and restlessness Mucosal bleeding Persistent vomiting Abdominal pain or tenderness Liver enlarged > 2 cm Clinical fluid accumulation Lab: increase in HCT with a concurrent rapid decrease in platelet count

Critical phase
Thrombocytopenia and hemoconcentration are usually detectable before the onset of shock HCT level correlates well with plasma volume loss and disease severity. However HCT values may be equivocal and hence unhelpful when there is frank hemorrhage or with untimely HCT determinations

Rising Hematocrit
Upper limit normal Hct
0.4 for children and adult female 0.45 for adult male

A > 20% rise in the Hct from the baseline is considered significant

Third space fluid accumulation

Pleural effusion:
Dyspnoeic, tachypnoeic, hypoxemic CXR: pleural effusion

Ascites

Abdominal distension and tenderness

Hemodynamic instablity
In more severe form of plasma leakage
Tachycardia Cool extremities and prolonged capillary filling time Systolic pressure remains normal initially Diastolic BP increases and the pulse pressure narrows Poor urine output Patients remain conscious and lucid

Critical Phase
With profound shock
Restless and agitated Multiple organ failure with advanced DIC

Other important manifestations

Hepatitis May be mild or severe regardless of the degree of plasma leakage Patients with liver failure have a high propensity to bleed esp. GIT bleeding

Other important manifestations

Neurological manifestations: mainly encephalitis or encephalopathy.
Encephalopathy is usually secondary to liver failure. These manifestations may coincide with onset of clinical features of DHF or may present on admission with no other features suggestive of dengue.

Other important manifestations

Acute abdomen
Other causes include acalculous cholecystitis, acute appendicitis Need to differentiate from surgical causes Fever before abdominal pain Leucopenia, thrombocytopenia, prolonged APTT with normal PT Improvement of pain with fluid resuscitation Most recover within 48-72 hours with conservative treatment

Clinical course of dengue infection

Febrile Phase

Lasts for 2 7 days Clinical features are indistinguishable between DF and DHF

Critical Phase

Happens often after the 3rd day of fever Clinical presentation depends on the presence and degree of plasma leakage Lasts for about 24-48 hours

Recovery Phase

In DHF patients plasma leakage stops and is followed by reabsorption of extravascular fluid

Recovery Phase
Plasma leakage stops after 24-48 hours of defervescence

This is followed by reabsorption of extravascular fluid

Patients general well being improves, appetite returns, gastrointestinal symptoms abate, hemodynamic status stabilises and diuresis ensues. Recovery of platelet count is typically preceded by the recovery of WCC count

Summary
Dengue infection has a wide spectrum of clinical presentation
Death is preventable if the warning signs of dengue are detected early and patients are promptly resuscitated

Thank You