2. 2 Module 1 Pathophysiology Clinical course WHO classification & limitation Other manifestations Dr Suresh Kumar Infectious Diseases Unit Hospital Sungai Buloh

3. 3 Dengue virus – Flavivirus Transmitted by Aedes aegypti and Aedes albopictus 4 distinct serotypes –DEN-1, 2, 3 and 4 Each episode –Induces life long immunity to homologous serotype –Only partial or transient protection to other serotypes

4. 4 Manifestations of the dengue syndrome Incubation period: 4-7 days (range 3-14) Spectrum of illness: Asymptomatic Undifferentiated fever No hemorrhage Unusual hemorrhage Dengue Fever DHF 1& 2 DHF 3&4 DSS Dengue Hemorrhagic Fever ( plasma leakage) Symptomatic Dengue virus Infection

5. 5 Risk factors for DHF Secondary infection –Due to antibody-dependent enhancement Viral virulence Viral load Host genetic background T-cell activation

6. 6 Pathophysiology of DHF - 1 Primary pathophysiological abnormality in DHF and DSS is an acute increase in vascular permeability Plasma leakage results in hemoconcentration and hypovolemia or shock Hypovolemia leads to reflex tachycardia and generalised vasoconstriction

7. 7 Clinical manifestations of vasoconstriction in various systems are; –Skin coolness, pallor and delayed capillary refill time –Cardiovascular system raised diastolic blood pressure and a narrowing pulse pressure –Renal system reducing urine output –Gastrointestinal system vomiting and abdominal pain –Central nervous system lethargy, restlessness, apprehension, reduced level of consciousness –Respiratory system tachypnoea (respiratory rate >20/min) Pathophysiology of DHF - 2

8. 8 Clinical course of dengue infection - Overview Febrile Phase Critical Phase Recovery Phase Lasts for 2 – 7 days Clinical features are indistinguishable between DF and DHF Happens often after the 3 rd day of fever Clinical presentation depends on the presence and degree of plasma leakage Lasts for about 24-48 hours In DHF patients – plasma leakage stops and is followed by reabsorption of extravascular fluid

10. 10 Febrile Phase Usually lasts for 2 – 7 days Fever is often accompanied by –Facial flushing, skin erythema, generalised body ache, myalgia, arthalgia and headache –Anorexia, nausea and vomiting are common Mild hemorrhagic manifestations may be seen –This may include positive tourniquet test, petechiae or mucosal bleeding Earliest abnormality in FBC is a progressive decrease in total WBC count These features are indistinguishable between DF and DHF

11. 11 Critical Phase - 1 Occurs either –Towards the late febrile phase Often after 3 rd day of fever or –Around defervescence Usually between 3 rd day to 5 th day of fever; but may go up to the 7 th day of fever. This phase lasts for 24- 48 hours

12. 12 Critical Phase - 2 During this phase if, Minimal or no plasma leakage occurs –Patient feels better as the temperature subsides Dengue fever Critical volume of plasma leakage occurs –Patient develops DHF –Varying degrees of circulatory disturbances occur depending on the degree of plasma leakage

13. 13 Critical Phase -3 In more severe form of plasma leakage –Patients may sweat, become restless, have cool extremities and prolonged capillary filling time –The pulse rate increases, diastolic BP increases and the pulse pressure narrows

14. 14 120 110 100 90 80 70 60 Blood pressure, pulse pressure, heart rate in hypovolemic shock Time LCS Lum Compensated shock Decompensated shock

15. 15 Critical Phase - 3 Clinical warning signs of severe dengue or high possibility of rapid progression to shock

16. 16 Critical phase - 4 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

17. 17 Recovery Phase Plasma leakage stops after 24-48 hours of defervescence This 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

18. 18 WHO classification - DHF Grade 1 In the presence of haemoconcentration, fever and symptoms, a positive TT and/or easy bruising Grade 2 spontaneous bleeding in addition to the manifestation from Grade 1 Grade 3* circulatory failure – rapid, week pulse and narrowing of pulse pressure or hypotension with the presence of cold, clammy skin and restlessness. Grade 4* profound shock – with undetectable blood pressure or pulse.

19. 19 Grade 1 & 2 – Non-shock DHF Grade 3 & 4 – DSS WHO classification - DHF

20. 20 Limitations of WHO classification 1.Patients may present with severe dengue with shock without fulfilling all the 4 criteria for DHF 2.The existing guideline does not account for severe dengue primarily due to organ dysfunction such as liver, respiratory, brain and cardiac dysfunction.

21. 21 3.Diagnosing plasma leakage in DHF based on HCT –Very often we do not have patient’s baseline HCT –Early fluid therapy and bleeding affects HCT value 4.Often not useful for disease management since correct diagnosis can only made retrospectively Limitations of WHO classification

22. 22 Other important manifestations Acute abdomen –Causes include hepatitis, acalculous cholecystitis and shock –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

23. 23 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

24. 24 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. Rarer neurological manifestations include myelitis and GBS Other important manifestations

25. Thank you