Jimmy Mendigo, MD Infectious Disease Specialist

1. DENGUE: WHO GUIDELINES FOR DIAGNOSIS AND TREATMENT Jimmy Mendigo, MD Infectious Disease Specialist Chrysanta D. Viernes, MD Internal Medicine- ITRMC

2. OBJECTIVES • Discuss the epidemiology and burden of disease of Dengue • Review the transmission • Discuss the new case classification • Discuss algorithms in the diagnosis and management of Dengue

3. EPIDEMIOLOGY • most rapidly spreading mosquito-borne viral disease in the world • incidence: 30-fold increase • increasing geographic expansion to new countries, and from urban to rural settings • 50 million dengue infections annually

4. EPIDEMIOLOGY

5. EPIDEMIOLOGY • 2001-2008: 1, 020,333 cases in Cambodia, Malaysia, Philippines and Vietnam • highest reported deaths in 2008 • Cambodia • Philippines

6. Burden of Disease •  WHO estimates that 2.5 billion people—over 40% of the world’s population-- are at risk for dengue infection. • Approximately 50-100 million infections (1 million confirmed) occur each year resulting in 500,000 hospitalizations and 20,000 deaths.

7. Dengue Virus Profile • Genus Flavivirus • Family Flaviviridae • Single-stranded RNA • 4 serotypes (DEN-1 to 4) • 50 nm diameter with multiple copies of 3 structural proteins ( membrane bilayer and single-stranded RNA)

8. Vector Profile • Aedes mosquitoes • A. aegypti • A. albopictus • A. polynesiensis • Tropical and subtropical species • Urban places • Immature stages are found in water-filled habitats

9. The Host • Incubation period: 4-10 days • Primary infection induce lifelong immunity to the infecting serotype • Protection from different serotype within 2-3 months of primary infection • No long-term cross-protective immunity

10. The Host • Individual risk factors: • Age, ethnicity, chronic diseases • Seroepidemiological studies (Cuba and Thailand) • Secondary heterotypic infection • Time interval between infections • Antibody-dependent enhancement of infection

11. Blood meal Released in circulation Replication and Transmission Viral Replication WBC and Lymphatics

12. Replication in the salivary gland Replication and Transmission • Extrinsic Incubation • 8--12 days Viral replication in midgut Female mosquito ingests infected blood

13. Dengue Fever • Wide spectrum of clinical presentation, with unpredictable clinical evolution and outcome • Three phases • Febrile phase • Critical phase • Recovery phase • Previously classified into • undifferentiated fever, dengue fever and DHF • Grade 1-IV

14. Dengue Fever Grade 1: fever, non specific constitutional symptoms; (+) TT- only hgic manifestation Grade 2: Grade 1 manifestation + spontaneous bleeding Grade 3: signs of circulatory failure (rapid weak pulse, narrow pulse pressure, hypotension, cold clammy skin) Grade 4: profound shock with undetectable pulse and BP

16. CLINICAL MANAGEMENT

17. Dengue Fever

18. Febrile Phase • facial flushing • skin erythema • generalized body ache • myalgia and arthralgia • headache • sorethroat, injected pharynx, and conjunctival injection • anorexia, nausea and vomiting • Sudden onset of high-grade fever • Lasts for 2-7 days

19. Febrile Phase • (+) TT increases the probability of dengue • (+) hemorrhagic manifestations • enlarged and tender liver earliest abnormality: progressive decrease in total wbc

20. Critical Phase • temperature drops to 37.5-38 (days 3-7) • (+) increase in capillary permeability with increasing hematocrit levels • significant plasma leakage lasts for 24-48 hours • progressive leukopenia followed by rapid decrease in platelet precedes plasma leakage

21. Critical Phase • if (-) increase in capillary permeability  improve • if (+) increase in capillary permeability  pleural effusion and ascites • degree of increase above the baseline hematocrit reflects the severity of plasma leakage

22. Critical Phase • shock: critical volume of plasma is lost • temperature may be subnormal • prolonged shock  organ hypoperfusion  organ impairment, metabolic acidosis, and DIC  severe hemorrhage • severe hepatitis, encephalitis or myocarditis

23. Recovery Phase • gradual reabsorption of extravascular compartment fluid (48-72 hours) • general well-being improves, appetite returns, GI symptoms abate, hemodynamic status stabilizes and diuresis ensues • (+) rash: “isles of white in the sea of red”

24. Recovery Phase • hematocrit stabilizes or may be lower due to dilutional effect of reabsorbed fluid • wbc starts to rise • recovery of platelet count occurs later

26. Approach to the Management • At primary and secondary levels, health care facilities are responsible for emergency/ ambulatory triage assessment and treatment • Triage is the process of rapidly screening patients soon after their arrival in the hospital or health facility in order to identify those • Severe dengue • With warning signs • Non-urgent cases

27. Approach to the Management

28. Approach to the Management • Referral centres receiving severely ill dengue patients must be able to give prompt attention to referred cases. • Beds should be made available to those patients who meet the admission criteria • There should be a designated area to cohort dengue patients, and a high-dependency unit for closer monitoring of those with shock. • Staffed by doctors and nurses

29. Approach to the Management Criteria for transfer: • early presentation with shock (on days 2 or 3 of illness); • severe plasma leakage and/or shock; • undetectable pulse and blood pressure; • severe bleeding; • fluid overload; • organ impairment (such as hepatic damage, cardiomyopathy, encephalopathy, • encephalitis and other unusual complications).

30. Approach to the Management Disease notification • In dengue-endemic countries, cases of suspected, probable and confirmed dengue should be notified • Public health measures • suspected cases • lives in or has travelled to a dengue-endemic area • fever for three days or more • low ordecreasing white cell counts • thrombocytopaenia ± positive tourniquet test.

31. Approach to the Management Management Decisions • Groups A • may be sent home • tolerate adequate volumes of oral fluids and pass urine at least once every 6 hours • no warning signs • Groups B • referred for in-hospital management • with warning signs, co-existing conditions, • with certain social circumstances • Groups C • require emergency treatment and urgent referral • severe dengue (in critical phase)

32. Group A Action Plan • Encourage intake of ORS, fruit juice and other fluids • Paracetamol and tepid sponge for fever • Advise to come back if with • no clinical improvement • severe abdominal pain • persistent vomiting • cold and clammy extremities, • lethargy or irritability or restlessness, • bleeding • not passing urine for more than 4–6 hours. • monitor: • temperature pattern, volume of fluid intake and losses, urine output, warning signs, signs of plasma leakage and bleeding, haematocrit, and white blood cell and platelet counts

33. Group B (with warning signs) Action Plan • reference hematocrit before fluid therapy • isotonic solutions • 5–7 ml/kg/hour for 1–2 hours, then reduce to 3–5 ml/kg/hr for 2–4 hours, and then reduce to 2–3 ml/kg/hr or less according to the clinical response • reassess: • haematocrit remains the same or rises only minimally  2–3 ml/kg/hr for another 2–4 hours • worsening vital signs and rising haematocrit rising  5–10 ml/kg/hour for 1–2 hours

34. Group B (with warning signs) Action Plan • Give minimum intravenous fluid volume: maintain good perfusion and urine output of about 0.5 ml/kg/hr • Intravenous fluids are usually needed for only 24–48 hours. • Reduce intravenous fluids gradually when the rate of plasma leakage decreases towards the end of the critical phase. • monitor: • vital signs and peripheral perfusion (1–4 hourly until the patient is out of the critical phase) • urine output (4–6 hourly) • hematocrit (before and after fluid replacement, then 6–12 hourly) • blood glucose • organ functions (renal profile, liver profile, coagulation profile)

35. Group B (without warning signs) Action Plan • Encourage oral fluids • If not tolerated, start intravenous fluid therapy of 0.9% saline or Ringer’s lactate with or without dextrose at maintenance rate • Patients may be able to take oral fluids after a few hours of intravenous fluid therapy. • Give the minimum volume required to maintain good perfusion and urine output. • Intravenous fluids are usually needed only for 24–48 hours. • Close monitoring

36. Group C Action Plan • admit to a hospital with access to intensive care facilities and blood transfusion • plasma losses should be replaced immediately and rapidly with isotonic crystalloid solution or, in the case of hypotensive shock, colloid solutions • blood transfusion: with suspected/severe bleeding • judicious intravenous fluid resuscitation: sole intervention required

37. Group C Action Plan • Goals of fluid resuscitation: • improving central and peripheral circulation • (decreasing tachycardia, improving BP, warm and pink • extremities, and capillary refill time <2 seconds) • improving end-organ perfusion • – i.e. stable conscious level (more alert or less restless), urine output ≥ 0.5 ml/kg/hour, • decreasing metabolic acidosis.

41. Treatment of Hemorrhagic Complications • Patients at risk of major bleeding are those who: • prolonged/refractory shock; • hypotensive shock and renal or liver failure and/or severe and persistent metabolic acidosis • given non-steroidal anti-inflammatory agents • pre-existing peptic ulcer disease • anticoagulant therapy • any form of trauma

42. Treatment of Hemorrhagic Complications • Blood transfusion is life-saving and should be given as soon as severe bleeding is suspected or recognized • Do not wait for the haematocrit to drop too low before deciding on blood transfusion • Risk of fluid overload.

43. Treatment of Hemorrhagic Complications • blood transfusion if with bleeding • 5-10 ml/kg of PRBC or 10-20 ml/kg FWB • repeat if with further blood loss or no rise in hematocrit after transfusion • little evidence to support transfusion of platelet concentrate and FFP • massive bleeding not managed by FWB/PRBC • may exacerbate fluid overload

44. Management of Complications • Fluid Overload • Causes: • – excessive and/or too rapid intravenous fluids; • – incorrect use of hypotonic rather than isotonic crystalloid solutions; • – inappropriate use of large volumes of intravenous fluids in patients with • unrecognized severe bleeding; • – inappropriate transfusion of FFP, platelet concentrates and • cryoprecipitates; • – continuation of IVF after plasma leakage has resolved • – co-morbid conditions such as congenital or ischaemic heart disease, chronic • lung and renal diseases

45. Management of Complications Clinical Features: – respiratory distress, difficulty in breathing; – rapid breathing; – chest wall in-drawing; – wheezing (rather than crepitations); – large pleural effusions; – tense ascites; • Other investigations: • CXR • ECG • ABG

46. Management of Complications • Oxygen therapy • Stop IVF • When to discontinue IVF: • – stable blood pressure, pulse and peripheral perfusion; • – haematocrit decreases in the presence of a good pulse volume; • – afebrile for more than 24–48 days (without the use of antipyretics); • – resolving bowel/abdominal symptoms; • – improving urine output • If necessary, give oral or intravenous furosemide 0.1–0.5 mg/kg/dose once or twice daily, or continuous infusion of furosemide 0.1 mg/kg/hour.

47. Management of Complications • If the patient has stable haemodynamic status but is still within the critical phase, reduce the intravenous fluid accordingly. Avoid diuretics during the plasma leakage phase • Patients who remain in shock with low or normal haematocrit levels but show signs of fluid overload may have occult haemorrhage. • Careful fresh whole blood transfusion • repeated small boluses of a colloid solution

48. Criteria for Discharge