1. Ida Safitri Laksono Dept of Child Health, Faculty of Medicine UGM RSUP Dr. Sardjito, Yogyakarta

2. Outline of presentation Introduction Overview of the three guidelines Dengue Guideline 1997 Background and evidence related to Dengue Guideline 2009 Dengue Guideline 2011 National Dengue Guideline? Summary

3. Introduction GLOBAL burden of dengue Global incidence of dengue has grown dramatically in recent decades About two fifths of the world's population are now at risk Dengue is found in tropical and sub-tropical climates worldwide, mostly in urban and semi-urban areas Dengue is the most prevalent arboviral disease with high morbidity, mortality & socio-economical costs.

4. Cont… Case management Despite its complexity in pathogenesis and manifestation  the management is relatively simple and inexpensive No specific treatment  rely on fluid management. Appropriately and timely implemented, it could save the lives of patients Current situation : the most effective way to prevent dengue transmission is to combat disease-carrying mosquitoes The development of vaccines and drugs is challenging but potential to change this.

5. 1997 2009 2011

6. Dengue guidelines 199720092011 Title Guideline for treatment of DF and DHF in small hospitals – WHO Searo 1999 Dengue – Guidelines for diagnosis, treatment, prevention and control – WHO TDR 2009 Comprehensive guideline for prevention and control of Dengue and DHF – WHO Searo 2011 Pages 33160212 Content Clinical manifestation, diagnosis, case management Chapters : (6) Epidemiology and burden of disease, clinical management, vector management, lab diagnostic tests, surveillance and emergency response, new avenues Chapters : (15) Epidemiology, disease burden,clinical manifestation and diagnosis, lab diagnosis, management, surveillance, vector, vector management, IVM, Combi, PHC approach, case investigation, monitoring, strategic plan (bi-regional plan)

7. Diagnosis Classification 199720092011 Dengue feverDengue without warning signs Dengue fever DHF grade IDengue with warning signs DHF grade I DHF grade II DHF grade IIISevere dengue ( severe plasma leakage, severe hemorrhage, severe organ involvement) DHF grade III DHF grade IV * Expanded dengue syndrome Adult management

9. Probable – an acute febrile illness with two or more of the following manifestations: Headache Retro-orbital pain Myalgia Arthralgia Rash Haemorrhagic manifestations Leukopenia; and Supportive serology (a reciprocal HI antibody titre ≥1280, a comparable IgG ELISA titre or a positive IgM antibody test on a late acute or convalescent-phase serum specimen ); or Occurence at the same location and time as other confirmed ases of dengue fever. Confirmed – a case confirmed by laboratory criteria Reportable – any probable or confirmed case should be reported

10. GradeSign and SymptompsLaboratory DFDHF without plasma leakage DHFIFever with non-specific constitutional symptoms; the only hemorrhagic manifestation is a positive tourniquet test &/or easy bruising evidence of plasma leakage Thrombocytopenia (platelet count  100,000/  L) IIDHF grade I plus spontaneous bleeding IIICirculatory failure manifested by a rapid, weak pulse, narrowing of pulse pressure, or hypotension, cold & clammy skin, restlessness IVProfound shock with undetectable blood pressure

11. WHO Dengue Classification 1997 DFDHF 1. Fever 2-7 days ++ 2. Bleeding tendency  Positive tourniquet test or  Spontaneous bleeding +/-+ 3. Thrombocytopaenia  ≤ 100,000/mm ³ +/-+ 4. Plasma leakage  Pleural effusion /ascites /hypoproteinaemia  ≥ 20% increase in HCT from baseline -+

13. Lancet Inf Dis 2006; 6: 297-302 Lancet 2006; 368: 170-173

14. The stages of the dengue case classification development Numerous publications describing the difficulties using DF/DHF/DSS A systematic review of the issue Bandyopadhyay S et al., TMIH 2006, Volume 11 no 8 pp 1238–1255 The DenCo study (dengue and control) Two expert consensus meetings La Habana 2007 and Kuala Lumpur 2007 A global expert consensus meeting Geneva 2008 Dengue guidelines validation studies (forthcoming publication) TDR report (summary recommendations) (planned for 03/2010) - numerous reports of the difficulties using DF/DHF/DSS: epidemiology has changed - confirmation of the above - clear evidence for classifying in dengue and severe dengue - large differences of DHF case definitions between countries; application difficult - dengue is just one disease entity with different clinical presentations and often with unpredictable clinical evolution and outcome -further design: 1) dengue with or without warning signs and 2) severe dengue - analysis showing user-friendliness and acceptance of dengue/severe dengue - final analysis and recommendations - overall summary report/recommendations DF/DHF/DSS application study Santamaria R et al., accepted at TMIH 2009, September 1 9 0 ´s - 2 0 9 A global expert meeting reviewing "chain of evidence“ (planned for 03/2010)

15. The full model of the revised WHO dengue case classification

16. Dengue without warning signs Probable dengue live in /travel to dengue endemic area. Fever and 2 of the following criteria: Nausea, vomiting Rash Aches and pains Tourniquet test positive Leucopenia Any warning sign

17. Dengue with warning signs Warning signs Abdominal pain or tenderness Persistent vomiting Clinical fluid accumulation Mucosal bleed Lethargy, restlessness Liver enlargement >2 cm Increase in HCT concurrent with rapid decrease in platelet count back

18. Severe Dengue Severe plasma leakage leading to: Shock (DSS) Fluid accumulation with respiratory distress Severe bleeding as evaluated by clinician Severe organ involvement Liver: AST or ALT ≥ 1000 CNS: Impaired consciousness Heart and other organs

19. Evidence from 2009 Dengue Guideline Multicentre prospective study on dengue classification in four South-east Asian and three Latin American countries (Neal Alexander et.al, 2011) Evaluation of the Traditional and Revised WHO Classifications of Dengue Disease Severity  Sensitivity and specificity to capture Category III care for DHF/DSS were 39.0% and 75.5%, respectively; sensitivity and specificity for SD were 92.1% and 78.5%, respectively (Federico Narvaez et.al, 2011)

20. Usefulness and applicability of the revised dengue case classification by disease: multicentre study in 18 countries (Judit Barniol et.al, 2010) Dengue—How Best to Classify It (Anon Srikiatkhachorn et.al, 2011) Evidence from 2009 Dengue Guideline Application of revised dengue classification criteria as a severity marker of dengue viral infection in Indonesia  Binary logistic regression showed the revised dengue classification system (p = 0.000, Wald:22.446) was better in detecting severe dengue infections than the WHO classification system (p = 0.175, Wald:6.339) ( Basuki PS et.al, 2010)

22. Dengue virus infection Asymptomatic Symptomatic Undefferentiated fever (viral syndrome) Dengue Fever (DF) Dengue Haemorrhagic Fever (DHF) (with plasma leakage) Without haemorrhage With unusual haemorrhage DHF non shock DHF with shock Dengue Shock Syndrome (DSS) Expanded Dengue syndrome/isolated organophaty (unusual manifestation) 2011

23. DF/ DHF GradeSigns and SymptomsLaboratory DF Fever with two of the following: Headache Retro-orbital pain Myalgia Athralgia/bone pain Rash Haemorrhagic manifestations No evidence of plasma leakage Leucopenia (WBC <5000 cells/mm3) Thrombocytopenia <150.000 cells/mm3) Rising Hct (5-10%) No evidence of plasma loss DHFI Fever and haemorrhagic manifestation (positive tourniquet test) and evidence of plasma leakage Thrombocytopenia <100.000 cells/mm3 Hct rise >20% DHFII As in Grade I plus spontaneous bleedingThrombocytopenia <100.000 cells/mm3 Hct rise >20% *DHFIII As in Grade I or II plus circulatory failure Thrombocytopenia <100.000 cells/mm3 Hct rise >20% *DHFIV As in Grade III plus profound shock with undetectable bloodpressure and pulse Thrombocytopenia <100.000 cells/mm3 Hct rise >20% *DHF III and IV are DSS WHO classification of Dengue infections and grading of severity of DHF (2011)

25. Admission Criteria 199720092011 SignsSigns of significant dehydration (>10% normal body weight) - Any warning signAny warning sign - Coexisting conditions: infancy, pregnancy, old age, obesity, diabetes mellitus, renal failure, hypertension, chronic hemolytic disease etc. - Social circumstances: living alone, living far from health facility, without reliable means of transport. - Shock: Resuscitation and admission. -Hypoglycemic patients without leucopenia and/or thrombocytopenia -Those with warning signs.warning signs - High-risk patients with leucopenia and thrombocytopeniaHigh-risk patients 199720092011 NoYes Home care card Admission criteria

26. Warning signs 2009 & 2011 20092011 Abdominal pain+ severe+ or tenderness Persistent vomiting,++, lack of water intake Clinical fluid accumulaton+- BleedingMucosal bleed Epistaxis, black stool, haematemesis, excessive menstrual bleeding, dark-coloured urine (haemoglobinuria) or haematuria. Lethargy and/or restlessness++, sudden behavioural changes Liver enlargement > 2 cm+- Increase in Hct concurrent with rapid decrease in platelet count +- No clinical improvement or worsening of the situation -+ Giddiness-+ Pale,cold, a clammy hands and feet-+ Less/no urine output for 4–6 hours-+.

27. Fluid management 199720092011 DHF grade I-IIDengue with warning signs DHF grade I-II 6-7 ml/kg/hour  5 ml/kg/hour  3 ml/kg/hour – stop after 24-48 hours isotonic solutions such as 0.9% saline, Ringer’s lactate, or Hartmann’s solution. Start with 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 maintenance (for one day) + 5% deficit (oral and IV fluid together), to be administered over 48 hours

28. Cont… 199720092011 DSSSevere Dengue- compensated shock DHF grade III 10-20 ml/kgBB bolus, repeat if necessary algorithm isotoniccrystalloid solutionsat 5–10 ml/kg/hour over one hour. →reassess 10 ml/kg in children or 300–500 ml in adults over one hour or by bolus, if necessary Further, fluid administration should follow the graphgraph

29. Cont… 20092011 Severe Dengue – hypotensive shockDHF grade IV Start with crystalloid or colloid solution (if available) at 20 ml/kg as a bolus given over 15 minutes to bring the patient out of shock as quickly as possible. 10 ml/kg of bolus fluid (10-15 min) When the blood pressure is restored, further intravenous fluid may be given as in Grade 3. If shock is not reversible after the first 10 ml/kg, a repeat bolus of 10 ml/kg and laboratory results should be pursued and corrected as soon as possible.

30. Transfusion in Severe Bleeding 20092011 Give 5–10ml/kg of fresh-PRC or 10– 20ml/kg of FWB at an appropriate rate and observe the clinical response. 10 ml/kg of FWB or 5 ml/kg of freshly PRC Reassess, repeat if necessary

31. Discharge criteria Criteria199720092011 Absence of fever24 hours without the use of anti- fever therapy 48 hours24 hours without the use of anti- fever therapy Clinical improvement ++ (general well-being, appetite, hemodynamic status, urine output, no respiratory distress) + Return of appetite+-+ Good urine output+-+ Stable hematocrit++ (without intravenous fluids)+ Elapse from shock recovery At least 2 days-At least 2-3 days No respiratory distress +-+ Platelet count > 50,000/  L Increasing trend > 50,000/  L

32. National guideline Ditjen PPM –PLP 2004Ditjen Yanmed, IDAI, PAPDI, IDSAI, PERDICI, PDS PATKLIN, PPNI - 2005

33. Summary Dengue disease burden is significantly increased across continents Case management is relatively simple and inexpensive  could saves the lives of patients Revised guidelines ( 2009 and 2011) are available Proposed National guideline ? Changes might be slowly, difficult but inevitable

35. Signs of Significant Dehydration - Tachychardia - Increased capillary refill time (>2 second) - Cool, mottled or pale skin - Diminished peripheral pulses - Changes in mental status - Oliguria - Sudden rise in haematocrit or continously elevated haematocrit despite administration of fluids - Narrowing of pulse pressure (< 20 mmHg) - Hypotension (a late finding representing uncorrected shock) back

36. Warning signs (2011) No clinical improvement or worsening of the situation just before or during the Transition to afebrile phase or as the disease progresses. Persistent vomiting, not drinking. Severe abdominal pain. Lethargy and/or restlessness, sudden behavioural changes. Bleeding: Epistaxis, black stool, haematemesis, excessive menstrual bleeding, darkcoloured urine (haemoglobinuria) or haematuria. Giddiness. Pale, cold and clammy hands and feet. Less/no urine output for 4–6 hours. back

37. Admission criteria 2009 – p 47 back Warning signsAny of the warning signs (Textbox C) Signs & symptoms related to hypotension (possible plasma leakage) Dehydrated patient, unable to tolerate oral fluids Giddiness or postural hypotension Profuse perspiration, fainting, prostration during deferescence Hypotension or cold extremities BleedingSpontaneous bleeding, independent of the platelet count Organ impairmentRenal, hepatic neurological or cardiac -enlarged, tender lier, although not yet in shock -Chest pain or respiratory distress, cyanosis Findings through further investigation Rising hematocrit Pleural effusion, ascites or asymptomatic gall bladder thickening Co-existing conditionsPregnancy Co-morbid conditions, such as diabetes mellitus, hypertension peptic ulcer, hamolitic anemias and others Overweight or obese (rapid venous access difficult in emergency) Infancy or old age Social circumstancesLiving alone, living far from healt facility, without reliable means of transport

38. High-risk patients (2011) infants and the elderly, obesity, pregnant women, peptic ulcer disease, women who have menstruation or abnormal vaginal bleeding, haemolytic diseases such as glucose-6-phosphatase dehydrogenase (G- 6PD) deficiency, thalassemia and other haemoglobinopathies, congenital heart disease, chronic diseases such as diabetes mellitus, hypertension, asthma, ischaemic heart disease, chronic renal failure, liver cirrhosis, patients on steroid or NSAID treatment, and others back

39. Rate of Infusion in DSS (2011) back

40. 1997 back