1. Severe Dengue: risk factors and management 高雄長庚感染科 李允吉醫師

2. Outline Dengue case management Clinical manifestations and risk factors for severe dengue Severe dengue in adults (KSCGMH preliminary data)

3. Dengue case management

5. Patient assessment Warning signs 1.Abdominal pain or tenderness 2.Persistent vomiting 3.Clinical fluid accumulation 4.Mucosal bleed 5.Lethargy, restlessness 6.Liver enlargement >2 cm 7.Laboratory: increase in HCT concurrent with rapid decrease in platelet count No warning signs Warning signs and/or co-existing conditions 1.Pregnancy 2.Infancy 3.Diabetes mellitus 4.Old age 5.Renal failure 1. Severe plasma leakage leading to shock or fluid accumulation with respiratory distress 2. Severe bleeding as evaluated by clinician 3. Severe organ involvement Outpatient management Inpatient management Emergency management

6. Initial patient assessment In which phase of disease is the patient? Day onset of illness How much oral fluid intake ? How much urine output ? Fluid losses: diarrhea, vomiting Presence of warning signs Risk factors: infancy, pregnancy, diabetes mellitus, old age, renal failure What was the patient’s pulse volume?

7. Patient assessment Hemodynamic assessment is the foundation of dengue clinical management Parameters Conscious level Organ perfusion (brain) Capillary refill time Peripheral perfusion Extremities (color, temp) Peripheral pulse volume Heart rate Cardiac output Pulse pressure Blood pressure Respiratory rate Respiratory compensation (tissue hypoxia) Urine output Organ perfusion (kidney) CCTV-R 1.Skin color 2.Capillary refill 3.Temperature 4.Pulse volume 5.Pulse rate

8. Principle of case management DON’T use corticosteroids. They are not indicated and can increase the risk of GI bleeding, hyperglycemia, and immunosuppression. DON’T give platelet transfusions for a low platelet count. Platelet transfusions do not decrease the risk of severe bleeding and may instead lead to fluid overload and prolonged hospitalization. DON’T give half normal (0.45%) saline. Half normal saline should not be given, even as a maintenance fluid, because it leaks into third spaces and may lead to worsening of ascites and pleural effusions. DON’T assume that IV fluids are necessary. First check if the patient can take fluids orally. Use only the minimum amount of IV fluid to keep the patient well-perfused. Decrease IV fluid rate as hemodynamic status improves or urine output increases. DON’T give ibuprofen, aspirin, or aspirin-containing drugs, and intramuscular injection.

9. Dengue fever without warning signs (Outpatient Management) Prevent dehydration ( 病人及家屬衛教 ): (1) Give plenty of fluids (not only water) (2) Watch for signs of dehydration ▶ Decrease in urination ▶ Few or no tears when child cries ▶ Dry mouth, tongue or lips ▶ Sunken eyes ▶ Listlessness, agitation, or confusion ▶ Fast heartbeat (>100/min) ▶ Cold or clammy fingers and toes ▶ Sunken fontanel in an infant Watch for warning signs

10. Dengue fever with warning signs (Adequate/inadequate oral fluid) Monitor fluid intake/output and encourage oral fluid intake Obtain baseline complete blood count Monitor vital signs every 4 hours Does patient have adequate oral fluid intake? Adequate oral fluid intake Observe for warning signs and early shock Inadequate oral fluid intake Inpatient Management

11. Dengue fever with warning signs (Inpatient Management) Inadequate oral fluid intake Check HCT Give isotonic crystalloids in stepwise manner: 1.5-7ml/kg/h for 1-2 h 2.3-5ml/kg/h for 2-4 h Stable and no change or minimal change in HCT Worsening vital signs and increasing HCT Continue isotonic crystalloids: 2-3ml/kg/h for 2-4 h Adequate fluid and urine output (0.5 ml/kg/h); HCT decreases to baseline. Stop IVF therapy within 24–48 h Isotonic crystalloids: 5-10ml/kg/h for 1-2 h Recheck HCT Reassess vital signs Patient improving: Reduce fluid (stepwise); reassess before each change 1.5-10 ml/kg/h for 1-2 h 2.3-5 ml/kg/h for 2-4 h 3.2-3 ml/kg/h for 2-4 h Stop IV fluids at 48 h Normal saline, Ringer’s lactate Not improved: Emergency management

12. ParametersCompensated shockHypotension shock Conscious levelClear and lucidRestless Capillary refill time> 2 secVery prolonged, mottled skin Extremities (color, temp)CoolCold, clammy Peripheral pulse volumeWeakFeeble, absent Heart rateTachycardiaSevere tachycardia or bradycardia in late shock Blood pressureNormal systolic pressure, rising diastolic pressure Hypotension; unrecordable BP Pulse pressureNarrowing, postural hypotension ≤ 20mmHg Respiratory rateTachypneaKussmaul breathing Urine outputReducedOliguria/anuria How long does plasma leakage last? 24 – 48 hours

13. Compensated shock Systolic pressure maintained but has signs of reduced perfusion Isotonic crystalloid § 5–10 ml/kg/h over 1 h Hemodynamic status improved Hemodynamic status not improved (HCT) Reduce fluid (stepwise): 1. 5–7 ml/kg/h for 1–2 h 2. 3–5 ml/kg/h for 2–4 h 3. 2–3 ml/kg/h for 2–4 h Recheck HCT; reassess clinical status If: adequate fluid intake and urine output; HCT at baseline or slightly below baseline, Then: DC intravenous fluids (stop at 48 hours) Increasing HCT Given isotonic crystalloid 10- 20ml/kg bolus 1h Improving: Reduce fluid to 7- 10ml/kg/h for 1-2 h Then reduce further Obtain HCT and organ function tests §Normal saline, Ringer’s lactate Decreasing HCT Initiate transfusion

14. Hypotensive shock Obtain HCT and organ function tests Give 20 ml/kg isotonic crystalloid or colloid § over 15 minutes Hemodynamic status improved Hemodynamic status not improved Isotonic crystalloid or colloid infusion at 10 ml/kg/h over 1 h Reassess clinical status and HCT; if improving, reduce fluid in stepwise manner (IV crystalloid) 1. 5–7 ml/kg/h for 1– 2 h 2. 3–5 ml/kg/h for 2–4 h 3. 2–3 ml/kg/h for 2–4 h If patient continues to improve, stop at 48 h Increasing HCT Give colloid 10–20 ml/kg over ½ to 1 hour Improving: Crystalloid/colloid 10 ml/kg/h for 1 hour, then reduce fluid Decreasing HCT Initiate transfusion Not improving; Repeat 2nd HCT Normal saline, Ringer’s lactate §Gelatin-based, dextran- based and starch-based solutions

15. Hematocrit levels IncreaseDecreaseNO change (or minimal change) Disease associated Plasma leakage1. Bleeding 2. Reabsorption Plasma leak + bleeding Treatment related Blood transfusion 1. Intravenous fluid therapy Disease + treatment Plasma leak + IV fluids or Bleeding + blood transfusion Phase of disease, day 3 vs. day 7 Hemodynamic state should be the principal driver of IV fluid therapy HCT level should only be guide

16. Rising or high HCT + Unstable hemodynamic state Active plasma leakage, fluid replacement Decrease HCT + Unstable hemodynamic state Bleeding, need for urgent transfusion Rising or high HCT + Stable hemodynamic state Does not require extra intravenous fluid, continue to monitor (encourage oral hydration) Decrease HCT + Stable hemodynamic state (+ phase of disease) Hemodilution or reabsorption, reduced or DC intravenous fluid

17. When to start and stop intravenous fluid therapy Febrile phase: oral fluid advice Critical phase: IV fluids are usually required for 24–48 hours Recovery phase: IV fluids should be stopped so that extravasated fluids can be reabsorbed

18. 4 Intravenous Fluid Regimens for DSS in the First Hour Dextran 70 (n = 55) Gelatin (n = 56) Lactated Ringer’s (n = 55) Normal saline (n = 56) P “Re-shock” rate, no. (%) of patients 16 (29.1)15 (26.8)16 (29.1)16 (28.6).992 Decrease in hematocrit at 1 h, % (mean) 11.5 (3.3)9.7 (3.0)5.7 (2.8)6.5 (2.9)<.001 Decrease in pulse at 1 h, beats/min (mean) 14.9 (9.9)18.5 (11.3)13.2 (9.2)13.5 (8.9).023 Total volume of iv fluid infused, mL/kg (mean) 134.3 (22.1)135 (23.5)134.2 (19.9)132.9 (16.6)954 Required frusemide, no. (%) of patients 5 (9.1)10 (17.9)8 (14.5)12 (21.4).328 Clin Infect Dis 2001; 32:204–13

19. Three Fluid Solutions for Resuscitation in DSS Kaplan–Meier Curves for Time from Study Entry to Initial (Panel A) and Sustained (Panel B) Cardiovascular Stability among Children in Group 1, According to the Resuscitation Fluid Received. N Engl J Med 2005; 353;9

20. Prophylaxis platelet transfusion in dengue Fever Dengue patients with platelet count < 20 X 10 3 /uL Clin Infect Dis 2009; 48:1262–5 Patients given platelet transfusion (n = 188) Patients not given platelet transfusion (n = 68) P Age, years40 (22–64)39 (22–58).54 Any bleeding1 (1)2 (3).17 Platelet increment the next day, x 10 3 platelets/mL 7 (-7 to 50)11 (-4 to 41).26 Time to platelet count ≥50 x 10 3 platelets/mL, days 3 (1–4)3 (1–5).59 Length of hospital stay, days 6 (4–8)5 (4–7).09 Death1 (1)0 (0)1.00

21. Preventive transfusion in dengue shock syndrome Significant differences in the development of pulmonary edema and length of hospitalization (P<.05) (in preventive transfusions group) were observed Preventive transfusions did not produce sustained improvements in the coagulation status in DSS J Pediatr. 2003 Nov; 143(5):682-4.

22. Platelet Transfusion in Dengue Fever Acute lung injury after platelet transfusion in a patient with dengue fever Asian J Transfus Sci. 2014 Jul-Dec; 8(2): 131–134

23. Platelet Transfusion in Dengue Fever Prophylactic platelet transfusions are not required in stable patients with platelet count below 20,000/μl. J Indian Med Assoc. 2011 Jan; 109(1):30-5. Blood componentIndication Platelet1. In general there is no need to give prophylactic platelets even at 20,000/μl. 2. Prophylactic platelet transfusion may be given at level of <10,000/μl in absence of bleeding manifestations. 3. Prolonged shock; with coagulopathy. 4. In case of massive bleeding, platelet transfusion may be needed in addition to red cell transfusion.

24. Oral Corticosteroid Therapy in Dengue Infection Randomized, Double-Blind Placebo Controlled Trial Clin Infect Dis 2012;55(9):1216–24

25. Balapiravir therapy in Dengue Infection Randomized, Double-Blind Placebo Controlled Trial J Infect Dis 2013;207:1442–50

26. Chloroquine therapy in Dengue Infection Double-blind, randomized, placebo-controlled trial PLoS Negl Trop Dis 2010; 4(8): e785

27. Clinical manifestations and risk factors for severe dengue

28. 台灣登革熱疫情 (1998-20150906) Source: Taiwan CDC

29. Rash

30. Cutaneous hemorrhage

31. Retinal hemorrhage

32. Gastrointestinal bleeding

33. Pleural effusion

34. Pulmonary congestion and acute respiratory distress syndrome

35. Gallbladder swelling

36. Ascites

37. Acute abdomen in dengue Am J Trop Med Hyg 2006; 74: 901 N= 3 N=1 The importance of differential diagnosis in patients with acute abdomen in a dengue- endemic setting.

38. Hyperlipasemia and acute pancreatitis in DHF Hyperlipasemia developed in 14 patients with DHF Pancreatitis was diagnosed in 3 patients Pancreas 2007; 35: 381

39. Spontaneous spleen rupture in DHF 29-year-old female patient Conservative management Am J Trop Med Hyg 2008; 78: 7

40. Myocarditis in dengue Int J Infect Dis. 2010 Oct;14(10):e919-22

41. Rhabdomyolysis in dengue Am J Trop Med Hyg. 2015 Jan;92(1):75-81

42. Hemophagocytic Lymphohistiocytosis MMWR / January 24, 2014 / Vol. 63 / No. 3

43. Acute transverse myelitis in dengue J Clin Virol 2006; 35; 312

44. Concurrent bacteremia in dengue Am J Trop Med Hyg 2005; 72: 221 N=3 Clinicians should be alert to the potential for concurrent bacteremia when treating patients with DHF/DSS

45. Case presentation 71-year-old woman Underlying: Senile dementia, hypertension, chronic anemia Fever and malaise for 5 days She was evaluated by her family physician and was prescribed some medication for a diagnosis of common cold Gum bleeding and gross hematuria were found one day before presentation at our emergency room

46. Case presentation On examination, the patient appeared clear consciousness. She was afebrile with a temperature of 37°C, pulse rate 95 beats/min, and blood pressure 126/66 mm Hg (day 7 onset of illness) Laboratory data showed leukopenia and thrombocytopenia She living in dengue endemic area; and dengue virus infection was confirmed by serology test

47. Case presentation Day 1 at ER (day 7 after illness onset) Day 2 at ER (day 8 after illness onset) Day 3 at ER (day 9 after illness onset) White blood cell (×10 9 cells/L)1.01.32.1 Hemoglobin g/dL12.612.39.8 Hematocrit (%)36.936.628.6 Platelet (×10 9 cells/L)384442 Creatinine mg/dL0.71 GOT U/L263 Platelet transfusion 12 units Admitted to ward at night time Intravenous fluid: N/S run 60cc/h (29%) No more gum bleeding and hematuria Haemodilution or reabsorption Dengue fever with warning signs

48. Case presentation Day 10 after illness onset Day 11 after illness onset Day 12 after illness onset White blood cell (×10 9 cells/L)3.14.0 Hemoglobin g/dL10.210.810.5 Hematocrit (%)30.331.129.8 Platelet (×10 9 cells/L)345370 - The patient became drowsy on the next day after admission (day 10 after illness onset). On examination she was unconsciousness with cold and clammy peripheries. Her blood pressure was 60/40 mmHg and with a heart rate of 95/minute. Immediately rapid saline intravenously infusion 1000cc (within 30 minute). Her blood pressure was 110/80 after fluid replacement. Additional fluid was given 500cc within 1 hour. - Maintenance intravenous fluid of 60cc/h and monitor hematocrit, platelet count and I/O. - Improvement of patient’s consciousness. Reduced intravenous fluid on day 2 after shock.

49. Case presentation Pleural effusion, ascites and gallbladder swelling

50. Case presentation Day from onset illness to shock: 10 th day Plasma leak: pleural effusion, ascites, hemoconcentration Critical phase: between 9th and 11th day after onset illness Warning signs: mucosal bleeding (gum bleeding, hematuria), increase hematocrit concurrent decrease platelet count, drowsy (onset to shock: hours) Day 7 after illness onset Day 17 after illness onset White blood cell (×10 9 cells/L)1.03.0 Hemoglobin g/dL12.69.0 Hematocrit (%)36.926.6 Platelet (×10 9 cells/L)38145 Day discharge from hospital Hemoconcentration (39%)

51. Dengue: dynamic disease Compensated shock in the early stage (normal or elevated blood pressure) Decompensated shock in the late stages (hypotension & unrecordable blood pressure) Fever ±Warning signs Compensated shock Hypotensive shock Cardiac arrest Hours Min Hours Self-limiting disease in most patients. NOT all patients will experience the critical phase. Severe disease in a small proportion of patients. Identification and treatment of early shock will improve clinical outcome. Host risk factors Stable

52. Risk for severe dengue 1. Strain virulence 2. Serotype Viral factors Epidemiological risk factors Individual risk factors 1.Number of susceptible 2.Vector high density 3.Wide viral circulation 4.Hyperendemicity 1.Age 2.Sex 3.Race 4.Nutritional status 5.Secondary infection 6.Host response Lancet Infectious Disease 2001: 2: 33 Antibody-Dependent Enhancement

53. Dengue Fever in the Elderly VariableAdults (<60y) n= 6694 Elderly (≥ 60y) n= 295 P DHF grade 1-21199 (17.9)80 (27.1)<0.001 DSS232 (3.5)6 (2)0.184 Severe dengue975 (14.6)60 (20.3)0.006 Severe bleeding401 (41.1)13 (21.7)0.003 Severe plasma leakage and organ involvement 30 (3.1)10 (16.7)<0.001 Severe bleeding, severe plasma leakage and organ involvement 13 (1.3)4 (6.7)0.014 Pneumonia36 (0.7)10 (3.8)<0.001 UTI17 (0.3)5 (1.9)0.003 PLoS Negl Trop Dis 2014: 8(4): e2777

54. DHF in the Elderly (KSCGMH) VariableElderly (≥ 65 years) (N=66) Non-elderly (19–64 years) (N=241) P Fever, n (%)60 (90.9)239 (99.2)0.002 Bone pain, n (%)24 (36.4)147 (61)< 0.001 Acute renal failure, n (%)8 (12.1)4 (1.7)0.001 Concurrent bacteremia, n/N (%) 4/23 (17.4)2/59 (3.4)0.049 Pleural effusion (bilateral or unilateral), n/N (%) 26/46 (56.5)60/173 (34.7)0.010 Gastrointestinal bleeding, n (%) 21 (32)47 (19.5)0.044 Length of hospital stay (day; mean ± SD) 7.9 ± 4.96.3 ± 2.90.049 Fatality (%)5 (7.6)2 (0.8)0.006 Am J Trop Med Hyg 2008;79:149 Atypical and more complicated clinical presentation in elderly patients with dengue

55. Fatality among adults dengue (Singapore) (n=28): comorbid condition 1. Diabetes mellitus 2. Hypertension 3. Renal disorder 4. Cardiac disorder PLoS ONE 2013; 8(11): e81060. (%) 2004-2008; age range 21-86 years

56. In vitro Diabetes’ Mononuclear Cells Infected with Dengue Virus Biomed Res Int. 2013;2013:965853 Third post-infection day in an in vitro infection model. Our result suggest that patients with T2DM are at higher risk for development of DHF/severe dengue

57. Diabetes: Risk Factor for Severe dengue PLoS Negl Trop Dis 2015; 9(4): e0003741

58. Warning signs before severe dengue (n=65) in adult dengue 1. Abdominal pain (26%) 2. Persistent vomiting (8%) 3. Hepatomegaly (0) 4. Hematocrit rise and rapid platelet count drop (3%) 5. Clinical fluid accumulation (2%) 6. Mucosal bleeding (10%) 7. Lethargy (26%) (%) PLoS Negl Trop Dis 2013; 7(1): e2023. Before severe dengue (n=65)

59. Warning signs for severe dengue (n=248) in adults (entire course) Warning signSD (n = 248) Entire clinical course Abdominal pain or tenderness109 (44) ←26% Persistent vomiting41 (16.5) ← 8% Hepatomegaly7 (2.8) ← 0 Hematocrit rise and rapid platelet count drop107 (43.1) ← 3% Clinical fluid accumulation55 (22.2) ← 2% Mucosal bleeding124 (50) ← 10% Lethargy78 (31.5) ← 26% PLoS Negl Trop Dis 2013; 7(1): e2023.

60. C-Reactive Protein Levels for Early Prediction Median CRP (range)/no, mg/L Phase of illnessNon-severe dengueSevere dengueP Febrile phase (days 1–3)14.4 (0.6–69)/8736.2 (3.3–205.5)/100.025 Critical phase (days 4–6)8 (0.5–215.5)/8129.2 (6.9–144)/40.053 Convalescent phase (days 7–10)3.3 (1.6–10.7)/81.2 (—)/1- BioMed Research International 2015; 2015: 936062 In the febrile phase of illness, a CRP cutoff level of 24.2 mg/L (0.717 AUC) was obtained with 70% sensitivity and 71.3% specificity for differentiating between non-severe dengue and severe dengue. Concurrent bacteremia was excluded

61. Fatal DHF in adults (Malaysia): cause of death Cause of deathNo. DHF1 DSS1 DSS with severe GI bleeding and acute renal failure1 DSS with severe GI bleeding and multi-organ failure3 DSS with severe GI bleeding1 DSS with myocarditis and cardiogenic shock1 DSS with pulmonary edema and sepsis1 PLoS Negl Trop Dis 2013; 7(5): e2194.

62. Fatal Dengue in Adults (KSCGMH) VariableFatal (n=10) Intractable massive GI bleeding with hypovolemic shock, no. (%) 4 (40%) DSS alone, no. (%)2 (20%) DSS with subarachnoid hemorrhage, no. (%)1 (10) Klebsiella pneumoniae bacteremia and meningitis, no. (%)1 (10) Sepsis due to mechanical ventilation associated pneumonia, no. (%) 1 (10) Enterococcus faecalis bacteremia and intractable massive GI bleeding with shock, no. (%) 1 (10) PLoS Negl Trop Dis. 2012;6(2):e1532 Median time lapses : between dengue onset and hospital presentation, 2 days (1-6); between hospital presentation to fatality, 4.5 days (2-18); between dengue onset to fatality, 7.5 days (4 -21)

63. Severe dengue in adults (KSCGMH preliminary data) Period: 2002 ~ 2014

64. Dengue cases (n=1063) Age group No. patient Incidence of severe dengue: Age, 18-59 yr (2%) vs. ≥ 60 yr (15%); P<0.001 Based on 2009 WHO dengue classification scheme.

65. 55 severe dengue (SD) cases (2009 WHO) VariableSevere dengue (n = 55) Median age (range), years66 (25-85) ≥ 60 years, no. (%)40 (73) Male, no. (%)32 (58.2) Comorbid condition, no. (%) Type 2 DM only1 (1.8) Hypertension only9 (16.4) Type 2 DM and hypertension10 (18.2) Type 2 DM, hypertension, and others6 (11) Hypertension and chronic kidney disease2 (3.6) Chronic kidney disease only1 (1.8) G6PD deficiency only1 (1.8) DENV serotype, no./No. (%) DENV 15/39 (12.8) DENV 232/39 (82.1) DENV 32/39 (5.1) DENV 40 1997 WHO dengue classification, no. (%) Dengue fever5 (9) Grades 1 and 2 DHF27 (49) DSS23 (41.8) 55% cases had at least one co-morbidity

66. 55 SD cases (2009 WHO) VariableSevere dengue Median time from illness onset to hospital presentation (range), days (n = 55) 3 (1-7) Median time from illness onset to severe dengue (range), days (n = 55) 5 (2-10) Median time from illness onset to shock (range), days (no.) (n = 23) 6 (2-10) Median time from hospital presentation to severe dengue (range), days (n = 55) 1 (1-5) Median time from hospital presentation to shock (range), days (no.) (n = 23) 1 (1-5)

67. Before severe dengue (≤ 3 days after onset illness) Warning signsSevere dengue* (n=28) Non-severe dengue (n=593) P Abdominal pain, no. (%)17 (45.9)120 (20.2)>0.99 Vomiting, no. (%)15 (40.5)173 (29.2)>0.99 Mucosal bleeding, no. (%) Gastrointestinal bleeding7 (18.9)2 (0.3)<0.001 Hemoptysis09 (1.5)>0.99 Gum bleeding1 (2.7)39 (6.6)0.502 Clinical fluid accumulation, no./No. (%) Pleural effusion9/34 (26.4)28/362 (7.7)>0.99 Ascites6/25 (24)19/233 (8.2)>0.99 Rise in hematocrit level >20% concurrent with drop in platelet count within 48 h after hospital presentation, no./No. (%) 4/30 (13.3)5/275 (1.8)>0.99 *Based on 2009 WHO dengue classification scheme

68. Before severe dengue (≤ 3 days after onset illness) Other symptoms/signs †, no. (%)Severe dengue* (n=28) Non-severe dengue† (n=593) P Fever34 (91.9)563 (78)>0.99 Orbital pain2 (5.4)68 (11.5)0.415 Bone pain14 (37.8)247 (41.7)0.732 Myalgia15 (40.5)228 (38.4)>0.99 Headache12 (32.4)257 (43.3)0.232 Diarrhea5 (13.5)88 (14.8)>0.99 Petechial4 (10.8)108 (18.2)0.374 Cough6 (16.2)151 (25.5)0.244 Rash2 (5.4)192 (32.3)<0.001 *Based on 2009 WHO dengue classification scheme †Data were obtained at the time of hospital presentation.

69. Before severe dengue (≤ 3 days after onset illness) Laboratory features † Severe dengue* (n=28) Non-severe dengue (n=593) P Leukocytosis (WBC >10 × 10 9 cells/L), no./No. (%) 9/37 (24.3)2/571 (0.4)<0.001 Increased hematocrit level >20% within 48 h after hospital presentation, no./No. (%) 5/30 (16.7)6/278 (2.2)>0.99 Median hematocrit % (range) (no.) Male37 (25-49)37.1 (28.5-50.4)0.442 Female34.6 (21.9-49.7)37.3 (21.4-51)0.151 Severity of thrombocytopenia, no./No. (%) Platelet count >150 × 10 9 cells/L6/37 (16.2)140/575 (24.3)Ref Platelet count 100–149 × 10 9 cells/L3/37 (8.1)192/575 (33.4)0.159 Platelet count 50–99 × 10 9 cells/L9/37 (24.3)138/575 (24)0.437 Platelet count <50 × 10 9 cells/L19/37 (51.4)105/575 (18.3)0.003 ALT ≥ 10× the upper limit of the normal range (normal value < 40 U/L), no./No. (%) 5/24 (20.8)6/352 (1.7)>0.99 AST ≥ 10× the upper limit of the normal range (normal value < 40 U/L), no./No. (%) 7/28 (25)8/395 (2)>0.99 *Based on 2009 WHO dengue classification scheme †Data were obtained at the time of hospital presentation.

70. Multivariable analysis Odds ratio95% CIP Age ≥ 60 years7.5023.084-18.251<0.001 Gastrointestinal bleeding, no. (%)113.733 13.910 ‒ 929.944 <0.001 Leukocytosis (WBC >10 × 10 9 cells/L), no. (%) 247.668 28.209 ‒ 2174.439 <0.001 Platelet count ≥100 × 10 9 cells/L0.037 0.002 ‒ 0.680 0.026

71. Parameters Phase of illness: day 4-7 Host factor 1. Age: Infant ( 60 y/o) 2. Pregnant 3. Diabetes mellitus 4. Chronic kidney disease Warning signs 1. Abdominal pain 2. Persistent vomiting 3. Fluid accumulation 4. Mucosal bleeding (gastrointestinal bleeding) Evaluation of hemodynamic status: BP CCTV-R Laboratory data 1. Increase hematocrit concurrent drop platelet count 2. WBC (leukocytosis) and CRP (> 25 mg/L)

72. Comment

73. Onset of warning signs to severe dengue in adult dengue Warning signsDays to severe dengue Abdominal pain or tenderness2 (8–2) Persistent vomiting2 (1–5.7) Hepatomegaly1.5 (1–2) Hematocrit rise and rapid platelet count drop3 (1–7.6) Clinical fluid accumulation3 (1–8) Mucosal bleeding2 (1–8.5) Lethargy3 (1–8) Warning signs occurred at median of two days before severe dengue PLoS Negl Trop Dis 2013; 7(1): e2023.