Best Practice in Dengue infections Professor Siripen Kalayanarooj Consultant, WHO Collaborating Centre for Case Management of Dengue/ DHF/ DSS (Director 1997-2015), Queen Sirikit National Institute of Child Health, Bangkok, Thailand

จำนวนผู้ป่วยไข้เลือดออกในประเทศไทย พ.ศ. 2501 - 2560 174,286 115,768 144,952 101,689 53,189 68,386 2,158 38,768 สำนักระบาดวิทยา กรมควบคุมโรค กระทรวงสาธารณสุข

อัตราป่วยตายของผู้ป่วยไข้เลือดออกในประเทศไทย พ.ศ. 2501 -2560 13.9 3.16 1.95 0.34 0.58 0.10 สำนักระบาดวิทยา กรมควบคุมโรค กระทรวงสาธารณสุข

Reported cases of dengue 2014-2017 2013 2014 2015 2016 2017 Morbidity 150,174 40,278 142,925 63,310 53,189 Dead 131 41 148 61 63 CFR 0.09 0.10 0.1

ใครบ้างที่มีโอกาสเป็นไข้เลือดออก 2501 -2530: เป็นโรคของเด็กๆ (อายุ < 15 ปี) 2530 – 2540: ผู้ใหญ่เริ่มมีรายงาน 10-15% 2552: จากรายงานของสำนักระบาดวิทยา – ผู้ใหญ่เป็นเท่ากับเด็ก 2553 – 2557: ผู้ใหญ่ป่วย 54% 2558: ผู้ใหญ่ป่วย 64.4% ตาย 66.2% 2559: ผู้ใหญ่ป่วย 62.1% ตาย 49.2%

เปรียบเทียบจำนวนผู้ป่วยไข้เลือดออกเด็กและผู้ใหญ่ พ.ศ. 2539 -2559 สำนักระบาดวิทยา กรมควบคุมโรค กระทรวงสาธารณสุข

Peak incidence of dengue infections: 2017 Age range (year) % 15-24 26.65 10-14 20.11 25-34 14.59 Top 5 provinces: Songkla – 175.26/แสน Pattalung – 152.62/แสน Pattani – 110.56/แสน Phuket – 100.04/ แสน Narathiwas – ตถใตจ/แสน Top Region: S – 88.31/แสน N – 27.68/แสน C – 23.45/แสน NE – 18.19/แสน

Situation in Thailand 2016-2017 60% in adults 40% in children CFR 0.10% Children 30% Adults 70% Oldest age 92 years! Youngest – before birth!!! (Vertical transmission)

Dengue Serotypes Queen Sirikit National Institute of Child Health 1973-2015 (April 15) AFRIMS

Dengvaxia SanofiPasteur Age >9 – 45 Years, dosage 0,6, 12 months Efficacy – 65% Against Den 1 – 50% Against Den 2 – 40% Against Den 3 – 70% Against Den 4 – 70% Reduce hospitalization 80% Reduce severity 90% Not use in sero-negative individual Repeated infections – more severe ADE – Antibody Dependent Enhancement

Dengue virus infection 10,000 Asymptomatic Symptomatic Viral syndrome Dengue fever DHF 1,000 9,000 100 500 400 Plasma leakage Expanded dengue syndrome Prolonged shock: liver failure, renal failure,…Encephalopathy… Co-morbidities 3. Co-infections 4. True dengue infection - encephalitis DHF DSS 1-5

Management targets on DHF/DSS with plasma leakage Among 1,000 dengue patients, probably 100 DHF with plasma leakage and 10-50 DSS (depends on early detection of plasma leakage) Majority of dengue patients are not severe No predictors of severe diseases at present

Dengue Fever (Infection) Headache Retro-orbital pain Myalgia Arthralgia/ bone pain (break-bone fever) Rash Hemorrhagic Manifestations Leukopenia (WBC < 5,000 cells/ mm3) Platelet count ≤ 150,000 cells/mm3 Rising HCT 5-10% Diagnosis : Tourniquet test positive + WBC  5,000 cells/cu.mm (positive predictive value = 83%)

Dengue Hemorrhagic Fever Clinical High, continuous fever 2-7 days Hemorrhagic manifestations: tourniquet test positive, petechiae, epistaxis, hematemesis, etc… (Liver enlargement) (Shock) Laboratory Evidence of plasma leakage; rising Hct ≥ 20%, pleural effusion, ascites, hypoalbuminemia (serum albumin < 3.5 gm% or <4 gm% in obese patients), UTZ Platelet count ≤ 100,000 cells/ mm3. Note: Patients who have definite evidence of plasma leakage, hemorrhagic manifestations and thrombocytopenia might not be present as the exception.

Severity of DHF Grade I – No shock Grade II – No shock, spontaneous bleeding Grade III – Shock Grade IV – Profound shock (immeasurable BP/ Pulse)

Pathophysiologic Hallmark of DHF Plasma leakage – major problems Abnormal hemostasis - usually minor bleeding in early febrile phase except in those with underlying peptic ulcer or those who took NSAID, Aspirin, Steroid

Tourniquet test + Natural course of DHF Fluid overload Day 1 2 3 4 5 6 7 8 9 Shock Fever Pleural effusion, Ascites Hematocrit Plasma leakage Stop leakage Reabsorption Fluid overload IV fluid: NSS, DAR, DLR Colloid: 10%Dextran-40 M+5% Deficit (= 4,600 ml in adult) WBC Tourniquet test + WBC 6,000-9,000 ≤5,000 Platelet count 200,000 ≤100,000 <50,000 Hct 35 38 45 (rising 20%) Albumin ≤3.5 gm% Cholesterol ≤100 mg% Professor Siripen Kalayanarooj

Prolonged shock > 10 hours untreated - Death!!! Liver failure- prognosis 50% Liver + Renal failure - prognosis10% 3 organs failure (+respiratory failure) – Prognosis is a miracle!!!

Compare using different classifications at QSNICH WHO 1997, 2011 WHO 2009 OPD (2009): 1,500 cases (TT positive + Leukopenia) IPD (3 months in 2009) 100 DHF/DSS cases for close monitoring Increase to 30,000 cases when applying only 2 warning signs (abdominal pain and vomiting) Increase to 300 SD for close monitoring

Lahore, Pakistan Experienced (Sep.-Nov. 11) Total suspected cases : 600,000 cases Confirmed 20,000 cases (< 4%) At the peak: 4,000-6,000 patients/day Admission 500-600 cases/day Death 10-15 cases per day

Multi-country study: 18 countries Validation study of the revised classification Revised not classified Dengue without Warning Signs Dengue With Warning Signs Severe dengue Total Not classify 23 57 159 29 268 DF 7 551 684 75 1,317 DHF 2 8 240 39 289 DSS 12 76 88 32 616 1,095 219 1,962 Barniol J et al: BMC Infectious Disease 2011,11: 106

Warning signs Non-specific, low specificity (20- 50%) Increase workload beyond management by existing healthcare personnel 20 times at OPD 3 times at IPD

High risk patients Infants, Elderly, Pregnancy Obese patients Prolonged shock Significant Bleeding Encephalopathy Underlying diseases

Important steps in Dengue Case management Early diagnosis of dengue infections Early detection of plasma leakage and proper IV fluid management Detect and correct common complications: ABCS, Fluid overload Management of bleeding Dx & Management of unusual cases: BBH

1. Early clinical Diagnosis Think of dengue in every patients who present with high fever (except in adults) High continuous fever Bleeding manifestations: petechiae, epistaxis, gum bleeding, hematemesi, melena, hematuria, hemoglobinuria, menstruation, abnormal vaginal bleeding… Ache and pain; headache, retro-orbital pain, myalgia, arthralgia/ bone pain Rash; Petechial, MP-rash

Case 1 : 21-year-old, 129 Kgs Fever for 5 days Headache Bodyache Poor appetite Nausea, no vomiting Loose stool 2 times/day since yesterday T 39 degree, BP 100/70 mmHg, P 94/min, RR 20/min Others – WNL, no skin rash

Case no. 1 : A 21-year-old man, 129 kgs

CBC Hb 15.1 gm%, Hct 45%, wbc 4,350, P 67, L 25, AL 8, platelet 35,000 cells/cumm.

LFT Albumin 3.6 gm% (normal > 4.0 gm%), Cholesterol 72 mg% (normal > 150mg%), AST 286, ALT 156 U

Follow up the next day (Day 6) Fever 38.1, BP 100/60, P 90, RR 20 Still nausea, no vomiting Poor appetite Hct q 6 hrs revealed: dropped from 45% to 43%, 42% and 41% this morning

Lessons Learnt Early diagnosis of dengue infections CBC: WBC, Platelet count, Hct - Not done even though they can refer patients to be done in the nearest hospital (recommend to do CBC starts from day 3 of illness – clinical or warning signs cannot help to detect plasma leakage) No NS1Ag available but most people prefer this even though it does not guide clinicians for IV fluid management

Dengue diagnostic options and sensitivity Fever phase (D1-5) NS1Ag – sensitivity 40-70% - specificity 99% Late phase (D>5) Dengue IgM – sensitivity 60% on shock day - specificity 99% Courtesy of Armed Forces Research Institute of Medical Sciences

2. Early detection of plasma leakage and proper IV fluid management Evidence of Plasma Leakage Rising Hct ≥ 20% Pleural effusion, ascites Physical examination CXR – Right lateral decubitus Ultrasound Hypoalbuminemia Albumin < 3.5 gm% in normal patients Albumin < 4 gm% in obese patients

Lessons Learnt Delay detection of plasma leakage - major cause of fluid overload and possible lead to dead Not isotonic Too early Too much Too long No Dextran available (other colloidal solutions are not effective including albumin) Too little - causes prolonged shock and organs failure

Indication for IV fluid in DHF patients Entering critical period – thrombocytopenia; platelet count ≤ 100,000 and throughout plasma leakage time, 1-2 days (and 12-24 hours beyond) Shock: difficult to detect because patients are in good consciousness, able to walk and talk Not before and after stop leakage, if IV fluid is extend beyond this leakage phase, patients are at risk of fluid overload which is one of the major causes of death

Principles of IV fluid in DHF patients during leakage period Isotonic salt solution: NSS, DAR, DLR with or without dextrose Check blood sugar if given IV without dextrose 30% of DSS patients have hypoglycemia Limited amount of fluid (oral + IV) during leakage period (M +5% deficit or 4.6 L in adults) – If give more IV fluid, more leakage that will interfere with respiration If more volume is needed, switch to Dextran-40 (hyper-oncotic), plasma expander

Principles of IV fluid in DHF patients during leakage period Adjust rate of IV fluid according to monitoring parameters: clinical, vital signs, Hct and amount of urine Discontinue IV fluid when reabsorption occurs (convalescence phase; stable Hct, diuresis, bradycardia, convalescence rash)

Dengue Shock Syndrome Plasma leakage Bleeding Narrowing of Pulse Pressure ≤ 20 mmHg Hypotension Systolic < 80 in adult < 70 + (Age in year X 2) in children Orthostatic hypotension Fainting Adults have more significant bleeding Aware of significant bleeding in: - Patients with menstruation or abnormal vaginal bleeding - Hemoglobinuria - Severe abdominal pain (concealed GI bleeding)

Other causes of shock in Dengue patients Hypoglycemia Excessive vomiting Co-infections

Rate of IV fluid Shock Non-shock DSS – NSS (D) 10 ml/kg/hr or 500 ml/hr in adult, If profound shock – free flow 15-30 mins, then reduce rate Non-shock: rate depends on degree of thrombocytopenia & rising Hct

Lessons Learnt 3. Detect and correct common complications: A – Acidosis – Prolonged shock with possible liver/ renal failure B – Bleeding – No rising Hct or dropping Hct C – Hypocalcemia and other electrolyte imbalance (Hypokalemia, hyponatremia) S – Hypoglycemia (30% in DSS) Fluid overload – Signs & symptoms of fluid overload or persistent high Hct > 25%

Practical management when no lab. for correction of A, B, C & S Check Blood Sugar 10% Ca gluconate 10 ml dilute to 20 ml IV push in 10 min (1 ml/kg/dose, maximum dose 10 ml) Vitamin K1 IV 10 mg NaHCO3 1 ml/kg IV if cyanosis or persisted cold, clammy skin after IV fluid resuscitation

Indications for switching to colloidal solution Signs and symptoms of fluid overload Puffy eyelids, distended abdomen with ascites Dyspnea/ Tachypnea Positive lungs signs: crepitation, rhonchi, wheezing Continue rising Hct Persistent high Hct > 25-30% Too much crystalloid solutions before plasma leakage

Type of Colloidal solution used in DHF/DSS Plasma expander (high osmolarity, high oncotic pressure than plasma) 10% Dextran-40 in NSS Plasma substitute 6%Dextran-70 or 6%Dextran-40 Starch Gelatin

Dextran infusion (10% Dextran-40 in NSS) Dextran rate 10 ml/kg/hr or 500 ml in adults Dextran will bring down PCV by 10 points, but not below baseline PCV If Hct drops > 10 points or below baseline – Think of bleeding Maximum dose per day = 30 ml/kg/day (may be used up to 60 ml/kg/hr in 48 hrs) All through the course, may use up to 6 doses Aware of sticky urine

Management of fluid overload Insert urinary catheter Furosemide 1 mg/kg/dose IV (with or without dextran) Record vital signs q 15 min X 4 times After 1 hr, change IV to crystalline solution at the rate appropriate for the timing 1 ml/kg/hr if overt signs of fluid overload and adjust the rate of IV according to urine output (0.5 ml/kg/hr) KVO if pass the critical period

Dextran + furosemide (in the middle or after 10-15 mins) Shock During critical period, Not in reabsorption phase Furosemide depletes intravascular volume, (not deplete ascites or pleural effusion) Dextran holds intravascular volume or draws back ascites and pleural effusion

4. INDICATION FOR BLOOD TRANSFUSION Significant blood loss: > 10% of total blood volume (> 6-8 ml/kg) HCT dropping but no clinical improvement in spite of adequate volume replacement (Usually blood transfusion when HCT 40-45%) No rising HCT enough to explain shock (Usually rising HCT about 20-30% from baseline for shock)

AMOUNT OF BLOOD REPLACEMENT Transfuse equal to the amount of estimated loss (if can estimate the amount of blood loss) Transfuse 10 ml/kg or 1 unit of whole blood if cannot estimate the blood loss or 5 ml/kg of packed red cell (PRC) if the patients have signs of fluid overload Do the HCT before and after transfusion to access the rising HCT (about 5 points in children for the above recommended dose) * Rate of transfusion depend on the patients’ conditions – usually as rapid as possible in 1-2 hours

ROLE OF PLASMA IN DHF/DSS Almost no role !!! The osmolarity of plasma is equal to the patients’plasma so it will not hold the plasma volume and it will leak into the pleural and peritoneal spaces To correct the abnormal coagulogram, the dose is 40-50 ml/kg (equal to the patients’ plasma volume). There is no available space for that large volume

INDICATION FOR PLATELET TRANSFUSION Significant blood loss. Indicate for all cases that need blood transfusion. Platelet transfusion is only the adjunct therapy. If no platelet concentrate available, the patients will recover anyway. Even with indication for platelet transfusion, if those patients have signs of fluid overload, platelet transfusion is contra-indicated! For it may cause life-threatening heart failure or acute pulmonary edema.

PLATELET PROPHYLAXIS No prophylaxis platelet transfusion in children even for those patients who have very low platelet count (< 10,000 cell/mm3) In adult patients who had underlying hypertension or heart diseases and platelet count < 10,000 cells/mm3, prophylaxis platelet transfusion is recommended.

Early Late convalescence

Convalescence A – appetite B – bradycardia C – Convalescence rash, itching D – Diuresis: aware of Hypokalemia

Lessons Learnt Management of bleeding Delayed blood transfusion because of concealed bleeding, normal Hct, no shock, good clinical Delayed transfer patients to the nearest hospitals that have blood bank until they have shock with massive bleeding and Hct markedly drops

5. Management of Unusual/ Complicated cases Cases present with shock and high fever ± Platelet < 100,000 cell/cumm. especially < 50,000 cells/cumm. Bleeding Look for evidence of plasma leakage: rising Hct, albumin < 3.5 gm% or < 4 gm% in obese patients, ascites, pleural effusion by CXR, UTZ

If evidence of plasma leakage Look for complications: DSS with superimposed bacterial infections DSS with concealed bleeding DSS with hepatitis (liver injury, liver failure)

Shock with fever DSS VS Septic shock Platelet usually ≤ 50,000 cells/cumm ESR ≤ 20 (usually < 5 mm/hr) Evidence of plasma leakage (pleural effusion, ascites) by UTZ, low serum albumin LFT: Albumin < 3,5 gm% in normal person (< 4 in obese person) Elevation of AST/ALT Platelet is not ≤ 50,000 cells/cumm at first presentation ESR - > 30 mm/hr No evidence of plasma leakage LFR Normal albumin > 3,5 gm% Mild or no elevation at presentation

Lessons Learnt 5. Management of unusual cases No experience and often misdiagnosis with septic shock or other diseases Patients came late with prolonged shock and organs failure Patients came with co-morbidity/ co-infections

DSS vs Hypovolemic shock (Diarrhea) Mild to moderate dehydration Rising Hct ≥ 20% May have history of few loose stool Severe dehydration Rising Hct not > 10% History of massive watery diarrhea

Usually misdiagnosed as Septic Shock Not typical as DSS No leukopenia – Leukocytosis and increase PMN No rising Hct – (Concealed) bleeding CXR - Portable and very difficult to detect pleural effusion Clinical: Pleural effusion & ascites - Too late when detect Usually misdiagnosed as Septic Shock Especially in adults

Lessons Learnt Causes of death: Thailand experience Fluid overload – 75% Delayed/ Miss diagnosis > 50% (including expanded dengue syndrome) Delayed blood transfusion – 40% Prolonged shock – 40% Organs failure (liver follows by kidney and respiratory failure) Expanded dengue syndrome – 20%

Thank you!