DENGUE EPIDEMIC: WHAT WE KNOW SO FAR TAN CHENG CHENG INTENSIVIST SULTANAH AMINAH JOHOR BAHRU

DENGUE EPIDEMIC: WHAT WE KNOW SO FAR TAN CHENG CHENG INTENSIVIST SULTANAH AMINAH JOHOR BAHRU

2 Dengue Virus Genome A single stranded RNA Genome is about 11000 ribonucleotides, encoding 3 structural proteins and 7 non-structural proteins Structural proteins: capsid protein (C), membrane protein (M) and envelope protein (E) The non structural proteins: NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5 The proteins are involved in the various stages of the dengue viral replication The envelope protein (E) is involved in the initial attachment of the virus particles on host cells

3 Dengue Virus 4 serotypes, namely DenV 1, DenV 2, DenV 3 and DenV 4 Further Classification into genotypes is dependent on the geographically region where the virus was isolated The number of genotypes for each serotype are as follows: DenV 1 (5), DenV 2 (6), DenV 3 (5) and DenV 4 (3) Malaysia hyperendemic as all serotypes could be isolated at any point of time

4 DENGUE SEROTYPES YEAR 2013, 2014 AND 2015 1992-1995: DENV3 1998-2000: DENV2 2001-2002: DENV3 2004-2006: DENV1 2008-2009: DENV3 70% 60% 2013 2014 2015 50% 40% 30% 20% 10% 0% DENV1 DENV2 DENV3 DENV4

5 NO PREDICTABLE CYCLE FOR DEN V INFECTION Four-year cycle outbreaks: 1974, 1978, 1982, 1986, 1990 No predictable cycle from 1991 Three-year cycle outbreak from 2008 Yearly cycle outbreak from 2012 Usually an outbreak whenever there was a change in the dengue virus serotype as fewer people would be immune to the serotype after the change Each individual can have 4 times of Den V infection in his/her lifetime

Serological Profile 6

7 ADE: ANTIBODY-DEPENDENT ENHANCEMENT OF DENV INFECTION ADAPTED FROM TAKADA AND KAWAOKA, 2003 Virus bound to Ab, is able to enter macrophages via the Fc receptor This makes the infection of macrophages more efficient and leads to the infection of a large number of macrophages, leading in turn to a more severe clinical presentation According to this hypothesis, DHF/DSS should occur only when there is more than one serotype of DV circulating in a specific area

microbewiki.kenyon.edu 8

DENGUE INCIDENCE RATE & CASE FATALITY RATE FOR YEAR 2000-2014, MALAYSIA 9

10 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 (till 18 July) 6543 14255 10146 7103 19429 16368 27381 19884 21900 Number of Cases 32767 31545 33895 39654 38556 48846 49335 41486 46171 43346 65396 108698 DENGUE CASES 1995 2015 (TILL 18 JULY), MALAYSIA 120000 100000 80000 60000 40000 20000 0 Year

11 DENGUE DEATHS 1997 2015 (TILL 18 JULY) MALAYSIA Jan-18 July 2015 65,396 cases with 174 deaths (compared 48,845 cases with 91 deaths in 2014) Increase of cases 34% and deaths 91% CFR 0.26% (target < 0.2%)

DISTRIBUTION OF DENGUE CASES BY URBAN AND RURAL AREA (1998 2014) 13

DENGUE MORTALITY ANALYSIS 2014 (N = 197 DEATHS) Male 31% : 50 years old 50% : 25 to 49 years 19% : < 25 years old

DENGUE MORTALITY ANALYSIS 2014 (N = 197 DEATHS) Duration between disease onset and patients sought 1 st treatment Patients did seek early treatment: 62% within 48h after onset

DENGUE MORTALITY ANALYSIS 2014 (N = 197 DEATHS) Duration in days between admission & onset of disease 90% of patients admitted early to hospital within 5 days of onset

DENGUE MORTALITY ANALYSIS 2014 (N = 197 DEATHS) Duration between admission and death

18 ORGAN INVOLVED IN DENGUE DEATH Organ involved % 2012 % 2013 % 2014 CNS: Impaired consciousness 21 33 25 Renal failure 3 33 6 Hepatitis 71 58 59 Multi-organ failure 71 76 59 Heart 29 31 41

Dengue Infection 2010 n = 1643 Dengue Infection 2011 n = 798 Dengue Infection 2012 n = 906 Dengue Infection 2013 n=1550 Dengue Infection 2014 n=3261 Age, years median (IQR) 28.8 (22.5 47.3) 29.5 (21.0 44.1) 32.8 (21.5-41.8) 31.3 (21.7-46.1) 34.6 (22.0-45.4) Interval from hospital to ICU admission, days median (IQR) Not available 0.5 (0.1 1.3) 0.5 (0.1-1.3) 0.5 (0.1-1.4) 0.4 (0.1-1.2) Length of ICU stay, days median (IQR) 1.9 (1.9 9.6) 2.0 (1.3 3.0) 1.9 (1.2-2.7) 1.9 (1.3-2.9) 2.8 (1.3-3.1) Length of hospital stay, days median (IQR) Length of mechanical ventilation, days median (IQR) Total SAPS II score, mean +/-SD Median (IQR) 5.5 (3.4 17.5) 3.8 (1.4 7.2) 5.8 (4.1 8.3) 3.6 (1.6-7.9) 5.2 (3.9-7.2) 4.2 (1.0-5.0) 5.3 (3.9-7.2) 2.9 (1.2-6.2) 7.1 (3.8-7.2) 5.0 (1.5-6.5) 19.0 + 14.1 19.6 + 16.0 17.4 + 13.0 18.6 + 13.2 18.6 + 15.0 15.0 (10.0-23.0) % Invasive mechanical ventilation 18.6 13.8 9.5 11.2% 12.1 % Co-morbid diseases 18.1 22.3 18.3 25 22.9 Main organ failure % Without organ failure 32.2 27.3 35.2 36.3 32.4 Respiratory failure 4.7 3.0 3.3 2.9 5.9 CVS failure 7.1 7.2 6.9 6.1 6.0 Neurological failure 0.6 0.4 0.1 0.7 0.4 Renal failure 0.9 0.7 0.8 1.1 1.2 Hepatic failure 0.4 0.1 0.1 0.3 0.4 Haematological failure SMR (95% CI) 0.75 (0.42-1.20) 54.0 40.9 53.4 52.5 53.6 0.50 (0.26-0.86) 0.51 (0.26-0.94) 0.50 (0.28-0.95) 0.57 (0.33-1.05)

Severe Dengue in Intensive Care: Evaluation of Mortality Risk Factors Foong KW 1, Teoh SC 2, Woon YL 3, Lee HS 3, Abdul Rahim AH 4, Ismail NI 5, Kumarasamy S 6, Mohd Noor MR 7, Wan Ismail WN 8, Kamalul Bahrin LK 9, Tong MG 10, Vellayuthapillai S 2, Supramaniam P 3, Tan CC 11 Objective: To determine the demography of severe dengue cases in Intensive Care Unit (ICU) and identify the predictors of mortality Methods: Retrospective study of all adult dengue patients admitted to the 49 MOH ICUs in year 2013 Patients were identified via MRIC Medical records were reviewed by two intensivists independently to identify SD patients and determine its onset of critical phase Demographic, clinical and intervention data were extracted For patients with missing medical record, we assumed those who died were SD, and relevant data were extracted for mortality patients who appeared in both MRIC and National Dengue Mortality Enquiry Report

1531 cases coded as dengue identified from Malaysian Registry of Intensive Care (MRIC) 1436 patients medical record traced and screened by 2 intensivists independently 95 patients medical record missing 84 patients survived and excluded from analysis 916 excluded from analysis: -21 paediatric -188 not dengue -707 not severe dengue 520 severe dengue patients identified 11 patients died (data from MRIC) 4 patients not found in National Dengue Mortality Enquiry Report and excluded 7 patients with partial data from MRIC and National Dengue Mortality Enquiry Report 527 severe dengue cases analyzed The flow of patient selection / recruitment

1531 cases coded as dengue identified from Malaysian Registry of Intensive Care (MRIC) 1436 patients medical record traced and screened by 2 intensivists independently 95 patients medical record missing 84 patients survived and excluded from analysis 916 excluded from analysis: -21 paediatric -188 not dengue -707 not severe dengue 520 severe dengue patients identified 11 patients died (data from MRIC) 4 patients not found in National Dengue Mortality Enquiry Report and excluded 7 patients with partial data from MRIC and National Dengue Mortality Enquiry Report 527 severe dengue cases analyzed The flow of patient selection / recruitment 34.4% of all dengue admitted to ICU

1531 cases coded as dengue identified from Malaysian Registry of Intensive Care (MRIC) 1436 patients medical record traced and screened by 2 intensivists independently 95 patients medical record missing 84 patients survived and excluded from analysis 916 excluded from analysis: -21 paediatric -188 not dengue -707 not severe dengue 520 severe dengue patients identified 11 patients died (data from MRIC) 4 patients not found in National Dengue Mortality Enquiry Report and excluded 7 patients with partial data from MRIC and National Dengue Mortality Enquiry Report 12.7% ie 67 deaths 527 severe dengue cases analyzed The flow of patient selection / recruitment 34.4% of all dengue admitted to ICU

Table 4: Laboratory results at onset of critical phase / organ dysfunction*

Table 5 : Independent risk factors for predicting mortality in severe dengue identified by multivariate logistic regression model Variables* Estimate Adjusted OR 95% CI SAPS 0.129 1.137 1.099 1.176 Tachycardia 1.111 3.038 1.202 7.680 Lethargy 0.988 2.687 1.008 7.165 Liver dysfunction 1.173 3.231 1.278 8.189 Plasma leakage 1.251 3.493 1.294 9.431 * The variables input in the models are diabetes mellitus, hypertension, breathlessness, dehydration, tachypnoe, oliguria, encephalitis, overbleeding, hematocrit on critical phase, platelet count on critical phase, SAPS II, tachycardia, lethargy, liver dysfunction and plasma leakage. The final model has a R-square of 0.658

Unusual Presentations of Severe Dengue Fever Encephalopathy Hepatic damage Cardiomyopathy Severe gastrointestinal hemorrhage

Unusual Presentations of Severe Dengue Fever Encephalopathy Hepatic damage Cardiomyopathy Severe gastrointestinal hemorrhage

Unusual Presentations of Severe Dengue Fever Encephalopathy Hepatic damage Cardiomyopathy Severe gastrointestinal hemorrhage

8 cases

Unusual Presentations of Severe Dengue Fever Encephalopathy Hepatic damage Cardiomyopathy Severe gastrointestinal hemorrhage

NATURE REVIEWS CARDIOLOGY REVIEW Cardiovascular manifestations of the emerging dengue pandemic Sophie Yacoub, Heiman Wertheim, Cameron P. Simmons, Gavin Screaton & Bridget Wills Nature Reviews Cardiology 11, 335 345 (2014) doi:10.1038/nrcardio.2014.40 Published online 08 April 2014 Evidence is increasing that dengue can also cause myocardial impairment, arrhythmias and, occasionally, fulminant myocarditis. Defining the role of cardiac dysfunction in the haemodynamic compromise of severe dengue has potentially important management implications.

Unusual Presentations of Severe Dengue Fever Encephalopathy Hepatic damage Cardiomyopathy Severe gastrointestinal hemorrhage

REVISED 2 ND EDITION OF 2010 CPG 2015 THE CHANGES Calculating weight Fluid management Electrolytes and acid-base balance ECG and ECHO monitoring Haemophagocytic syndrome

Non-obese and non-overweight patients Maintenance fluid can be calculated based on the following formula : - 1.2-1.5 ml/kg/hour Obese and overweight patients Maintenance fluid can be calculated based on adjusted body weight Adjusted bodyweight (ABW) can be calculated using this formula. o ABW = IBW + 0.4(actual weight - IBW)* o Ideal bodyweight (IBW) can be estimated based on the following 72, level III formula. Female: 45.5 kg + 0.91(height -152.4) cm Male: 50.0 kg + 0.91(height -152.4) cm *Adapted : GlobalRPH 2015, calculator adjusted body weight (available at http://www.globalrph.com/ibw_calc.htm)

REVISED 2 ND EDITION OF 2010 CPG 2015 THE CHANGES Calculating weight Fluid management Electrolytes and acid-base balance ECG and ECHO monitoring Haemophagocytic syndrome

ALGORITHM A FLUID MANAGEMENT IN COMPENSATED SHOCK COMPENSATED SHOCK (systolic pressure maintained but has signs of reduced perfusion) Fluid resuscitation with isotonic crystalloid 5 10ml/kg/h over 1h FBC, HCT, before and after fluid resuscitation, BUSEC, LFT, RBS, PT/APTT, Lactate/HCO 3, GXM YES IV crystalloid 5 7ml/kg/h x 1 2h, then: IMPROVEMENT* Check HCT NO reduce to 3 5 ml/kg/h for 2 4h reduce to 2 3 ml/kg/h for 2 4h If patient continues to improve, fluid can be further reduced. Monitor HCT 4 6 hourly If the patient is not stable, act according to HCT levels: If HCT, consider bolus fluid administration or fluid administration If HCT decreases, consider transfusion with fresh whole blood Consider to stop IV fluid at 48h of plasma leakage / defervescence. HCT or high Administer 2 nd bolus of fluid (colloid)** 10 20 ml/kg/h for 1h IMPROVEMENT* YES If patient improves, reduce to 7-10 ml/kg/h for 1 2h Then reduce further HCT Consider significant occult/over bleed Initiate transfusion with fresh blood 2 (whole blood/packed cell) NO * Reassess the patient s clinical condition, vital signs, pulse volume, capillary refill time, urine output and temperature of extremities. ** Colloid is preferable if the patient has already received previous boluses of crystalloid

ALGORITHM B FLUID MANAGEMENT IN DECOMPENSATED SHOCK Fluid resuscitation with 20 ml/kg/h colloid 15-30 minutes Try to obtain a HCT level before fluid resuscitation FBC, HCT, before and after fluid resuscitation, BUSEC, LFT, RBS, PT/APTT, Lactate/HCO 3, GXM YES IMPROVEMENT* NO Review 1 st HCT Crystalloid/colloid 10ml/kg/hx1h, then continue with: HCT or high HCT HCT Unchanged IV crystalloid 5 7 ml/kg/h for 1 2h reduce to 3-5 ml/kg/h for 2 4h reduce to 2 3 ml/kg/h for 2 4h If patient continues to improve, fluid can be further reduced. Monitor HCT q4h or more frequent as indicated If the patient is not stable, act according to HCT levels : If HCT, consider bolus fluid administration or fluid administration If HCT decreases, consider transfusion with fresh whole blood Consider to stop IV fluid at 48h of plasma leakage / defervescence Administer 2 nd bolus of fluid (colloid)** 10 20ml/kg ½ to 1h YES Repeat 3rd HCT IMPROVEMENT* NO YES Consider significant occult/overt bleed Initiate transfusion with fresh blood 2 (whole blood/packed cell) HCT or high NO Repeat 2 nd HCT HCT Administer 3 rd bolus of fluid (colloid) 10 20 ml/kg over 1h IMPROVEMENT* REFER ALGORITHM C * Reassess the patient s clinical condition, vital signs, pulse volume, capillary refill time, urine output and temperature of extremities. Colloid is preferable if the patient has already received previous boluses of crystalloid ** In absence of colloid, crystalloid can be used

ALGORITHM C FLUID MANAGEMENT IN DECOMPENSATED SHOCK (WITH PRESENCE OF BLEEDING & LEAKING AND OTHER CAUSES SHOCK) HAEMATOCRIT REMAIN UNCHANGED AFTER FIRST FLUID RESUSCITATION Consider other causes of shock Bleeding and leaking at same time Look for source of bleeding (eg.ogds) Evidence of leaking (USG) Correct coagulopathy Transfused blood and blood products Cardiac dysfunction Septic shock Vasodilated state Liver failure with severe metabolic acidosis from lactate accumulation Cytokine storm Low CO: Inotrope (eg. dobutamine) High CO: Vasodilated shock with myocardia; dysfunction Inotropes + vasopressor (eg. Noradrenaline + dobutamine) Noradrenaline titrated to MAP 65 mmhg Vasopressor + Supportive care + Continuous renal replacement therapy (CRRT) Noradrenaline and fluids All the above types of shocks need to be supported by echocardiography and non-invasive cardiac output monitoring and treatments tailor to each patient.

REVISED 2 ND EDITION OF 2010 CPG 2015 THE CHANGES Calculating weight Fluid management Electrolytes and acid-base balance ECG and ECHO monitoring Haemophagocytic syndrome

ELECTROLYTES AND ACID-BASE BALANCE Hyponatraemia common observation in severe dengue - a marker of disease severity - underlying mechanism not fully understood -? GI loss or? use of hypotonic solution Metabolic acidosis -? Leakage and shock - consider severe bleeding, liver failure, sepsis, or cardiac dysfunction

REVISED 2 ND EDITION OF 2010 CPG 2015 THE CHANGES Calculating weight Fluid management Electrolytes and acid-base balance ECG and ECHO monitoring Haemophagocytic syndrome

79 patients (adult and children) with dengue infection with 3 severity grades ECHO exam of intravascular volume + myocardial tissue Doppler Imaging preload independent of cardiac function parameters after immediate resus, at 24h and at hospital discharge Systolic and diastolic impairment with segmental wall abnormalities of the septum and right ventricular wall Least severe dengue transient More severe dengue more frequently to have

RECOMMENDATION All cases of severe dengue in shock should have Echocardiography to look for evidence of cardiac dysfunction and to guide in fluid management. Adequate fluid resuscitation is a pre-requisite before myocardial dysfunction can be diagnosed. Cautious volume resuscitation is required in those with myocardial dysfunction to avoid risk of iatrogenic fluid overload.

REVISED 2 ND EDITION OF 2010 CPG 2015 THE CHANGES Calculating weight Fluid management Electrolytes and acid-base balance ECG and ECHO monitoring Haemophagocytic syndrome

HEMOPHAGOCYTIC SYNDROME A potentially fatal hyperinflammatory condition caused by highly stimulated but dysregulated and often ineffective immune responses Cardinal features: fever, hepato-splenomegaly, pancytopenia, and widespread histiocytic tissue infiltration 2 major forms: i. primary (hereditary) form - in early childhood ii. secondary (reactive) form - at any age - may be related to infection, malignancy, or autoimmune disease Dengue associated haemophagocytic syndrome increasingly reported in case reports and case series in past few years in both primary and secondary dengue infections - South East Asia & among returned travelers from tropical countries. Often missed or delayed as its presentation mimics sepsis

DIAGNOSIS OF HLH Table 2. Proposed HLH diagnostic criteria, 2009. 1. Molecular diagnosis of hemophagocytic lymphohistiocytosis (HLH) or X-linked lymphoproliferative syndrome (XLP). 2. Or at least 3 of 4: a. Fever b. Splenomegaly c. Cytopenias (minimum 2 cell lines reduced) d. Hepatitis 3. And at least 1 of 4: a. Hemophagocytosis b. Ferritin c. sil2rα (age based) d. Absent or very decreased NK function 4. Other results supportive of HLH diagnosis: a. Hypertriglyceridemia b. Hypofibrinogenemia c. Hyponatremia

Limitation: Goodness of fit 0.93 aroc - 0.97 Retrospective sample selection bias medical records, results of bone marrow aspirate, ICD-10 classification Classification of patients 4 investigators, independent Goodness of fit 0.76 aroc 0.95 Small validation sample 27 patients compared to 312 patients in development sample Validated mainly among population with autoimmune diseases - used with caution in infection associated HS

MANAGEMENT OF HS Mainly supportive Not so severe cases can recover spontaneously Sometimes, short course dexamethasone (10mg/m2 BSA) could be adequate Due to the transient nature of HS in dengue, full HLH 2004 treatment protocol which includes chemotherapy is not necessary For severe cases, HS specific therapy i.e IV methylprednisolone + IV Ig to be tapered off rapidly as patients improve clinically and biochemically In patients with co-existing sepsis and/or GIT bleeding, risks and benefits on use of steroids need to be weighed

TAKE HOME MESSAGE Do not forget the basics ie history, physical examination, investigations and diagnosis Look at the BIG picture do not fix your mind on one or two parameter Make a diagnosis after knowing the parameters more fluids, less fluids, on the right track, other diagnosis, further investigations Monitor response and medical condition Remember if you are on the right track, patient should get better

TAKE HOME MESSAGE Do not forget the basics ie history, physical examination, investigations and diagnosis Look at the BIG picture do not fix your mind on one or two parameter/s Make a diagnosis after knowing the parameters more fluids, less fluids, on the right track, other diagnosis, further investigations Monitor response and medical condition Remember if you are on the right track, patient should get better

TAKE HOME MESSAGE Do not forget the basics ie history, physical examination, investigations and diagnosis Look at the BIG picture do not fix your mind on one or two parameter Make a diagnosis after knowing the parameters more fluids, less fluids, on the right track, other diagnosis, further investigations Monitor response and medical condition Remember if you are on the right track, patient should get better

TAKE HOME MESSAGE Do not forget the basics ie history, physical examination, investigations and diagnosis Look at the BIG picture do not fix your mind on one or two parameter Make a diagnosis after knowing the parameters more fluids, less fluids, on the right track, other diagnosis, further investigations Monitor response and medical condition Remember if you are on the right track, patient should get better

TAKE HOME MESSAGE Do not forget the basics ie history, physical examination, investigations and diagnosis Look at the BIG picture do not fix your mind on one or two parameter Make a diagnosis after knowing the parameters more fluids, less fluids, on the right track, other diagnosis, further investigations Monitor response and medical condition Remember if you are on the right track, patient should get better

ACKNOWLEDGEMENTS Dr Rose Nani Mudin Public Health Physician (Epidemiologist) Head of Vector Borne Disease Sector, Disease Control Division, Ministry of Health Malaysia Dr Shaharom Nor Azian Che Mat Pengarah, Makmal Kesihatan Awam Dr Shanthi Ratnam Consultant Intensivist, Hospital Sungai Buloh Dr Kan Foong Kee Consultant ID, Hospital Sultanah Aminah

THANKS

PEARLS ON SEVERE DENGUE INFECTION Patient will not have plasma leakage before 72h of fever. Rise in hematocrit likely means dehydration. Oral rehydration usually suffices Transition from febrile phase to critical phase could be as early as day 3 or as late as day 7 or 8 Critical phase usually 24-48h Total white cell count (instead of leukopenia) may increase in patients with severe disease at critical phase Liver enzymes are frequently elevated during the critical and recovery phases

PEARLS ON SEVERE DENGUE INFECTION Warning sign of severe abdominal pain can be mistaken as a surgical condition fever precedes pain, tender but not guarded, pain improves with fluid resuscitation Tense abdomen after IV fluid therapy - due to ascites + liver congestion can cause abdominal pain - consider fluid overload instead! If IV fluid therapy increases, this can cause acute pulmonary oedema

MANAGEMENT PEARLS OF SEVERE DENGUE INFECTION History: Ask open-ended questions 3 golden questions to ask: How much oral fluid intake: quantity and quality? How much urine output: frequency, volume and time of most recent voiding? What activities can the patient do during the febrile illness? Examination: 5-in-1 maneuver magic touch CCTV-R Investigations: NS1, IgM, IgG and or PCR Diagnosis, phase of disease and severity: Does the patient have dengue or other illnesses? Which phase of dengue (febrile/critical/recovery)? How severe the disease is? -hydration state? warning signs present? haemodynamic state? Best medical plan: monitoring

PEARLS ON IV FLUID THERAPY IV fluid therapy is a Careful Budget of in and out with only one priority ie to maintain tissue perfusion In outpatient setting, patient should drink enough fluids to pass urine about 4 to 6 times a day A patient with dengue shock should pass at least 0.5 ml/kg/h urine. If urine volume exceeds 0.5ml/kg/h, consider reducing IV fluid therapy Remember uncontrolled diabetes or hyperglycemia - shock becomes worse because of glycosuria Remember changes in haematocrit may be masked by IV fluid therapy

PEARLS ON MONITORING Monitoring CCTV-R + investigations Big picture Make a diagnosis after knowing the parameters more fluids, less fluids, on the right track, other diagnosis, further investigations Remember if you are on the right track, patient should get better For severe disease with multi-organ involvement, consider hemophagocytic syndrome