CME Faculty of Medicine University of Trisakti 2012 Pathogenesis of Dengue Hemorrhagic Fever and How to Diagnose based on WHO Guidelines? Hendarto Natadidjaja Department of Internal Medicine Faculty of Medicine University of Trisakti AGENDA The Epidemiology of Dengue Hemorrhagic Fever The General Pathogenesis of Dengue Hemorrhagic Fever Dengue Hemorrhagic Fever Diagnostic Criteria : The Comparison among 1997,2009,2011 Dengue Laboratory Diagnostic Test Fluid Management in Dengue Hemorrhagic Fever Conclusion The Epidemiology of Dengue Hemorrhagic Fever CME Faculty of Medicine University of Trisakti 2012 Global Impact of Dengue 2.5 billion people (2/5ths of world population) are at risk for dengue 50 million to 100 million dengue cases worldwide every year (WHO) 500,000 cases require hospitalization (90% are pediatric cases) Leading cause of childhood death and hospitalization in >8 southeast Asian countries. 25,000 fatalities annually Source: Ron Rosenberg, CDC Forth Collin, 2008 CME Faculty of Medicine University of Trisakti 2012 Worldwide Extension of Dengue Transmission, 2000 - 2006 CME Faculty of Medicine University of Trisakti 2012 IR is high in Jakarta (303.5), East Kalimantan (174.6)& Bali(170.1) MOH 2009 CME Faculty of Medicine University of Trisakti 2012 Serology and Diagnosis Pediatric Ward – Cipto Mangunkusumo Hospital 2007 Dengue Fever Dengue Hemorrha gic Fever Primary infection 2008 2009 2 5(14.71%) 9(56.25%) (16.67%) Secondary infection 10(83.33 %) 29(85.29 %) 7(43.75%) Primary infection 12(14.46 %) 9(7.38%) 7(20%) Secondary infection 71(85.54 %) 113(92.62 %) 28(80%) CME Faculty of Medicine University of Trisakti 2012 SEROTYPE OF DENGUE IN CIPTO MANGUNKUSUMO HOSPITAL DENV-1 2006 141 cases 15 2007 97 cases 1 2009 52 cases 5 DENV-2 43 20 4 DENV-3 25 20 11 DENV-4 4 1 2 Dengue Shock Syndrome was mostly caused by DENV-3 serotype (54,54%). Sudiro, MT, et al. Department of Microbiology, Faculty of Medicine, University of Indonesia, 2009 The General Pathogenesis of Dengue Hemorrhagic Fever KONAS PETRI-ACEH.2012 CME Faculty of Medicine University of Trisakti 2012 Dengue Virus Characteristics 1. Single Stranded RNA Virus 2. Core dan Capsid 3. Late replication in target cells, starting within 15 hours post infection Noisakran S, Guey CP. Alternate hypothesis on the pathogenesis of Dengue Hemorrhagic Fever (DHF)/ De ngue Shock Syndrome (DSS) in Dengue Virus Infection. Exp Biol Med 2008;233:401-8. KONAS PETRI-ACEH.2012 CME Faculty of Medicine University of Trisakti 2012 Dengue Target Cells Noisakran S, Guey CP. Alternate hypothesis on the pathogenesis of Dengue Hemorrhagic Fever (DHF)/ Dengue Shock Syndrome (DSS) in Dengue Virus Infection. Exp Biol Med 2008;233:401-8. KONAS PETRI-ACEH.2012 CME Faculty of Medicine University of Trisakti 2012 Dengue Target Cells : 1. Langerhans cells 2. Dendritic cells 3. Lymphocyte, Monocyte 4. Hepatocyte 5. Macrophage 6. Endothelium CME Faculty of Medicine University of Trisakti 2012 DENGUE SPECIALITIES LEUCOPENIA SUPRESION ROLLING APOTOSIS Decreasing of Platelets SUPRESION ADHESION ANTIBODY BLEEDING ENDOTEL DISFUNC. SHEAR STRESS DIC CME Faculty of Medicine University of Trisakti 2012 PLASMA LEAKAGE •Cell anchored to extracellular matrix •Present in tissues subject to shear or lateral stress •Hemi=half CME Faculty of Medicine University of Trisakti 2012 Macromolecules Can Cross The Endothelial Barrier in Three Ways: 1.Between the cells, through cell junctions (paracellular) 2.Through the EC, via pores (diaphragms or fused vesicles) 3.Transcellularly, via shuttling vesicles (transcytosis) and specific receptors (transcellular). Dengue Hemorrhagic Fever Diagnostic Criteria : The Comparison among 1997,2009,2011 KONAS PETRI-ACEH.2012 CME Faculty of Medicine University of Trisakti 2012 Dengue Haemorrhagic Fever Guidelines WHO, 1997 WHO, 2009 WHO, 2011 KONAS PETRI-ACEH.2012 CME Faculty of Medicine University of Trisakti 2012 Diagnosis Classification 1997 2009 2011 Dengue fever Dengue without warning signs Dengue fever DHF grade I Dengue with warning signs DHF grade I DHF grade II DHF grade III DHF grade II Severe dengue ( severe plasma leakage, severe hemorrhage, severe organ involvement) DHF grade IV DHF grade III DHF grade IV lExpanded dengue syndrome Adult management Adult management CME Faculty of Medicine University of Trisakti 2012 Criteria of Clinical Diagnosis DHF (WHO 1997) Fever: acute onset, high and continuous, lasting 2 to 7 days. Any of the following hemorrhagic manifestations (including at least a positive tourniquet test: petechiae, purpura, echymosis, epistaxis, gum bleeding, and hematemesis and/or melena). Thrombocytopenia (100,000/mm3 or less) Any of the following signs of plasma leakage: – Increment of > 20% hematocrit compared to standard age and sex – Decrement of > 20% hematocrit after fluid therapy, compared to previous hematocrit level – Pleural effusion, ascites, Pericardial effusion or hypoprotreinemia WHO.1997 KONAS PETRI-ACEH.2012 CME Faculty of Medicine University of Trisakti 2012 Diagnostic Criteria 2009 2009 Dengue guidelines for diagnosis, treatment, prevention, and control. World Health Organization, UNICEF, UNDP. New Edition 2009. CME Faculty of Medicine University of Trisakti 2012 DENGUE HEMORRAGHIC FEVER PHASES (WHO 2009) DENGUE. GUIDELINES FOR DIAGNOSIS, TREATMENT, PREVENTION AND CONTROL. CME Faculty of Medicine University of Trisakti 2012 WHO 2009 Group A / Probable Dengue Patients who may be sent home Able to tolerate adequate volumes of oral fluids Pass urine at least once every six hours Do not have any of the warning signs, particularly when fever subsides. CME Faculty of Medicine University of Trisakti 2012 WHO 2009 Group B Should be referred for in-hospital management – patients with warning signs – co-existing conditions that may make dengue or its management more complicated (such as pregnancy, infancy, old age, obesity, diabetes mellitus, renal failure, chronic haemolytic diseases) – certain social circumstances (living alone, or living far from a health facility without reliable means of transport) CME Faculty of Medicine University of Trisakti 2012 WHO 2009 Group C / Severe Dengue Require emergency treatment and urgent referral when they have severe dengue – severe plasma leakage leading to dengue shock and/or fluid accumulation with respiratory distress; – severe haemorrhages; – severe organ impairment (hepatic damage, renal impairment, cardiomyopathy, encephalopathy or encephalitis). Dengue Laboratory Diagnostic Test CME Faculty of Medicine University of Trisakti 2012 Concentration Immunity Response Against DHF Early symptoms IgG cut off Early symptoms IgG HAI 1:2500 Virus Infection 1 IgM Virus Days IgM IgM cut off Infection 2 WD Santoso,2009 CME Faculty of Medicine University of Trisakti 2012 Immunity Response Diagnostic Onset of symptoms NS1 Ag Bite Antibody DA -7 -6 -5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12 Y Ag/Ab level ACUTE PHASE WD Santoso,2009 CONVALESENCE PHASE IgM IgG NS1 Ag Day Fluid Management in Dengue Hemorrhagic Fever CME Faculty of Medicine University of Trisakti 2012 DHF Case Management With Ht Increase > 20% 5 % fluid deficiency Initial fluid administration Cristaloid 6-7 ml/kg/hr 3-4 hr evaluation Improvement Decrease in Ht & HR Normal BP, Increase in Urin Output Cristaloid 5 ml/kg/hr Improvement Worsening in Vital Sign and Ht Cristaloid 10 ml/kg/hr Improvement Worsening Cristaloid 15 ml/kg/hr Cristaloid 3 ml/kg/hr Worsening (shock signs) Improvement Stop Fluid therapy 24-48 hr No Improvement Increase in Ht & HR BP decrease < 20 mmHg Decrease Urin Improvement Shock & Hemorrhage Management Protocol WHO,2009 CME Faculty of Medicine University of Trisakti 2012 WHO,2009 Arterial Catheter As soon as practical 2005 Guideline Central Venous Catheter Conclusion 1. 2. 3. 4. 5. Dengue Hemorrhagic Fever is epidemiologically spread in tropic area, included Indonesia Working diagnostic of DHF supposed to be based on WHO diagnostic criteria Serologic examination can be done as a diagnostic supportive test Based on WHO guidelines 2009, Group A of DHF can be managed in primary care, but group B and C should be revered to hospital Fluid therapy is a role of DHF treatment, and it should be properly to decrease dengue morbidity and mortality