NASRONUDIN 4/17/2013. DENVs of each type are grouped into several genotypes.

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NASRONUDIN Institute of Tropical Disease, Airlangga University-Tropical and Infectious Diseases Division, Department of Internal

Soetomo Hospital Disampaikan pada 14 th Jakarta Antimicrobial Update (JADE) 2013 Hotel Shangri-La Jakarta, 14 April 2013 Four types of

approximately 2.5 billion people are at risk of infection. DENVs of each type are grouped into several genotypes.

sylvatic (Malaysia); (IV) West Pacific Islands and Australia; and (V) America, West Africa and Asia.

Displacement of the Predominant Dengue Virus from Type 2 to Type 1 with a Subsequent Genotype Shift from IV to I in Surabaya, Indonesia

1 NASRONUDIN Institute of Tropical Disease, Airlangga University-Tropical and Infectious Diseases Division, Department of Internal Medicine Medical Faculty-Dr. Soetomo Hospital Disampaikan pada 14 th Jakarta Antimicrobial Update (JADE) 2013 Hotel Shangri-La Jakarta, 14 April 2013 Four types of dengue viruses (DENV 1-4), mosquito-borne flaviviruses, are distributed throughout tropical and subtropical areas of the world, where approximately 2.5 billion people are at risk of infection. DENVs of each type are grouped into several genotypes. Phylogenetic studies have revealed that DENV1 comprise five genotypes: (I) Southeast Asia, China and East Africa; (II) Thailand; (III) sylvatic (Malaysia); (IV) West Pacific Islands and Australia; and (V) America, West Africa and Asia. Yamanaka A, Mulyatno KC, Susilowati H, Hendrianto E, Ginting AP, Sary DD, Rantam FA, Soegijanto S, Konishi E, Displacement of the Predominant Dengue Virus from Type 2 to Type 1 with a Subsequent Genotype Shift from IV to I in Surabaya, Indonesia PLoS ONE 6(11): e doi: /journal.pone Dengue infection is a systemic and dynamic disease A wide clinical spectrum that includes both severe and nonsevere clinical manifestations After the incubation period, the illness begins abruptly and is followed by three phases- febrile, critical and recovery 1

RNA viral Genus: Flavivirus Famili : Flaviviridae 4 SEROTYPES DEN-1, DEN-2, DEN-3, DEN-4 GENOTYPES ssrna sense + Single-stranded sense positive SORF Single Open Reading Frame TWO PROTEINS S

2 RNA viral Genus: Flavivirus Famili : Flaviviridae 4 SEROTYPES DEN-1, DEN-2, DEN-3, DEN-4 GENOTYPES ssrna sense + Single-stranded sense positive SORF Single Open Reading Frame TWO PROTEINS S (Structural) (25% total protein) C (core protein, capsid) M, Prm (membrane, premembrane protein) E (envelope protein ) NS (Non Structural) (75% total protein) NS1 NS2A, NS2B NS3 NS4A NS4B NS5 5 and 3 nontranslated region 2

PHENOGENETIC ANALYSIS Sequencing Heterogenicity Immunogenicity Structural C > Prm > M > E Non Structural NS1 > NS2A > NS2B > NS3 > NS4A > NS4B > NS5 The monthly number of dengue isolates Yamanaka A,

3 PHENOGENETIC ANALYSIS Sequencing Heterogenicity Immunogenicity Structural C > Prm > M > E Non Structural NS1 > NS2A > NS2B > NS3 > NS4A > NS4B > NS5 The monthly number of dengue isolates Yamanaka A, Mulyatno KC, Susilowati H, Hendrianto E, Ginting AP, Sary DD, Rantam FA, Soegijanto S, Konishi E, Displacement of the Predominant Dengue Virus from Type 2 to Type 1 with a Subsequent Genotype Shift from IV to I in Surabaya, Indonesia PLoS ONE 6(11): e doi: /journal.pone Phylogenetic tree based on the E gene sequence of DENV1 strains constructed using the neighborjoining method. Yamanaka A, Mulyatno KC, Susilowati H, Hendrianto E, Ginting AP, Sary DD, Rantam FA, Soegijanto S, Konishi E, Displacement of the Predominant Dengue Virus from Type 2 to Type 1 with a Subsequent Genotype Shift from IV to I in Surabaya, Indonesia PLoS ONE 6(11): e doi: /journal.pone

Biphasic rash: evanescent, then maculopapular, scarlatiniform, morbilliform, or petechial changes from extremities to torso. Leukopenia and thrombocytopenia in the hemorrhagic form.

4 Exposure 7-10 days before onset. Sudden onset of high fever, chills, severe myalgias and arthralgias, headache, sore throat, and depression. Biphasic fever curve: initial phase, 3-7 days; remission, few hours to 2 days; second phase, 1-2 days. Biphasic rash: evanescent, then maculopapular, scarlatiniform, morbilliform, or petechial changes from extremities to torso. Leukopenia and thrombocytopenia in the hemorrhagic form. Shandera WX, Roig IL, Current Medical Diagnosis & Treatment. Pp Without With warning sign 1. Severe plasma leakage 2. Severe haemorrhage 3. Severe orhan impairment CRITERIA FOR DENGUE ± WARNING SIGNS PROBABLE DENGUE WARMING SIGNS 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 warming sign Laboratory-confirmed dengue (important when no sign of plasma leakage) Abdominal pain or tenderness Persistent vomiting Clinical fluid accumulation mucosal bleed Lethargy, restlessness Liver enlargement > 2 cm Laboratory: increase in HCT concurrent with rapid decrease in platelet count * (requiring strict observation and medical intervention) 4

plasma leakage Leading to: Shock (DSS) Fluid accumulation with respiratory distress Severe bleeding as evaluated by

5 Clinical Abdominal pain or tenderness Persistent vomiting Clinical fluid accumulation Mucosal bleed Lethargy, restlessness Liver enlargement >2 cm Laboratory Increase in HCT concurrent with rapid decrease in platelet count 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 The Course of Dengue Illness 5

6 DIFFERENTIAL DIAGNOSIS OF DENGUE FEVER Conditions that mimic the febrile phase of dengue infection Flu-like syndromes Influenza, measles, Chikungunya, infectious mononucleosis, HIV seroconversion illness Illnesses with a rash Rubella, measles, scarlet fever, meningococcal infection, Chikungunya, drug reactions Diarrhoeal diseases Rotavirus, other enteric infections Illnesses with neurological manifestations Meningo/encephalitis Febrile seizures Conditions that mimic the critical phase of dengue infection Infectious Acute gastroenteritis, malaria, leptospirosis, typhoid, typhus, viral hepatitis, acute HIV seroconversion illness, bacterial sepsis, septic shock Malignancies Acute leukaemia and other malignancies Other clinical pictures Acute abdomen acute appendicitis acute cholecystitis perforated viscus Diabetic ketoacidosis Lactic acidosis Leukopenia and thrombocytopaenia ± bleeding Platelet disorders Renal failure Respiratory distress (Kussmaul s breathing) Systemic Lupus Erythematosus LABORATORY DIAGNOSIS: Laboratory diagnosis methods for confirming dengue virus infection may involve detection of the virus, viral nucleic acid, antigens or antibodies, or a combination of these techniques After onset of illness, the virus can be detected in serum, plasma, circulating blood cells and other tissues for 4-5 days During the early stages of the disease, virus isolation, nucleic acid or antigen detection can be used to diagnose the infection At the end of the acute phase of infection, serology is the method of choice for diagnosis NS1 detection Virus isolation RNA detection Viraemia O.D IgM primary IgM secondary O.D IgG secondary IgG secondary infection >90 Days Onset of symptoms (days) 6

COMPARISON OF DIAGNOSTIC TESTS ACCORDING TO THEIR ACCESSIBILITY AND CONFIDENCE ACCESSIBILITY DIRECT METHODS INDIRECT METHODS Virus isolation Genome detection NS1 detection Serology IgM Serology IgG

7 COMPARISON OF DIAGNOSTIC TESTS ACCORDING TO THEIR ACCESSIBILITY AND CONFIDENCE ACCESSIBILITY DIRECT METHODS INDIRECT METHODS Virus isolation Genome detection NS1 detection Serology IgM Serology IgG CONFIDENCE INTERPRETATION OF DENGUE DIAGNOSTIC TESTS [ADAPTED FROM DENGUE AND CONTROL (DENCO) STUDY] Highly suggestive Confirmed One of the following: 1. IgM + in a single serum sample 1. PCR + 2. IgG + in a single serum sample with a HI titre of 1280 or greater One of the following: 2. Virus culture + 3. IgM seroconversion in paired sera 4. IgG seroconversion in paired sera or fourfold IgG titer increase in paired sera 7

AAP ZIKA ECHO (EXTENSION FOR COMMUNITY HEALTHCARE OUTCOMES)

AAP ZIKA ECHO (EXTENSION FOR COMMUNITY HEALTHCARE OUTCOMES) HOUSEKEEPING ITEMS For educational and quality improvement purposes, this ECHO session will be recorded Project ECHO collects participation data