Kuliah DHF

Dengue :Dengue : Clinical presentation and managementClinical presentation and management

Dr. Dr. Gunawan KosasihGunawan Kosasih

History (1)History (1)

• The word “ Dengue” is presumed to be derived from the Swahili phrase “Ka-dinga pepo”, which describes the disease as being caused by an evil spirit.The Swahili word “dinga” may possibly have its origin in the Spanish word “dengue” (fastidious or careful), describing the gait of a person suffering dengue fever.

• 1779 Dengue fever was first described by David Bylon under the name of joint fever.

• 1779-80 The first reported epidemics of DF occurred in Asia, Africa, and North America.

History (2)History (2)

• 1789 The first definitive case was reported and is attributed to Benjamin Rush, who coined the term “breakbone fever”.

• 1906 Bancroft was the first to suggest that transmission might be due to Aedes aegypti.

• 1907 The etiological agent of Dengue a filterable virus was first proved by Ashburn and Craig.

IntroductionIntroduction (1) (1)

• Dengue fever (DF) / dengue haemorrhagic fever (DHF) is a growing public health problem in the subtropics.

In South-East Asia,

* total population of 1.5 billion + 1.3 billion

people at risk of acquiring DF or DHF.

* Currently, DHF the leading cause of

hospital admissions and death among

children.

IntroductionIntroduction (2) (2)Indonesia is the largest country in SEA, 245 million inhabitans.

Almost 60% of the people live on Java Island most severely afflicted by periodic outbreaks of this disease.

Endemic in many large cities and small towns and has also spread to certain smaller villages, where population movement and density are high.

Epidemic DF has been reported in all 27 Indonesian provinces, whereas in 1968 only two provinces had reported dengue cases

• Dengue virus believed to be the most common arthropod-borne disease in the world.

• WHO estimates : 50 million cases of dengue infection worldwide every year.

• About 250,000 individuals per year manifest these severe forms mortality rate about 10 percent.

IntroductionIntroduction (3) (3)

IntroductionIntroduction (4) (4)• World Health Organization has classified this

disease as a major international public health concern.

• Attack rates among susceptible : 40 – 50%, but may go up to 80 – 90%.

• Case Fatality Rates can exceed 20% due to lack of proper treatment. It is possible to reduce it to less than 1% with modern intensive supportive therapy.

POLA SEPULUH PENYAKIT TERBANYAK PASIEN RAWAT INAPPOLA SEPULUH PENYAKIT TERBANYAK PASIEN RAWAT INAPDI RUMAH SAKIT TAHUN 2006DI RUMAH SAKIT TAHUN 2006

No DTD ICD Golongan Sebab SakitJumlah Pasien %

1 5 A 09Diare dan gastroenteritis oleh penyebab

infeksi tertentu (kolitis inf) 177.517 7.95

2 032.1 A 91 Demam Berdarah Dengue 81.392 3.64

3 2 A 01 Demam tifois dan paratifoid 72.804 3.26

9 43 B 50 - B 54 Malaria (termasuk semua jenis malaria) 36.865 1.65

Sumber: Ditjen Bina Yanmedik, Depkes RI, 2007 ( dari buku: Profil Kesehatan Indonesia 2006, Depkes RI)

EpidemiologyEpidemiology

• In Indonesia, the number of adult pts. tend to increase. Formerly, Dengue infection was known as a disease of childhood period.

• Gender: Male = Female• Depkes RI: 1993, age > 15 yrs 23.5%

1997, age > 15 yrs 35.5%

East Java: 1989, age 15-44 yrs 6.15%

age > 45 yrs 0.18%

1999, age 15-44 yrs 34.5%

age > 45 yrs 2.84%

Dengue VirusesDengue Viruses• SS-RNA arbovirus (genus Flavivirus, Famili Flaviviridae)

• 4 serotypes (DEN-1, 2, 3, 4)– Based on envelop glycoprotein– DEN-1 and 3 are more closely related– DEN-3 : dominant serotype in Indonesia and related to severe

cases.– DEN-4 less closely related to others– Virulent variants (genotypes) within serotype

• Infection with any serotype confers specific lifelong immunity

• Transient cross-protection to other serotypes

• Any serotype can cause severe / fatal disease

VectorVector

• Dengue is transmitted to humans by the Aedes aegypti (rarely Aedes albopictus) mosquito, which feeds during the day

• Dengue transmitted by infected female mosquito

• Most important vectors worldwide

• Primarily a daytime feeder

• Lives around human habitation

• Lays eggs and produces larvae preferentially in artificial containers

AeAedesdes aegyptiaegypti

Transmission of Transmission of Dengue Dengue virusesviruses

Incubation Period: 3-14 days

Viraemia & Fever: 5-7 days

VectorHumidity: Rainfall & Temp.

Susceptible hosts,(population)

Source patients

ExtrinsicIncubation Period: 1-2 weeks

HUMAN # 1 HUMAN # 2

Illness IllnessDAYS

Viremia Viremia

0 5 8 12 16 20 24 28

acquires virusMOSQUITO FEEDS MOSQUITO REFEEDS

acquires virus

Extrinsic

Incubation

Period

Intrinsic

Incubation

Period

Transmission of Dengue Virus

by by Aedes aegyptiAedes aegypti

1. Virus transmitted to human in mosquito saliva

2. Virus replicates in target organs

3. Virus infects white blood cells and lymphatic tissues

4. Virus released and circulates in blood

5. Second mosquito ingests virus with blood

6. The virus replicates in the mosquito midgut, the ovaries, nerve tissue and fat body. It then escapes into the body cavity, and later infects the salivary glands.

7. The virus replicates in the salivary glands and when the mosquito bites another human, the cycle continues.

Transmission steps of Dengue FeverTransmission steps of Dengue Fever

PathogenesisPathogenesis

Human infection with this flavivirus is initiated by deposition of virus through the skin via the saliva of an infected arthropod. Virus replicates locally and in regional lymph nodes and results in viremia

Mosquito

PathogenesisPathogenesis

Manifestations of dengue virus infectionManifestations of dengue virus infection 圖表標題

Dengue virus infection

Asymptomatic Symptomatic

Undifferentiated fever ( viral syndrome)

Dengue fever syndromeDengue haemorrhagic fever

(plasma leakage)

Without haemorrhage With unusual haemorrhage No shock Dengue shock syndrome

Clinical symptoms of DengueClinical symptoms of Dengue

There are actually four dengue clinical syndromes:

1. Undifferentiated fever

2. Classic dengue fever (Dengue Fever syndrome)

3. Dengue hemorrhagic fever (DHF without shock)

4. Dengue shock syndrome or DSS.

Undifferentiated FeverUndifferentiated Fever

• Undifferentiated fever may be the most common manifestation of dengue.

• A prospective study of dengue infections in 4- to 16-year-old students, 87% of the students who became infected by dengue virus were either asymptomatic or mildly symptomatic, and were absent from school only one day.

• Other prospective studies including all age groups have also demonstrated this type of “silent” dengue transmission.

Dengue Fever Syndrome (1)Dengue Fever Syndrome (1)

Dengue fever is an acute viral illness characterized by:

1. Fever, often with sudden onset;

2. Severe headache, often described as retro-ocular;

3. Myalgias and arthralgias that can be very severe;

4. Nausea and vomiting;

5. Rash that may present at different stages of the illness, and whose appearance can be variable— it may be maculopapular, petechial, or erythematous

6. Hemorrhagic manifestations

Dengue Fever Syndrome (2)Dengue Fever Syndrome (2)

• Patients may also report other symptoms, such as itching and aberrations in the sense of taste, particularly a metallic taste.

• There have been reports of severe depression after the acute phase of the illness.

• In some cases it may be present with or develop encephalitic or encephalopathic signs and symptoms associated with Dengue fever such as:

– Decreased level of consciousness— lethargy, confusion, and coma;– Seizures;– Nuchal rigidity

Hemorrhagic Manifestations ofHemorrhagic Manifestations of DengueDengue

• Skin hemorrhages: petechiae, purpura, ecchymoses

• Gingival bleeding

• Nasal bleeding

• Gastrointestinal bleeding: hematemesis, melena, hematochezia

• Hematuria

• Increased menstrual flow

Dengue Hemorrhagic Fever (DHF)Dengue Hemorrhagic Fever (DHF)

Clinical case definition (WHO)

1. Fever, or recent history of acute fever

2. Hemorrhagic manifestations (see previous slide)

3. Low platelet count (100,000/mm3 or less)

4. Objective evidence of “leaky capillaries:” Elevated hematocrit (20% or more over baseline) Low albumin Pleural or other effusions

FOUR grades of DHFFOUR grades of DHF

• Grade 1, fever and nonspecific constitutional symptoms are present

andthe only hemorrhagic manifestation is provoked, that is, apositive tourniquet test (which will soon be described).

• Grade 2, Grade I manifestations PLUS spontaneous bleeding.

• Grade 3incipient shock with signs of circulatory failure.

• Grade 4profound shock, with undetectable pulse and blood pressure.

Grades 3 and 4 are Dengue Shock Syndrome.

Dengue Shock SyndromeDengue Shock Syndrome

• The four criteria for DHF (see previous slide), PLUS

• Evidence of circulatory failure manifested

indirectly by all of the following:

Rapid and weak pulse Narrow pulse pressure (< 20 mm Hg) OR

hypotension for age Cold, clammy skin and altered mental status Frank shock is direct evidence of circulatory failure

Tourniquet TestTourniquet Test

• Inflate BP cuff to a point midway between systolic and diastolic pressure for 5 minutes

• After deflating the cuff, wait for the skin to return to its normal color, and then count the number of petechiae visible in a one-inch square area on the ventral surface of the forearm.

• Positive test: 20 or more petechiae per 1 inch² (6.25 cm²)

Danger Signs in DengueDanger Signs in Dengue Hemorrhagic FeverHemorrhagic Fever

• Abdominal pain - intense and sustained

• Persistent vomiting

• Abrupt change from fever hypothermia, + sweating and prostration

• Change in the mental status going to be restlessness or somnolence.

All of these are signs of impending shock and should alert clinicians that the patient needs close observation and fluids.

Warning signs for Dengue ShockWarning signs for Dengue Shock

Laboratory exams (1)Laboratory exams (1)

• Leucocyte: normal or decrease.

day 3 - : relative lymphocytosis, plasma cells

• Thrombocyte: decrease between day 3-8

• Hematocrite (PCV): plasma leakage PCV > 20%,

staring at day 3 -

• Protein: hypoalbuminemia due to plasma leakage

Laboratory exams (2)Laboratory exams (2)

• LFT: AST/ALT may increase• RFT: increase if renal deterioration +• SEROLOGY:

Hemagglutination Inhibition test: mainly for research

IgM anti DHF: (+) by day 3-5, increase till week 3,

(-) after 60–90 days

IgG anti DHF: primary inf. : (+) after day 14

secondary inf. : (+) after day 2

NS-1 protein Ag: (+) by day 2- , function ??• Dengue Rapid Test : False positive • Virus isolation• PCR : expensive

Short description about NS-1 ProteinShort description about NS-1 Protein

• Plasma levels of secreted NS1 (sNS1) correlate with viral titres, higher in patients with DHF compared with DF

• Elevated free sNS1 levels within 72 hours of onset identify patients at risk of developing DHF.

• Very high levels of NS1 protein are detected in acute phase samples from patients with secondary dengue infections but not primary infections. NS1 may contribute to formation of circulating immune complexes (an important role in the pathogenesis of severe dengue infections ??).

Differential Diagnosis of DengueDifferential Diagnosis of Dengue Fever Fever

• Infectious mononucleosis.• Chikungunya viral infections.• Coxsackie and other enteroviral infections.• Rickettsial infections.• Rubella.• Parvovirus B19 infections.• Leptospirosis.• Influenza.

Differential Diagnosis of Differential Diagnosis of DengueDengue Hemorrhagic Fever Hemorrhagic Fever

• Leptospirosis.

• Chikungunya viral infections.

• Kawasaki disease.

• Yellow fever.

• Hanta viral infections.

• Other viral haemorrhagic fevers.

• Meningococcal septicaemia.

Clinical disease courseClinical disease course

• Dengue feverDengue fever is usually a self-limiting disease

• DHF/DSSDHF/DSS occurs mostly in endemic areas

Outcome of DHF/DSS improved with early diagnosis and treatment

Case definition for dengue feverCase definition for dengue fever• PROBABLE

An acute febrilefebrile illness with 2 or more of the following manifestations:--        HeadacheHeadache--         Retro-orbital painRetro-orbital pain--          MyalgiaMyalgia--          ArthralgiaArthralgia--          RashRash--          Haemorrhagic manifestationsHaemorrhagic manifestations--          LeucopeniaLeucopenia

    AND – HAI / IgG ELISA antibody titre HAI / IgG ELISA antibody titre 1280 or positive IgM in late 1280 or positive IgM in late

acute or convalescent serumacute or convalescent serum

Confirmed Dengue feverConfirmed Dengue fever

• A clinically compatible case confirmed by isolation of dengue virus, detection of dengue virus genome or 4-fold in antibody titre

Early recognition of DHFEarly recognition of DHF

• 1. Max. risk : 3-7th day of illness

• 2. Hct

• 3. Platelet

• 4. Raised AST

DHF DHF

•DF + haemorrhage ≠DHF

•DHF: increased vascular permeability plasma leakagehaemoconcentration

Unusual manifestationsUnusual manifestations

• Acute liver failure

• Central nervous system dysfunction

Outpatient triageOutpatient triage• 1.1. BPBP• 2.2. Evidence of bleeding in skin or other sitesEvidence of bleeding in skin or other sites• 3.3. Hydration statusHydration status• 4.4. Evidence of increased vascular permeabilityEvidence of increased vascular permeability CBCBCC: WBC, platelet count, haematocrit;: WBC, platelet count, haematocrit; clotting profileclotting profile• Home treatmentHome treatment :Normal blood results, no :Normal blood results, no

haemorrhagic manifestations and patient is haemorrhagic manifestations and patient is well-hydratedwell-hydrated

Indications for admissionIndications for admission

• High haematocrit and/or platelet < 100 x 109/L

• Haemorrhagic manifestations or dehydration

• Warning signs (even without profound shock) or DSS

• Decreased conscious level

TreatmentTreatment

• Fluid rehydration• Rest• Antipyretics • Monitor BP, haematocrit, platelet

count, RFT, LFT, level of consciousness, signs of bleeding

• Oxygen, sedation and blood product transfusion as required

Penatalaksanaan (PAPDI – UI)Penatalaksanaan (PAPDI – UI)5 Protokol Penanganan:• Protokol 1: tersangka DBD tanpa shock

• Protokol 2: pemberian cairan pd tersangka DBD di ruang rawat

• Protokol 3: DBD dengan peningkatan PCV > 20%

• Protokol 4: DBD dengan Perdarahan spontan

• Protokol 5: DSS

Protokol 1Protokol 1

• Sebagai petunjuk dalam menentukan indikasi rawat

– Hb, PCV, PLT normal, atau PLT 100.000-150.000 px dpt dipulangkan dengan anjuran kontrol tiap hari (+ lab) atau jika keadaan memburuk segera kembali ke UGD

– Hb, PCV normal, tetapi PLT < 100.000 anjurkan rawat inap

– Hb, PCV meningkat dan PLT normal atau turun anjurkan rawat inap

Protokol 2Protokol 2

• Tersangka DBD tanpa perdarahan spontan / masif beri cairan kristaloid:– 1500 ml + (20 x (BB dalam kg -20) ) ml

• Setelah pemberian cairan, periksa Hb, PCV tiap 24 jam evaluasi ulang– Hb, PCV naik 10 - 20%, PLT < 100.000 pemberian cairan

tetap, pemantauan tiap 12 jam

– Hb, PCV naik > 20%, PLT < 100.000 pemberian cairan sesuai protokol 3

Protokol 3Protokol 3• Peningkatan PCV > 20% menunjukkan tubuh defisit

cairan ~ 5%• Pemberian cairan kristaloid: 6 - 7 ml/kg.BB/jam

pantau tiap 3-4 jam – Perbaikan: Nadi membaik, tekanan darah stabil, produksi urin

normal cairan diberikan 5 ml/kg.BB/jam membaik cairan 3 ml/kg.BB/jam membaik cairan stop dalam 24-48 jam.

– Memburuk: Nadi dan PCV meningkat, tekanan nadi turun (< 20 mmHg), produksi urin turun cairan 10 ml/kg.BB/jam

evaluasi 2 jam membaik cairan 5 ml/kg.BB/jam dst memburuk cairan 15 ml/kg.BB/jam – protokol 5

Protokol 4Protokol 4• Perdarahan spontan dan masif pada DBD:

– Epistaksis tak terkendali, perdarahan saluran cerna, perdarahan sal. kencing, perdarahan otak, perdarahan tersembunyi dengan jumlah 4-5 ml/kg.BB/jam

• Cairan diberikan sesuai protokol 3 – evaluasi tiap 3-4 jam (tanda fisik dan laboratorium)

• Heparin diberikan bila klinis dan lab menunjukkan DIC• Transfusi komponen darah sesuai indikasi• Transfusi Trombosit (TC) diberikan hanya bila ada

perdarahan spontan dan masif dan trombosit < 100.000, dengan atau tanpa DIC

Protokol 5Protokol 5• Penggantian cairan intravaskular yang hilang harus

segera dilakukan, sebab angka kematian pasien DSS 10 - 20x lipat pasien tanpa shock.

• Cairan kristaloid pilihan utama, + Oksigen 2-4 l/mnt

Fase awal: 10-20 ml/kg.BB/jam evaluasi 15-30 menit- membaik: Sistole > 100 mmHg, tekanan nadi > 20 mmHg, denyut

nadi < 100 bpm, akral hangat, kulit tidak pucat, produksi urin membaik (0.5-1 ml/kg/jam) cairan 7 ml/kg.BB/jam membaik 1-2 jam cairan 5 ml/kg.BB/jam membaik 1-2 jam cairan 3 ml/kb.BB/jam stop dalam 24-48 jam.

• Jika shock tak teratasi, cairan diberikan 20-30 ml/kg.BB/jam evaluasi 20-30 menit.

• Evaluasi PCV. • Jika PCV meningkat plasma leakage masih terjadi

beri cairan koloid.

• Jika PCV menurun terjadi perdarahan internal berikan transfusi darah segar 10 ml/kg.BB jika terjadi perdarahan nyata dan mengancam jiwa

Pemulangan pasien (Depkes)Pemulangan pasien (Depkes)

Pasien dapat dipulangkan, apabila1. Keadaan umum /kesadaran dan

hemodinamik baik, serta tidak demam2. Pada umumnya Hb, PCV dan jumlah

trombosit dalam batas normal serta stabil dalam 24 jam, tetapi dalam beberapa keadaan, walaupun jumlah trombosit belum mencapai normal (diatas 50.000) pasien sudah dapat dipulangkan.

• Absence of fever for 24 hours (without anti-fever therapy) and return of appetite

• Visible improvement in clinical picture

• Stable hematocrit

• 3 days after recovery from shock

• Platelets >50,000/mm³

• No respiratory distress from pleural effusions/ascites

Indications for HospitalIndications for Hospital DischargeDischarge (WHO) (WHO)

Prevention and ControlPrevention and Control

• No vaccine is available till now for the prevention of dengue.

• No specific drugs for treatment. • The control of DF/ DHF mainly depends on the

control of Ae. aegypti. • Need to adopt an integrated approach to

mosquito control by including all appropriate methods (environmental, biological and chemical), which are safe, cost-effective and environmentally acceptable

• Personal Protectionmandatory for avoiding man - vector contact.

• Environmental Methods

• Biological control

• Chemical control

THANK YOU VERY MUCH

FOR YOUR ATTENTION

Any more questions ???

yohanesko@rocketmail.com