Dengue Hemorrhagic Fever is caused by dengue viruses of the Flavivirus family. There are four serotypes of the virus. The virus is transmitted to humans through the bites of infected female Aedes mosquitoes. Diagnosis involves identifying thrombocytopenia, hemoconcentration, and other clinical manifestations. Treatment depends on the clinical classification and involves supportive care, fluid management, and close monitoring, especially during the critical leakage phase when plasma is leaking from blood vessels.

1. Dengue Hemorrhagic Fever

2. Dengue Hemorrhagic Fever CAUSED D engue viruses Family flaviviride There are four 4 serotypes (90 %) serotypes DEN-1, serotypes DEN-2, serotypes DEN-3, serotypes DEN-4

3. Transmission Vector female Aedes mosquitoes They tend to bite during the day

4. พยาธิกำเนิดจากกลไกภูมิคุ้มกัน พยาธิกำเนิด ชนิดของเชื้อแดงกีเชื้อไวรัสแดงกี เป็น single strnded RNA ไวรัสมีด้วยกัน 4 ชนิด (serotype) DEN1 DEN2 DEN3 DEN4 ซึ่ง มี antigen ร่วมกันบางส่วน ทำให้ เมื่ อเกิดการติดเชื้อชนิดหนึ่งจะเกิดภูมิคุ้มกันต่อ เ ชื้ออีกชนิดหนึ่ง แต่ภูมิที่เกิดจะอยู่ได้ 6-12 เดือน ส่วนภูมิที่เกิดกับเชื้อที่ป่วยจะมีตลอดชีวิตเช่นหากเป็นไข้เลือดออกจากเชื้อ DEN1 ผู้ป่วยจะมีภูมิต่อเชื้อนี้ตลอดชีวิต แต่จะมีภูมิต่อเชื้อแดงกีชนิดอื่นเพียง 6-12 เดือน เท่านั้นจาก ก ารศึกษาพบว่าการติดเชื้อซ้ำหรือการติดเชื้อครั้งที่สองจะเป็นสาเหตุของโรคแดงกีได้ถึงร้อยละ 80-90 เชื้อสายพันธ์ที่สอง DEN2 เริ่มกลับมาพบมากขึ้นและมีอัตราการตายสูงเนื่องจากเป็นเชื้อที่หากเป็นแล้วจะเกิดอาการรุนแรงการ บทบาทของการตอบสนองของภูมิคุ้มกันชนิด เซลล์ Denque virus มีผลทำให้ระดับ CD4 และ CD8 ลดลง

5. บทบาทของแอนติบอดีต่อพยาธิกำเนิด Primary Infection neutraliz ing Antibody การติดเชื้อ Denque virus กระตุ้นให้ร่างกายสร้างแอนติบอดี ซึ่งป้องกันการติดเชื้อ Denque virus สายพันธุ์ที่ได้รับ แอนติบอดีชนิดนี้จะคงอยู่ในร่างกายเป็นเวลานานอาจถึงตลอดชีวิต ในขณะเดียวกันแอนติบอดีนี้สามารถสามารถป้องกันการติดเชื้อต่างสายพันธ์ได้ในระยะเวลาอันสั้น ( ประมาณ 6 เดือน ) Secondary Infection Enhancing Antibody แอนติบอดีซึ่งไม่สามารถทำลายไวรัส แต่ในทางตรงกันข้ามกลับส่งเสริมการเพิ่มจำนวนของไวรัสในเซลล์เป้าหมาย

6. criteria for the diagnosis High continuous fever for 2-7 days. Haemorrhagic manifestations i.e. Positive tourniquet test (A positive tourniquet test is ³ 10 dots/square inch ) Enlargement of liver. Circulatory disturbances (as shock in severe cases). Thrombocytopenia < 100,000 cells/ cu.mm.( normal 150000-400000/ cu.mm) Haemoconcentration: hematocrit (Hct) ( normal 31-43%) increased by 20% or other evidence of plasma leakage i.e. pleural effusion and/or ascites.

7. Differential Diagnosis (Consultations Infectious disease) Leptospirosis – Increased ESR + WBC + Neutrophilia + BUN + CR Respiratory Infections – Influenza cough, sore throat, nasal discharge Diagnosis can be made by chest telerradiography and sputum bacterioscopy by the method of Gram. Measles - The presence of ‘Koplik’ lesions in the jugal mucous membrane just before the exantematic phase is a pathognomonic sign of measles Rubella (German measles) - Fever with an insidious onset, absence of systemic symp t oms and linfoadenomegaly (retroauricular, suboccipital, cervical) preceeding a rash which usually begins on the face are typical of rubella Malaria - Diagnosis is made by detection of Plasmodium forms on serial blood examination. Yellow Fever - Laboratory findings include leukopenia and neutrophilia, a very low erythrocyte sedimentation rate (near by 0mm) and a marked increase in the serum transaminases levels Meningoencephalitis - The evaluation of the cerebral spinal fluid is the basis of diagnosis, because in dengue fever the CSF is usually normal. P y elonephritis – The diagnosis is made based on the urine bacterioscopy by the method of Gram and urinocultures Septicemy - hemocultures.

8. Laboratory Investigation Laboratory Criteria CBC 1.Thrombocytopenia (<100,000/mm3) 2.Hemoconcentration(>20% increase in HCT level ) Electrolytes Coagulation studies (PT ,APTT ,TT) Prothrombin time(PT) , Activated partial thromboplastin time (APTT), Thrombin time (TT ) Biochemistry L FT (SGOT,SGPT,ALBUMIN ) UA (high Specific gravity) (The normal range is from 1.003 to 1.030) ,microscopic RBC, Proteinuria Stool Exam BUN ESR Blood gases EKG (ST-WAVE change) Tourniquet test (causes petechiae below the tourniquet) X-ray of the chest (may demonstrate pleural effusion)

9. Lab in high risk patient Blood grouping/ matching Blood sugar Electrolyte, Ca++ Blood gas Coagulogram : PT, PTT, TT Liver function test BUN , Cr , Uric acid

10. High risk patients Young infants <1-year old. DHF grade IV or prolonged shock. Overweight patients. Patients with massive bleeding. Patients with changes of consciousness (encephalopathy). Patients with underlying diseases, e.g. thalassemia, G-6-PD deficiency, congenital heart disease, etc. Referred patients

11. Special Investigation Serologic studies (demonstrate antibodies to Dengue viruses Detection of IgM antibodies after the 3rd – 5th of illness Haemagglutination Inhibition test (HI Test) (after the 5th of illness) Dengue viruses antibodies IgM Dengue viruses antibodies IgG Dengue IgM > 40 unit = Definite Diagnosis Dengue IgM < 40 unit = Secondary Infection Dengue IgM : IgG >1.8:1 = Primary Infection antigen to Dengue viruses NS1 Antigen (test day 1-9 ) Dengue Type Denque PCR (test day 1-5 )

12. Interpretation of test results

13. Denque NS1 Antigen

14. Clinical classification Dengue virus infections may be asymptomatic or may have three main clinical manifestations 1) Undifferentiated febrile illness (UF) or viral syndrome Early symptoms Fever Headache Muscle aches Joint aches Malaise รู้สึกไม่สบาย Decreased appetite Vomiting 2) Dengue fever (DF) 3) Dengue hemorrhagic fever (DHF) DHF without shock; Dengue shock syndrome (DSS). Sweaty (diaphoretic) Cold, clammy extremities Restlessness followed by: Worsening of earlier symptoms Petechiae Ecchymosis Generalized rash

15. World Health Organization classification : Grading

16. World Health Organization classification Grade I - thrombocytopenia + hemoconcentration. Absence of spontaneous bleeding. Grade II - thrombocytopenia + hemoconcentration. Presence of spontaneous bleeding. Grade III - thrombocytopenia + hemoconcentration. Hemodynamic instability: filiform pulse, narrowing of the pulse pressure (< 20 mmHg), cold extremities, mental conffusion. Grade IV - thrombocytopenia + hemoconcentration. Declared shock, patient pulseless and with arterial blood pressure = 0 mmHg (dengue shock syndrome - DSS).

17. Criteria for Admission to Hospital Very weak and cannot have adequate oral intake. Bleeding. Platelet < 100,000 cells/cu.mm. and/or rising Hct 10-20%. Clinical deterioration when defervescence occurs( ไข้ลง ). Acute, severe abdominal pain/ vomiting. Shock/impending shock. Rapid pulse and no fever. Capillary refill >2 seconds. Cold, clammy skin, mottling, restless. Pulse pressure < 20 mm.Hg., e.g. 100/80, 90/70, Hypotension. No urine for 4-6 hours. Change of consciousness, stuporous( ง่วงงง ) or aggressive behaviour which may indicate more severe disease, encephalopathy. live far away from the hospital.

18. Indications for Admission to ICU Impending respiratory failure Persistent shock not responding to 60ml/kg of fluid resuscitation Cerebral protection Need for close monitoring

19. The management of DHF divided according to these three phases. 1. Febrile phase (2-7 days) 2. Critical or leakage phase (24-48 hours) 3. Convalescence phase (2-7 days)

20. 1. Febrile phase Supportive and symptomatic treatment. Give paracetamol 10 mg/kg/dose prn T > 39 C q 4-6 hr., (aspirin and ibuprofen are contraindicated) Apply tepid sponges if a patient still has high fever after a dose of paracetamol. For nutritional support, advise soft diet, fruit juice, milk or ORS. has signs of dehydration and had severe vomiting, give 5% D/N/2 to correct dehydration and discontinue IV fluid as soon as possible, preferably within 24 hours. If IV fluid cannot be discontinued, give only a minimal amount - about half of the maintenance amount.

21. To follow these patients closely Ask the history of bleeding (admit and give blood transfusion if there is a significant amount of blood loss, ~10% of total blood volume). Do physical examination: Vital signs - signs of shock: rapid and weak pulse, narrowing of pulse pressure, hypotension - if present, give IV fluid immediately and admit. Palpate the liver - liver enlargement and tenderness indicate nearness to or entering the critical phase; observe closely or admit. Repeat tourniquet test if it was negative. Do CBC and follow CBC everyday: Leukopenia < 5,000 cells/ cu.mm. and lymphocytosis, increase in atypical lymphocyte indicates that within the next 24 hours, the patient will have no fever (7) and will enter critical phase if they are DHF cases. Thrombocytopenia < 100,000 cells/cu.mm. indicates that the patient is entering a critical phase and needs close observation in the hospital. Rising Hct 10-20% indicates that the patient is in the critical period and needs IV fluid therapy if he cannot have good oral intake. Admit this patient and give isotonic salt solution

22. 2. Critical/Leakage phase General management of patients Put all dengue patients together in the dengue ward or dengue corner for close observation. This ward should have mosquito net to prevent nosocomial dengue transmission. Vital signs should be measured q 1-2 hours; if unstable vital signs are present, it should be done more frequently, i.e. q 10-15 minutes. Hct should be done q 4-6 hours; if unstable vital signs and suspected internal bleeding, more frequently, i.e. q ?-1 hour. This is very critical, especially in cases with concealed bleeding. Record intake/output. Should have flow chart at bedside for recording clinical signs and symptoms, vital signs, Hct, intake/output, which is very important for adjusting the rate and type of fluid therapy. Give oxygen via face mask/nasal canular in cases with shock. Stop bleeding by proper methods, e.g. nasal packing in cases with epistaxis. Avoid unnecessary invasive procedures, e.g. do not insert naso-gastric tube in cases with upper GI bleeding. Closely observe the patients by both physicians and nurses.

23. Fluid management Indication for IV fluid Thrombocytoperia <100,000 cells/ cu.mm., rising Hct 10-20%, platelet < 100,000 cell/cu.mm. and patient cannot have adequate oral intake. Shock or impending shock. Type of IV fluid : Isotonic salt solution Isotonic salt solution, e.g. Acetate Ringer (AR), Lactate Ringer (LR) or normal saline solution (NSS) with or without 5% dextrose (preferably with 5% dextrose). In young infants, during shock use isotonic solution; if not in shock, use 5% D/N/2. Amount of IV fluid: เท่ากับจำนวน Plasma ที่รั่วออกนอก Cell During the critical period of plasma leakage (24-48 hours), DHF patients should receive the total amount of IV fluid for maintenance + 5% deficit (M + 5% D). Based on the observation that the average amount of IV fluid given through the period of leakage in DHF grade III patients is equal to that.

24. Rate of IV fluid In non-shock cases, start with: 5 ml/kg/hr. (BW between 15-40 kg). 3-4 ml/kg/hr. (BW > 40kg.). 6-7 ml/kg/hr. (BW < 15 kg). In DHF grade III, start with 10 ml/kg/hr. In DHF grade IV, start with 10 ml/kg IV push or drip free flow for 10-15 minutes until blood pressure (BP) and pulse can be measured, then reduce to 10 ml/kg/hr. Adjusting the rate of IV fluid Clinical conditions: general appearance, capillary refill, appetite. Vital signs: BP, P, temperature (T) and respiratory rate (RR). Hct. Urine output.

25. Monitoring of shock After initial fluid resuscitation, evaluate the patient at 1-2 hours. If the rate of IV fluid cannot be reduced to <10 ml/kg/hr. because of unstable vital signs (still narrowing of pulse pressure and rapid and weak pulse), Repeat the Hct: If there is an increase, change IV fluid to colloidal solution (Dextran-40 is preferred) at a rate of 10 ml/kg/hr. If there is a decrease, change IV fluid to colloidal solution (Dextran-40 is preferred) at a rate of10 ml/kg/hr. and cross match for fresh whole blood (FWB) and re-evaluate the patient again after one hour whether he needs blood transfusion or not. In grade IV patients, If the initial Hct is very low, i.e. 40%-45%, think of possible internal haemorrhage and follow Hct more frequently and give blood transfusion as soon as indicated. Correct the possible metabolic and electrolyte disturbance, e.g. hypoglycemia, hyponatremia, hypocalcemia, acidosis. After 6 hours, if Hct is decreasing and in spite of a large amount of volume replacement, still cannot reduce the rate of IV fluid to < 10/ml/kg/hr., consider blood transfusion as soon as possible.

26. The recommended colloidal solution Dextran-40 (10% dextran-40 in NSS which is a plasma expander) is recommended because of its hyperoncogenicity (osmolarity ~3 times that of plasma), so it can hold the volume better. Other colloidal solutions, including plasma itself, are the plasma substitute and have osmolarity ~ 1-1.4 times that of plasma. The rate of dextran-40 should be 10 ml/kg/hr so that it can maintain maximum osmolarity when administered to the patients. The maximum dosage of dextran-40 is 30 ml/kg/day. Do not exceed this amount for it may cause acute renal failure. Duration of IV fluid The duration of IV fluid administration should not exceed 24-48 hours. Indication for blood transfusion Significant amount of blood loss, i.e. > 10% of total blood volume (TBV). TBV = 80 ml/kg. Give FWB replacement equal to the amount observed. Patients with haemolysis due to their underlying diseases, e.g. G-6-PD deficiency, thalassemia. Patients with concealed bleeding. Hct dropped and unstable vital signs in spite of large amount of volume replacement, give FWB 10 ml/kg/dose or pack red cell (PRC) 5 ml/kg/dose at a time. Indication for platelet transfusion Platelet concentrate is indicated only in cases with massive bleeding. Give 0.2 unit/kg/dose

28. 3. Convalescence phase In general, most DHF patients will recover rapidly without complication within 24-48 hours after shock. Indicators for recovery include: Improved general condition. Gain appetite. Stable vital signs: wide pulse pressure, slow and strong pulse. Hct stable and decrease to baseline value, 35%-40%. Diuresis. Some (~ 30% ) developed confluent petechial rash with characteristic, scattered small, whitish round areas on their lower extremities, may be itchy. Sinus bradycardia. IV fluid should be discontinued immediately if they enter convalescence phase. If the patient does not gain appetite and has distended abdomen with decreased or no bowel sound, check for hypokalemia which is commonly found in this phase (due to diuresis). Fruit or fruit juice or KCl solution orally are recommended to correct this electrolyte abnormality

29. Complications of DHF/DSS Primary complications Gastrointestinal bleeding Liver failure Dengue encephalopathy Acute renal failure Secondary Complications Respiratory failure secondary to massive pleural effusion and gross ascites Acute pulmonary oedema Acute respiratory distress syndrome Nosocomial infection

30. 4. Indications for discharge At least 24 hours after defervescence without using antipyretic. Good appetite. Visible good general conditions. Diuresis. Stable Hct at baseline value 35%-40%. At least 2 days after shock. No dyspnea or tachypnea. Platelet ³ 50,000 cell/cu.mm. No complications.

31. Prognosis Morens states that the rapid clinical response to aggressive fluids and electrolytes in even moribund children with DHF/DSS &quot;is among the most dramatic events in clinical medicine.&quot; Treated promptly, children in shock and coma can wake up and return to near normalcy within hours. Convalescence may be prolonged, with weakness and mental depression. Continued bone pain, bradycardia, and premature ventricular contractions (PVCs) are common. Survival is related directly to early hospitalization and aggressive supportive care. Dengue fever is not contagious through person-to-person contact.

32. Prevention AND Mortality/Morbidity methods guarantee prevention of Dengue fever. Avoid mosquito bites Mosquito repellant Protective clothing Window screens Remove water-filled mosquito breeding areas Dengue vaccine - not yet available but being researched. Mortality/Morbidity Treated DHF/DSS is associated with a 3% mortality rate. Untreated DHF/DSS is associated with a 50% mortality rate. Key words: Dengue haemorrhagic fever, Tourniquet test, Leukopenia, Fluid Management, Colloidal solutionIntroduction