The document discusses dengue and dengue hemorrhagic fever (DHF) in adults. It provides epidemiological data showing over 2.5 billion people in 100 countries are at risk of dengue infection. It reviews clinical manifestations and laboratory findings in adults with dengue fever (DF) and DHF. Key points include thrombocytopenia being common, with over 25% of DHF patients having platelet counts less than 20,000/mm3. Bleeding is a risk, especially for those with severe thrombocytopenia, liver dysfunction, or shock. Proper fluid management and monitoring are important for treating DHF to avoid complications.

2. DEN 1 DEN 2 DEN 3 DEN 4

6. Expert consensus groups in Latin America (Havana, Cuba, 2007), South-East Asia (Kuala Lumpur, Malaysia, 2007), and at WHO headquarters in Geneva, Switzerland in 2008 agreed that: “ dengue is one disease entity with different clinical presentations and often with unpredictable clinical evolution and outcome”; Who Guideline 2009

8. DF and DHF in Thailand Year Number of patients 0-4 years 5-9 years 10-14 years > 15 years Total 1998 19,837 48,171 36,427 25,519 (20%) 12,954 1999 4,101 8,163 6,747 5,814 (23%) 24,826 2000 2,758 6,181 5,260 4,418 (23%) 18,617 2001 16,952 43,813 40,213 38,337 (27%) 139,355 2002 11,380 33,299 35,248 34,960 (30%) 114,833

11. Travel - Associated Dengue Infections - United States, 2001-2004 The median age of the 71 patients for whom age was reported was 38 years ( range : 8 months--72 years ). The most commonly reported symptoms were fever ( 54 patients [ 96% ]) , headache ( 36 [ 64% ]) , myalgias ( 32 [ 57% ]) , chills ( 19 [ 34% ]) , and rash ( 20 [ 36% ]). Fourteen patients ( 25% ) had at least one hemorrhagic symptom ( e . g . , petechiae, purpura, hemoptysis, hematemesis, hematuria, or epistaxis ) , and nine ( 16% ) had elevated liver transaminases . 15 patients ( 27% ) required hospitalization, including one who died . Travel destinations were available for 66 patients ( 86% ) ; 20 patients ( 30% ) reported recent travel to a Caribbean island during the 2 weeks before illness onset, 14 ( 21% ) to Pacific islands , 11 ( 17% ) to Asia , 10 ( 15% ) to Central America , 10 ( 15% ) to South America , and one ( 2% ) to Africa .

12. J Travel Med 2009

13. Eli Schwartz ; EID 2008

14. Severe Dengue Virus Infection in Travelers: Risk Factors and Laboratory Indicators Ole Wichmann, ; Clin Infect Dis 2007 219 dengue virus infections imported from various regions of endemicity were reported. Serological analysis revealed a secondary immune response in 17 %. Spontaneous bleeding was observed in 17(8%) patients and was associated with increased serum alanine and aspartate aminotransferase levels and lower median platelet counts. 23(11%) travelers had severe clinical manifestations (internal hemorrhage, plasma leakage, shock, or marked thrombocytopenia). A secondary immune response was significantly associated with both spontaneous bleeding and other severe clinical manifestations.

15. Dengue virus infection Asymptomatic Symptomatic Undifferentiated fever Dengue fever Dengue hemorrhagic fever Without Unusual No shock Dengue shock hemorrhage hemorrhage syndrome (DSS) DF DHF Primary infection Secondary infection ?

16. Dengue Fever Fever , myalgia, headache Breakbone fever Rash : petechiae Tourniquet test-positive Leukopenia( WBC < 5,000 /cumm ) , thrombocytopenia Unusual hemorrhage

17. Criteria for diagnosis of DHF Clinical : 1. Fever , acute onset, high continuous for 2-7 days 2. Haemorrhagic manifestations including a positive tourniquet test and any of the following: petechiae, purpural, echymosis epistaxis, gum bleeding, hematemesis, 3. Enlargement of liver 4. Shock Laboratory 1. Thrombocytopenia ( < 100,000/mm 3 ) 2. Hemoconcentration ( > 20% increase in Hct level) Leakage syndrome : High Hct, pleural effusion, ascitis, thickening gallbladder

18. A. T. A. Mairuhu ATA; Eur J Clin Microbiol Infect 2004 Dengue: an arthropod-borne disease of global importance

19. Clinical manifestations of DF/DHF in adults(Tantawichien T) DF/DHF DF DHF (n = 140) (n=89) (n=51) Age :Mean + SD (years) : Range (years) : Median (years) 15-20 years (%) >20-30 years (%) >30 years (%) Total duration of fever Mean + SD (days) Range (days) Fever 5-7 days 26.9 15-67 24 41.4 31.4 27.2 5.2 2-8 75.7% 28.6 + 13.2 15-67 38.3 34.8 5.26 + 1.1 2-8 23.4 + 7.6 15-44 47 17.6 5.22 + 0.96 3-8 80.4

20. Dengue infection 14 yr boy

21. Dengue infection 14 yr boy

22. แนวทางการวินิจฉัยและการรักษาไข้เดงกี และไข้เลือดออกเดงกีในผู้ใหญ่ สมาคมโรคติดเชื้อแห่งประเทศไทย สมาคมโลหิตวิทยาแห่งประเทศไทย สมาคมเวชบำบัดวิกฤติแห่งประเทศไทย

25. Who Guideline 2009

26. Severe dengue should be considered if the patient is from an area of dengue risk presenting with fever of 2–7 days plus any of the followings • There is evidence of plasma leakage, such as: – high or progressively rising haematocrit; – pleural effusions or ascites; – circulatory compromise or shock (tachycardia, cold and clammy extremities, capillary refill time greater than three seconds, weak or undetectable pulse, narrow pulse pressure or, in late shock, unrecordable blood pressure). • There is significant bleeding. • There is an altered level of consciousness (lethargy or restlessness, coma, convulsions). • There is severe gastrointestinal involvement (persistent vomiting, increasing or intense abdominal pain, jaundice). • There is severe organ impairment (acute liver failure, acute renal failure, encephalopathy or encephalitis, or other unusual manifestations, cardiomyopathy) or other unusual manifestations. Who Guideline 2009

27. Pitfalls in Management of DF/DHF in Adults Severe bleeding : severe thrombocytopenia, operation Hemodynamic abnormality DSS in adults Monitoring in DHF/DSS adult patients Rate and volume of IV replacement in DHF/DSS Avoid inadequate volume / volume overload Elevated liver enzyme : More unnecessary drugs ( toxicity, adverse reaction) Unusual manifestations in a few cases :

29. Dx Dengue shock syndrome 22/11/09 Lab Hct 46.6 % WBC 3,620 PMNs 70 Lymp 18 Plt 20,900

30. Date Time BP Fluid Rate (ml/h) In- takE (ml) Out- put (ml) Med Lab D 1 80/50 5%DNSS NSS Dextran 500-1,000 1.5h 100/60 60 2.5h 110/80 FFP2u PRC2u 5%DNSS Hct46  36% + Vaginal bleed 3,125 1,155 Hct = 46%

31. Date Time BP Fluid Rate (ml/h) In- takE (ml) Out- put (ml) Med Lab D 2 110/60 5%DNSS Dextran FFP2U 200 Hct46% Plt11,500 WBC 5,380 (N65%,L20%) AST/ALT994/411 TB/DB 1.89/1.05 PT20.3,PTT64 INR 1.8 16 h 4,000 2,455

33. Follow to command BP 90/50 Hct 49.4 , Plt 9,000 , WBC 14,600(N 81%,L5%) AST/ALT 3,567/996,ALP 110 TB/DB 3.32/2.07 PT 22 , PTT 75, INR 2 BUN/Cr 24/2.41 NG content: fresh blood, hematochesia FU Hct 49  33  20 MN : FFP(6u),LPRC(7U),Plt CVVH IV PPI Ceftriaxone 2 g iv KCMH D1 Fever D7 KCMHD2 Fever D8 KCMHD3 Fever D9 KCMHD4 KCMHD5 KCMHD6

34. Pitfalls in Management of DF/DHF in Adults Severe bleeding : severe thrombocytopenia, operation Hemodynamic abnormality DSS in adults Monitoring in DHF/DSS adult patients Rate and volume of IV replacement in DHF/DSS Avoid inadequate volume / volume overload Elevated liver enzyme : More unnecessary drugs ( toxicity, adverse reaction) Unusual manifestations in a few cases:

35. If major bleeding occurs it is usually from the gastrointestinal tract, and/or vagina in adult females. Internal bleeding may not become apparent for many hours until the first black stool is passed. Patients at risk of major bleeding are those who: – have prolonged/refractory shock; – have hypotensive shock and renal or liver failure and/or severe and persistent metabolic acidosis; – are given non-steroidal anti-inflammatory agents; – have pre-existing peptic ulcer disease; – are on anticoagulant therapy; – have any form of trauma, including intramuscular injection. Patients with haemolytic conditions are at risk of acute haemolysis with haemoglobinuria and will require blood transfusion.

37. Platelet counts (x10 3 /mm 3 ) Day -2 : mean + SD Day 0 : mean + SD < 20,000/mm 3 on day 0 Tantawichien T. Laboratory findings of DF/DHF in adults DF/DHF DF DHF (n=140) (n=89) (n=51) 94.6 + 39.4 38.0 + 34.6 91.2 + 39.5 47.2 + 34.6 25.3% 102.2 + 42.8 22.8 + 17.8* 56.9%

38. DIFFERENCES IN DENGUE SEVERITY IN INFANTS, CHILDREN, AND ADULTS IN A 3-YEAR HOSPITAL-BASED STUDY IN NICARAGUA SAMANTHA NADIA HAMMOND : Am J Trop Med Hyg 2005

39. Jacqueline Deen, Lucy Lum, Eric Martinez, Lian Huat Tan. Dengue: guidelines for diagnosis, treatment, prevention and control -- New edition. WHO 2009 Severe bleeding can be recognized by: – persistent and/or severe overt bleeding in the presence of unstable haemodynamic status, regardless of the haematocrit level; – a decrease in haematocrit after fluid resuscitation together with unstable haemodynamic status; – refractory shock that fails to respond to consecutive fluid resuscitation of 40-60 ml/kg; – hypotensive shock with low/normal haematocrit before fluid resuscitation; – persistent or worsening metabolic acidosis + a well- maintained systolic blood pressure, especially in those with severe abdominal tenderness and distension.

40. Clinical manifestations of DF/DHF in adults(Tantawichien T) DF/DHF DF DHF (n = 140) (n=89) (n=51) Bleeding manifestations Petechiae Epistaxis Gum bleeding Hematemesis Vaginal bleeding Bleeding > 2 sites 35.7% 22.1% 7.8% 7.1% 2.1% 24.6% 27% 24.7% 14.6% 4.4% 5.5% 0% 21% 6.7% 54.9% 35.2% 14.3% ’ 10.2% 5.9% 31.6% 19.6%

41. Gastroduodenoscopic findings in 26 Dengue patients Findings No. of cases % DU 11 42.3 GU + superficial gastritis 3 11.5 DU + superficial gastritis 3 11.5 GU + DU + superficial 3 11.5 gastritis GU or DU or hemorrhagic 6 23 gastritis or erosion Tsai CJ; Am J Gastroenterology 1991

42. Chiu YC, Am J Trop Med 2005 Patients having PU with recent hemorrhage require more transfusions with PRBCs and FFP for management of UGI bleeding than do those without recent hemorrhage. PU with recent hemorrhage is encountered during an endoscopic procedure, endoscopic injection therapy is not an effective adjuvant treatment of hemostasis in dengue patients with UGI bleeding.

43. A FATAL CASE OF SPONTANEOUS RUPTURE OF THE SPLEEN DUE TO DENGUE VIRUS INFECTION: CASE REPORT AND REVIEW. Southeast Asian J Trop Med Hyg 2008 Apatcha Pungjitprapai, Terapong Tantawichien.

45. Lack of efficacy of prophylactic platelet transfusion for severe thrombocytopenia in adults with acute uncomplicated dengue infection . Lyn DC; Clin Infect Dis 2009 Thrombocytopenia in dengue infection raises concerns about bleeding risk . Of 256 patients with dengue infection who developed thrombocytopenia ( platelet count, < 20 x 10 3 platelets / microL ) without prior bleeding , 188 were given platelet transfusion . Subsequent bleeding, platelet increment, and platelet recovery were similar between patients given transfusion and patients not given transfusion . Prophylactic platelet transfusion was ineffective in preventing bleeding in adult patients with dengue infection .

46. Pitfalls in Management of DF/DHF in Adults Severe bleeding : severe thrombocytopenia, operation Hemodynamic abnormality DSS in adults Monitoring in DHF/DSS adult patients Rate and volume of IV replacement in DHF/DSS Avoid inadequate volume / volume overload Elevated liver enzyme : More unnecessary drugs ( toxicity, adverse reaction) Unusual manifestations in a few cases:

47. Natural History of DHF ; 3 stages Acute febrile stage Fever 2-7 days, nausea /vomiting, myalgia, flushed face, rash Critical stage Plasma leakage - hypotension , abdominal pain, liver tenderness, abnormal bleeding Convalescent stage Increased appetite, rash , normotention, bradycardia and decreased Hct

53. Anon Srikiatkhachorn ,Pediat Infect Dis J 2007

54. Physical findings of DF/DHF in adults(Tantawichien T) DF/DHF DF DHF (n = 140) (n=89) (n=51) Hypotension/a pulse pressure < 20 mmHg Pleural effusion (by CXR) Epigastrium/RUQ tenderness Hepatomegly (+by U/S) Splenomegaly (by U/S only) Ascites (by U/S only) 2.1% 18.6% 21.4% 2.1% 3.6% 0% 0% 10.1% 11.2% 0% 0% 5.8% 29.4% 29.4% 39.2% 5.9% 9.8%

55. DIFFERENCES IN DENGUE SEVERITY IN INFANTS, CHILDREN, AND ADULTS IN A 3-YEAR HOSPITAL-BASED STUDY IN NICARAGUA SAMANTHA NADIA HAMMOND : Am J Trop Med Hyg 2005

56. Wichmann O: Tropical Med Int Health 2004

57. DIFFERENCES IN DENGUE SEVERITY IN INFANTS, CHILDREN, AND ADULTS IN A 3-YEAR HOSPITAL-BASED STUDY IN NICARAGUA SAMANTHA NADIA HAMMOND : Am J Trop Med Hyg 2005

58. DIFFERENCES IN DENGUE SEVERITY IN INFANTS, CHILDREN, AND ADULTS IN A 3-YEAR HOSPITAL-BASED STUDY IN NICARAGUA SAMANTHA NADIA HAMMOND : Am J Trop Med Hyg 2005

59. 0 6 12 18 24 Hour after Shock 10 8 6 4 2 IV fluid mL/kg/hr Rate of IV Fluid for DHF ( Shock ) Crystalloid: 5% D/NSS NSS, 5% D/RA 5%D/RL Colloid : FFP, Dextran 10-5 5 3 3-1 Hct q 4 hr,record I/O Criteria : leakage, increased Hct > 20 % narrow pulse pressure

61. Causes of fluid overload are: – excessive and/or too rapid intravenous fluids; – incorrect use of hypotonic rather than isotonic crystalloid solutions; – inappropriate use of large volumes of intravenous fluids in patients with unrecognized severe bleeding; – inappropriate transfusion of fresh-frozen plasma, platelet concentrates and cryoprecipitates; – continuation of intravenous fluids after plasma leakage has resolved (24–48 hours from defervescence); – co-morbid conditions such as congenital or ischaemic heart disease, chronic lung and renal diseases. WHO Guideline 2009

62. Yes Possible-DHF stage II High Hct (>50%) or Leakage syndrome :  ed Hct > 20%, pleural effusion, ascites or Hypotension Hypotension, pulse pressure < 20 mmHg, poor tissue perfusion Consider vasopressor/ Invasive monitoring Check volume loss eg. GI bleeding Close monitoring facility Monitoring Vital sign every 1-4 hrs Clinical sign/symptom Serial Hct (1-4 times/day), platelet count ( option ) - Intake/output (u/o 0.5-1 ml/kg/hr ) Keep urine sp. gr. 1010-1020 v/s Oral/iv fluid+ monitor Resuscitation: supportive care, IV NSS,(loading 500-1000 ml/hr) 1-2 hr after resuscitation 2 hrs after resuscitation Hypotension -Change IV fluid to: Plasma expanders, NSS + albumin

65. Natural History of DHF ; 3 stages Acute febrile stage Fever 2-7 days, nausea /vomiting, myalgia, flushed face, rash Critical stage Plasma leakage - hypotension , abdominal pain, liver tenderness, abnormal bleeding Convalescent stage Increased appetite, rash , normotention, bradycardia and decreased Hct

67. Pitfalls in Management of DF/DHF in Adults Severe bleeding : severe thrombocytopenia, operation Hemodynamic abnormality DSS in adults Monitoring in DHF/DSS adult patients Rate and volume of IV replacement in DHF/DSS Avoid inadequate volume / volume overload Elevated liver enzyme : More unnecessary drugs ( toxicity, adverse reaction) Unusual manifestations in a few cases:

68. Day of fever 4 5 6 7 8 9 10 11 39 BT 38 37 BP stable Bradycardia Fever no diarrhea N/V N/V N/V Hct 42 44 WBC/mm 4200 2,200 N/L (%) 65 /25 100 / 70 Platelet/mm3 80.000 47,000 SGOT/SGPT 5650/2690 849/862(TB/DB 4.5/3.5) 324/287( TB 2) AP 152 Albumin 3.5 Hemoculture neg no pleural effusion 24 year - old patient (male) 80/ Fever Hepatitis Thrombocytopenia Investigation ?

69. Liver function test in DF/DHF patients Kuo CH* Kalaganaroaj S** Tantawichien T. DF DF DHF DF DHF n=230 n=20 n=21 n=38 n=30 Age:Mean + SD SGOT : Mean + SD Range SGPT : Mean + SD Range Bilirubin Abnormal/range Akaline phasphatase Abnormal/range 41 + 12 220 + 341 17-3210 146 + 178 8-1177 7.2%0.2-35 16%320-536 3.7 + 1 64 + 46 35 + 18 4.3 + 1.2 124 + 166 51 + 59 28.6 + 13.2 258 + 436 17-2128 184 + 255 19-1171 0% all<1.5 23.4+7.6 399 + 554 15-2580 261+321 3-1382 1 case (5) all<1.5 *Kuo CH; Am J Trop Med Hyg 1992 **Kalayanarooj S; JID 1997

70. Mean transaminase levels ( U/I ) in relation to days after symptom onset in 270 patients. Days after onset of symptom Kuo CH; Am J Trop Med Hyg 1992

71. - Gastrointestinal - Nausea/vomiting, diarrhea - GI bleeding - Liver involvement - Hepatitis/fulminant liver failure 1) Viral factor 2) Prolonged shock 3) Reye ’ s syndrome 4) Drug intoxication 5) Pre-existing liver diseases - Ascites - Appendicitis - Splenomegaly Manifestations in dengue virus infection

72. Transactions of the Royal Society of Tropical Medicine and Hygiene 2007 The mean time from onset of fever to abdominal pain was 2.2 days ( SD 0.9) . Leucocytopenia and thrombocytopenia occurred by the third or fourth day of illness in all patients.

73. Pitfalls in Management of DF/DHF in Adults Severe bleeding : severe thrombocytopenia, operation Hemodynamic abnormality DSS in adults Monitoring in DHF/DSS adult patients Rate and volume of IV replacement in DHF/DSS Avoid inadequate volume / volume overload Elevated liver enzyme : More unnecessary drugs ( toxicity, adverse reaction) Unusual manifestations in a few cases:

74. Viral Etiology of Encephalitis in Thailand Japanese encephalitis virus Dengue virus Herpes simplex Enteroviruses Rabies Others: mumps virus, HIV, HHV-6...

75. Details of the co-infections in the 14 dengue patients Sex Age Coinfections Distinctive Clinical Clues (yr) Organism Diagnosis F M F M F F F F F M M M M F 9/12 4 7 14 3/12 1 6 9 11 12 1 3/12 6 6/12 Burkholderia pseudomallei Burkholderia pseudomallei Varicella zoster Salmonella Shigella Salmonella Escherichia coli Salmonella Herpes simplex Escherichia coli Mycobacterium tuberculosis Streptococcus pneumoniae Shigella Mycoplasma pneumoniae Escherichia coli Melioidosis Melioidosis, disseminated Chickenpox Salmonellosis Shigellosis Diarrhea Vaginitis Salmonellosis Herpes labialis UTI Tuberculosis, pulmonary Pneumococcal bacteremia Shigellosis Mycoplasma pneumonia UTI Persistence of fever and dyspnea Persistence of fever, ARDS Vesicles Prolonged fever, diarrhea Drowsiness, convulsion Diarrhea, leukocytosis Diarrhea, convulsion Leukocytosis Vesicles Prolonged fever and cough Persistence of fever, leukocytosis Diarrhea Prolonged fever and cough

76. CLINICAL CHARACTERISTICS AND RISK FACTORS FOR CONCURRENT BACTEREMIA IN ADULTS WITH DENGUE HEMORRHAGIC FEVER LEE IK; J Trop Med Hyg 2004 C oncurrent bacteremia (dual infection =5.5% ) in patients DHF/DSS 100 patients with DHF/DSS ( 7 with a dual infection and 93 with DHF/DSS alone [controls]) Patients with a dual infection were older, and tended to have prolonged fever, higher frequencies of acute renal failure, GI bleeding, altered consciousness, unusual dengue manifestations, and DSS. Acute renal failure (odds ratio [OR] 51.45,P=0.002 , and prolonged fever (> 5 days) (OR 26.07 , p=0.017 were independent risk factors for dual infection. Bacteremia : Klebsiella pneumoniae, enterococci, Moraxella, Rosemonas

77. Concurrent Chikungunya and Dengue Virus Infections during Simultaneous Outbreaks, Gabon, 2007 Eric M. Leroy : Emerg Infect Dis 2009 An outbreak of febrile illness occurred in Gabon in 2007, with 20,000 suspected cases. Chikungunya or dengue-2 virus infections were identifi ed in 321 patients; 8 patients had documented co-infections. Aedes albopictus was identifi ed as the principal vector for the transmission of both viruses.

79. Wagner D, Emerg Infect Dis 2004

80. Tamblay PA; N Engl J Med 2008

81. Twelve (0.07%) of 16,521 blood donations tested were TMA-positive ( transcription-mediated amplification ) . Four were positive by RT-PCR (DENV serotypes 2 and 3). Virus was cultured from 3 of 4 RT-PCR – positive donations. One of the 12 TMA-positive donations was IgM-positive. Transfusion 2008

82. Treatment Supportive treatment, hydration Drugs : Acetaminophen,Anti-gastritis ; H2 blocker,NSAIDs Unnecessary drugs; muscle relaxant …… Antibiotic treatment ( 20-30 % case ) Transfusion : Platelet transfusion, PRC, FFP Procedure : catheter, NG tube, endoscopy, operation Adjunctive therapy : Steroid, IVIG Carbazochrom sodium sulfonate (AC-17), Recombinant activated factor VII, Desmopressin

84. Rajapakse S : Trans Royal Society Trop Med Hyg 2009 103 , 122 — 126

85. Efficacy of low dose dexamethasone in severe thrombocytopenia caused by dengue fever: a placebo controlled study S A M Kularatne, Postgrad Med 2009

87. Pitfalls in Management of DF/DHF in Adults Severe bleeding : severe thrombocytopenia, operation Hemodynamic abnormality DSS in adults Monitoring in DHF/DSS adult patients Rate and volume of IV replacement in DHF/DSS Avoid inadequate volume / volume overload Elevated liver enzyme : More unnecessary drugs ( toxicity, adverse reaction) Unusual manifestations in a few cases :

88. Thank you