1. The Perils of Travel Jeffrey H. Phillips, M.D., F.A.C.P. Internal Medicine Clinical Update October 26, 2005

2. Case History 50 year old plaintiff attorney and his wife vacationed in Costa Rica 6/12 – 6/20 50 year old plaintiff attorney and his wife vacationed in Costa Rica 6/12 – 6/20 4 days after returning home, he developed chills, weakness, nausea, and fever to 104 o. 4 days after returning home, he developed chills, weakness, nausea, and fever to 104 o. Went to PHP ER 6/26 where WBC 5600, Hct 40.7, platelets 185,000, normal urine and CMP, malaria smear negative, and CXR normal Went to PHP ER 6/26 where WBC 5600, Hct 40.7, platelets 185,000, normal urine and CMP, malaria smear negative, and CXR normal “…the sickest I have ever been.” “…the sickest I have ever been.”

3. Case history (continued) Seen in office 6/29 with T 99.5 o ; diffuse erythematous maculopapular rash over extremities and thorax, no petechiae; exam of pharynx, chest, heart, and abdomen normal; no adenopathy Seen in office 6/29 with T 99.5 o ; diffuse erythematous maculopapular rash over extremities and thorax, no petechiae; exam of pharynx, chest, heart, and abdomen normal; no adenopathy Lab: WBC 1800, Hct 47, and platelets not counted “due to significant platelet clumping” Lab: WBC 1800, Hct 47, and platelets not counted “due to significant platelet clumping” Dengue fever antibodies drawn 6/29: IgM 43 (positive > 11); IgG 2 (positive > 11) Dengue fever antibodies drawn 6/29: IgM 43 (positive > 11); IgG 2 (positive > 11)

4. What is dengue? Disease caused by any one of four closely related viruses (DEN-1, DEN-2, DEN-3, or DEN-4) Disease caused by any one of four closely related viruses (DEN-1, DEN-2, DEN-3, or DEN-4) Most common arboviral disease in the world; more than 2/5 of world population at risk (2.5 billion people) Most common arboviral disease in the world; more than 2/5 of world population at risk (2.5 billion people) Estimated 50-100 million cases annually Estimated 50-100 million cases annually 250,000-500,000 with dengue hemorrhagic fever 250,000-500,000 with dengue hemorrhagic fever 24,000 deaths 24,000 deaths

5. History From African word that means “bone breaking” From African word that means “bone breaking” First reports of dengue fever epidemics occurred simultaneously in 1779-80 in three locations: Africa, Asia and North America (Philadelphia). First reports of dengue fever epidemics occurred simultaneously in 1779-80 in three locations: Africa, Asia and North America (Philadelphia). After World War II, largely due to increased international travel, dengue fever became established as a global pandemic. After World War II, largely due to increased international travel, dengue fever became established as a global pandemic. Today, dengue epidemic activity is found in large portions of Central and South America, the Caribbean, Africa, Southeast Asia, and even parts of Australia and New Zealand. Today, dengue epidemic activity is found in large portions of Central and South America, the Caribbean, Africa, Southeast Asia, and even parts of Australia and New Zealand.

7. Dengue Virus Belongs to the family Flaviviridae (flavoviruses) Belongs to the family Flaviviridae (flavoviruses) Transmitted by the Aedes aegypti and A. albopictus mosquitoes Transmitted by the Aedes aegypti and A. albopictus mosquitoes Composed of single-stranded RNA Composed of single-stranded RNA Infection with one serotype is thought to produce lifelong immunity to that serotype but only a few months immunity to the others Infection with one serotype is thought to produce lifelong immunity to that serotype but only a few months immunity to the others Mosquito remains infected for life but only causes illness in humans Mosquito remains infected for life but only causes illness in humans

8. Aedes aegypti Mosquito

9. Epidemiology Aedes mosquitos found worldwide between latitudes 35 o N and 35 o S Aedes mosquitos found worldwide between latitudes 35 o N and 35 o S Aedes mosquitos are efficient vectors: Aedes mosquitos are efficient vectors: Highly susceptible to dengue virus Highly susceptible to dengue virus Feeds preferentially on human blood Feeds preferentially on human blood Daytime feeder with imperceptible bite Daytime feeder with imperceptible bite Restless; several people may be bitten in a short period for one blood meal Restless; several people may be bitten in a short period for one blood meal Incidence in travelers returning from tropics Incidence in travelers returning from tropics 2 % in early 1990s to 16 % in early 2000s 2 % in early 1990s to 16 % in early 2000s

10. Reinfestation by Aedes aegypti in the Americas 1970 2002

11. Worldwide increase of DHF South East Asia: South East Asia: 1960s: <10,000 cases 1960s: <10,000 cases 1990s: > 200,000 cases 1990s: > 200,000 cases Americas: Americas: 1980s: 15,000 cases 1980s: 15,000 cases 1990s: 56,000 cases 1990s: 56,000 cases 2001 alone: 15,000 cases 2001 alone: 15,000 cases

12. Dengue in the U.S.A. Dengue epidemics occurred in the USA in the 1800s and the first half of the 1900s Dengue epidemics occurred in the USA in the 1800s and the first half of the 1900s Recent indigenous transmission (Texas) Recent indigenous transmission (Texas) 1980: 23 cases, first locally acquired since 1945 1980: 23 cases, first locally acquired since 1945 1986: 9 cases 1986: 9 cases 1995: 7 cases 1995: 7 cases 1997: 3 cases 1997: 3 cases 1998: 1 case 1998: 1 case 1999: 18 cases 1999: 18 cases 2001 (Hawaii); Aedes albopictus implicated in 122 dengue infections 2001 (Hawaii); Aedes albopictus implicated in 122 dengue infections

13. Replication and Transmission of Dengue Virus (Part 1) 1. Virus transmitted to human in mosquito saliva 2. Virus replicates in regional nodes 3. Virus infects white blood cells and lymphatic tissues 4. Virus released and circulates in blood 3 4 1 2

14. Replication and Transmission of Dengue Virus (Part 2) 5. Second mosquito ingests virus with blood 6. Virus replicates in mosquito midgut and other organs, infects salivary glands 7. Virus replicates in salivary glands 6 7 5

15. Dengue Clinical Syndromes Undifferentiated febrile illness Undifferentiated febrile illness Classic dengue fever Classic dengue fever Dengue hemorrhagic fever Dengue hemorrhagic fever Dengue shock syndrome Dengue shock syndrome Other unusual syndromes Other unusual syndromes

16. Undifferentiated Fever May be the most common manifestation of dengue May be the most common manifestation of dengue Most infections in children under 15 years are asymptomatic or minimally symptomatic Most infections in children under 15 years are asymptomatic or minimally symptomatic Often accompanied by maculopapular rash and URIs, especially pharyngitis Often accompanied by maculopapular rash and URIs, especially pharyngitis

17. Classic Dengue Fever Older children, adolescents, and adults Older children, adolescents, and adults Incubation period 3 to 14 days (usual 4 to 7) after bite Incubation period 3 to 14 days (usual 4 to 7) after bite Sudden onset of fever in all patients; lasts 5 to 7 days Sudden onset of fever in all patients; lasts 5 to 7 days Frontal headache and retro-orbital pain Frontal headache and retro-orbital pain Severe myalgias and arthralgias (“break bone fever”) Severe myalgias and arthralgias (“break bone fever”) Maculopapular rash in about 50 % Maculopapular rash in about 50 % Nausea/vomiting; taste aberrations Nausea/vomiting; taste aberrations Leukopenia, thrombocytopenia, elevated LFTs, and hyponatremia Leukopenia, thrombocytopenia, elevated LFTs, and hyponatremia

19. Hemorrhagic manifestations of dengue Skin hemorrhages: petechiae, purpura, ecchymoses Skin hemorrhages: petechiae, purpura, ecchymoses Gingival and nasal bleeding Gingival and nasal bleeding GI bleeding: hematemesis, melena, hematochezia GI bleeding: hematemesis, melena, hematochezia Hematuria Hematuria Gum bleeding, epistaxis; menorrhagia less common Gum bleeding, epistaxis; menorrhagia less common Positive tourniquet test for capillary fragility Positive tourniquet test for capillary fragility

20. Tourniquet test Inflate blood pressure cuff to a point midway between systolic and diastolic for 5 minutes Inflate blood pressure cuff to a point midway between systolic and diastolic for 5 minutes Positive test: 20 or more petechiae in a 1-in square patch on the forearm Positive test: 20 or more petechiae in a 1-in square patch on the forearm

21. Dengue hemorrhagic fever Primarily a disease of children < 15 Primarily a disease of children < 15 Begins as fever subsides; patients get restless or lethargic, exhibit bleeding manifestations, and have abdominal pain and vomiting Begins as fever subsides; patients get restless or lethargic, exhibit bleeding manifestations, and have abdominal pain and vomiting Hallmark of DHF is really capillary leakage, not hemorrhage Hallmark of DHF is really capillary leakage, not hemorrhage Autopsies show serous effusions of pericardial, peritoneal, and fluid spaces as well as petechial hemorrhages over most organs Autopsies show serous effusions of pericardial, peritoneal, and fluid spaces as well as petechial hemorrhages over most organs

22. A B PEI = A/B x 100 Pleural effusion Pleural effusion

23. Clinical Case Definition for Dengue Hemorrhagic Fever Fever, or recent history of acute fever Fever, or recent history of acute fever Hemorrhagic manifestations Hemorrhagic manifestations Low platelet count (100,000/mm 3 or less) Low platelet count (100,000/mm 3 or less) Objective evidence of “leaky capillaries:” Objective evidence of “leaky capillaries:” elevated hematocrit (20% or more over baseline) elevated hematocrit (20% or more over baseline) low albumin low albumin pleural, peritoneal, or pericardial effusions pleural, peritoneal, or pericardial effusions 4 Necessary Criteria:

24. Signs and Symptoms in 57 Hospitalized Cases of DHF, Puerto Rico, 1990 - 1991 SIGNS AND SYMPTOMS FREQUENCY PERCENT Fever57100 % Rash27 47.4% Hepatomegaly 6 10.5% Effusions 3 5.3% Frank shock 3 5.3% Coma 2 3.5% Any hemorrhage57100 %

25. Hemorrhagic Signs and Symptoms in 57 Hospitalized Cases of DHF, Puerto Rico, 1990 - 1991 SIGNS & SYMPTOMS FREQUENCY PERCENT Microscopic hematuria28 51.9% Petechiae26 45.6% Epistaxis13 22.8% Gingival hemorrhage 8 14.0% Blood in stools 8 14.0% Positive tourniquet test 5 31.3%

26. Hemorrhagic Signs and Symptoms in 57 Hospitalized Cases of DHF, Puerto Rico, 1990 - 1991 SIGNS & SYMPTOMS FREQUENCY PERCENT Blood in vomitus 4 7.0% Bleeding venipuncture 4 7.0% Hemoptysis 3 5.3% Vaginal hemorrhage 2 3.5% Gross hematuria 2 3.5% Other hemorrhage 2 3.5%

27. Warning signs in DHF that shock is impending Abdominal pain - intense and sustained Abdominal pain - intense and sustained Persistent vomiting Persistent vomiting Abrupt change from fever to hypothermia, with sweating and prostration Abrupt change from fever to hypothermia, with sweating and prostration Change in level of consciousness (restlessness or somnolence) Change in level of consciousness (restlessness or somnolence) Sudden decrease in platelet count Sudden decrease in platelet count

28. Clinical Case Definition for Dengue Shock Syndrome 4 criteria for DHF plus… 4 criteria for DHF plus… Evidence of circulatory failure manifested indirectly by all of the following: Evidence of circulatory failure manifested indirectly by all of the following: Rapid and weak pulse Rapid and weak pulse Narrow pulse pressure ( 20 mm Hg) OR hypotension for age Narrow pulse pressure (  20 mm Hg) OR hypotension for age Cold, clammy skin, altered mental status Cold, clammy skin, altered mental status Frank shock is direct evidence of circulatory failure Frank shock is direct evidence of circulatory failure

29. Who is at risk for DHF and DSS? Major factor is pre-existing anti-dengue antibody Major factor is pre-existing anti-dengue antibody previous infection previous infection maternal antibodies in infants maternal antibodies in infants Virus strain and serotype (DEN-2>3>4>1) Virus strain and serotype (DEN-2>3>4>1) Age (youngest and oldest more likely) Age (youngest and oldest more likely) Host genetics (HLA determined susceptibility) Host genetics (HLA determined susceptibility) Hypothesis of antibody-dependent enhancement Hypothesis of antibody-dependent enhancement

30. Neutralizing antibody to Dengue 1 virus 1 1 Dengue 1 virus 1 Homologous Antibodies Form Non-infectious Complexes Non-neutralizing antibody 1 1 Complex formed by neutralizing antibody and virus

31. Non-neutralizing antibody to Dengue 1 virus Dengue 2 virus 2 2 2 2 2 Heterologous Antibodies Form Infectious Complexes Complex formed by non-neutralizing antibody and virus 2

32. 2 2 2 2 2 2 2 2 2 2 Heterologous Complexes Enter More Monocytes, Where Virus Replicates Non-neutralizing antibody Dengue 2 virus 2 Complex formed by non- neutralizing antibody and Dengue 2 virus 2

33. …infected monocytes release vasoactive substances …results in an amplified cascade of cytokines and complement activation …causing endothelial dysfunction, platelet destruction, and consumption of coagulation factors …leading to plasma leakage and hemorrhagic manifestations

34. Cases/hospitalizations – Brazil (Siquiera, et al; Emerging Infectious Diseases; Vol. 11, No. 1, p 50)

35. Other unusual syndromes Encephalopthy Encephalopthy Mono- and polyneuropathies Mono- and polyneuropathies Transverse myelitis Transverse myelitis Myocarditis Myocarditis Parotitis Parotitis Hepatic damage and jaundice Hepatic damage and jaundice Severe GI hemorrhage Severe GI hemorrhage

36. Making the diagnosis

37. Travel History Important for assessment of symptomatic patients in non-endemic areas Important for assessment of symptomatic patients in non-endemic areas Determine whether the patient traveled to a dengue- endemic area Determine whether the patient traveled to a dengue- endemic area Determine when the travel occurred Determine when the travel occurred If the patient developed fever more than 2 weeks after travel, eliminate dengue from the differential diagnosis If the patient developed fever more than 2 weeks after travel, eliminate dengue from the differential diagnosis

40. Other Flavivirus infections in travelers Yellow fever (Sub-Saharan Africa; South America) Yellow fever (Sub-Saharan Africa; South America) Japanese encephalitis (Asia) Japanese encephalitis (Asia) Tick-borne encephalitis (Europe) Tick-borne encephalitis (Europe) West Nile fever (Africa; Middle East; Europe; North America) West Nile fever (Africa; Middle East; Europe; North America) Dengue fever (Asia; Central, South, and North Americas; Pacific; Africa) Dengue fever (Asia; Central, South, and North Americas; Pacific; Africa)

41. Differential diagnosis of dengue Arboviruses Arboviruses Chikungunya (often mistaken for dengue in SE Asia) Chikungunya (often mistaken for dengue in SE Asia) Viral diseases Viral diseases Hantavirus; measles; rubella; enteroviruses; influenza Hantavirus; measles; rubella; enteroviruses; influenza Bacterial diseases Bacterial diseases Meningococcemia; scarlet fever; typhoid Meningococcemia; scarlet fever; typhoid Parasitic diseases Parasitic diseases Leptospirosis; rickettsial diseases; malaria Leptospirosis; rickettsial diseases; malaria

42. Clinical Evaluation Blood pressure Blood pressure Evidence of bleeding in skin or other sites Evidence of bleeding in skin or other sites Hydration status Hydration status Evidence of increased vascular permeability- - pleural effusions, ascites Evidence of increased vascular permeability- - pleural effusions, ascites Tourniquet test Tourniquet test

43. Tourniquet test Inflate blood pressure cuff to a point midway between systolic and diastolic for 5 minutes Inflate blood pressure cuff to a point midway between systolic and diastolic for 5 minutes Positive test: 20 or more petechiae in a 1-in square patch on the forearm Positive test: 20 or more petechiae in a 1-in square patch on the forearm

44. Laboratory Tests in Dengue Fever Clinical laboratory tests Clinical laboratory tests CBC--WBC, platelets, hematocrit CBC--WBC, platelets, hematocrit Albumin Albumin Liver function tests Liver function tests Urine--check for microscopic hematuria Urine--check for microscopic hematuria Dengue-specific tests Dengue-specific tests Virus isolation Virus isolation Serology Serology

46. Temperature, Virus Positivity and Anti-Dengue IgM, by Fever Day Dengue IgMMean Max. TemperatureVirus Adapted from Figure 1 in Vaughn et al., J Infect Dis, 1997; 176:322-30. Fever Day 0 20 40 60 80 100 Percent Virus Positive -4-3-20123456 39.5 39.0 38.5 38.0 37.5 37.0 Temperature (degrees Celsius) Dengue IgM (EIA units) 300 150 0 75 225

47. Treatment

48. Mild and classic dengue Outpatient treatment Outpatient treatment Acetaminophen (not aspirin or NSAIDs) Acetaminophen (not aspirin or NSAIDs) Fluid replacement Fluid replacement Bedrest Bedrest Avoid injections Avoid injections Recheck platelets and Hct every 24 hours Recheck platelets and Hct every 24 hours

49. DHF and DSS If platelets < 100,000/mm 3 or hemorrhagic manifestations, admit to hospital If platelets < 100,000/mm 3 or hemorrhagic manifestations, admit to hospital Typically occurs on day of defervescence (4 to 7 days after onset of illness); decrease in platelets precedes rise in Hct (diagnostic of dengue) Typically occurs on day of defervescence (4 to 7 days after onset of illness); decrease in platelets precedes rise in Hct (diagnostic of dengue) Rise in Hct of 20% indicates considerable plasma loss and requires ICU care and IVFs Rise in Hct of 20% indicates considerable plasma loss and requires ICU care and IVFs Worsening shock requires colloid or crystalloid Worsening shock requires colloid or crystalloid Monitor Hct and reduce IVFs when Hct < 40 Monitor Hct and reduce IVFs when Hct < 40

50. Rehydrating Patients > 40 kg Volume required for rehydration is twice the recommended maintenance requirement Volume required for rehydration is twice the recommended maintenance requirement Formula for calculating maintenance volume: 1500 + 20 x (weight in kg - 20) Formula for calculating maintenance volume: 1500 + 20 x (weight in kg - 20) For example, maintenance volume for 80 kg patient is: 1500 + 20 x (80-20) = 2700 ml For example, maintenance volume for 80 kg patient is: 1500 + 20 x (80-20) = 2700 ml The rehydration volume would be 2 x 2700, or 5400 ml (225ml/hr) The rehydration volume would be 2 x 2700, or 5400 ml (225ml/hr)

51. Mosquito avoidance Only needed until fever subsides, to prevent Aedes aegypti mosquitoes from biting patients, acquiring the virus, and biting others Only needed until fever subsides, to prevent Aedes aegypti mosquitoes from biting patients, acquiring the virus, and biting others Keep patient indoors or in a screened sickroom Keep patient indoors or in a screened sickroom Remember that virus positivity follows the fever Remember that virus positivity follows the fever

52. Temperature, Virus Positivity and Anti-Dengue IgM, by Fever Day Dengue IgMMean Max. TemperatureVirus Adapted from Figure 1 in Vaughn et al., J Infect Dis, 1997; 176:322-30. Fever Day 0 20 40 60 80 100 Percent Virus Positive -4-3-20123456 39.5 39.0 38.5 38.0 37.5 37.0 Temperature (degrees Celsius) Dengue IgM (EIA units) 300 150 0 75 225

53. Prognosis Classic dengue Classic dengue full recovery; convalescence may take weeks because of asthenia and depression full recovery; convalescence may take weeks because of asthenia and depression Dengue hemorrhagic fever Dengue hemorrhagic fever 10-20% mortality without aggressive fluid replacement 10-20% mortality without aggressive fluid replacement 0.2% with treatment 0.2% with treatment Dengue shock syndrome Dengue shock syndrome > 40% mortality without aggressive fluid replacement > 40% mortality without aggressive fluid replacement < 1% mortality with treatment < 1% mortality with treatment

54. Prevention

55. Personal measures Mosquito repellants with 20% to 30% DEET Mosquito repellants with 20% to 30% DEET Protective clothing that is permethrin- impregnated Protective clothing that is permethrin- impregnated Insecticides should be applied in dark areas indoors Insecticides should be applied in dark areas indoors Avoid repeated travel to countries where dengue is endemic (to avoid exposure to another serotype) Avoid repeated travel to countries where dengue is endemic (to avoid exposure to another serotype) Eliminate containers that could contain water Eliminate containers that could contain water

56. Reasons for Dengue Expansion in the Americas Extensive vector infestation, with declining vector control Extensive vector infestation, with declining vector control Unreliable water supply systems Unreliable water supply systems Increasing non-biodegradable containers and poor solid waste disposal Increasing non-biodegradable containers and poor solid waste disposal Increased air travel Increased air travel Increasing population density in urban areas Increasing population density in urban areas

57. Historical anecdote 1950’s and 60’s - the Pan American Health Organization tried to eradicate the Aedes aegypti in Central and South America. 1950’s and 60’s - the Pan American Health Organization tried to eradicate the Aedes aegypti in Central and South America. This isolated dengue fever outbreaks to parts of the Caribbean that had no eradication programs This isolated dengue fever outbreaks to parts of the Caribbean that had no eradication programs 1970’s - the program was discontinued due to incompetent funds and lack of priority in the political agenda 1970’s - the program was discontinued due to incompetent funds and lack of priority in the political agenda The mosquito soon started to re-infest regions in which it had been nearly eradicated. The mosquito soon started to re-infest regions in which it had been nearly eradicated. Today - the Aedes aegypti mosquito inhabits a broader geographical region than before eradication Today - the Aedes aegypti mosquito inhabits a broader geographical region than before eradication

58. Reinfestation by Aedes aegypti 1930s 1970 1998

59. Vector Control Methods: Chemical Control Larvicides may be used to kill immature aquatic stages Larvicides may be used to kill immature aquatic stages Ultra-low volume fumigation ineffective against adult mosquitoes Ultra-low volume fumigation ineffective against adult mosquitoes Mosquitoes may have resistance to commercial aerosol sprays Mosquitoes may have resistance to commercial aerosol sprays

60. Vector Control Methods: Biological and Environmental Control Biological control Biological control Largely experimental Largely experimental Option: place fish in containers to eat larvae Option: place fish in containers to eat larvae Environmental control Environmental control Elimination of larval habitats Elimination of larval habitats Most likely method to be effective in the long term Most likely method to be effective in the long term

61. Community Approaches Define communities at risk Define communities at risk Involvement at all levels of age, education Involvement at all levels of age, education Advantages: built-in manpower, help develop resources and empower community organizations Advantages: built-in manpower, help develop resources and empower community organizations Disadvantages: more difficult to organize, take longer to get off the ground Disadvantages: more difficult to organize, take longer to get off the ground

62. Example of Community Programs: Puerto Rico Elementary school and Head Start programs to teach children about dengue control Elementary school and Head Start programs to teach children about dengue control Public service announcements Public service announcements Interactive exhibit at the Children’s Museum Interactive exhibit at the Children’s Museum Boy Scout merit badge program Boy Scout merit badge program

63. Dengue Vaccine? No licensed vaccine at present No licensed vaccine at present Effective vaccine must be tetravalent (4 serotypes) Effective vaccine must be tetravalent (4 serotypes) Field testing of an attenuated tetravalent vaccine currently underway Field testing of an attenuated tetravalent vaccine currently underway Effective, safe and affordable vaccine will not be available in the immediate future Effective, safe and affordable vaccine will not be available in the immediate future

64. Trouble Ahead 2.5 billion people at risk world-wide 2.5 billion people at risk world-wide Widespread abundance of Aedes aegypti in at-risk areas Widespread abundance of Aedes aegypti in at-risk areas Increasing number of DHF cases due to reinfection Increasing number of DHF cases due to reinfection in the Americas, 50-fold increase in reported cases of DHF during 1989-1993 compared to 1984-1988 in the Americas, 50-fold increase in reported cases of DHF during 1989-1993 compared to 1984-1988

65. Summary Dengue is the most common cause of arboviral disease worldwide Dengue is the most common cause of arboviral disease worldwide The disease is more prevalent now that at any other time, and its prevalence is expected to increase The disease is more prevalent now that at any other time, and its prevalence is expected to increase A severe manifestation of dengue is dengue hemorrhagic fever, which is more common after a secondary infection A severe manifestation of dengue is dengue hemorrhagic fever, which is more common after a secondary infection A cost effective vaccine is needed A cost effective vaccine is needed

66. Case report - finale 50 year old attorney became ill 6/24, 4 days after returning from Costa Rica 50 year old attorney became ill 6/24, 4 days after returning from Costa Rica One week later, repeat WBC 5800, platelets 385,000 One week later, repeat WBC 5800, platelets 385,000 Convalescent titers: IgG rose > 4 x baseline level Convalescent titers: IgG rose > 4 x baseline level Out of work 2 weeks; full recovery over 4 weeks Out of work 2 weeks; full recovery over 4 weeks

67. CDC Outbreak Notice Released: July 19, 2005 “Dengue in Travelers, Costa Rica and Other Tropical and Subtropical Regions” Florida State Health Dept. reported 4 ill travelers who visited Costa Rica between June 18 and June 26 Florida State Health Dept. reported 4 ill travelers who visited Costa Rica between June 18 and June 26 All complained of fever and headache, 3 required hospitalization All complained of fever and headache, 3 required hospitalization In response, Ministry of Health in Costa Rica enhanced surveillance and mosquito control measures In response, Ministry of Health in Costa Rica enhanced surveillance and mosquito control measures

68. Big question… Why did this particular attorney not suffer the more severe forms of dengue from the bite of that annoying, bloodsucking pest? Why did this particular attorney not suffer the more severe forms of dengue from the bite of that annoying, bloodsucking pest? Professional courtesy Professional courtesy