Dengue

Clinical Manifestations and Epidemiology

CENTERS FOR DISEASE CONTROL AND PREVENTION

I. Virus, Vector and Transmission

Dengue Virus
Causes dengue and dengue hemorrhagic fever Is an arbovirus Transmitted by mosquitoes Composed of single-stranded RNA Has 4 serotypes (DEN-1, 2, 3, 4)

Dengue Viruses
Each serotype provides specific lifetime immunity, and short-term cross-immunity All serotypes can cause severe and fatal disease Genetic variation within serotypes Some genetic variants within each serotype appear to be more virulent or have greater epidemic potential

Transmission of Dengue Virus by Aedes aegypti

Mosquito feeds / acquires virus Extrinsic incubation period Mosquito refeeds / transmits virus

Intrinsic incubation period

Viremia
0 5 8 12 16 20

Viremia
24 28

Illness Human #1

DAYS
Human #2

Illness

Replication and Transmission of Dengue Virus (Part 1)

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

1
2 4 3

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

Aedes aegypti Mosquito

Aedes aegypti
Dengue transmitted by infected female mosquito Primarily a daytime feeder Lives around human habitation Lays eggs and produces larvae preferentially in artificial containers

II. Disease Surveillance and Control

Proactive Surveillance: Goals and Objectives

Provide early and precise information

time location virus serotype disease severity

Predict dengue transmission and guide implementation of control measures Link clinical and entomologic surveillance

Proactive Surveillance in Puerto Rico

Organization and Functions:

Blood samples obtained by private physicians, health centers, public and private hospitals Samples transported by staff from Health Department and private laboratories Samples tested at the CDC Dengue Branch Results provided to submitting source and Health Department vector control staff Analyses disseminated via Dengue Surveillance Summary

Vector Control Methods: Chemical Control

Larvicides may be used to kill immature aquatic stages Ultra-low volume fumigation ineffective against adult mosquitoes Mosquitoes may have resistance to commercial aerosol sprays

Vector Control Methods: Biological and Environmental Control

Biological control

Largely experimental Option: place fish in containers to eat larvae

Environmental control

Elimination of larval habitats Most likely method to be effective in the long

term

Purpose of Control
Reduce female vector density to a level below which epidemic vector transmission will not occur Based on the assumption that eliminating or reducing the number of larval habitats in the domestic environment will control the vector The minimum vector density to prevent epidemic transmission is unknown

Programs to Minimize the Impact of Epidemics

Education of the medical community Implementation of emergency contingency plan Education of the general population

III. Clinical Manifestations of Dengue and Dengue Hemorrhagic Fever

CENTERS FOR DISEASE CONTROL AND PREVENTION

Dengue Clinical Syndromes

Undifferentiated fever Classic dengue fever Dengue hemorrhagic fever Dengue shock syndrome

Undifferentiated Fever
May be the most common manifestation of dengue Prospective study found that 87% of students infected were either asymptomatic or only mildly symptomatic Other prospective studies including all agegroups also demonstrate silent transmission

DS Burke, et al. A prospective study of dengue infections in Bangkok. Am J Trop Med Hyg 1988; 38:172-80.

Clinical Characteristics of Dengue Fever

Fever Headache Muscle and joint pain Nausea/vomiting Rash Hemorrhagic manifestations

Signs and Symptoms of Encephalitis/Encephalopathy Associated with Acute Dengue Infection

Decreased level of consciousness: lethargy, confusion, coma Seizures Nuchal rigidity Paresis

Hemorrhagic Manifestations of Dengue

Skin hemorrhages: petechiae, purpura, ecchymoses Gingival bleeding Nasal bleeding Gastro-intestinal bleeding: hematemesis, melena, hematochezia Hematuria Increased menstrual flow

Clinical Case Definition for Dengue Hemorrhagic Fever

4 Necessary Criteria:
Fever, or recent history of acute fever Hemorrhagic manifestations Low platelet count (100,000/mm3 or less) Objective evidence of leaky capillaries:

elevated hematocrit (20% or more over baseline) low albumin pleural or other effusions

Clinical Case Definition for Dengue Shock Syndrome

4 criteria for DHF 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

Four Grades of DHF

Grade 1

Fever and nonspecific constitutional symptoms Positive tourniquet test is only hemorrhagic manifestation

Grade 2

Grade 1 manifestations + spontaneous bleeding

Grade 3

Signs of circulatory failure (rapid/weak pulse, narrow

pulse pressure, hypotension, cold/clammy skin)

Grade 4

Profound shock (undetectable pulse and BP)

Danger Signs in Dengue Hemorrhagic Fever

Abdominal pain - intense and sustained Persistent vomiting Abrupt change from fever to hypothermia, with sweating and prostration Restlessness or somnolence

Martnez Torres E. Salud Pblica Mex 37 (supl):29-44, 1995.

Warning Signs for Dengue Shock

Four Criteria for DHF: Fever Hemorrhagic manifestations Excessive capillary permeability 100,000/mm3 platelets Alarm Signals: Severe abdominal pain Prolonged vomiting Abrupt change from fever to hypothermia Change in level of consciousness (irritability or somnolence)

Initial Warning Signals: Disappearance of fever Drop in platelets Increase in hematocrit

When Patients Develop DSS: 3 to 6 days after onset of symptoms

Signs and Symptoms in 57 Hospitalized Cases of DHF, Puerto Rico, 1990 - 1991
SIGNS AND SYMPTOMS Fever Rash Hepatomegaly Effusions Frank shock Coma Any hemorrhage** FREQUENCY* PERCENT 57 27 6 3 3 2 57 100 % 47.4% 10.5% 5.3% 5.3% 3.5% 100 %

* Minimum estimate, search was not uniform for all patients ** Only 2 (3.5%) cases had severe hemorrhagic manifestations

Hemorrhagic Signs and Symptoms in 57 Hospitalized Cases of DHF, Puerto Rico, 1990 - 1991
SIGNS & SYMPTOMS Microscopic hematuria Petechiae Epistaxis Gingival hemorrhage Blood in stools Positive tourniquet test FREQUENCY* 28 26 13 8 8 5 PERCENT** 51.9% 45.6% 22.8% 14.0% 14.0% 31.3%

* Minimum estimate; the search was not uniform for all patients ** Percents were calculated using the number of patients among whom each symptom was sought as the denominator

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

* Minimum estimate; the search was not uniform for all patients ** Only 2 (3.5%) cases had severe hemorrhagic manifestations

Clinical Laboratory Analyses in 57 Hospitalized Cases of DHF, Puerto Rico, 1990 - 1991
Test with Abnormal Result
Thrombocytopenia Platelet count Increased Capillary Permeability Hemoconcentration 0.20 Low serum protein Low serum albumin

Frequency*

Mean Result (Range)

57/57 (100%)

45,980 (9 - 99,000)

34/57 (59.6%) 18/51 (35.3%) 35/52 (67.3%)

0.26 (0 - 1.0) 6.3 (3.8 - 8.3) 3.5 (2.3 - 4.9)

* Average result in the tested cases

Profile of the Progression of Illness

Mean Days from Onset of Symptoms, and Mean Value ( 2 SD) of Selected Clinical Tests
Maximum 45.2 Hematocrit (%)

Lowest Diastolic 65.6 (mm Hg)

42

5 6 DAYS AFTER ONSET Average admission - day 4.5 Average discharge - day 11 Puerto Rico, 1990-1991 (N=57 patients)

Platelets 45,980 per mm3 9,000 7

34

8 8

Minimum Hematocrit (%) 36.3 99,000

57 44

23
8

Unusual Presentations of Severe Dengue Fever

Encephalopathy Hepatic damage Cardiomyopathy Severe gastrointestinal hemorrhage

IV. Epidemiology

World Distribution of Dengue 1999

Areas infested with Aedes aegypti Areas with Aedes aegypti and recent epidemic dengue

Reported Cases of Dengue in the Americas, 1980 - 1999

800

Reported Cases (Thousands)

700 600 500 400 300 200 100 0 80 82 84 86 88 90 92 94 96 98

* Provisional data for 1999

Mean Annual Number of DHF Cases

Thailand, Indonesia and Vietnam, by Decade
200 180

Reported Cases (Thousands)

160 140 120 100 80 60 40 20 0

1950s

1960s

1970s

1980s

1990s*

* Provisional data through 1998

Reported Cases of DHF in the Americas, 1970 - 1999

60

Reported Cases (Thousands)

50 40 30 20 10 0

1970s
* Provisional data through 1999

1980s

1990s*

Presence of DEN-3 in the Americas, 1994 -1999

1994 1995 1997 1998 1999

SOURCE: Pan American Health Organization, 1994 -1999

Recent Dengue in the U.S.A. (Texas)

Dengue epidemics occurred in the USA in the 1800s and the first half of the 1900s Recent indigenous transmission

1980: 23 cases, first locally acquired since 1945 1986: 9 cases 1995: 7 cases 1997: 3 cases 1998: 1 case 1999: 18 cases

Lack of recent transmission likely due to changes in life-style

Reasons for Dengue Expansion in the Americas

Extensive vector infestation, with declining vector control Unreliable water supply systems Increasing non-biodegradable containers and poor solid waste disposal Increased air travel Increasing population density in urban areas

Trouble Ahead
2.5 billion people at risk world-wide In the Americas, 50-fold increase in reported cases of DHF (1989-1993 compared to 1984-1988)* Widespread abundance of Aedes aegypti in at-risk areas

* Organization of American States, Human Health in the Americas, 1996

V. Disease Pathogenesis

Risk Factors Reported for DHF

Virus strain Pre-existing anti-dengue antibody

previous infection maternal antibodies in infants

Host genetics Age

Risk Factors for DHF (continued)

Higher risk in secondary infections Higher risk in locations with two or more serotypes circulating simultaneously at high levels (hyperendemic transmission)

Increased Probability of DHF

Hyperendemicity

Increased circulation of viruses Increased probability of occurrence of virulent strains

Increased probability of secondary infection Increased probability of immune enhancement

Increased probability of DHF

Gubler & Trent, 1994

Hypothesis on Pathogenesis of DHF (Part 1)

Persons who have experienced a dengue infection develop serum antibodies that can neutralize the dengue virus of that same (homologous) serotype

Homologous Antibodies Form Non-infectious Complexes

Dengue 1 virus Neutralizing antibody to Dengue 1 virus Non-neutralizing antibody Complex formed by neutralizing antibody and virus

Hypothesis on Pathogenesis of DHF (Part 2)

In a subsequent infection, the pre-existing heterologous antibodies form complexes with the new infecting virus serotype, but do not neutralize the new virus

Heterologous Antibodies Form Infectious Complexes

Dengue 2 virus Non-neutralizing antibody to Dengue 1 virus

Complex formed by non-neutralizing antibody and virus

Hypothesis on Pathogenesis of DHF (Part 3)

Antibody-dependent enhancement is the process in which certain strains of dengue virus, complexed with non-neutralizing antibodies, can enter a greater proportion of cells of the mononuclear lineage, thus increasing virus production

Heterologous Complexes Enter More Monocytes, Where Virus Replicates

Dengue 2 virus Non-neutralizing antibody

Complex formed by non-neutralizing antibody and Dengue 2 virus

Hypothesis on Pathogenesis of DHF (Part 4)

Infected monocytes release vasoactive mediators, resulting in increased vascular permeability and hemorrhagic manifestations that characterize DHF and DSS

Viral Risk Factors for DHF Pathogenesis

Virus strain (genotype)

Epidemic potential: viremia level, infectivity

Virus serotype

DHF risk is greatest for DEN-2, followed by

DEN-3, DEN-4 and DEN-1

VI. Diagnosis

General Recommendations for Medical Care

Epidemiologic considerations

Season of year Travel history

Diagnosis Treatment Follow-up

Seasonal Trends in Dengue Incidence: Puerto Rico

Total Samples Received per Week
2000

90 1991
1500

1992 1993 1994

1995

1996 1997 1998

1000
500

0
30 50 10 30 50 10 30 50 10 30 50 10 30 50 10 30 50 10 30 50 10 30 50 10 30 50

Week Number
3-week moving average: June, 1990 - December, 1998

Travel History
Important for assessment of symptomatic patients in non-endemic areas Determine whether the patient travelled to a dengue-endemic area Determine when the travel occurred

If the patient developed fever more than 2

weeks after travel, eliminate dengue from the differential diagnosis

Differential Diagnosis of Dengue

Influenza Measles Rubella Malaria Typhoid fever Leptospirosis Meningococcemia Rickettsial infections Bacterial sepsis Other viral hemorrhagic fevers

Clinical Evaluation in Dengue Fever

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

Petechiae

Pleural Effusion Index

PEI = A/B x 100

B A
Vaughn DW, Green S, Kalayanarooj S, et al. Dengue in the early febrile phase: viremia and antibody responses. J Infect Dis 1997; 176:322-30.
CENTERS FOR DISEASE CONTROL AND PREVENTION

Tourniquet Test
Inflate blood pressure cuff to a point midway between systolic and diastolic pressure for 5 minutes Positive test: 20 or more petechiae per 1 inch2 (6.25 cm2)

Pan American Health Organization: Dengue and Dengue Hemorrhagic Fever: Guidelines for Prevention and Control. PAHO: Washington, D.C., 1994: 12.

Positive Tourniquet Test

Laboratory Tests in Dengue Fever

Clinical laboratory tests

CBC--WBC, platelets, hematocrit Albumin Liver function tests Urine--check for microscopic hematuria
Virus isolation Serology

Dengue-specific tests

Laboratory Methods for Dengue Diagnosis, CDC Dengue Branch

Virus isolation to determine serotype of the infecting virus IgM ELISA test for serologic diagnosis

Virus Isolation: Cell Culture

Virus Isolation: Cell Culture

Virus Isolation: Mosquito Inoculation

Virus Isolation: Fluorescent Antibody Test

ELISA Test for Serologic Diagnosis

ELISA Plate

Collection and Processing of Samples for Laboratory Diagnosis

Type of Specimen Time of Collection Type of Analysis
Virus isolation and/or serology

Acute-phase When patient presents; blood collect second sample (0-5 days after onset) during convalescence

Convalescent-phase Between days 6 and 21 blood after onset ( 6 days after onset)

Serology

Procedures for Diagnosing a Suspected Dengue Fatality

Inform the laboratory processing the samples that the case was fatal Obtain a blood sample to attempt virus isolation and serology Obtain tissue samples for separate tests of virus isolation and immunohistochemistry

Temperature (degrees Celsius)

Temperature, Virus Positivity and Anti-Dengue IgM , by Fever Day

Percent Virus Positive
39.5
39.0 38.5 300 225 80

60
40 20 0 -4 -3 -2 -1 0 1 Virus 2 3 4 5 6 150 75 0

38.0
37.5 37.0

Fever Day
Mean Max. Temperature Dengue IgM

Adapted from Figure 1 in Vaughn et al., J Infect Dis, 1997; 176:322-30.

Dengue IgM (EIA units)

100

VII. Treatment

Outpatient Triage
No hemorrhagic manifestations and patient is well-hydrated: home treatment Hemorrhagic manifestations or hydration borderline: outpatient observation center or hospitalization Warning signs (even without profound shock) or DSS: hospitalize

Patient Follow-Up

Patients treated at home

Instruction regarding danger signs Consider repeat clinical evaluation

Patients with bleeding manifestations

until temperature normal for 1 to 2 days

Serial hematocrits and platelets at least daily

If blood sample taken in first 5 days after onset,
need convalescent sample between days 6 - 30 All hospitalized patients need samples on admission and at discharge or death

All patients

Treatment of Dengue Fever (Part 1)

Fluids Rest Antipyretics (avoid aspirin and non-steroidal anti-inflammatory drugs) Monitor blood pressure, hematocrit, platelet count, level of consciousness

Mosquito Barriers
Only needed until fever subsides, to prevent Aedes aegypti mosquitoes from biting patients and acquiring virus Keep patient in screened sickroom or under a mosquito net

Treatment of Dengue Fever (Part 2)

Continue monitoring after defervescence If any doubt, provide intravenous fluids, guided by serial hematocrits, blood pressure, and urine output The volume of fluid needed is similar to the treatment of diarrhea with mild to moderate isotonic dehydration (5%-8% deficit)

Fluid for Moderate Dehydration (Intravenous)

weight in lbs ml/lb/day weight in kgs ml/kg/day

< 15 16 - 25 26 - 40 41 - 88

100 75 60 40

<7 7 - 11 12 - 18 19 - 40

220 165 132 88

Adapted from Guidelines for Treatment of Dengue Fever/ Dengue Haemorrhagic Fever in Small Hospitals, WHO, 1999.

Rehydrating Patients Over 40 kg

Volume required for rehydration is twice the recommended maintenance requirement Formula for calculating maintenance volume: 1500 + 20 x (weight in kg - 20) For example, maintenance volume for 55 kg patient is: 1500 + 20 x (55-20) = 2200 ml For this patient, the rehydration volume would be 2 x 2200, or 4400 ml

Pan American Health Organization: Dengue and Dengue Hemorrhagic Fever: Guidelines for Prevention and Control. PAHO: Washington, D.C., 1994: 67.

Treatment of Dengue Fever (Part 3)

Avoid invasive procedures when possible Unknown if the use of steroids, intravenous immune globulin, or platelet transfusions to shorten the duration or decrease the severity of thrombocytopenia is effective Patients in shock may require treatment in an intensive care unit

Indications for Hospital Discharge

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

Pan American Health Organization: Dengue and Dengue Hemorrhagic Fever: Guidelines for Prevention and Control. PAHO: Washington, D.C., 1994: 69.

Common Misconceptions about Dengue Hemorrhagic Fever

Dengue + bleeding = DHF

Need 4 WHO criteria, capillary permeability

Patient dies as a result of shock Poorly managed dengue can be more severe, but DHF is a distinct condition, which even well-treated patients may develop Tourniquet test is a nonspecific indicator of capillary fragility

DHF kills only by hemorrhage

Poor management turns dengue into DHF

Positive tourniquet test = DHF

More Common Misconceptions about Dengue Hemorrhagic Fever

DHF is a pediatric disease All age groups are involved in the Americas
DHF is a problem of low income families All socioeconomic groups are affected Tourists will certainly get DHF with a

second infection
Tourists

are at low risk to acquire DHF

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

VIII. Prevention

Early Eradication Campaigns Succeeded

Adequate local and external funding for personnel, equipment and insecticides Emphasis on source reduction Effective residual insecticide Centralized, vertically-structured programs with military-type organization, strict supervision, high level of discipline

Reinfestation by Aedes aegypti

1930s 1970 1998

Hemispheric Eradication of Aedes aegypti No Longer Realistic

Problem greater than during previous campaign Insufficient resources Resistance to vertical disease control programs and use of insecticides Lack of effective insecticides Low priority, lack of sustainability

Lessons for Future Dengue Prevention Programs

Efforts should focus on sustainable environmental control rather than eradication Control programs should be communitybased and -integrated. They cannot rely solely on insecticides nor require large budgets Need to promote dengue as a priority among health officials and the general public

Community Approaches
Typically define communities geographically More likely to be sustainable Advantages: built-in manpower, help develop resources and empower community organizations Disadvantages: more difficult to organize, take longer to get off the ground

Community Participation

First must educate the public in the basics of dengue, such as:

Where the mosquito lays her eggs The link between larvae and adult mosquitoes General information about dengue
transmission, symptoms and treatment

Skills Deficit
Knowledge is not sufficient to produce behavior change People may lack the skills necessary to carry out the recommended behaviors Need to address this skills deficit

Barriers and Motivation (Part 1)

Knowledge combined with skills still may not be sufficient to change behavior Need to understand what barriers may prevent the behavior, and what factors may motivate people to take the desired action Barriers and motivating factors vary in different regions

Barriers and Motivation (Part 2)

Structural factors

laws regarding Aedes aegypti habitats lack of potable water, need to store water inadequate solid waste disposal beliefs: causes, treatment, prevention of febrile illnesses community history and structure other priority problems in the community

Environmental factors

Attitudinal factors

Community factors

Cues for Dengue Preventive Behaviors

People need reminders when they are learning a new behavior Behavioral cues are prompts or signals to remind the person to engage in the desired behavior

Cues: Feedback
Use regular feedback of entomologic and epidemiologic data Every time someone receives the information, it can serve as a reminder to act If the data indicate control activities are successful, they serve as positive reinforcement

Cues: Presence of Adult Mosquitoes

Idea to promote:

Person sees adult mosquito Asks him/herself, Where did it come from? Immediately searches for larval habitats Eliminates or controls all potential habitats
found

Cues: Water Shortages and Rationing

For locations where there are seasonal or other temporary water shortages Provide information on how to properly store water

Cues: Rainfall
Link rainfall to the creation of larval habitats This mental link can remind people to look for and eliminate larval habitats after it rains Eliminates larval habitats influenced by rainfall, and perhaps others as well

Example of Community Programs: Puerto Rico

Elementary school and Head Start programs to teach children about dengue control Public service announcements Interactive exhibit at the Childrens Museum Boy Scout merit badge program

The Challenge
Achieve active community involvement Solicit input from the earliest program planning stages Encourage community ownership Programs that emphasize telling communities what to do, without involving them or taking their views into account, are not likely to be effective True community participation is key