The Perils of Travel

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The Perils of Travel

• Jeffrey H. Phillips, M.D., F.A.C.P.
• Internal Medicine Clinical Update
• October 26, 2005

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Case History

• 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 104o.
• 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.

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Case history (continued)

• Seen in office 6/29 with T 99.5o 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
• Dengue fever antibodies drawn 6/29 IgM 43
  (positive gt 11) IgG 2 (positive gt 11)

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What is dengue?

• 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)
• Estimated 50-100 million cases annually
• 250,000-500,000 with dengue hemorrhagic fever
• 24,000 deaths

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History

• 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). 
• 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.

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Dengue Virus

• Belongs to the family Flaviviridae (flavoviruses)
• Transmitted by the Aedes aegypti and A.
  albopictus mosquitoes
• 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
• Mosquito remains infected for life but only
  causes illness in humans

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Aedes aegypti Mosquito
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Epidemiology

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

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Worldwide increase of DHF

• South East Asia
• 1960s lt10,000 cases
• 1990s gt 200,000 cases
• Americas
• 1980s 15,000 cases
• 1990s 56,000 cases
• 2001 alone 15,000 cases

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Dengue in the U.S.A.

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

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Replication and Transmissionof 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
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Replication and Transmissionof 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
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Dengue Clinical Syndromes

• Undifferentiated febrile illness
• Classic dengue fever
• Dengue hemorrhagic fever
• Dengue shock syndrome
• Other unusual syndromes

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Undifferentiated Fever

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

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Classic Dengue Fever

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

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Hemorrhagic manifestations of dengue

• Skin hemorrhages petechiae, purpura, ecchymoses
• Gingival and nasal bleeding
• GI bleeding hematemesis, melena, hematochezia
• Hematuria
• Gum bleeding, epistaxis menorrhagia less common
• Positive tourniquet test for capillary fragility

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Tourniquet test

• 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

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Dengue hemorrhagic fever

• Primarily a disease of children lt 15
• 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
• Autopsies show serous effusions of pericardial,
  peritoneal, and fluid spaces as well as petechial
  hemorrhages over most organs

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Pleural effusion
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Clinical Case Definition forDengue 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, peritoneal, or pericardial effusions

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

• Abdominal pain - intense and sustained
• Persistent vomiting
• Abrupt change from fever to hypothermia, with
  sweating and prostration
• Change in level of consciousness (restlessness or
  somnolence)
• Sudden decrease in platelet count

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Clinical Case Definition for Dengue Shock Syndrome

• 4 criteria for DHF 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, altered mental status
• Frank shock is direct evidence of circulatory
  failure

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Who is at risk for DHF and DSS?

• Major factor is pre-existing anti-dengue antibody
• previous infection
• maternal antibodies in infants
• Virus strain and serotype (DEN-2gt3gt4gt1)
• Age (youngest and oldest more likely)
• Host genetics (HLA determined susceptibility)
• Hypothesis of antibody-dependent enhancement

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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
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Heterologous Antibodies Form Infectious Complexes
Dengue 2 virus
Non-neutralizing antibody to Dengue 1 virus
Complex formed by non-neutralizing antibody and
virus
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Heterologous Complexes Enter More Monocytes,
Where Virus Replicates
Dengue 2 virus
Non-neutralizing antibody
Complex formed by non-neutralizing antibody and
Dengue 2 virus
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• 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

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Cases/hospitalizations Brazil (Siquiera, et
al Emerging Infectious Diseases Vol. 11, No. 1,
p 50)
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Other unusual syndromes

• Encephalopthy
• Mono- and polyneuropathies
• Transverse myelitis
• Myocarditis
• Parotitis
• Hepatic damage and jaundice
• Severe GI hemorrhage

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Making the diagnosis
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Travel History

• Important for assessment of symptomatic patients
  in non-endemic areas
• Determine whether the patient traveled 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

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Other Flavivirus infections in travelers

• Yellow fever (Sub-Saharan Africa South America)
• Japanese encephalitis (Asia)
• Tick-borne encephalitis (Europe)
• West Nile fever (Africa Middle East Europe
  North America)
• Dengue fever (Asia Central, South, and North
  Americas Pacific Africa)

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Differential diagnosis of dengue

• Arboviruses
• Chikungunya (often mistaken for dengue in SE
  Asia)
• Viral diseases
• Hantavirus measles rubella enteroviruses
  influenza
• Bacterial diseases
• Meningococcemia scarlet fever typhoid
• Parasitic diseases
• Leptospirosis rickettsial diseases malaria

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Clinical Evaluation

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

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Tourniquet test

• 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

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Laboratory Testsin Dengue Fever

• Clinical laboratory tests
• CBC--WBC, platelets, hematocrit
• Albumin
• Liver function tests
• Urine--check for microscopic hematuria
• Dengue-specific tests
• Virus isolation
• Serology

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Temperature, Virus Positivity and Anti-Dengue IgM
, by Fever Day
39.5
39.0
38.5
Temperature (degrees Celsius)
Dengue IgM (EIA units)
Percent Virus Positive
38.0
37.5
37.0
-4
-3
-2
-1
0
1
2
3
4
5
6
Fever Day
Dengue IgM
Mean Max. Temperature
Virus
Adapted from Figure 1 in Vaughn et al., J Infect
Dis, 1997 176322-30.
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Treatment
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Mild and classic dengue

• Outpatient treatment
• Acetaminophen (not aspirin or NSAIDs)
• Fluid replacement
• Bedrest
• Avoid injections
• Recheck platelets and Hct every 24 hours

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DHF and DSS

• If platelets lt 100,000/mm3 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)
• Rise in Hct of 20 indicates considerable plasma
  loss and requires ICU care and IVFs
• Worsening shock requires colloid or crystalloid
• Monitor Hct and reduce IVFs when Hct lt 40

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Rehydrating Patients gt 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 80 kg patient
  is 1500 20 x (80-20) 2700 ml
• The rehydration volume would be 2 x 2700, or 5400
  ml (225ml/hr)

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Mosquito avoidance

• 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
• Remember that virus positivity follows the fever

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Temperature, Virus Positivity and Anti-Dengue IgM
, by Fever Day
39.5
39.0
38.5
Temperature (degrees Celsius)
Dengue IgM (EIA units)
Percent Virus Positive
38.0
37.5
37.0
-4
-3
-2
-1
0
1
2
3
4
5
6
Fever Day
Dengue IgM
Mean Max. Temperature
Virus
Adapted from Figure 1 in Vaughn et al., J Infect
Dis, 1997 176322-30.
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Prognosis

• Classic dengue
• full recovery convalescence may take weeks
  because of asthenia and depression
• Dengue hemorrhagic fever
• 10-20 mortality without aggressive fluid
  replacement
• 0.2 with treatment
• Dengue shock syndrome
• gt 40 mortality without aggressive fluid
  replacement
• lt 1 mortality with treatment

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Prevention
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Personal measures

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

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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

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Historical anecdote

• 1950s and 60s - 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
• 1970s - 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. 
• Today - the Aedes aegypti mosquito inhabits a
  broader geographical region than before
  eradication

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Reinfestation by Aedes aegypti
1930s 1970 1998
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Vector Control MethodsChemical 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

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Vector Control MethodsBiological 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

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Community Approaches

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

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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

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Dengue Vaccine?

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

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Trouble Ahead

• 2.5 billion people at risk world-wide
• Widespread abundance of Aedes aegypti in at-risk
  areas
• 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

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Summary

• 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
• A severe manifestation of dengue is dengue
  hemorrhagic fever, which is more common after a
  secondary infection
• A cost effective vaccine is needed

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Case report - finale

• 50 year old attorney became ill 6/24, 4 days
  after returning from Costa Rica
• One week later, repeat WBC 5800, platelets
  385,000
• Convalescent titers IgG rose gt 4 x baseline
  level
• Out of work 2 weeks full recovery over 4 weeks

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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
• All complained of fever and headache, 3 required
  hospitalization
• In response, Ministry of Health in Costa Rica
  enhanced surveillance and mosquito control
  measures

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Big question

• Why did this particular attorney not suffer the
  more severe forms of dengue from the bite of that
  annoying, bloodsucking pest?
• Professional courtesy

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