Transcript The Perils of Travel

The Perils of Travel
Jeffrey H. Phillips, M.D., F.A.C.P.
Internal Medicine Clinical Update
October 26, 2005
Case History
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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.”
Case history (continued)
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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 > 11); IgG 2 (positive > 11)
What is dengue?
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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
History
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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.
Dengue Virus
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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
Aedes aegypti Mosquito
Epidemiology
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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
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Incidence in travelers returning from tropics
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2 % in early 1990s to 16 % in early 2000s
Reinfestation by Aedes aegypti in the Americas
1970
2002
Worldwide increase of DHF
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South East Asia:
1960s: <10,000 cases
 1990s: > 200,000 cases
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Americas:
1980s: 15,000 cases
 1990s: 56,000 cases
 2001 alone: 15,000 cases
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Dengue in the U.S.A.
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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
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2001 (Hawaii); Aedes albopictus implicated in
122 dengue infections
Replication and Transmission
of Dengue Virus (Part 1)
1. Virus transmitted
to human in mosquito
saliva
1
2
4
2. Virus replicates
in regional nodes
3. Virus infects white
blood cells and
lymphatic tissues
4. Virus released and
circulates in blood
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
6
7
5
Dengue Clinical Syndromes
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Undifferentiated febrile illness
Classic dengue fever
Dengue hemorrhagic fever
Dengue shock syndrome
Other unusual syndromes
Undifferentiated Fever
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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
Classic Dengue Fever
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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
Hemorrhagic manifestations of
dengue
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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
Tourniquet test
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Inflate blood pressure
cuff to a point midway
between systolic and
diastolic for 5 minutes
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Positive test: 20 or more
petechiae in a 1-in square
patch on the forearm
Dengue hemorrhagic fever
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Primarily a disease of children < 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
Pleural effusion
PEI = A/B x 100
B
A
Clinical Case Definition for
Dengue Hemorrhagic Fever
4 Necessary Criteria:
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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
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 %
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%
Hemorrhagic Signs and
Symptoms in 57 Hospitalized
Cases of DHF, Puerto Rico,
1990 - 1991
SIGNS & SYMPTOMS
Blood in vomitus
Bleeding venipuncture
Hemoptysis
Vaginal hemorrhage 2
Gross hematuria
Other hemorrhage
FREQUENCY
PERCENT
4
4
3
7.0%
7.0%
5.3%
3.5%
2
2
3.5%
3.5%
Warning signs in DHF that shock
is impending
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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
Clinical Case Definition for
Dengue Shock Syndrome
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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
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Frank shock is direct evidence of
circulatory failure
Who is at risk for DHF and DSS?
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Major factor is pre-existing anti-dengue antibody
previous infection
 maternal antibodies in infants
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Virus strain and serotype (DEN-2>3>4>1)
Age (youngest and oldest more likely)
Host genetics (HLA determined susceptibility)
Hypothesis of antibody-dependent enhancement
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
Heterologous Antibodies
Form Infectious Complexes
Dengue 2 virus
Non-neutralizing antibody to Dengue 1
virus
Complex formed by non-neutralizing
antibody and virus
Heterologous Complexes Enter
More Monocytes, Where Virus
Replicates
Dengue 2 virus
Non-neutralizing antibody
Complex formed by nonneutralizing antibody and
Dengue 2 virus
…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
Cases/hospitalizations – Brazil
(Siquiera, et al; Emerging Infectious Diseases; Vol. 11, No. 1, p 50)
Other unusual syndromes
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Encephalopthy
Mono- and polyneuropathies
Transverse myelitis
Myocarditis
Parotitis
Hepatic damage and jaundice
Severe GI hemorrhage
Making the diagnosis
Travel History
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Important for assessment of symptomatic patients in
non-endemic areas
Determine whether the patient traveled to a dengueendemic area
Determine when the travel occurred
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If the patient developed fever more than 2 weeks
after travel, eliminate dengue from the
differential diagnosis
Other Flavivirus infections in
travelers
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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)
Differential diagnosis of dengue
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Arboviruses
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Viral diseases
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Hantavirus; measles; rubella; enteroviruses; influenza
Bacterial diseases
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Chikungunya (often mistaken for dengue in SE Asia)
Meningococcemia; scarlet fever; typhoid
Parasitic diseases
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Leptospirosis; rickettsial diseases; malaria
Clinical Evaluation
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Blood pressure
Evidence of bleeding in skin or other sites
Hydration status
Evidence of increased vascular permeability- pleural effusions, ascites
Tourniquet test
Tourniquet test
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Inflate blood pressure
cuff to a point midway
between systolic and
diastolic for 5 minutes
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Positive test: 20 or more
petechiae in a 1-in square
patch on the forearm
Laboratory Tests
in Dengue Fever
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Clinical laboratory tests
CBC--WBC, platelets, hematocrit
 Albumin
 Liver function tests
 Urine--check for microscopic hematuria
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Dengue-specific tests
Virus isolation
 Serology
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38.5
38.0
37.5
37.0
300
80
225
60
150
40
75
20
0
-4
-3
-2
-1
0
1
2
3
4
5
Fever Day
Mean Max. Temperature
Adapted from Figure 1 in Vaughn et al.,
J Infect Dis, 1997; 176:322-30.
Virus
Dengue IgM
6
0
Dengue IgM (EIA units)
39.0
Percent Virus Positive
Temperature (degrees Celsius)
39.5
Temperature, Virus Positivity
and Anti-Dengue IgM , by
Fever Day
100
Treatment
Mild and classic dengue
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Outpatient treatment
Acetaminophen (not aspirin or NSAIDs)
Fluid replacement
Bedrest
Avoid injections
Recheck platelets and Hct every 24 hours
DHF and DSS
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If platelets < 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 < 40
Rehydrating Patients > 40 kg
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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)
Mosquito avoidance
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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
39.0
38.5
38.0
37.5
37.0
300
80
225
60
150
40
75
20
0
-4
-3
-2
-1
0
1
2
3
4
5
Fever Day
Mean Max. Temperature
Adapted from Figure 1 in Vaughn et al.,
J Infect Dis, 1997; 176:322-30.
Virus
Dengue IgM
6
0
Dengue IgM (EIA units)
39.5
100
Percent Virus Positive
Temperature (degrees Celsius)
Temperature, Virus Positivity and
Anti-Dengue IgM , by Fever Day
Prognosis
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Classic dengue
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Dengue hemorrhagic fever
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full recovery; convalescence may take weeks because of
asthenia and depression
10-20% mortality without aggressive fluid replacement
0.2% with treatment
Dengue shock syndrome
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> 40% mortality without aggressive fluid replacement
< 1% mortality with treatment
Prevention
Personal measures
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Mosquito repellants with 20% to 30% DEET
Protective clothing that is permethrinimpregnated
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
Reasons for Dengue Expansion
in the Americas
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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
Historical anecdote
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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
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.
Today - the Aedes aegypti mosquito inhabits a broader
geographical region than before eradication
Reinfestation by Aedes aegypti
1930s
1970
1998
Vector Control Methods:
Chemical Control
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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
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Biological control
Largely experimental
 Option: place fish in containers to eat
larvae
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Environmental control
Elimination of larval habitats
 Most likely method to be effective in the
long term
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Community Approaches
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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
Example of Community
Programs: Puerto Rico
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Elementary school and Head Start
programs to teach children about
dengue control
Public service announcements
Interactive exhibit at the Children’s
Museum
Boy Scout merit badge program
Dengue Vaccine?
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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
Trouble Ahead
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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
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in the Americas, 50-fold increase in reported cases
of DHF during 1989-1993 compared to 1984-1988
Summary
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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
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 > 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…
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Why did this particular attorney not suffer the
more severe forms of dengue from the bite of
that annoying, bloodsucking pest?
 Professional
courtesy