Transcript Document

Travel Medicine:
Dengue and Malaria
Review for Deployers
Col Jim Fike, USAF, MC, FS
[email protected]
Outline
• Clinical Manifestations
• Pathogen and Pathogenesis
• Epidemiology
• Management: Diagnosis and Therapy
• Prevention and Control
Case Study
• 38 y. o. returned home (to US) after supporting a
NGO building a community center in El Salvador
• Four days of intermittent fever associated with:
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Abdominal pain
Retro-orbital headache
General flushing of the skin
Myalgias/arthralgias
• No sig PMH/PSH
• PE – only remarkable for centrifugal
maculopapular rash with + tourniquet test
Dengue: Initial Presenting Signs
Taiwan 2002
Adults
Children
Univariate
DENV2
+RT-PCR or Serologies
Wang CC, et al. Trans R Soc Trop Med Hyg. 2009 Sep;103(9):871-7.
Dengue: Initial Presenting Signs
Martinique 2005-8
Men
Women
DENV2>4>>3>1
+RT-PCR or Serologies
Thomas L, et al. Med Mal Infect. 2009 Nov 29. [Epub ahead]
Dengue: Dermatologic Findings
Dengue Outbreak in PR
- If 5-15yo in this outbreak… suspected Dengue with rash and no
cough had PPV 100% IgM rapid or RT-PCR positivity.
Ramos MM et al. Trans R Soc Trop Med Hyg 2009 Sep;103(9):878-84.
Dengue Spectrum of Disease
Dengue Virus Infection
Asymptomatic
3-18:1 ???
Symptomatic
Undifferentiated Fever vs. Dengue Fever
DHF (plasma leak)
2-7% of cases
No Hemorrhage
With Hemorrhage
20-40% ???
No Shock
WHO. Dengue Hemorrhagic Fever, 2nd Ed. 1997
Thomas L, et al. Med Mal Infect. 2009 Nov 29. [Epub ahead]
Tomashek KM, et al. Am J Trop Med Hyg. 2009 Sep;81(3):467-74.
Balmaseda A, et al. J Infect Dis. 2010 Jan 1;201(1):5-14.
DSS
Dengue: Differential Diagnosis
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Depends on where you are
Alpha viruses: e.g. Chikungunya
Leptospirosis
Influenza (H1N1?)
Rickettsioses
Malaria, Typhoid
HIV, Secondary Syphilis, CMV/ EBV, …
If hemorrhagic fevers… lepto, VHF,
meningococcemia
Flaviviridae
Mapping based
upon NS5.
Enveloped
Single stranded +RNA
Gaunt MW, et al. J Gen Virol.
2001 Aug;82(Pt 8):1867-76.
The Global Map of Dengue
Reservoir: Mosquitos?
Amplifying hosts…
Humans
Sylvatic cycles with
non-human primates
No Dengue here?
Likely reporting- surveillance issue.
Case rates per 100,000 population.
WHO DengueNet acc. Feb 2010
CCDM, 19th Ed. 2008
Dengue Vector
• Aedes aegypti > albopictus
• Broadly distributed
• Anthropophilic
• Anthropophagic
• Trans-ovarial transmission in
the mosquito?
• Eggs overwinter
Galveston County
Mosquito Control
Gratz NG. Med Vet Entomol. 2004 Sep;18(3):215-27.
Lifecycle of the Mosquito
http://www.cdc.gov/Dengue/entomologyEcology/m_lifecycle.html
Dengue Season: Martinique
Typical incubation
period 4-7 days.
Thomas L, et al. Med Mal Infect. 2009 Nov 29. [Epub ahead]
CCDM, 19th Ed. 2008
Rapid Testing for Acute Dengue
• Studies highly variable
in setting, structure,
quality. Not FDA
approved.
• Sens 0.45-1, Spec 0.57-1
• Reference laboratories
can accomplish nonrapid testing… NMRC
Hazell S, et al. Poster 2004 acc www.panbio.com
Blacksell SD, et al. Trans R Soc Trop Med Hyg. 2006 Aug;100(8):775-84.
Putnak JR, et al. Am J Trop Med Hyg. 2008 Jul;79(1):115-22.
Real time diagnosis is clinical
Laboratory Findings
D1 = first Fever
Thomas L, et al. Med Mal Infect.
2009 Nov 29. [Epub ahead]
Dengue Case Definitions
Dengue Fever
Dengue Hemorrhagic Fever
• Probable:
• Fever (acute presentation)
2-7 days, +/- biphasic, +1:
Acute Febrile Illness, and/or
suggestive serology, + 2:
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HA
Myalgia/arthralgia
Rash
Retro-orbital pain
Hemorrhage
Leukopenia
• Confirmed (sp. Labs)
• Reportable (both of the
above)
• +Tourniquet Test
• Petechiae, ecchymoses,
purpura
• Bleeding from mucosa, GI,
injection sites, other
• Hematemesis or melena
• Thrombocytopenia
• Plasma leakage
WHO. Dengue Hemorrhagic Fever, 2nd Ed. 1997
Dengue Management
• Supportive care
• WHO Chapter 3, Clinic Management in
Dengue Hemorrhagic Fever, 2nd Ed.
1997
• http://www.who.int/topics/dengue/en/
• http://www.paho.org/english/ad/dpc/cd/
dengue.htm
Prevention and Control
• Personal Protective Measures
– Long sleeved, long legged clothing
– Bed nets
– DEET Application in exposed areas
• Environmental Measures
– Habitat reduction
– Screens
– Air conditioning when available
Target the Vector
Erlanger TE, et al. Med Vet Entomol. 2008 Sep;22(3):203-21.
Outdoor Spraying
Using the Breteau Index.
Erlanger TE, et al. Med Vet Entomol. 2008 Sep;22(3):203-21.
Biologic Controls
Using the Container Index.
Erlanger TE, et al. Med Vet Entomol. 2008 Sep;22(3):203-21.
Vaccine Strategies
Phase I/II of a Tetravalent vaccine candidate.
Morrison D, et al. J Infect Dis. 2010 Feb 1;201(3):370-7.
Malaria Case #1
• 24 year old woman from Washington, DC
– Previously healthy
• 3 day visit to Costa Rica
– Visited rain forest
– No malaria chemoprophylaxis
• One day after returning home, developed
severe weakness, high fever
– No respiratory, GI, or GU symptoms
• Exam: Normal except orthostatic
hypotension
Malaria Case #2
• 25 year old man, living in Washington DC
– Native of Haiti, but lived in US for 23 years
• Visited Haiti x 10 days, 6 weeks ago
– No prophylaxis
• 4 weeks ago: fever, abdominal pain, diarrhea
– Resolved with erythromycin
• 2 weeks ago: fever, headache, fatigue
– Resolved with erythromycin
• 1 week ago: dry cough, lethargy, anorexia
• Now: Severe abdominal pain, lethargy, T >40oC
Malaria Case #3
• Asymptomatic 74 year old woman
• Splenomegaly found on routine exam
• No exposure to malaria in over 40 years
– History of malaria at age 3, resolved
without therapy
• Diagnosed as lymphoma
• Methotrexate given
• After 7 days, intermittent fever
developed
• Blood smears negative
Malaria Case #4
• 18 year old American serviceman
deployed to Sub-Saharan Africa
– Taking malaria chemoprophylaxis
• 2 days Prior to Admission:
– Dyspnea
– Chills & fever to 104oF
Malaria
Geographic distribution
Clinical Presentation:
Uncomplicated Malaria
• Symptoms: fever, chills, headache,
body pains, diarrhea, vomiting, cough
• Prodrome of other sxs can occur 1-2 d
prior to fever onset
• Signs: anemia, thrombocytopenia
• Symptoms may be very nonspecific
• Classical patterns (48 hr or 72 hr
periodicity) seen more in P. vivax
Clinical Presentation:
Serious/Complicated Malaria
• Decrease in conscious level, neurological
signs or fits
• Splenomegaly
• Severe anemia – Hematocrit < 15%
• Hyperpyrexia
• Hyperparasitemia > 5%
• Hypoglycemia (glucose < 2.2 mmol/L)
• Renal impairment or oliguria
• Pulmonary edema, hypoxia, acidosis
• Circulatory collapse or shock
• Hemostasis abnormalities – hemolysis, DIC
Diagnosis: Microscopy
• Benchmark diagnostic standard for over
100 years
• In expert hands: Highly sensitive,
specific
– 10-50 parasites/mcl reliably detectable
• Single assay provides wealth of
clinically important data
• Stained slide serves as permanent
record
Microscopy
• Giemsa stain or Field’s stain
• Thick smear to identify parasitemia
– Read > 200 oil/HPF fields before calling negative
• Thin smear to identify species
• Quantify low parasitemias against WBCs:
(# parasites counted/200 WBCs counted) x
WBCs/mcl
• Quantify high parasitemias against RBCs:
# parasites counted/1000 RBCs counted) x
RBCs/mcl
Microscopy
• Negative blood smear in suspected
malaria?
– ? P. falciparum, sequestered phase of RBC
cycle
– ? Low parasitemia
– ? Quality of slide, microscopist
• Mandatory:
– Recheck smears every 8 (6-12) hours for
48 hours
Diagnosis
• Thick and thin blood smears are gold standard
– Identify species and quantify density
– If can not identify species, treat for P.f.
• Re-examine smears or use alternative
diagnostic tool
• Suspect P.falcipurum
– If critically ill, suspect P.f.
– If returned from Sub-Saharan Africa, > 95 %
chance of P.f. pure or mixed infection
– Parasitemia > 1%
– Doubly infected cells
Malaria – Vectors
Anopheles balabacensis
A. freeborni
A. gambiae
A. stephensi
Malaria – Vectors (cont.)
Malaria Transmission Cycle
Exo-erythrocytic (hepatic) Cycle:
Sporozoites infect liver cells and
develop into schizonts, which release
merozoites into the blood
Sporozoites injected
into human host during
blood meal
Parasites
mature in
mosquito
midgut and
migrate to
salivary
glands
MOSQUITO
Parasite undergoes
sexual reproduction in
the mosquito
HUMAN
Some merozoites
differentiate into male or
female gametocyctes
Dormant liver stages
(hypnozoites) of P.
vivax and P. ovale
Erythrocytic Cycle:
Merozoites infect red
blood cells to form
schizonts
Plasmodium falciparum
Sporozoites/liver schizonts
Malaria
Red blood cell invasion
P. falciparum – Blood stages
Uninfected RBC
4 hr.
2 hr.
12 hr.
Antimalarial drug actions
• Actions
– Causal (true) – drug acts on early stages in liver, before
release of merozoites into blood
– Blood schizontocidal drugs (suppressive or clinical)–
attack parasite in RBC, preventing or ending clinical
attack
– Gametocytocidal – destroy sexual forms in human,
decreases transmission
– Hypnozoitocidal – kill dormant hypnozoites in liver,
antirelapse drugs
– Sporontocidal – inhibit development of oocysts in
mosquito, decreases transmission
Sites of Action for
Antimalarial Drugs
TISSUE SCHIZONTOCIDES:
primaquine
pyrimethamine
proguanil
tetracyclines
MOSQUITO
SPORONTOCIDES:
primaquine
pyrimethamine
proguanil
HUMAN
GAMETOCYTOCIDES:
primaquine
BLOOD
SCHIZONTOCIDES:
chloroquine
mefloquine
quinine/quinidine
tetracyclines
halofantrine
sulfadoxine
pyrimethamine
artemisinins
Drugs Used to Treat Malaria
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Chloroquine (Aralen, Dawaquine)
Amodiaquine (Camoquine)
Quinine and Quinidine
Sulfa combination drugs (Fansidar,
Metakelfin)
Mefloquine (Lariam)
Halofantrine (Halfan)
Atovaquone-proguanil (Malarone)
Atemisinin derivatives (Paluther)
Considerations for managing
P. falciparum infections
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Can underestimate severity
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Significant damage occurs at certain times during
repeated cycles of development and reproduction
Patient can deteriorate quickly
Low parasite density does not mean infection is trivial
Complications can arise after parasites clear
peripheral blood, parasites can sequester in tissues
Monitor for neurological changes and hypoglycemia
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Severe malaria and antimalarials can cause
hypoglycemia
Pregnant women are at particular risk
Adjunct Treatment of
Uncomplicated Malaria
• Fever
– Acetominophen, paracetamol
• Avoid aspirin in kids due to risk of Reyes Syndrome
– Sponge baths
• Anemia
– Transfusion of RBCs may be needed
– Iron, folic acid
• Rehydration
– Solutions with extra glucose
Malaria - Treatment
Artemisinin
Malaria Case #1
• 24 year old woman from Washington, DC
– Previously healthy
• 3 day visit to Costa Rica
– Visited rain forest
– No malaria chemoprophylaxis
• One day after returning home, developed
severe weakness, high fever
– No respiratory, GI, or GU symptoms
• Exam: Normal except orthostatic
hypotension
Malaria Case #1
• Clinical course
– Progressed to overt septic shock
– Multiple blood cultures positive for Shigella
– Recovered completely to fluids, antibiotics
• Teaching points:
– Clinical presentation of malaria overlaps
widely with other infections: Specific
diagnosis essential
– Incubation period probably too brief for
malaria
Malaria Case #2
• 25 year old man, living in Washington DC
– Native of Haiti, but lived in US for 23 years
• Visited Haiti x 10 days, 6 weeks ago
– No prophylaxis
• 4 weeks ago: fever, abdominal pain, diarrhea
– Resolved with erythromycin
• 2 weeks ago: fever, headache, fatigue
– Resolved with erythromycin
• 1 week ago: dry cough, lethargy, anorexia
• Now: Severe abdominal pain, lethargy, T >40oC
Malaria Case #2
• Clinical Course:
– BUN: 97 mg/dl; creatinine 5.6 mg/dl
– P. falciparum on blood smear, 3% of RBCs
– Head CT, LP negative
– Treated with IV quinidine/IV doxycycline
– At 12 hours: 5% parasitemia
– Day 4: Parasitemia cleared
– Day 5: Afebrile
Malaria Case #2
• Clinical course (cont.)
– Day 14: Renal failure cleared (hemodialysis x 5)
– Slow but complete CNS improvement
• Teaching points:
– Native-born at risk for severe disease when
returning after absence
– Early worsening of parasitemia after therapy
started
– Multi-system organ failure
• Aggressive, specific, intravenous therapy
• Early, comprehensive critical care
Malaria Case #3
• Asymptomatic 74 year old woman
• Splenomegaly found on routine exam
• No exposure to malaria in over 40 years
– History of malaria at age 3, resolved
without therapy
• Diagnosed as lymphoma
• Methotrexate given
• After 7 days, intermittent fever
developed
• Blood smears negative
Malaria Case #3
• Clinical course:
– Patient given empirical therapy with chloroquine
– Symptoms & splenomegaly completely resolved
– PCR analysis of pre-treatment blood showed
presence of P. malariae rRNA
• Teaching points:
– Microscopy may miss low-level parasitemia
– P. malariae may last decades without symptoms
– Altered immune status may allow disease
breakthrough
Malaria Case #4
• 18 year old American serviceman
deployed to Sub-Saharan Africa
– Taking malaria chemoprophylaxis
• 2 days Prior to Admission:
– Dyspnea
– Chills & fever to 104oF
Malaria Case #4
• Admission: P. falciparum diagnosed
– Transferred without therapy
• Hospital day 2, on arrival at 2nd hospital:
– Afebrile, RR: 24; CXR negative; smears (+)
P.f.
– Therapy started
• Course:
– HD #3: T = 105oF; RR = 30
– HD #4: Afebrile, blood smears negative; RR
= 40, cyanotic; CVP = 5 cm
Malaria Case #4
• Course (cont.):
– HD #5:
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Net negative fluid balance
RR = 60-70
CXR c/w pulmonary edema
Blood smears negative; T = 102.6oF
Antibiotics added
– HD #6: Death
Malaria Case #4
• Teaching points:
– Respiratory presentation
– Progression of ARDS despite parasite
clearance
– No volume overload
– ? role of delay in therapy
• Probably not decisive
Malaria - Prevention
Antimalarial
Chemoprophylaxis
• Prevents disease, not infection
• Appropriate for non-immune travelers
• Practical only for some populations in
endemic areas
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immune status
intensity/duration of exposure
parasite drug resistance
resources for diagnosis and treatment
Personal Protection
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Protective clothing
Insect repellants
Household insecticide products
Window and door screens
Bed nets
Links to Malaria Support
• WHO malaria guidelines (2010)
• http://www.who.int/malaria/publications/ato
z/9789241547925/en/index.html
• CDC Malaria Home Page
• http://www.cdc.gov/malaria/
• Malaria interactive map:
• http://cdc-malaria.ncsa.uiuc.edu/