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Transcript of Travel Medicine: Dengue and Malaria Review for Deployers Col Jim Fike, USAF, MC, FS...
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Outline
• Clinical Manifestations
• Pathogen and Pathogenesis
• Epidemiology
• Management: Diagnosis and Therapy
• Prevention and Control
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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:– 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
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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.
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Dengue: Initial Presenting SignsMartinique 2005-8
MenWomen
DENV2>4>>3>1+RT-PCR or Serologies
Thomas L, et al. Med Mal Infect. 2009 Nov 29. [Epub ahead]
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Dengue: Dermatologic Findings
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Dengue Outbreak in PR
Ramos MM et al. Trans R Soc Trop Med Hyg 2009 Sep;103(9):878-84.
- If 5-15yo in this outbreak… suspected Dengue with rash and no cough had PPV 100% IgM rapid or RT-PCR positivity.
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Dengue Spectrum of Disease
Dengue Virus Infection
Asymptomatic Symptomatic
DHF (plasma leak)
No Shock DSS
Undifferentiated Fever vs. Dengue Fever
No Hemorrhage With Hemorrhage
WHO. Dengue Hemorrhagic Fever, 2nd Ed. 1997Thomas 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.
2-7% of cases
20-40% ???
3-18:1 ???
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Dengue: Differential Diagnosis
• 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
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Flaviviridae
Gaunt MW, et al. J Gen Virol. 2001 Aug;82(Pt 8):1867-76.
Mapping based upon NS5.
EnvelopedSingle stranded +RNA
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The Global Map of Dengue
WHO DengueNet acc. Feb 2010CCDM, 19th Ed. 2008
Case rates per 100,000 population.
No Dengue here?
Likely reporting- surveillance issue.
Reservoir: Mosquitos?Amplifying hosts…HumansSylvatic cycles with non-human primates
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Dengue Vector
• Aedes aegypti > albopictus
• Broadly distributed
• Anthropophilic
• Anthropophagic
• Trans-ovarial transmission in the mosquito?
• Eggs overwinterGalveston County Mosquito Control
Gratz NG. Med Vet Entomol. 2004 Sep;18(3):215-27.
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Lifecycle of the Mosquito
http://www.cdc.gov/Dengue/entomologyEcology/m_lifecycle.html
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Dengue Season: Martinique
Thomas L, et al. Med Mal Infect. 2009 Nov 29. [Epub ahead]CCDM, 19th Ed. 2008
Typical incubation period 4-7 days.
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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 non-rapid testing… NMRC
Hazell S, et al. Poster 2004 acc www.panbio.comBlacksell 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.
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Real time diagnosis is clinical
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Thomas L, et al. Med Mal Infect. 2009 Nov 29. [Epub ahead]
D1 = first Fever
Laboratory Findings
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Dengue Case Definitions
Dengue Fever
• Probable:Acute Febrile Illness, and/or
suggestive serology, + 2:• HA• Myalgia/arthralgia • Rash• Retro-orbital pain• Hemorrhage• Leukopenia
• Confirmed (sp. Labs)• Reportable (both of the
above)
Dengue Hemorrhagic Fever
• Fever (acute presentation) 2-7 days, +/- biphasic, +1:
• +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
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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
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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
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Target the Vector
Erlanger TE, et al. Med Vet Entomol. 2008 Sep;22(3):203-21.
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Outdoor Spraying
Using the Breteau Index.
Erlanger TE, et al. Med Vet Entomol. 2008 Sep;22(3):203-21.
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Biologic Controls
Using the Container Index.
Erlanger TE, et al. Med Vet Entomol. 2008 Sep;22(3):203-21.
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Vaccine Strategies
Phase I/II of a Tetravalent vaccine candidate.
Morrison D, et al. J Infect Dis. 2010 Feb 1;201(3):370-7.
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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
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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
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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
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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
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MalariaGeographic distribution
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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
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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
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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
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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
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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
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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
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Malaria – Vectors
Anopheles balabacensis
A. freeborni
A. gambiae
A. stephensi
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Malaria – Vectors (cont.)
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Malaria Transmission Cycle
Parasite undergoes sexual reproduction in the mosquito
Some merozoites differentiate into male or female gametocyctes
Erythrocytic Cycle: Merozoites infect red blood cells to form schizonts
Dormant liver stages (hypnozoites) of P. vivax and P. ovale
Exo-erythrocytic (hepatic) Cycle: Sporozoites infect liver cells and develop into schizonts, which release merozoites into the blood
MOSQUITO HUMAN
Sporozoites injected into human host during blood meal
Parasites mature in mosquito midgut and migrate to salivary glands
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Plasmodium falciparumSporozoites/liver schizonts
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MalariaRed blood cell invasion
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P. falciparum – Blood stages
Uninfected RBC
2 hr.
4 hr.
12 hr.
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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
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Sites of Action forAntimalarial Drugs
SPORONTOCIDES:primaquine pyrimethamineproguanil
MOSQUITO HUMAN
GAMETOCYTOCIDES:primaquine
TISSUE SCHIZONTOCIDES:primaquinepyrimethamineproguaniltetracyclines
BLOOD SCHIZONTOCIDES:chloroquinemefloquinequinine/quinidinetetracyclineshalofantrinesulfadoxinepyrimethamineartemisinins
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Drugs Used to Treat Malaria
• Chloroquine (Aralen, Dawaquine)• Amodiaquine (Camoquine)• Quinine and Quinidine• Sulfa combination drugs (Fansidar,
Metakelfin)• Mefloquine (Lariam)• Halofantrine (Halfan)• Atovaquone-proguanil (Malarone)• Atemisinin derivatives (Paluther)
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Considerations for managingP. falciparum infections
Can underestimate severity 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
Severe malaria and antimalarials can cause hypoglycemia
Pregnant women are at particular risk
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Adjunct Treatment ofUncomplicated 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
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Malaria - Treatment
Artemisinin
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Malaria Case #4
• Course (cont.):– HD #5:
• Net negative fluid balance• RR = 60-70• CXR c/w pulmonary edema• Blood smears negative; T = 102.6oF • Antibiotics added
– HD #6: Death
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Malaria Case #4
• Teaching points:– Respiratory presentation– Progression of ARDS despite parasite
clearance– No volume overload– ? role of delay in therapy
• Probably not decisive
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Malaria - Prevention
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AntimalarialChemoprophylaxis
• Prevents disease, not infection• Appropriate for non-immune travelers• Practical only for some populations in
endemic areas• Consider:
• immune status• intensity/duration of exposure• parasite drug resistance• resources for diagnosis and treatment
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Personal Protection
• Protective clothing• Insect repellants• Household insecticide products • Window and door screens• Bed nets
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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/