Travel Medicine:Dengue and Malaria

Review for Deployers

Col Jim Fike, USAF, MC, FSjim.fike@ang.af.mil

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:– 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 2002Adults 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 SignsMartinique 2005-8

MenWomen

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

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.

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 ???

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

Flaviviridae

Gaunt MW, et al. J Gen Virol. 2001 Aug;82(Pt 8):1867-76.

Mapping based upon NS5.

EnvelopedSingle stranded +RNA

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

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

Thomas L, et al. Med Mal Infect. 2009 Nov 29. [Epub ahead]CCDM, 19th Ed. 2008

Typical incubation period 4-7 days.

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.

Real time diagnosis is clinical

Thomas L, et al. Med Mal Infect. 2009 Nov 29. [Epub ahead]

D1 = first Fever

Laboratory Findings

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

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

MalariaGeographic 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

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

Plasmodium falciparumSporozoites/liver schizonts

MalariaRed blood cell invasion

P. falciparum – Blood stages

Uninfected RBC

2 hr.

4 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 forAntimalarial Drugs

SPORONTOCIDES:primaquine pyrimethamineproguanil

MOSQUITO HUMAN

GAMETOCYTOCIDES:primaquine

TISSUE SCHIZONTOCIDES:primaquinepyrimethamineproguaniltetracyclines

BLOOD SCHIZONTOCIDES:chloroquinemefloquinequinine/quinidinetetracyclineshalofantrinesulfadoxinepyrimethamineartemisinins

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)

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

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

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: • 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

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

Personal Protection

• 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/