Travel Medicine: Dengue and Malaria Review for Deployers

1. Travel Medicine: Dengue and Malaria Review for Deployers Col Jim Fike, USAF, MC, FS jim.fike@ang.af.mil

2. Outline • Clinical Manifestations • Pathogen and Pathogenesis • Epidemiology • Management: Diagnosis and Therapy • Prevention and Control

3. 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

4. Dengue: Initial Presenting SignsTaiwan 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.

5. Dengue: Initial Presenting SignsMartinique 2005-8 Men Women DENV2>4>>3>1 +RT-PCR or Serologies Thomas L, et al. Med Mal Infect. 2009 Nov 29. [Epub ahead]

6. Dengue: Dermatologic Findings

7. 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.

8. 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 DSS 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.

9. 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

10. Mapping based upon NS5. Flaviviridae Enveloped Single stranded +RNA Gaunt MW, et al. J Gen Virol. 2001 Aug;82(Pt 8):1867-76.

11. 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

12. 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.

13. Lifecycle of the Mosquito http://www.cdc.gov/Dengue/entomologyEcology/m_lifecycle.html

14. 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

15. 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.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.

16. Real time diagnosis is clinical

17. Laboratory Findings D1 = first Fever Thomas L, et al. Med Mal Infect. 2009 Nov 29. [Epub ahead]

18. Dengue Case Definitions Dengue Fever 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 • 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) WHO. Dengue Hemorrhagic Fever, 2nd Ed. 1997

19. 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

20. 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

21. Target the Vector Erlanger TE, et al. Med Vet Entomol. 2008 Sep;22(3):203-21.

22. Outdoor Spraying Using the Breteau Index. Erlanger TE, et al. Med Vet Entomol. 2008 Sep;22(3):203-21.

23. Biologic Controls Using the Container Index. Erlanger TE, et al. Med Vet Entomol. 2008 Sep;22(3):203-21.

24. Vaccine Strategies Phase I/II of a Tetravalent vaccine candidate. Morrison D, et al. J Infect Dis. 2010 Feb 1;201(3):370-7.

25. 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

26. 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

27. 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

28. 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

29. MalariaGeographic distribution

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. Malaria – Vectors Anopheles balabacensis A. gambiae A. freeborni A. stephensi

37. Malaria – Vectors (cont.)

38. 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 Dormant liver stages (hypnozoites) of P. vivax and P. ovale HUMAN MOSQUITO Erythrocytic Cycle: Merozoites infect red blood cells to form schizonts Some merozoites differentiate into male or female gametocyctes Parasite undergoes sexual reproduction in the mosquito

39. Plasmodium falciparumSporozoites/liver schizonts

40. MalariaRed blood cell invasion

41. P. falciparum – Blood stages 4 hr. Uninfected RBC 12 hr. 2 hr.

43. 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

44. Sites of Action for Antimalarial Drugs TISSUE SCHIZONTOCIDES: primaquine pyrimethamine proguanil tetracyclines HUMAN MOSQUITO BLOOD SCHIZONTOCIDES: chloroquine mefloquine quinine/quinidine tetracyclines halofantrine sulfadoxine pyrimethamine artemisinins SPORONTOCIDES: primaquine pyrimethamine proguanil GAMETOCYTOCIDES: primaquine

45. 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)

46. 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

47. 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

48. Malaria - Treatment Artemisinin

49. 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

50. 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