Travel Prophylaxis: A Step Not to Avoid

1. Travel Prophylaxis: A Step Not to Avoid Laura Mutter, M.D. Dr. Jonathon Sellman, M.D.

2. The Case HPI: 52 year old male presented with a one week history of fevers, chills, myalgias, and jaundice, in addition to nausea and vomiting. Returned from Malawi on 3/03/05. Had not taken disease prophylaxis there. Returned from a trip to Thailand and Burma on 1/13/05 during which he used no disease prophylaxis.

3. H & P Continued PMH: Unremarkable. Patient has no medication allergies. Allergies: No medication allergies Social History: Patient is married and lives at home with his wife. He makes trips to foreign countries as a missionary teacher.

4. Review of Systems GEN: C/o fever, chills, generalized fatigue Skin: No skin rashes or lesions HEENT: Headache. No change in vision. No difficulty swallowing. No oral lesions. Respiratory: No shortness of breath or cough. GU: Urine dark. MSK: Diffuse severe body aches

5. Physical Examination: VS: T 97.6, BP = 112/55, Pulse 125, RR = 15 GEN: A & O X III. Thoughts are linear, logical and coherent. Skin: Markedly jaundiced HEENT: Sclera icteric. No conjunctival lesions/erythema. OP: Dry mucous membranes. NECK: Supple, no LAD Lymphatics: No signs of adenopathy

6. Physical Exam Continued Gen: Patient appeared markedly fatigued Lungs: CTA �B. Symmetrical chest rise. CV: RRR, S1, S2, nl. No M/R/G. ABD: Soft, TTP in left and right upper quadrants but no hepatosplenomegally appreciated. EXT: Normal muscle tone and bulk SKIN: Jaundiced.

7. Jaundice

8. Labs from Outside Medical Center

9. Regions Labs/Studies Peripheral blood smear: 5.2% parasite load. Pathological diagnosis: Falciparum malaria, extensive involvement. CBC: Hbg: 12.5, Plt Ct = 35 EKG: Sinus Tachycardia, otherwise WNL.

10. Hospital Course: Falciparium Malaria Treatment with Mefloquine was initiated: 500 mg followed by 500 mg 12 hours later. Patient was closely monitored in the ICU setting. Parisitemia trended downward shown in the table below and he improved clinically

11. Hospital Course: P. falciparum Unfortunately, after a couple of days, the patient�s parasitemia increased despite treatment with mefloquine as shown below.

12. Hospital Course: Falciparium malaria ID consultants had been aware of the patient�s travel to the Thai-Bermese border area and therefore observed closely for treatment failure on mefloquine. When patient worsened, he was given 1 dose of Malarone (Atovaquone plus Proguanil) The patient was subsequently treated with quinidine and doxycycline for 72 hours.

13. Hospital Course: Falciparium Malaria After treatment with quinidine and doxycycline for 72 hours, the patient�s parasitemia gradually decreased and eventually resolved. EKG: QT prolongation

14. Hospital Course: Elevated LFT�s The patient�s LFT�s were elevated on admission, and increased to a max AST of 407 and ALT of 251. Maximum bilirubin = 21. Abdominal ultrasound showed: liver WNL, gallbladder sludge, and mild splenomegally. Blood flow in hepatic vessels and IVC was WNL.

15. Hospital Course: LFT�s continued to trend downward and were as follows at the time of discharge: t-bili � 5.7, alkaline phosphatase -176, and AST = 43.

16. Other Common Manifestations of P. falciparum experienced by Pt. ARF: Creatinine of 2.0 was initially thought to be due to infection Plasmodium falciparum. Creatinine improved to 1.7 with hydration. Thrombocytopenia: Platelet count in 30�s. Electrolyte abnormalities: Hypokalemia, hypomagnesemia, hypophosphatemia, hypocalcemia were corrected.

17. Important Points All travelers to regions with Malaria should receive prophylaxis Physicians should be aware of the distribution of drug resistance when initiating treatment or prophylaxis for travelers. CDC info on malaria and drug resistance www.cdc.gov/travel. To be revisted�

18. Overview of Malaria Caused by one of four species of protozoan: Plasmodium falciparum, P.vivax, P. ovale, P. malariae. Transmitted by infected female Anopheles mosquito. 300-500 million infections worldwide and 1 million deaths annually. Presents as febrile illness with chills and rigors, followed by fever spikes to 104 F, followed by extreme fatigue.

20. Overview of Malaria Fevers Paroxysms last several hours, occur with a periodicity coinciding with the simultaneous rupture of blood schizonts, and are associated with very high levels of TNF�a. Paroxysms occur in 48 h or 72 h cycles, or almost continuously in cases of P. falciparum.

22. Physical Exam Physical exam findings include pallor and hepatosplenomegally. Jaundice or a decreased level of consciousness Diagnostic features of severe malaria include the following: cerebral malaria, respiratory distress, prostration, hyperparisitemia, anemia, hypoglycemia, jaundice, renal insufficiency, hemoglobinuria, shock, cessation of eating and drinking, repetitive vomiting, and hyperpyrexia.

23. Common Lab Results Anemia Decreases in hemoglobin, hematocrit, and haptoglobin and increases in LDH in L. falciparum infections Platelets may be normal, or slightly low, but are <70,000/microL in P. falciparum infection. Acidemia (pH less than 7.35), acidosis (bicarb less than 15mmol/L), and lactate levels greater than 5 mmol/L in severe P. falciparum infection. Renal impairment (increased creatinine, proteinuria, and hemoglobinuria) is common in falciparium infection.

24. P. Falciparum: Typically more acute and severe than malaria caused by other Plasmodium species. Severe manifestations of P. falciparum malaria are responsible for most deaths and include the following: cerebral malaria, severe anemia, and respiratory failure. Contributory factors include lactic acidosis and hypoglycemia. Multiple organ failure.

25. Smears

26. Diagnostic Studies Thick smears concentrate RBC layers 40-fold and are used to screen a large amount of blood for the presence of parasites. Parasites are visualized outside RBC�s Repeat smear negative slides Q 12 hours until a diagnosis is made or ruled out. Report positive results to CDC Parasite density is associated with disease severity Monitor during and after treatment to ensure resolution

27. Diagnostic Studies Continued Thin blood smears Used for speciation of malaria parasites. P. falciparum infections thin delicate rings that may be juxtaposed against the inner surface of the RBC membrane multiply infected cells containing signet forms banana-shaped gametocytes Absence of trophozoites and schizonts (sequestered in the microvasculature).

28. F. falciparum: Banana Gametocytes

29. Distribution of Malaria and Drug Resistance P. falciparum and P. malariae are found worldwide. P. vivax is uncommon in most of sub-Saharan Africa, but common elsewhere. P. ovale occurs in Africa and in foci within Asia and Oceana.

31. Distribution of Drug Resistance Chloroquine-resistant P. falciparum malaria is present in subSaharan Africa, Asia, and Latin America as well as in areas of the Middle East including Iran, Yemen, Oman, and Saudi Arabia. It is not present in Mexico, other regions of Central America West of the Panama Canal, Haiti, or the Dominican Republic.

33. Distribution of Drug Resistance Mefloquine-resistant P. falciparum malaria occurs at the border of Thailand with Burma and Cambodia, in Western Cambodia, and Eastern Burma. The area of mefloquine resistance is expanding Updates at http://www.cdc.gov/travel Atovoquone/proguanil can be used as prophylaxis by travels to areas with mefloquine resistant strains of P. falciparum.

34. Mefloquine Resistant Malaria

35. Distribution of Drug Resistance Resistance to sulfadoxine-pyrimethamine (SP) is widespread through much of Southeast Asia, the Amazon Basin, and also occurs in sub-Saharan Africa. The prevalence of SP resistance is highly variable in Africa, with some areas of West Africa showing relatively low rates of resistance. For this reason, SP has replaced chloroquine as first line therapy for treatment of chlroquine-resistant infections in many African countries.

36. Distribution of Drug Resistance Reduced susceptibility to quinine has been mostly reported in Southeast Asia, sub-Saharan Africa, and South America. Artemisinin resistance has not been detected.

37. Recent Outbreak: Dominican Republic Since February 18, the CDC has received 21 cases of malaria in travelers to resort areas of the Dominican Republic where malaria had not previously been reported. Rural Dominican Republic, P. falciparum endemic. Highest risk in Western region of the country. Prophylaxis with chloroquine long been recommended.

38. Malaria Outbreak: Dominican Republic Given the recent outbreak of cases in the La Altagracia and Duarte provinces, on 11/24/05, the CDC expanded its recommendations for chloroquine prophylaxis to include the entirety of the La Altagracia and Duarte provinces. The ministry of Health (MoH) in the Dominican Republic confirmed no cases reported between 2003-2004 in Duarte.

39. Malaria Outbreak: Dominican Republic In La Altagracia, the MoH uncovered an increase in malaria cases starting in November 2004 among migrant workers in the Bravaro Zone, 10 miles from the Punta Cana resort area. MoH instituted the following control measures: Treatment of all hotel and construction workers with chloroquine and primaquine Insecticide spraying Application of larvicide to breeding sites.

41. Malaria Outbreak: Dominican Republic Contributing factors Hurricane Jeanne Sept. 2004, bringing heavy rains and floods to the East Coast Construction in Punta Cana and Bravaro Zone have brought in migrant workers from areas where malaria is endemic. Pattern � 1999-2000 Hurricanes Mitch and George Malaria infected migrant workers

42. Malaria Outbreak: Dominican Republic Lessons learned Fast communication among surveillance networks throughout multiple countries can lead to prompt diagnoses and early public health interventions. Increased surveillance is prudent in the wake of hurricanes or migration of groups of persons from areas where malaria is endemic.

43. Malaria Treatment: General Principles All cases of malaria should be treated as falciparum malaria until proven otherwise Patients infected with P. falciparum malaria with no immunity should be hospitalized for > 48 hours to ensure adequate response to therapy given the unpredictable course. Infections with P. vivax, P. ovale, and P. malariae are treated with chloroquine unless they are acquired in geographic areas where the species are known to be chloroquine resistant or there is a doubt about the parasite species/mixed infection. Non-falciparum infections likely to be chloroquine resistant are treated with mefloquine, quinine plus doxycycline, or atovaquone plus proguanil.

44. Malaria Treatement Chloroquine phosphate Safe in pregnant women, children, adults Side effects include N/V/HA, dizziness, blurred vision. Produces nonallergic pruritis in dark-skinned persons and may exacerbate psoriasis.

45. Amodiaquine Related in structure to chloroquine Partially susceptible to mechanism of cloriquine resistance Rarely causes agranulocytosis, hepatotoxicity and aplastic anemia with long term use, and therefore is not available in the United States.

46. Mefloquine Useful for treatment of the majority of chloroquine-resistant parasites except for strains in areas such as Thailand, Myanmaar, Cambodia, and Vietnam where resistance to this drug is present. Side effects include GI upset, dysphoria, dreams and mood changes in 5% of the population. Uncommonly causes reversible neuropsychiatric reactions. May prolong the corrected QT interval Caution in patients with conduction abnormalities Avoid concurrent use with quinine

47. Quinine plus Doxycycline Effective against multidrug-resistant parasites. Quinine may cause GI upset and cinchonism (nausea, vomiting, dysphoria, tinnitis, tone deafness). Doxycycline also causes GI upset and vaginal candidiasis. Contraindicated in pregnant women and children <8 years old.

48. Atovaquone plus Proguanil (AP) Used to treat multi-drug resistant parasites. Rare resistance Well tolerated Few severe adverse reactions

49. Quinidine plus Gluconate Only approved parenteral treatment for severe malaria in the United States ICU cardiopulmonary monitoring. QT prolongation and risk of torsade de pointes Risk: hyperinsulinemic hypoglycemia Blood smears Q 6-8 7 day course of treatment completed with combination of quinine tablets and doxycycline.

50. References: CDC. The yellow book: health information for international travel, 2003-2004. Atlanta, GA: US Department of Health and Human Services, CDC; 2003. CDC Public Health Image Library. C Kay, MD and D Patrick MD et al. MMWR weekly. Transmission of Malaria in Resort Areas � Dominican Republic, 2004. Jan 7, 2005/53(51 &52); 1195-1198. Mandell, Douglas, and Bennett�s. Infectious Diseases. 6th Ed. Vol II. 3121-3144. Re VL III and Gluckman SJ. Prevention of Malaria in Travelers. American Family Physician. August 1, 2003. Vol 68, Number 3. Talisuna, AO, Bloland P, and D�Alessandro U. History, Dynamics, and Public Health Importance of Malaria Parasite Resistance. Clinical Microbiology Reviews. Jan. 2004, p. 235-254.