Travel Medicine

1. Travel Medicine Melissa Huang Kevin Coleman Shannon Dunlay

2. Learning Objectives • Identify the most common causes of morbidity/ mortality in the international traveler • Discuss epidemiology, diagnosis, and treatment of common travel illnesses • Traveler’s diarrhea • Malaria • Hepatitis A • Discuss appropriate pre-travel clinical evaluation • Discuss appropriate evaluation of fever in the returning traveler • Identify useful resources for patients & physicians • Quiz questions

3. Central & South America Arthropod borne: Malaria, Dengue, Leshmania, Chagas, RMSF Food/water borne: Traveler’s diarrhea, Leptospirosis, Hep A, Cholera, Typhoid East Asia Arthropod borne: Malaria, Japanese encephalitis, Dengue, yellow fever, typhoid Food/ water borne: Diarrhea, Cholera, Typhoid, Hep A&E, poliomyelitis, schistosomiasis (avoid swimming in fresh water) Southeast Asia Similar to East Asia but chloroquine-resistant P. falciparum is more widespread Sub-Saharan Africa Malaria, dengue, yellow fever, African trypanosomiasis, Leishmaniasis, Onochocercosis, Typhus, hemorrhagic fever (Lassa fever, Rift Valley fever, Ebola, Marburg Common Diseases Vary by Region

4. The leading causes of morbidity and mortality in international travelers include: • Motor vehicle accidents • Traveler’s diarrhea • Malaria • Upper respiratory infections • Hepatitis A • Sexually transmitted diseases

5. Motor Vehicle Accidents • Leading cause of morbidity/ mortality in travelers • Prevention is the key: • Importance of wearing seat belts • Following driving safety precautions • Risks associated with blood transfusions from potentially unsafe blood products

6. Traveler’s Diarrhea Definitions: 3 classifications used to define traveler’s diarrhea1: • Classic: Passage of 3 or more unformed stools in 24 hrs + at least one of the following symptoms: nausea, vomiting, abdominal pain/ cramping, fever, blood in stools • Mild: Passage of 1-2 unformed stools in 24 hrs without additional symptoms • Moderate: Passage of 1-2 unformed stools in 24 hrs + at least one of the following symptoms: nausea, vomiting, abdominal pain/ cramping, fevers, blood in stools OR passage of >2 unformed stools in 24 hrs without other symptoms

7. Traveler’s Diarrhea: Epidemiology • 40-60% of traveler’s to developing nations develop traveler’s diarrhea2 • Transmission is primarily via food and water • Epidemiology and risk depends on geographic locations, seasons, exposures • Risk factors: • Burden of ingested organisms • Patient profile, i.e., patients with altered GI anatomy, abnormal motility, suppressed gastric acid secretion (on PPI or H2 blockers)

8. Traveler’s diarrhea Diagnosis: clinical- distinguish between: watery diarrhea vs. dysentery (bloody) vs. chronic diarrhea • Causes: • Often no etiologic agent identified; usually self-limited • When symptoms are severe or persist >48-72hrs, medical intervention and work-up may be warranted (stool cultures, O&P)

10. Traveler’s diarrhea: prevention is key • Food and water precautions: • Eat only foods that are thoroughly cleaned and recently cooked • Wash all fruits and vegetables with clean water • Peel all raw fruits and vegetables • Avoid raw meat, fish, vegetables, salads, unpasteurized dairy; particularly when dining out • Avoid drinking tap water or using ice- even bottled water isn’t always safe! • Look for carbohydrate beverages and confirm presence of carbonation upon open • Purify drinking water by boiling it, treating with chlorine or iodine or filtering it when clean water is not available • CDC sound byte: “Boil it, cook it, peel it, or forget it.”

11. Prevention • Prevention • A recent study found that travelers to Mexico who were given rifaximin had a significant reduction in the development of travelers diarrhea compared with placebo (14.74% vs. 53.7%, risk ratio 0.27)5 • The primary cause of traveler’s diarrhea in Mexico is ETEC and there are no studies in countries where invasive pathogens are more common • Previously prophylactic antibiotics were discouraged due to side effects, drug reactions, false sense of security leading to lapse in precautionary measures, and antibiotic resistance

12. Traveler’s Diarrhea: Treatment • Fluid replacement/ oral rehydration: • Most important!!! • Oral rehydration therapy (ORT) contains both carbohydrate and salt as glucose facilitates water reabsorption & Na/ glc absorption are coupled • Antimotility agents: addition of loperamide may reduce duration to <1day, but avoid if diarrhea bloody or w/ fevers

13. Treatment • Treatment once diarrhea develops • Shortens disease duration to about 1 day after initiation • Abx options (2-3 day course): fluoroquinolone, azithromycin • Rifaximin does not work to treat invasive pathogens (bloody) • Physicians should provide a prescription for antibiotics for travelers to take & fill if diarrhea develops during travel

14. Malaria: Epidemiology and Diagnosis • 4 species of Plasmodia cause human malaria: falciparum (most dangerous), malariae, ovale, vivax • While traveling, several hundred U.S. citizens contract malaria annually5 • Diagnosis: requires heightened clinical suspicion when a febrile illness occurs in a patient that recently traveled to an endemic area • Made by ID of parasites on Giemsa stained thick and thin blood smear microscopy • Clinical presentation: fevers, chills, headache, myalgias, arthralgias, nausea, vomiting, diarrhea

15. Malaria Epidemiology

16. Malaria: Treatment

17. Malaria: Prevention • Physicians should provide travelers with advice • Antimicrobial prophylaxis based on resistance patterns, risk of malaria in travel region, side effects/ contraindications • Initiate chemoprophylaxis prior to arrival and continue after departure • It is still possible to acquire malaria on chemoprophylaxis • Mosquito avoidance techniques • Mosquitoes that transmit malaria usually feed at night • Remain in screened areas as much as possible • Use mosquito netting treated with Permethrin • Cover exposed skin w/ Permethrin treated clothing **should repel mosquitoes for >1wk even with washing6 • Apply DEET containing insect repellant (30-50% concentration) • No effective malaria vaccines are currently available

18. Malaria: Chemoprophylaxis Agents • Chloroquine • 1st line agent effective against all 4 malaria species • 500mg Qwk 1-2 wks prior to arrival and for 4 wks after departure • SE: GI, dizziness, H/A, blurred vision, RARE ocular toxicity • Mefloquine • Primary choice in areas w/ Chloroquine-Res P. falciparum • Dosing: 250mg PO QDx3D, then 250mg PO Qwk • SE: Neuropsychiatric (nightmares, seizures, psychosis)7, nausea, dizziness, vertigo • Alternative agents in chloroquine-resistant areas: • Atovaquone-proguanil: fewer side effects than mefloquine • Doxycycline: requires daily administration and has photosensitivity8 • Primaquine: hemolysis if G6PD deficient, eradicates hepatic stages of P. vivax and ovale9 • Pyrimethamine/ sulfa: can cause severe mucocutaneous rxns.

19. Hepatitis A • Epidemiology • Occurs worldwide • Spread via fecal-oral route- more common in areas with poor sanitation • Can be spread via contaminated food and water • Clinical manifestations • Prodrome of fatigue, malaise, anorexia, fever, RUQ pain • Few days later dark urine, jaundice, pruritis • 2 most common physical findings are jaundice (70%) and hepatomegaly (80%)10 • Laboratory: AST, ALT (often >1000), bilirubin, alk phos

20. Hepatitis A • Diagnosis • Serum IgM Anti-HAV antibodies is gold standard • Remain positive 4-6 months • Treatment • Generally self-limited (full recovery in 3-6 mo) • Supportive Care • Rarely develop fulminant hepatic infection, mainly in patients with concomitant hepatitis C • Prevention • Food and water precautions • Vaccine available: some indications include travel to specific areas, sexually active gay men, chronic liver disease, occupational risks, illegal drug users

21. Sexually Transmitted Diseases • Sexual contact with new partners during travel is common • Study of 782 travelers, 19% reported a new sexual partner and 6% acquire an STD11 • Gonorrhea was diagnosed in 3 per 1000 per month in returning travelers in a study of >10,000 Swiss citizens traveling to a developing nation for <3 months12 • Other STDs include: syphilis, HIV, hepatitis A, B, & C, CMV • Physicians should counsel patients about the risks of STDs and prevention Secondary syphilis rash

22. Pre-travel Evaluation • All persons traveling to a foreign country should seek advice from their doctor or a travel medicine provider 4-6 wks in advance of their travel • Patients should receive counseling, immunizations, and prophylaxis based on their destination • Safe food and water • Insect and arthropod protection • Immunizations • Chemoprophylaxis and possible Rx for traveler’s diarrhea • Medical help available in the area of travel • Patients should always ensure that they have a sufficient supply of their regular prescription medications prior to travel

23. Pre-travel Evaluation: Immunizations • CDC divides into three categories: routine, recommended, and required • Routine • E.g. tetanus-diphtheria, influenza vaccine, pneumococcal vaccine, hepatitis B, MMR, varicella as appropriate • Recommended (depends on travel destination- see CDC website at www.cdc.gov/travel) • Most common are hepatitis A&B, typhoid, meningococcal (sub-Saharan Africa May-June), Japanese encephalitis • Required • Yellow fever to some sub-Saharan Africa and tropical S. America. • Meningococcal vaccine for travel to Saudi Arabia during Hajj • Vaccine contraindications: • Live virus vaccines (yellow fever, polio, MMR)- pregnant, immunocompromised • Yellow fever vaccine contains egg protein- check for allergy

24. Pre-travel Consideration: Travel Insurance • Know your policy- not all major insurers provide coverage for emergencies while traveling • Social Security/ Medicare does not provide coverage outside the U.S. • Consider counseling patients to obtain supplemental health insurance for international travel • Evacuation insurance • Less than $50/yr vs. out of pocket costs >$100,000 • Can provide evacuation to major medical areas • See U.S. Department of State website for list of travel insurers/ medical evacuation providers: http://travel.state.gov/travel/index.html

25. Primary Care: Fever in a Returning Traveler • 38% of travelers who sought advice prior to travel reported illness upon return13 • 53% of hospitalized returning travelers with fever presented w/in 1 wk of return. Most common diagnoses were malaria (27%), URI (24%), gastroenteritis (14%), dengue fever (8%), bacterial pneumonia (6%)14 • Diarrhea and URIs are the most common infections overall in travelers • Signs requiring urgent intervention: hemorrhagic manifestations, respiratory distress, hypotension, hemodynamic instability, confusion, lethargy, meningismus, focal neurologic findings

26. Fever in Returning Traveler: Evaluation • Requires a systematic approach: • Detailed travel history • Geography, dates of travel, transportation, accommodations • Exposures: sexual contacts, animals, arthropods, needle/ blood exposures, food & beverages, soil & water contact • Clinical Evaluation • Age, sex, PMH, prior infections, meds, chemoprophylaxis, vaccines • PE: skin findings, lymphadenopathy, hepatosplenomegaly, genital lesions, neuro findings, retina/ conjunctiva • Screening labs: CBC w/ diff, GI panel, bld cultures, malaria smears, CXR • Differential diagnosis • Tailored based on above information • Include malaria if patient traveled to endemic region

27. Resources for Patients & Physicians • Duke University Medical Center Travel Clinic • Th & F at Duke South and M&T at Southpoint • Appointments can be made at 681-6261 • CDC website: http://www.cdc.gov/travel • Yellow book: a reference for health care providers advising international travelers on health risks. More info: http://www2.ncid.cdc.gov/travel/yb/utils/ybBrowseC.asp • Wilderness Medical Society (WMS) provides courses for physicians wishing to serve as expedition medical staff

28. References • Lancet 2000; 356:133 • UpToDate, “Traveler’s Diarrhea,” October 4, 2005. • Arch Virol Suppl 1996; 11:171. • Morbidity/ Mortality Weekly Report 1997; 46:536. • CDC, Health Information for International Travel. www.cdc.gov • J Am Mosq Control Assoc 1989; 5:176. • Lancet 1993; 341:1299. • Ann Intern Med 1997; 126:963. • N Engl J Med 2003; 349:1510. • J Infect Dis 1995; 171S1: S15-18. • AIDS 1994; 8:247. • J Infect Dis 1987; 156:84. • J Travel Med 1997; 4:61. • Clin Inf Dis 2001; 33: 603 • Morbidity/ Mortality Weekly Report 2004; 53:21. • J R Coll Physicians Lond 1998; 32:235. • Emerg Infect Dis 2005; 11:436. • J Allergy Clin Immunol 1995; 95:1064 • JAMA 1994; 272:885.

29. Quiz Question #1: A 26 year old female who recently relocated to the U.S. from Honduras 6 months ago presents to the emergency department with a three day history of fever, abdominal pain and vomiting. She reports that she was treated for malaria 9 months ago with chloroquine in El Salvador when she presented with similar symptoms. A thick and thin smear obtained in the ED reveal plasmodium vivax, 1% parasitemia. What is the most likely explanation for this patient’s recurrence of malaria? • She did not complete her full course of chloroquine in El Salvador • She caught malaria from her cousin who is visiting her from El Salvador • She had reactivation of liver hypnozoites from the first episode of malaria • She was reinfected by a mosquito carrying malaria here in Durham • There is no way she has malaria- the ED is wrong again.

30. Quiz Question #2 Referring to the patient in question #1, what is the most appropriate treatment for her illness? • Chloroquine 600mg PO x1, then 300mg PO daily x3 days • Chloroquine 600mg PO x1, then 300mg PO daily x3days, followed by primaquine 15mg PO daily x14 days • Quinidine 10mg/kg IV over 1-2 hrs, then 0.02mg/kg/min IV followed by doxycycline 100mg PO/ IV Q12hrs • There is no treatment available that will cure her recurrent malaria

31. Quiz Question #1&2: Explanation Correct answer #1: C Correct answer #2: B Explanation: P. vivax and P. ovale remain dormant in the liver in hypnozoite form. This form is not eradicated by treatment with chloroquine alone, so this patient was not adequately treated during her 1st episode 9 months ago. Correct treatment would entail chloroquine (El Salvador is not an area with chloroquine-resistant malaria) followed by primaquine to eradicate liver hypnozoites to prevent another recurrence. In addition, she should be tested for G6PD deficiency prior to use of primaquine as this medication can cause hemolysis in G6PD-deficient patients.

32. Quiz Question #3: A 30-year HIV positive male recently returned from a trip to sub-Saharan Africa. He did not take chemoprophylaxis prior to his trip. His sister notices that he has had a high fever and is developing altered mental status and rushes him to the Duke Emergency Department. Upon presentation, the patient is febrile to 39.5C. He is only oriented to person and has a generalized seizure shortly after presentation. Thick & thin smears reveal banana-shaped gametocytes within red blood cells. What plasmodium species is this patient infected with? • Plasmodium falciparum • Plasmodium vivax • Plasmodium ovale • Plasmodium malariae

33. Question #3 Explanation Answer: A Explanation: This patient is having symptoms c/w cerebral malaria. This can occur in patients infected w/ p. falciparum. Clinical findings consist of an altered level of consciousness and seizures. Risk factors include HIV infection, pregnancy, age (old or young), prior splenectomy. Patients living in endemic areas are much less likely to get cerebral malaria even if infected w/ P. falciparum than non-immune individuals. It is universally fatal if untreated and is associated with 20% mortality with treatment.

34. Quiz Question #4 A 20-year old female college student presents to the acute care clinic for evaluation of jaundice. She recently returned from a Spring Break trip to Cancun, Mexico. On examination she is grossly jaundiced and has appreciable hepatomegaly on exam. Laboratory data is significant for an AST of 1200, ALT 1800, total bilirubin 8.2, INR 1.1. What laboratory test would help to identify the most likely diagnosis? • Anti-hepatitis C virus antibody • Hepatitis B surface antibody • Monospot • IgM anti-hepatitis A virus antibody • IgG anti-hepatitis A virus antibody

35. Quiz Question #5: Referring to the patient in question #4, what is the most appropriate treatment at this time? • Supportive care only • Doxycycline 100mg PO BID x7 days • Pegylated interferon alone • Pegylated interferon plus ribavirin

36. Quiz Question #6 Referring to the patient in question #4, what is the most likely outcome from this illness? • Fulminant hepatic failure • Chronic infection with resultant cirrhosis over time • Resolution without permanent hepatic damage • It depends on the treatment used

37. Questions #4-6 Explanations Question #4 Answer: D Question #5 Answer: A Question #6 Answer: C Explanation: This student most likely has acute hepatitis A virus infection. This is transmitted primarily by fecal-oral route and is common in areas with poor sanitation. In patients with appropriate clinical findings, the diagnosis can be confirmed by an elevated hepatitis A virus IgM antibody level. The vast majority of cases resolve with AST/ ALT levels returning to normal within 3 months (85%) and treatment is supportive.

38. Quiz Question #7 A 30-year old male presents to your clinic for evaluation prior to a trip to Central America. He wants to avoid getting traveler’s diarrhea during his trip and is wondering if there is anything he can do to prevent this. What advice do you offer? • Only drink bottled water and you should be fine. • Salads are the safest food to eat while dining out. • Only eat food that is thoroughly cleaned and recently cooked and concentrate on drinking carbonated beverages. • There is nothing you can do to prevent traveler’s diarrhea.

39. Quiz Question #7 Explanation Correct answer: C Explanation: Prevention is key while traveling to avoid traveler’s diarrhea. Bottled water is not always safe and can come from a contaminated source. In addition you should avoid eating fresh vegetables or salads at restaurants- only eat those that are cooked or fruits/ vegetables you can peel yourself. Carbonated beverages are a safe drink if you make sure to verify the presence of carbonation upon opening.