Travel and Tropical Medicine

1. Travel and Tropical Medicine Roger Thomas, MD, Ph.D, CCFP. MRCGP

2. RISKS of Travel to Developing Countries Diarrhea 34% (ETEC causes 30-60% of these cases) Respiratory 26% Skin disorder 8% Acute mountain sickness 6% Accident and injury 5% Illness with fever 3%

3. Mortality from travel in developing world 50% is cardiovascular (older travelers with pre-existing cardiac condition), but rates are not increased by travel In younger travelers injuries are main cause of death: accidental death rate in 15-44 year olds is 2-3 times domestic rate (MVA, scooters, drowning)

4. Traffic accidents worldwide 2004 1.7 million deaths, single major cause of death in males 15-45 > 750 US citizens die, > 25,000 injured annually on foreign roads, some are permanent residents abroad, (implying > 75 Canadians and > 2,500 accidents) 30 million injuries Egypt, Kenya, India, S. Korea, Turkey, Morocco most dangerous Advise do not drive at night, especially rural areas; do not drive motorbike or bike

5. OUTLINE Take a history past medical history, medications, vaccinations planned travel unplanned excursions and sports Bring childhood vaccinations up to date (MMR, polio, tetanus) Vaccinations and medications needed for trip Ask their understanding of risks; your advice Print off CDC data and have them read and underline it Malaria: prevention; diagnosis; treatment Traveller�s diarrhea: prevention; diagnosis; treatment Helminths 9. Other

6. Let�s begin with a 60 year old going to Peru and Ecuador PMH: HTN, hyperlipidemia, well controlled; never smoker What are his/her travel plans? Review CDC website cdc.gov Identify risks and prescribe

7. 60 year old visiting Peru and Ecuador Update childhood vaccinations Check for egg allergy if plan MMR, influenza, Yellow Fever vaccines GI risk: cholera? typhoid? Bacterial diarrhea? Hepatitis? (Twinrix) Helminths? Yellow Fever? Malaria risks? High altitude sickness risks? (he/she is going to 3,600 meters rapidly by plane, no slow ascent; risks begin above 2,400 meters) PE from air travel (5/million)

8. 60 year old visiting Peru and Ecuador: Other risks? Helminths such as Amebiasis, echinococcus American trypanosomiasis (Chagas� disease) Cutaneous and mucocutaneous Leishmaniasis Paragonimiasis (oriental lung fluke) Brucellosis Bartonellosis (Oroya fever) on western slopes of Andes up to 3000 m Louseborne typhus in mountainous areas of Peru

9. 28 year old veterinarian, visiting Malawi, South Africa, advising for WHO PMH: LMP 6 weeks ago, rising ?HcG titres, planning to be in Africa during 1st and 2nd trimesters GI risks? Malaria risks? Rabies risks? Risks to pregnancy?

10. Live-attenuated vaccines in pregnancy MMR and varicella are live-attenuated and contrandicated in pregnancy because of theoretical risk to fetus However, no evidence of harm from inadvertent rubella vaccination ?226 pregnant females 1971- 1989 in US caused subclinical infection in 1-2% of fetuses, no evidence of congenital rubella ?Motherisk found no evidence of increased rate of fetal malformations in 94 women vaccinated with rubella 3 months before conception or during pregnancy

11. Live-attenuated vaccines in pregnancy No evidence of harm from inadvertent varicella vaccination ? in 362 women vaccinated during pregnancy, no cases of congenital varicella

12. Vaccines in pregnancy No evidence of increased risk of adverse reactions, teratogenic or embryotoxic effects in pregnancy All classes of maternal IgG transported across placenta, mostly in 3rd trimester maternal IgG has half life of 3-4 weeks in infant, waning after 6-12 months of life. Strong evidence of benefits of vaccines

13. Canadian Immunization Guide Advice for pregnancy Safe ? Influenza (good idea as pregnant women have 4 x hospitalisation rate for influenza compared to non-pregnant due to increased CVS volume, HR and O2 consumption) ? Diptheria/tetanus ? Polysaccharide meningococal vaccine (no evidence for conjugate vaccine) ? Salk poliomyelitis vaccine

14. Canadian Immunization Guide Advice for pregnancy No apparent risk, recommended in women at risk ? Hepatitis B No apparent risk, consider in high-risk situations ? Hepatitis A ? Pneumococcal polysaccharide ?Cholera (no data) ?Typhoid (no data) ?Pertussis (no data) ? Live Japanese encephalitis (no data) Contraindicated (unless high risk travel unavoidable) ? Yellow fever (6/million risk of visceral and 6/million risk of cerebral complications for all vaccinees)

15. Malaria Incubation: for Plasmodium falciparum: 7-14 days (up to 6 weeks) Partial immunity from long-term residence is against erythrocytic stages and diminishes within 6-12 months of leaving endemic area Clinical presentation: (clinical diagnosis is inaccurate as malaria is a great imitator; must do thick and thin films) Prodrome of tiredness, malaise and aching in the back, joints and abdomen, anorexia and nausea and vomiting. Tender splenomegaly. Conjunctivae suffused. Patient febrile for 2-3 hours before paroxysm.

16. Malaria �Cold stage� of rigors (15-60 minutes): ? sudden feeling of cold and apprehension ? pulse rapid and low volume ? mild shivering turns into violent teeth chattering and shaking of the whole body. Patients try to cover themselves with bedclothes ? core temperature is high but peripheral vasoconstriction with skin cold and goose- pimpled

17. Malaria �Hot stage� up to 104F (2-6 hours): (�Ague attack� resembles the �endotoxin reactions� of lobar pneumonia or pyelonephritis) ? restless, unbearably hot, throws off all the bedclothes, excited ? severe throbbing headache, palpitations, tachypnea, postural syncope ? may vomit ? may become confused, convulse ? skin dry flushed and burning ? splenomegaly may be detected first the first time in this stage �sweating stage� (2-4 hours): temperature returns to normal and patient sleeps

18. WHO criteria for Severe malaria Identify patients with severe malaria for special treatment with one or more of: Cerebral malaria Respiratory distress Severe normocytic anemia Renal failure Hyperparasitemia Pulmonary edema Hypoglycemia Circulatory collapse Spontaneous bleeding Generalised convulsions

19. Cerebral malaria (encephalitis) impairment of consciousness or generalised convulsion followed by coma high fever can cause irritability, obtundation, psychosis, and febrile convulsions (children) so urgently treat impairment of consciousness may thrash or lie immobile with eyes open or have dysconjugate gaze

20. Cerebral malaria (encephalitis) brainstem signs: ? doll�s eyes (in children) ? may be decorticate (flexion of elbows and wrists, supination of the arm) suggests severe bilateral damage to the midbrain ? may be decerebrate (extension of wrists and elbows with pronation of the arms suggests damage to the midbrain or the caudal diencephalon)

21. Cerebral malaria (encephalitis) children may have subtle convulsions (nystagmoid eye movements, salivation, shallow irregular respirations, clonic movements of an eyebrow, finger, toe or mouth) with excellent care mortality is 15-20%; death within hours for children respiratory distress (compensation for metabolic acidosis), laboured breathing, intercostal recession, nasal flaring, accessory muscles of respiration)

22. Malarial Anemia (defined as < 5 g/dl): children with severe anemia usually have acidosis (deep Kussmaul breathing); malarial anemia kills as many children as cerebral malaria (mortality = 5-15%; mortality from acidosis = 24%; mortality from severe anemia + acidosis = 35%) also common in pregnant women

23. Jaundice and hypoglycemia in malaria Jaundice 1/3 of adults; associated with cerebral malaria, acute pulmonary edema Hypoglycemia Anxiety, breathlessness, lightheadedness, tachycardia, impairment of consciousness, seizures, abnormal posturing can be misinterpreted as due only to the malaria Pregnant women: ? cell-mediated immunity is altered to favour survival of the fetus (more so in primigravidae), the placenta is heavily parasitized (the parasites adhere to chondriotin sulphate on the syncytiotrophoblast) The peripheral blood film may show no parasites ?risk is greatest for primigravidae in areas of unstable malaria

24. Chemoprophylaxis of malaria Causal prophylaxis: atovaquone and primaquin act on exo-erythrocytic cycle in liver Schizontocides: atovaquone, mefloquine, chloroquine, doxycycline, proguanil act on intra-erythrocytic parasites Terminal prophyaxis: Primaquine acts on latent hypnozoites in liver to prevent relapses in P Ovale and P vivax

25. Chemoprophylaxis of malaria Mefloquine PO (Begin 1 week before departure, continue 4 weeks after return) 62.5 mg weekly children 3 months � 5 years 125 mg weekly 6-8 years 187.5 mg 9-14 years 250 mg weekly adults

26. Chemoprophylaxis of malaria Doxycycline PO 1.5mg/kg daily. Do not use children < 12 years and pregnant or lactating women; can begin 2 days before enter malarious area Pyrimethamine-dapsone (Malaquine) PO 1 tablet = 12.5 mg pyrimethamine + 100 mg dapsone � tablet weekly children 1-5 years 1/2 tablet weekly children 6-11 years 1 tablet weekly children >11 years and adults

27. Prevention of malaria Bednets & clothes impregnated with pyrethroids. Cochrane review by Gamble (2006) found for 4 RCTs of treated nets vs. no nets a reduction in relative risks: RR 95%CI ?placental malaria 0.79 0.63 to 0.98 ?low birth weight 0.77 0.61 to 0.98 Avoid going out at night, wear long sleeves and long trousers (80% of bites on ankles) Compliance with medication

28. Treatment of Malaria ARTEMISINS (halve parasite clearance time compared to quinine, but RCTs do not show reduction in mortality compared to quinine) Uncomplicated disease: artesunate or artemether by mouth 4mg/kg x 3 days. Give each day in divided doses. Artesunate suppositories are easy to use. Use with second drug (e.g. mefloquine) to prevent recrudescence)

29. Treatment of Malaria Severe disease: ? Artesunate: 2.4 mg/kg IV or IM; then 1.2 mg/kg IM daily. To make artesunate: dissolve 60 g in 0.6 ml of 5% NaHCO3, dilute to 5 ml with 5% dextrose and give IV or IM. ? Artemether: Loading dose 3.2 mg/kg IM then maintenance 1.6 mg/kg IM. Do not give artemether IV, only orally, by suppository or IM. [Complete the therapy with oral sulfadoxine/pyrimethamine]

30. Treatment of Malaria QUININE Uncomplicated disease: 10m/kg quinine SALT by mouth three times daily x 7 days. Once parasites eradicated, change to tetracycline 4mg/kg PO four times daily OR doxycycline 3mg/kg PO once daily Severe disease: starting dose: 20mg/kg quinine SALT IV over 2-4 hours THEN 10mg/kg infused over 2 hours every 8 hours until tolerates oral medication (sulfadxine/pyrimethamine). [If given IM, dilute to 60mg/ml and split between sites if volume exceeds 5ml] Give IV doses in 500ml of 5% glucose over 4 hours Reduce rate if cardiac arrhythmias Pregnant women: quinine is the drug of choice.

31. Falciparum strains adjust to antibiotic pressure Treatment of malaria must take into account local sensitivity to medications and shifts in parasite genome due to antibiotic pressure Zongo (Lancet 2007) showed in children older than 6 months in a 28 day RCT in Burkina Faso that risk of recurrent malaria was: amodiaquine + sulfadoxine-pyrimethamine 1.7% artemether-holofantrine 10.2%

32. Large family going to Mexico for daughter�s wedding. They are worried about getting traveller�s diarrhea Advise on risks, precautions and treatment

33. TRAVELERS� DIARRHEA: PREVENTION Hand washing: 30 seconds with soap Boil, cook or peel, eat when piping hot. Avoid salads, ice cubes, food vendors, cans cooled in water (probably from a stream), shellfish, undercooked seafood ? However, most travelers commit a food indiscretion within the first 72 hours due to being tempted by the sight of snacks, pre-paid buffets and the unavailability of hot food ?Studies of US naval ships abroad showed the more indiscretions ashore (salads, ice in drinks, food vendors � ) the more were on sick parade the next day with diarrhea.

34. TRAVELERS� DIARRHEA: PREVENTION 3. Take a micropore filter. Cryptosporidium can pass through a 1 micropore filter, so needs subsequent halogenation Chlorine is less effective in acid or alkaline or cool water, so lengthen contact time (2 hours for Giardia, 10 minutes for bacteria). Resistance to halogenation increases from bacteria, viruses, protozoan cysts, bacterial spores to parasitic ova and larvae Potassium Permanganate to wash fruit and veg Kettle to boil water (boiling for 1 minute kills even Cryptosporidium

35. TRAVELERS� DIARRHEA: PREVENTION 6. Pepto-bismol: 2 tablets qid reduces risk by 65% (children > 3 years: 1 tablet qid) ? Indications: Prophylactic Pepto-bismol for a short trip: Consider if immunocompromised, HIV+, severe inflammatory bowel disease, renal failure, poorly controlled insulin dependent diabetes. Or of you are a conference speaker or a musical performer who must be well at a specific time. ? Contraindications: (a) 2 tablets have the salicylate content of one 325 mg aspirin, so contraindicated if allergy to aspirin, bleeding disorder, taking warfarin, history of GI bleed. (b) If taking doxycycline: Pepto-bismol inhibits absorption of doxycycline (an important anti-malarial).

36. TRAVELERS� DIARRHEA: PREVENTION 7. Dukoral cholera vaccine: provides 60% cross-over protection against ETEC. 8. Antibiotics: considering side-effects, best to use antibiotics for treatment in the case of diarrhea rather than prophylaxis

37. DIAGNOSIS of TRAVELLER�s DIARRHEA On a 3 week trip the indiscreet traveler is most likely to get diarrhea in the first week, and will need guidance about self-treatment. >60% is bacterial: Most common is E. Coli, then Shigella, Salmonella, Campylobacter Attack rate remains same in long-term travelers and expatriates for several years

38. Diagnosis of Traveller�s Diarrhea by Clinical Presentation: Watery diarrhea (60%): Mostly enterotoxigenic E. Coli; also Salmonella, Campylobacter, Vibrios. Parasites such as Giardia, Cryptosporidium, Cyclospora and Isospora can cause watery diarrhea. 10% is viruses. Symptoms last 3-5 days and range from several watery stools per day to more explosive profuse but non-bloody diarrhea. Some may have nausea, cramps, vomiting, low grade fever.

39. Diagnosis of Traveller�s Diarrhea by Clinical Presentation: Dysentery (15%): Usually Shigella. Other causes: Salmonella, Campylobacter, Yersinia, E. Coli serotype 0157:H7, more rarely amebiasis. Symptoms: small volume stools with mucous, high fever, abdominal pain and tenderness, prostration, feeling of incomplete evacuation. Blood seen in only 50% of patients. Treatment: Treat all bloody diarrhea with antibiotics; fluids to prevent dehydration.

40. Diagnosis of Traveller�s Diarrhea by Clinical Presentation: Chronic diarrhea, lasting > 1 month (3-5%): Usually Giardia or Campylobacter. In many cases tests are negative and is attributed to postinfectious lactose intolerance and IBS. Symptoms: vague abdominal pain, bloating, nausea, weight loss, low grade fever.

41. Treatment of Diarrhea while Travelling 1. Oral rehydration Severe dehydration:. WHO is glucose based, CeraLyte is rice based. If not available, make your own with 1 teaspoon salt and 2 tablespoons sugar or honey in 1 L water. Continue to drink even if vomiting. Moderate: drink 3 L water/day, add soup + salty crackers, avoid dairy Mild: infants - continue usual breast feeding/formula/ fluids

42. Treatment of Diarrhea while Travelling 2. Loperamide: 2 mg. capsules: two STAT then 1 capsule for every loose stool, max 16 mg/day reduces frequency of stools and duration of illness by 80% due to anti-motility and anti-secretory actions. Young children are more susceptible to side effects: drowsiness, vomiting and paralytic ileus. Not approved for children < 2 years. 3. Pepto-bismol (do not exceed 16 tablets/day): reduces diarrhea by 50% because of anti-peristaltic and anti-secretary effects.

43. Treatment of Diarrhea while Travelling 4. Antibiotics: If copious or bloody stools, or fever. ? Ciprofloxacin 750 mg once or 500 mg bid. If unwell continue for a total of three days. Resistance: 90% in Thailand, 50% Nepal, 40% Egypt ? Alternatives: Levaquin 500 mg once or 500 mg daily x 3 days Azithromycin 1000 mg once or 500 mg daily for 3 days (also effective against Shigella, Salmonella, E. Coli, Campylobacter and typhoid fever. In Thailand more effective against Campylobacter than ciprofloxacin. ? Flagyl 250 mg tid x 5-7 days if you consider you may have Giardia and cannot get medical help. Do not use with alcohol.

44. Treatment of Diarrhea while Travelling Treat all bloody diarrhea with antibiotics. Treat pregnant women with ciprofloxacin, best alternative is azithromycin. Consider whether the rapid diarrhea is limiting antibiotic absorption.

45. Returning travellers: how many will have symptoms? Which symptoms are most frequent?

46. Returned travellers Freedman�s (NEJM 2006) study of 17,353 ill returned travellers from 30 GeoSentinel sites in developing countries per 1000 travellers Systemic febrile illness 226 Acute diarrhea 222 Dermatologic disorder 170 Chronic diarrhea 113 Nondiarrheal GI disorder 82 Respiratory disorder 77 Death 1

47. Returned travellers: basic approach to diagnosis Detailed history of symptoms if persistent fever malaria thick and thin films and repeat in 12-24 hours Detailed history of itinerary and exposures Careful physical exam CBC, LFTs, creatinine, electrolytes (if had diarrhea) (hepatitis Ags and Abs as appropriate) 2 fresh stools

48. Investigation of prolonged diarrhea (> 14 days) 2 fresh stools for Parasites: Giardia, Cyclospora, Cryptosporidium, Microsporidum, Entamoeba histolytica Bacteria: Enteropathogenic E. Coli, Shigella, Salmonella, Aeromonas, enteroaggreagative E. Coli, noncholera Vibrios If all tests negative, consider ciprofloxacin 500 mg tid x 5 days if not yet given, then flagyl 250 mg tid x 7 days If diarrhea continues, sigmoidoscopy or upper GI endoscopy A few patients progress to IBS after Campylobacter

49. Investigation of persistent fever without focal disease: Blood cultures Bacterial endocarditis Bacterial sepsis Bartonellosis Brucellosis Leptospirosis Listeriosis Meliodosis Meningococcemia typhoid

50. Investigation of persistent fever without focal disease: blood or CSF for parasites Babesiosis borreliae African and American trypanosomiasis malaria microfilariae visceral leishmaniasis loiasis

51. Investigation of persistent fever without focal disease: serology Cytomegalovirus Epstein-Barr viral hepatitis Leptospirosis Rickettsiae viral hemorrhagic fevers Dengue syphilis relapsing fever toxoplasmosis

52. You are going to work as a physician in a SubSaharan country (Sudan) for 2 years; What can you contribute? Train health professionals Be able to do and teach a safe C-section and vacuum delivery Reduce infectious disease risks by public health interventions Involve other experts in increasing food production in each household Encourage an organisation to come in and start small loans to households to start businesses (Gramin banks)

53. Sudan: Infectious Diseases: Arthropod borne diseases malaria (except above 2600 m) filariasis onchocerciasis (river blindness) cutaneous and mucocutaeous leishmaniasis visceral leishmaniasis trypanosomiasis (sleeping sickness) relapsing fever louse- flea- and tick-borns typhus Tungiasis viral hemorrhagic fevers (from mosquitoes, ticks, sand flies) Yellow Fever

54. Sudan: Food and water-borne infections helminths bacterial diarrhea; typhoid hepatitis A and E hepatitis B cholera

55. Sudan: Food and water-borne infections: Helminths Metazoa Flat worms Round worms (nematodes) Cestodes Trematodes (tape worms) (flukes)

56. Sudan: Food and water-borne infections: Helminths: nematodes (round worms) Ascaris lumbricoides Trichuris trichiura Enterobius vermicularis Stronglyoides Ancyclostoma duodenale Necator americanus Trichinella spiralis Wucheria bancrofti Loa loa Onchocerca volvulus

57. Sudan: Food and water-borne infections: Helminths: Cestodes (tape worms) Taenia solium Taenia saginata Echinococcus granulosus Echinococcus multilocularis

58. Sudan: Food and water-borne infections: Helminths: Trematodes (flukes) Schistosoma haematobium, mansoni and japonicum