Travel and Tropical Medicine

Travel and Tropical Medicine

Travel and Tropical Medicine Roger Thomas, MD, Ph.D, CCFP, FCFP, MRCGP OUTLINE: 6 KEY TASKS 1. Past medical history, medications, 2. 3. 4. 5. 6. vaccinations, planned travel, unplanned excursions and sports Update childhood vaccinations (MMR, polio, tetanus) Print off CDC data: ask patient read and underline Ask their understanding of risks

Vaccinations and medications needed for trip Specific situations for their travel Prevent exposures through sexual contact or procedures Sex: Surveys : 4-19% of travellers have casual sexual contact abroad, 50% without condoms (condoms may be hard to find) In Switzerland 10% HIV acquired abroad, IN UK, 2/3 acquired from sub-Saharan Africa Clubbing: If invited by people you dont know by moped? Accept? Procedures: 15% have tattoos, acupuncture, piercing, dental hygienist, cosmetic surgery, medical tourism e.g. renal transplants (source of high resistance pathogens)

Prevent diarrrhea, insect and animal bites Peel it, cook it, boil it, or forget it Prevention of all insect bites (bednets) Dont go barefoot: larvae of hookworm, Strongyloides, jigger fleas can penetrate feet; small cuts can cause superinfected ulcers Dont walk at night without flashlight. You must see where you are putting your feet (snakes, scorpions, spiders); Empty shoes of scorpions Outline

1. Global disease burden: HIV, TB, Malaria 2. Mortality from Travel in developing world 3. Traffic accidents 4. Case 1. Peru. Mountain Sickness 5. Case 2. Malawi: Vaccines in pregnancy Malaria: life cycle, prevention, chemoprophylaxis, symptoms, Outline 6. Case 3. Travellers diarrhea. Pathogens, revention, Diagnosis, Treatment 7. Ebola 8. Zika 9. Yellow Fever 10. Dengue

11. Schistosomiasis Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014 HIV 18 million new HIV infections (95% uncertainty interval 17 to 21 million) 292 million prevalent cases (281 to 317) 13 million HIV deaths (13 to 15) Due to interventions including PMTCT and ART, 191 million life-years (166 to 215 million) saved,

703% (654% to 761%) in developing countries 101 countries (74 of which are developing) still have increasing HIV incidence Global disease burden 2013 TB (HIV-negative) incidence 71 million (69 million to 73 million) prevalence 112 million (108 million to 116 million) deaths 13 million (12 million to 14 million). Annualised rates of change (ARC) for incidence, prevalence, and death negative after 2000. TB in HIV-negative individuals disproportionately occurs in men and boys 640% of cases (636 to 643) and 647% of deaths (608 to 703).

Global disease burden 2013 Malaria Cases rapidly increased 1990 to peak 232 million (143 to 387 million) in 2003 12 million deaths (11 to 14 million) 2004 Since 2004, child deaths from malaria in sub-Saharan Africa decreased by 315% (157% to 441%). Outside of Africa, malaria mortality 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) Traffic accidents worldwide 1.7 million deaths, major cause of death in males 15-45 (mostly urban pedestrians in

developing countries) Of 309 Canadian travellers who died abroad, 25% accidents (mostly MVA) 1 death/million km in USA, 23 Sri Lanka, 44 Turkey; also high rates Egypt, Kenya, India, S. Korea, Morocco 30 million injuries; in Ghana <10% pedestrian injuries reported Do not drive at night, rural areas; motorbike or bike Lets begin with a 60 year old going to Peru PMH: HTN, echocardiogram < 40% ejection fraction What are his/her travel plans? (3 months at agricultural research stations in Amazonas and Madre de Dios regions, then archaelogical dig at high altitude)

Review CDC website cdc.gov For the 6 basic planning tasks (slide 2) identify risks and prescribe 60 year old visiting Peru: Plan 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 Cuzco 3,500 meters rapidly by plane, no slow ascent; risks begin above 2,400 meters) PE from air travel to Peru (5/million?) Acute Mountain Sickness, HACE, HAPE Acute Mountain Sickness: 22% adults ascending to 7000-9000 feet; 42% to 10,000; 75% to 15,000 High Altitude Cerebral Edema: brain edema and increased intracranial pressure > Ataxia, confusion, disorientation, irrationality, lethargy, severe nausea and vomiting. Time to coma < 12 hours.

High Altitude Pulmonary Edema: hypoxia causes increased PA pressure and fluid leaks, and a low hypoxic ventilatory response permits extreme hypoxemia, especially when sleeping 60 year old visiting Peru: CDC lists these risks At the country level CDC usually lists all risks and you need to be cautious and use other sources to assess relative risk Also you need to know if risks for travelers differ from locals with prolonged exposure 1. Dengue fever (avoid daytime bites from Aedes aegyptii) Northern coastal and lowland urban areas. Peru not listed as dengue epidemic area 2. Malaria in certain regions 3. Yellow Fever. CDC recommends

vaccination. 60 year old visiting Peru: CDC lists these risks 4. Filariasis (daytime bites from urban Culex fatigans and rural Anopheles mosquitoes transmitting Wucheria bancroftii) However, need chronic exposure to develop disease. 5. American trypanosomiasis (Reduviid (assassin) bug feces on skin transmitting American trypanosomiasis = Chagas disease). However, need chronic exposure to develop disease. No cases in returning travelers 6. Bartonellosis (Oroya fever) on western slopes of Andes up to 3000 m. Very rare 7. Louseborne typhus in mountainous areas of Peru. Very rare. Prevention of Acute Mountain Sickness Kayser B. High Altitude Medicine and Biology 2012;13(2)

Acetazolamid e N RCTs Relative risk 95%CI 250 mg/day 5 0.55 0.42, 0.74 500 mg/day

14 0.50 0.40, 0.63 750 mg/day 6 0.45 0.34, 0.61 Acetazolamide NNT to prevent AMS if climbing (AMS rate in controls 34%) NNT to prevent AMS if transport

then climbing (AMS rate in controls 61%) 250 mg/day 6.5 3.7 500 mg/day 5.9 3.3 750 mg/day 5.3

3.0 28 year old veterinarian, visiting Malawi, South Africa, advising for WHO PMH: LMP 6 weeks ago, rising HcG HcG titres, planning to be in Africa during 1st and 2nd trimesters Risks to pregnancy? Malaria risks? GI risks? Rabies risks? Vaccines 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 Canadian Immunization Guide (2013) Recommended in pregnancy Influenza inactivated vaccine High priority as increased risk of influenzarelated morbidity & adverse neonatal outcomes. No adverse events after H1N1 vaccine in 100,000 pregnant women in Canada and 500,000 in Europe. Pregnant women have 4 x hospitalisation rate for influenza compared to non-pregnant due to increased CVS volume, HR and O2 consumption).

Avoid live vaccines, e.g. nasal Canadian Immunization Guide (2013) Recommended in pregnancy Hepatitis B Test all pregnant women for HBsAg If no markers of Hep B infection and at high risk of Hep B during pregnancy, give complete series Canadian Immunization Guide (2013) May be indicated in in pregnancy Hepatitis A, if travel to endemic area, as can cause severe disease in pregnancy. No RCTs in pregnancy. No theoretical reason to suspect increased risk. Td. No increased adverse events Tdap. (acellular pertussis) If have not

received as adult, give post-partum IPV (inactivated polio). May give if at increased risk of wild polio virus. Canadian Immunization Guide (2013) May be indicated in in pregnancy Pneumococcal. Review says is safe. Give if at high risk of invasive pneumococcal disease. To improve antibody response can given Pneu-C-13 vaccine then Pneu-P-23 8 weeks later. Cochrane review found insufficient evidence for protection of infant as an indication for maternal vaccination Meningococcal. Not studied in pregnancy.

Consider if high risk. Rabies. If exposed, give post-exposure prophylaxis Cholera & Japanese encephalitis vaccines Your 28 year old patient going to Malai Assess risks using the 6 tasks on slide 2 Provide vaccination advice Malaria life cycle Hepatic stage: Sporozoites enter liver cells. Each P. falciparum sporozoite asexually

reproduces 30,000 merozoites; each P. vivax 10,000 Erythrocytic stage: Hepatocytes burst and release merozoites into blood stream. Ring form matures and asexually reproduces 632 merozoites, which then invade other RBCs After 2 weeks some merozoites develop into gametocytes. If female mosquito bites a human and ingests them the gametocytes develop in her gut and 10 Malaria Incubation: for Plasmodium falciparum: hepatic stage (5-7 days) from bite to symptoms 8-25 (avg 12 days); erythrocytic

stage (2 days) 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. Prevention of malaria Bednets & clothes impregnated with pyrethroids. Cochrane review by Gamble 2007 found

for 4 RCTs of treated nets vs. no nets relative risks: RR 95%CI placental malaria 0.79 0.66 to 0.90 low birth weight 0.77 0.61 to 0.98 miscarriages/stillbirths 0.67 0.47 to 0.97 Avoid going out at night, wear long sleeves Bednets (average use 42%) + chemoprevention, Uganda, 0-24 month olds Bigira P. et al. Protective Efficacy and Safety of Three Antimalarial Regimens for the Prevention of Malaria in Young Ugandan Children: A Randomized Controlled Trial. PLoS Med 11(8): e1001689. doi:10.1371/journal.pmed.1001689. Intervention

No of episodes of malaria per infant per year Control 6.95 monthly sulfadoxine-pyrimethamine 6.73 Daily trimethoprimsulfamethoxazole 5.21 monthly dihydroartemisininpiperaquine (Protective efficacy 58% (95% CI 45%67%; p = 0.001) 3.02

Malaria prevention: Domestic spraying 13 heterogeneous studies Relative risk for reducing malaria prevalence 0.38 (95% CI 0.31 to 0.46) More effective if: high initial prevalence multiple rounds of spraying DDT regions with a combination of Plasmodium falciparum and P. vivax malaria. Kim D, et al. Reduction of malaria prevalence by indoor residual spraying: a meta-regression analysis. Am J Trop Medicine Hyg 2012;87(1):117-24. Chemoprophylaxis of

malaria Causal prophylaxis: atovaquone and primaquine act on exoerythrocytic cycle in liver Schizonticides: atovaquone, mefloquine, chloroquine, doxycycline, proguanil act on intraerythrocytic parasites Terminal prophyaxis: Primaquine acts on latent hypnozoites in liver to prevent relapses in P.Ovale and P. vivax Chemoprophylaxis Medication Adult dose Regimen Begin before exposure

End after exposure Atovaquone- 250/100mg proguanil Daily 1 day 7 days Mefloquine 250mg Weekly 1-3 weeks

4 weeks Doxycycline 100mg Daily 1-2 days 4 weeks Primaquine * 30mg (base) Daily 1 day

3-7 days *G6PD testing mandatory Chemoprophylaxis of malaria: Mefloquine Children: 9 kg 4.6 mg of base/kg weekly 10-19kg: tablet weekly 20-30 kg: tablet weekly 31-45 kg: tablet weekly 50% resistance Thai-Cambodian and Thai-Burmese borders Questionnaires about adverse events: 1:6000 British soldiers, 1:10,000 European and 1:20,000

Mefloquine Side-effects: Headache, dizziness, confusion, vertigo, seizures, peripheral neuropathy, insomnia, dreams, anxiety, psychosis Only drug approved for 2nd & 3rd trimesters of pregnancy in chloroquine-resistant areas. Limited data suggest safe for 1st trimester Do not prescribe for persons with major psychiatric disorders even if currently stable Chemoprophylaxis of malaria: Atovaquone-Proguanil (Malarone) Acts on both liver and erythrocyte

stages Efficacy 95-100% Adverse effects: Lowest withdrawal rate (2%) for adverse effects compared to mefloquine and doxycyline Can be used in children > 5 kg Do not use if creatinine clearance Chemoprophylaxis of malaria: Doxycycline Do not use children < 8 years and pregnant or lactating women 95% effective against P. falciparum Adverse effects; abdominal pain, nausea, vomiting, diarrhea,

photosensitivity (~ 20%?), vaginal candidiasis (2.8%) Advantages: preventive for leptospirosis, rickettsial disases and travelers diarrhea Chemoprophylaxis of malaria: Primaquine Intended for radical cure of P. vivax Efficacy against P. falciparum Kenya 85%, Irian Jaya (NE Indonesoia) 94.5%, Colombian soldiers 94% Must test for G6PD deficiency; otherwise 2% adverse effects Diagnosis of malaria Thick blood film: sensitive to 0.001% parasitemia Thin blood film: insensitive to <

0.05% parasitemia PfHRPS dipstick or card: sensitive to > 0.001% parasitemia Plasmodium LDH dipstick or card: sensitive to > 0.001% parasitemia Plasmodium falciparum malaria Treatment: Artemisinin combination therapy Recommended 1st line therapy worldwide but decreased artemisinin susceptibility (slower parasite clearance time) reported in SE Asia. 27 clinical trials vs. comparators 1999-2009, intention-totreat analysis 15,017 (77% children < 6 years of age) patients treated for uncomplicated P. falciparum malaria, 44 sites in subSaharan Africa

Average parasite load before treatment = 27,125/muL Results: Persistent parasitaemia Day 2 8.6%, 1.5% Day 3 Parasite clearance 31 hours (p=0.001 all comparisons) Zwang J, et al. Plasmodium falciparum clearance in clinical studies of artesunate-amodiaquine and comparator treatments in sub-Saharan Africa, 1999-2009. Malaria Journal 2014;13:114. 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

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

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 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 Cerebral malaria (encephalitis) brainstem signs: dolls 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)

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) 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 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 chondroitin sulphate on the syncytiotrophoblast) The peripheral blood film may show no parasites risk is greatest for primigravidae in areas of unstable malaria Provide advice to your 28 year old patient and her two children aged 2 and 4 going to Malai How to reduce the risk of malaria

The symptoms of malaria Prescribe to reduce the risk of malaria Large family going to a tropical country for wedding. They are worried about getting travelers diarrhea Advise on risks, precautions and treatment Risk of travellers diarrhea = 40% in high risk countries of Latin America, Africa and S. Asia (unchanged over past 50 years) Pathogens in diarrhea Lat Am Africa

Indian subcontinent ETEC 34% 31% 31% EAEC 24% 2% 16% Shigella

7% 9% 8% Salmonella 4% 6% 7% Campylobacter 3% 5%

8% Norovirus 17% 13% ? Protozoa 3% 3% 9% Diarrhea in children in Asia and Africa (GEMS

study, unpublished data first 2 years) EPEC = : E coli enteropathogenic; ETEC = E coli enterotoxigenic. Erlich P et al. Infections intestinales aigus: vaccins actuels et futurs. Presse Med 2013;42:93-101. Age 0-11 months 12-23 months 24-59 months 1st Rotavirus Rotavirus/Shigella Shigella 2nd Cryptosporidium

Cryptosporidium/ Rotavirus Rotavirus 3rd EPEC ETEC ETEC/Vibrio cholerae 4rd ETEC/ Campylobacter jejuni Shigella/Vibrio cholerae

Vibrio Cholerae/ campylobacter jejuni 5th Shigella Norovirus/ Entamoeba histolytica Norovirus Diarrhea symptoms Travellers diarrhea 3 unformed stools/24 hours symptoms in table, OR <3 stools/24 hours with symptoms Watery stools 66% Cramping

45% Vomiting 24% Fever 22% Blood 1.5% Activity modification 35% Why diarrhea?

Enormous no of microorganisms ingested with every meal Peace Corps found arrivals switched to local gut flora within a few days Shigella, enterohemorrhagic E. coli, Giardia, Entamoeba require as few as 10-100 organisms to cause infection, can be ingested e.g. during water sports Enterotoxigenic E. coli produces colonization factor antigen that colonizes upper small intestine then produces enterotoxins Shigella dystenteriae type 1, vibrio parahemolyticus, C. difficile, produce cytotoxins

Handwashing worldwide Freeman MC. Hygiene and health: systematic review of handwashing practice worldwide and update on health. Trop Med Int Health 2013 19(8):906-916 42 studies; 19% of world population wash hands with soap and water after touching excreta Studies RR diarrheal disease after handwashing 95%CI All studies 0.60

0.53, 0.68 Excluding unblinded studies 0.77 0.32, 1.86 TRAVELERS DIARRHEA: PREVENTION 1.Hand washing: 30 seconds with soap 2.Boil, cook or peel, eat when piping hot. Avoid salads, ice cubes, food vendors, cans cooled in water, 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 TRAVELERS DIARRHEA: PREVENTION 3. Micropore filter. First Need (General Ecology, Exton, PA) and Sawyer Biological viral filter (Sawyer Products, Safety Harbor, Fl) meet EPS standards 4. 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 5. Potassium Permanganate to wash fruit/veg 6. Kettle to boil water (boiling for 1 minute kills even Cryptosporidium) TRAVELERS DIARRHEA: PREVENTION 7. 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 antimalarial). TRAVELERS DIARRHEA: PREVENTION 8. Dukoral cholera vaccine: 3 RCTs show provides no cross protection against ETEC. 9. Antibiotics: considering side-effects, best to use antibiotics for treatment in the case of diarrhea rather than prophylaxis 10. Rotavirus vaccines: Rotarix (contains G1 serotype and P8), two doses at 2 and 4 months, 80% to 96 % effective in industrialised countries, 50% to 70% in developing countries Rotateq (contains G1, G2, G3, G4 serotypes and P)

three doses at 2, 4, and 6 months. 98% effective in in industrialised countries, 51% to 64 % in Asia and Africa. Erlich P et al. Infections intestinales aigus : vaccins actuels et futurs. Presse Med 2013;42:93101. Inactivated cholera vaccine: Dukoral Erlich P et al. Infections intestinales aigus : vaccins actuels et futurs. Presse Med 2013;42:93-101. 67% effective against O1, not effective against O139 and other vibrios whole cell V. Cholerae O1 Inawa and Ogaba strains + recombinant B subunit of cholera toxin 2 doses 1-6 weeks apart, lasts 2 years (for children 2-5 years 3 doses, lasts months) Typhoid vaccines

Route Dosing Minimum age Typhoid O live attenuated (oral) (Vivotif (Berna) Oral 1 Capsule days 1,3,5,7 in 4 oz warm water. 1 hour before or 2 hours after meal. Swallow not chew. Population of antibody-secreting cells peaks between 7 to 10 days after first dose. Each dose

replicates 3-5 times then lyses over 48 hours. Maximum interval between doses must be < 72 hours and all capsules taken within 10 days. 3 years Typhoid I (Typhim Vi, Typherix) IM 1 5 years Vaccines for rotavirus, cholera,

ETEC, shigella DAS JK. Vaccines for the prevention of diarrhea due to cholera, shigella, ETEC and rotavirus. BMC Public Health 2013;13 Suppl 3 24 studies Rotavirus 74% mortality reduction Cholera incidence 52% reduction Mortality reductions for cholera, ETEC & shigella in children < 5 years: insufficient evidence Your family going to a tropical country Advise them how to minimise risks of

diarrhea DIAGNOSIS of TRAVELLERs 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 (undercooked poultry) Attack rate remains same in longterm travelers and expatriates for several years 5 clinical syndromes of Travellers Diarrhea: 1. Watery diarrhea (60%) Mostly enterotoxigenic E. Coli; also

Salmonella, Campylobacter, Vibrio parahemolyticus and vulnificus (seafood). Parasites: Giardia, Cryptosporidium, Cyclospora & Isospora 10% viruses (norovirus, rotavirus) Cause usually not identified Symptoms last 3-5 days and range from several watery stools/day to more explosive profuse but non-bloody diarrhea. Some may have nausea, cramps, vomiting, mild fever. 5 Clinical syndromes of Travellers Diarrhea

2. Dysentery (15%) Usually Shigella. Other causes: Salmonella, Campylobacter, Yersinia, E. Coli serotype 0157:H7, more rarely non-colera vibrios and Aeromonas 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. 5 Clinical syndromes of Travellers Diarrhea

3. Acute gastroenteritis Vomiting, little diarrhea Staph aureus Incubation 2-7 hours, recovery in 12-18 hours C. perfringens Incubation 8-14 hours Bacillus cereus produces two toxins. One toxin produces symptoms like Staph aureus and the other like C. perfringens 4. Typhoid fever Febrile illness and systemic toxicity. 5 Clinical syndromes of Travellers Diarrhea 5. Chronic diarrhea, lasting > 14 days (3-5%) Usually Giardia or Campylobacter. Also enteroaggregative E. Coli,

Aeromonas, Plesiomonas. 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. Diagnosing the type of diarrhea Check out your familys diarrhea symptoms and diagnose Treatment of Diarrhea while Travelling 1. Oral rehydration: Severe: WHO per L purified

water sodium chloride 3.5 g Potassium chloride 1.5 g Sodium bicarbonate 2.5 g Glucose 20g 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 dehydration: drink 3 L water/day, add soup + salty crackers, avoid dairy Mild: infants - continue usual breast feeding/formula/ fluids

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 antimotility 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 antisecretary effects. Treatment of Diarrhea while Travelling Need calories to repair gut cells so eat Steamed or baked fish, chicken, vegetables, toast, bananas,

applesauce, soup, soft drinks, dilute fruit juice, saltine crackers. Avoid dairy. 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. HOWEVER: Resistance: 90% in Thailand, 50% Nepal, 40% Egypt Alternatives: levofloxacin 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. Treatment of Diarrhea while Travelling Reseve antibiotics for invasive enterocolitis with fever and dysentery, profuse diarrhea with more than three liquid stools within 12 hours. Duration of antibiotherapy 1 to 5 days. Treat pregnant women with ciprofloxacin, best alternative is azithromycin. Consider whether the rapid diarrhea is limiting antibiotic absorption.

Problems with fluoroquinolones High resistance to fluoroquinolones in MRSA, P. aeruginosa, anaerobes, and pathogens isolated from ICUs Increasing resistance in community-acquired E.coli and N. gonorrhea. 10-30% of community acquired respiratory tract infections (CARTIs), H. influenzae and S. pneumoniae harbour 1st step mutations in quinolone resistance determining region. These mutants pass susceptibility testing unnoticed and are primed to acquire high-level fluoroquinolone resistance rapidly, especially in elderly and immunocompromised patients Dalhoff A. Global Fluoroquinolone Resistance Epidemiology and Implications for

Clinical Use. Interdisciplinary Perspectives on Infectious Diseases 2012; Article ID 976273, 37 pages doi:10.1155/2012/976273 Problems with fluoroquinolones 1/3 to 2/3 of Enterobacteriaceae producing extended spectrum -lactamases (ESBL) are also fluoroquinolone resistant, and others are primed to acquire high-level resistance during treatment. Fluoroquinolones select for methicillin resistance in staphylococci, limiting use in skin infections Co-selection of fluoroquinolone resistance by lactams or aminoglycosides, and vice versa -lactam- or aminoglycoside resistance by fluoroquinolones demonstrates that chemically unrelated drug classes select for drug resistant mutants and even multidrug resistant strains

Antiemetics for diarrhea DAS JK The effect of antiemetics in childhood gastroenteritis. BMC Public Health 2013 Suppl 3 750,000 children < 5 die annually from gastroenteritis Medication RR vomiting 95%CI Rectal dimenhydrinate 0.60 0.44, 0.82 IV ondansetron

0.50 0.24, 1.04 Oral ondansetron 0.35 0.26, 0.46 IV metoclopramide 0.80 0.50, 1.28 Total 0.46

0.35, 0.61 Please treat your familys diarrhea Discuss with your family their options and prescribe Ebola Schieffelin JS, et al. Clinical Illness and Outcomes in Patients with Ebola in Sierra Leone. NEJM October 29, 2014DOI: 10.1056/NEJMoa1411680 10,100 cases reported in Guinea, Sierra Leone, Liberia, Senegal, Nigeria, and Mali to October 25, 2014 Kenema Government Hospital, Sierra Leone: 213 patients

symptoms of Lassa hemorrhagic fever or Ebola (106 Ebola) Incubation: 6-12 days, symptoms to hospitalisation 6 days Symptoms: fever (89%), headache (80%), weakness (66%), dizziness (60%), diarrhea (51%), abdominal pain (40%), sore throat (34%), vomiting (34%), conjunctivitis (31%) Rx: Fluids, 55% antimalarials, 93% antibacterials (ceftriaxone) Prognostic factors associated with death: > 45 years, 38C, weakness, dizziness, diarrhea on presentation Death: 33% if < 100,000 Ebola copies/ml of serum; 94% if >10 million copies/ml (P=0.003) Zika Virus Single stranded RNA Flavivirus Transmission: Aedes aegyptii, Aedes albopictus mosquitoes. Aggressive daytime biters indoors & outdoors, live in water containers Distribution: 39 countries in

Americas, 8 Oceania/Pacific, 1 Africa Incubation: 3 days to 2 weeks Zika Virus Symptoms: Many asymptomatic. Fever. Maculopapular rash, conjunctivitis, headache, arthralgia, myalgia, several days to a week DDx: leptospirosis, malaria, rickettsia, rubella, measles, parvovirus, enterovirus, adenovirus; (chikungunya, Mayaro, Ross River, onyomng-nyong, sindbis viruses) Zika Virus Tests Detection: RNA detected in acute phase 7 days up to 13 days post symptom onset, up to 62 days in pregnant females Zika virus rRT-PCR in urine up to 14

days post symptom onset CDC Trioplex rRT-PCR for Zika, dengue and chickungunya viruses DC Zika MAC-ELISA (IgM Ab capture ELISA) Will measure IGM detectable soon after Yellow Fever Marked underreporting of cases 45 endemic countries in Africa and Latin America (900 million) >> 550 million doses of yellow fever vaccine given worldwide. Planned vaccination of additional 174 million in Africa and Latin America 2011-2020 estimated will avoid 34,849 deaths Brighton Collaboration definitions of serious adverse events after yellow fever vaccination: Viscerotropic disease: Multiple organ system dysfunction following vaccination, with spectrum from relatively mild multi-system disease to severe multiple

system organ failure and death involving hypotension, hemorrhage, and acute renal and respiratory failure. Yellow Fever Vaccine is very safe Encephalitis: demonstration of acute inflammation of central nervous system parenchyma ( meninges) by histopathology. Anaphylaxis: an acute hypersensitivity reaction with multi-organ-system involvement that can present as, or rapidly progress to, a severe life-threatening reaction.1 Published cases which meet Brighton Collaboration criteria: neurologic criteria (1 death); 42 Viscerotropic Disease criteria (24 deaths) (includes 2 with both viscerotropic and neurologic criteria); 33 Anaphylaxis; 2 Wild Virus

Published cases with insufficient detail to be assessed with Brighton Collaboration criteria: 108 additional neurological cases, 58 viscerotropic cases Yellow Fever Unvaccinated traveler: the risk of disease during endemic periods = 1/267; death = 1/1,333 in an endemic African country (levels 10 times lower in South America)

Thomas RE, Lorenzetti D, Spragins W, Jackson D, Williamson T. A systematic review of yellow fever vaccineassociated serious adverse events. World Health Organization. 1 December 2010 Thomas RE, et al. Active and passive surveillance of yellow fever vaccine 17D or 17DD-associated serious adverse events: Systematic review. Vaccine. 2011; 29(28):4544-4555. Thomas RE, et al. Reporting Rates of Yellow Fever Vaccine 17D or 17DD-Associated Serious Adverse Events in Pharmacovigilance Data Bases: Systematic Review. Current Drug Safety 2011;6(3): 145-154. Thomas RE, et al. The Safety of Yellow Fever Vaccine 17D or 17DD in Children, Pregnant Women, HIV+ Individuals, and Older Persons: Systematic Review. J. Trop. Med. Hyg. 2012;86(2):359372. doi:10.4269/ajtmh.2012.11-0525. Thomas RE, et al. Mortality and Morbidity Among Military Personnel and Civilians During the 1930s and World War II From Transmission of Hepatitis During Yellow Fever Vaccination: Systematic Review. Am J Pub Health. 2013;103(3):e16-29. doi:10.2105/AJPH.2012. 301158) Dengue Flavivirus with 4 serotypes DEN-1, DEN-2, DEN-3, DEN-4. Infection confers long-term

immunity only to that serotype Transmitted by Aedes aegyptii and Aedes albopicticus, worldwide in tropics & subtropics 2.5 billion at risk 100 million/year. Most common Asia (esp Thailand). Also Caribbean, Pacific islands, Americas, 19,000 deaths/year No vaccine or medications available Dengue diagnosis immunochromatographic test (ICT) manufactured by Panbio. (Results in

< 60 minutes) Sensitivity 0.45 to 1.0 Specificity 0.57 to 1.0 Diagnostic odds ratio 4.5 to 1287 Positive likelihood ratio 2.3 to 59 Negative likelihood ratio 0.01 to 0.56 Blacksell SD, et al. A systematic review and meta-analysis of the diagnostic accuracy of rapid immunochromatographic assays for the detection of dengue virus IgM antibodies during acute infection. Trans Royal Soc Trop Med Hyg 2006;100(8):775-84. Dengue Hemorrhagic fever (DHF) and shock syndrome (DSS) 250,000/year DHF grades 1 and 2 = plasma leakage DSS grades 3 and 4 = life-threatening shock (mortality

50x no shock) Sudden onset high fever (5-7 days), headache, fatigue, severe myalgia, arthralgias, 50% maculopapular rash Platelets < 100,000/mm3 Capillary leakage: ascites, pleural effusion. US demonstrates 10x more cases than clinical exam Tourniquet test for capillary fragility: 20 petechiae/inch2 after Bp cuff deflated Mortality 10-20% but 0.2% in experienced hospitals; Decreased mortality in Thailand over past 40 years Dengue Shock Syndrome

DSS more likely if: serotype 2 in Thailand younger (children, immature immune system) female gender (differences in seeking care?) neurological signs nausea/vomiting, abdominal pain, gastrointestinal bleeding, hepatomegaly, increased ALT or AST Increased hemoconcentration, ascites, pleural effusion, hypoalbuminemia, hypoproteinemia,, thrombocytopenia, coagulation dysregulation secondary infection Huy NT, et al. Factors Associated with Dengue Shock Syndrome A Systematic Review and Meta-Analysis. PLoS Negl Trop Dis 7(9): e2412. doi:10.1371/journal.pntd.0002412.

Dengue Control Due to impure water supply many houses in developing countries have open water containers. Mosquitoes like to breed in water containers in or near houses Integrated vector management most effective to reduce number of immature parasites per water container (relative effectiveness 0.12 (95% CI 0.02 to 0.62) [lower numbers show more effective] Best to provide pure piped water Erlanger TE, et al. Effect of dengue vector control interventions on entomological parameters in developing countries: a systematic review and meta-analysis. Medical and Veterinary Entomology (2008) 22, 203221

No evidence peridomestic spraying effective. Esu E, et al. Effectiveness of peridomestic space spraying with insecticide on dengue transmission; systematic review. Tropical Medicine & International Health 2010;15(5):619-31. Schistosoma haematobium (trematode) Africa and Egypt A human urinates eggs into fresh water, snails ingest eggs, replicate in snail, released into fresh water as cercariae, which then penetrate human skin

(swimmers itch) Cercariae change to schistomules and migrate to lungs, causing Katayama syndrome 2-8 weeks after exposure high fever, cough, SOB, wheezing, headache, splenomegaly, urticarial rash Flukes then migrate to genitourinary S. mansoni and S. japonicum S. mansoni Africa and Brazil; S. japonicum Asia (Laos) Humans excrete eggs in stool, and another human ingests them by mouth Final destination of schistosmules is mesenteric venules, causing granulomas and calcification Resources

www.cdc.gov go to travelers, then destinations (best on line source) Canadian Immunization Guide, 8th edition 2013. www.phac-aspc.gc.ca or www.naci.gc.ca Public Health Agency of Canada http://www.travelhealth.gc.ca Includes official EBM statements from CATMAT (Committee to Advise on Tropical Medicine and Travel), which are a bit wordy World Health Organisation www.who.int/ith Schwartz E. Tropical Diseases in Travelers. Oxford: WileyBlackwell, 2009. (good for specific diseases).

Rose SR, Keystone JS. International Travel Health Guide. (Philadelphia: Mosby. (For patients, updated annually, chapter on each country, patients can buy this). Jong EC, McMullen R. (Eds.)The Travel & Tropical Medicine Manual. (4TH ed.) Philadelphia: W.B. Saunders, 2008 (best short book). Keystone JS (ed.). Travel Medicine (2nd ed). Mosby Elsevier, 2011. Also online Jeffrey HC, Leach RM. Atlas of Medical Helminthology and Protozoology. Edinburgh & New York: Churchill Livingstone.

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