Viatges de risc i falta d estoc: ràbia, febre groga i febre tifoide. Christoph Hatz Vall d Hebron Hospital, Barcelona, 6 juny 2014

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1 Viatges de risc i falta d estoc: ràbia, febre groga i febre tifoide Christoph Hatz Vall d Hebron Hospital, Barcelona, 6 juny 2014

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3 Global (terrestrial) rabies endemicity Density of dogs Rabies in 150 countries 3.3 billion people at risk 17. Juni

4 Rabies epidemiology Worldwide human deaths/y. reported Primarily a zoonosis Global Alliance for Rabies Control, Sept 2013; Juni

5 Wandering along nerves to various organs, e.g. salivary gland Behaviour disturbance -> paralysis -> death Major replication in the brain and cord: nerve cells destroyed 51% of all potential bites in travellers are from dogs Wandering along cord to brain Replication in salivary gland: excretion with saliva Wandering along nerve to spinal cord Place of bite Transmission by bite Minor replication in muscle; no antibody production 99% of human deaths following a dog bite

6 Rabies risk and recommendations for travellers Rabies disease is (almost) invariably fatal but very rare (45 deaths in travellers from ) 40% of bitten persons by suspect rabid animals are children < 15 y. Rabies risk obviously much smaller than risk of road accident (0.4% potential contacts per month, but 2% of all expats have potential rabies exposure, 7% are aware of the risk*. (Small) Children and travellers on two wheels are at highest risk => - Sharpen risk perception, - Avoid contact with animals, - Act in case of exposure: Wound management and vaccination * Hatz et al., 1995, Altmann, 2009; Gautret, 2012

7 Pre-exposure Rabies management Doses on days 0, 7, (plus day 365, memory). If bitten any time after primovaccin.: 2 doses (0,3 days) Post-exposure management Clean wound with soap and water (povidine-iodine) Human IG: 20 IU/kg body weight, injected around/into the wound + i.m. (Equine IgG) Active vaccination: 1 ml i.m. on days 0,3,7,14 (21-28). (check antibodies on day 21?). If no IG avaialble: Active vacc (days 0, 7, 21) 17. Juni

8 WHO recommendations for active rabies immunization after exposure where rabies vaccines are in short supply In countries where both availability and/or affordability of rabies biologicals are limited, two reduced intradermal treatment regimens also fulfill WHO requirements. A "2-site regimen prescribes injection of 0.1 ml at 2 sites (1 in each of the deltoid and thigh) on days 0, 3, 7 and 28. ( WHO Strategic Advisory Group of Experts on Immunization, 2007; WHO Guidelines for Post-Exposure Prophylaxis, WHO Expert Consultation on Rabies, TRS 931, WHO 2005). accessed

9 Problems with pre-exposure vaccination brain-storming on solutions Costs and availability Number of injections > lack of compliance, vaccine shortage Option of post-exposure prophylaxis: often illusory Can traditional pre-exposure prophylaxis be modified? Abbreviated schedule: days 0, 3, 7 (no dose saved) Less doses (14 subjects only): - Primary series (priming): 0.1 ml ID x2 (same day) - Simulated PostExpP : 0.1 ml ID d 360, 363 with PVRV (also 3 years later) > Accelerated immune response, no RIG needed More research needed Khawplod P. et al. J Travel Med 2007;14: and Dev Biol 2008;131: Kuenzli E. Rabies pre- and post-exposure vaccinations, 2012

10 Future of rabies management Shorter pre-exposure regimens: Feasible? Single visit intradermal application of pre- and postexposure vaccination: Quality of application (feasibility)? Human neutralizing antibody fragment Fab091 against rabies virus instead of immunoglobulins, human monoclonal cocktail (CL184): Cost? Save vaccine doses for postexp. treatment Khawplod, J Travel med 2007, Chen Li, Acta Pharmacologica Sinica Juni

11 A 68-y. old Alaska trapper who - over 47 years - shot and skinned (without gloves) more than 3000 arctic foxes (Alopex lagopus) is tested for rabies antibodies 2.30 I.U./ml. (unvaccinated) First and only report of an unvaccinated person acquiring rabies virus antibody (> 0.5 I.U./ml) considered acceptable by WHO Follmann et al, Epidemiol. Infect 113: (1994) Hattwick, 1972; Black, 1986; Orr, 1988; Gilbert, AJTMH Juni

12 Monkey bites in travellers Nice... not so nice! 14

13 Infection risk? Tetanus Rabies (> 90% Dogs; Monkeys??) Herpes B-Virus (Cercopithecine herpesvirus 1, Herpesvirus simiae: Asia and North Afrika); 50 human cases described: few local findings, encephalomyelitis, fever, muscle weakness, paraesthesia (letality up to 80%). 81% of pig tail macaques in Bali infected. Incubation time: days to weeks. Diagnosis: sero-testing controversial: symptomatic or all contacts? Management: disinfection; post-exposure-prophylaxis: effect not proven in man: Acyclovir (Valacyclovir) is given, based on studies in rabbits: start 5 up to 11 days after bite: Valacyclovir: 1 gr tid (children 20 mg/kg tid) x 14 days. NB: 51% of bites/scratches by dogs, 21% by monkeys 15 Shaz, 2003; Gautret, 2007, Ritz, 2009

14 Yellow fever: Epidemiology No yellow fever in Asia > 200,000 cases each year 16

15 Yellow fever in the 21 st Century Africa (Subsahara) INCREASE in W Africa: CFR 11%. 124 cases (53%) in 8 countries and 13 in 2004 (20%) Humanitarian crisis, uncontrolled urbanization 2005: 39% ---- ev. 2020: 63% Routine immunization present South America 111 cases (47%) in 5 countries. CFR 47%! 80% from Bolivia, Brazil, Columbia, Peru, Venezuela. Paraguay; reemergence in 2008 (last report before: 1974) Routine immunization present 17

16 Risk of yellow fever Residents Africa S America at risk (disease) 500 Mio (50/ ) 250 Mio (10/ ) cases reported 5624 under-reported Vacc under-reported Infect. rate estimate 131/ in risk areas : 8 fatal yellow fever cases among travelers. How big is the risk of a fatal case? 1/ in West Africa, 1/ in S America? We do not know the figures as many travelers are vaccinated. 18

17 What to do during shortage of yellow fever vaccination? All travels to endemic areas with risk (whithout mandatory vacc.): 1. Vaccinate once (documented) 2. No second or third doses. exemption for medical reasons If required on entry of country: 1. «mandatory/ mandatory even for airport transit => Vaccination repeated after 10 years, if country does not value WHO recommendations EKRM, 2013

18 B. Beck

19 Suggested vaccination card

20 from the Victoria Falls to Johannesburg Immunization required by South African authorities Page 22

21 Typhoid fever: 1906 infamous story about Mary Malone, the Typhoid Mary 1. chronic carrier 2. cook in New York 3. typhoid spread by contaminating food & water 4. infected at least 53 people, of which 5 died 1%-5% of patients become chronic carriers Huckstep R.L: Typhoid Fever, Edinburgh, London: Livingstone, 1962, p

22 Typhoid fever While there are 2000 serovars of Salmonella the most important are: - S. typhi - S. paratyphi A and B 1. motile, flagella 2. gram-negative, +/- capsule 3. no antigen variation

23 Global Burden of Typhoid Fever Crump et al, 2004, Bulletin of WHO Ivanoff et al. (1994) 17 million cases and 600,000 deaths Crump et al. (2004) 21.6 million cases and 216,000 deaths

24 Typhoid fever- Incidence in travellers Sporadic cases in industrial countries (Crump et al., 2004) 1. US: 500/y, 74% acquired while travelling 2. Risk of typhoid fever to travellers 3. e.g., approx. 1/1 000 travellers to India 4. Efficacy/safety studies in traveller difficult Recommendation 1. Although typhoid fever is rare in industrial countries, vaccination has been strongly requested, even for persons planning short-term travel to high-risk areas (Steinberg et al., 2004)

25 Typhoid infection: high risk countries / regions (importation records, Switzerland ) per 100,000 Countries, areas Pakistan (56) > Nepal (20) > India (12) (limited data: Bangla Desh) 5-10 Peru (9) > Sri Lanka (8) > Indonesia, Cameroon, Madagascar (5) 1-5 Tanzania (3) > Egypt (2) > Brazil, Morocco, Mexico (1) <1 China, Kenya, Malaysia, Philippines, Thailand, Tunesia, Turkey; S-Europe Keller A,

26 Reported cases of S. Typhi & Paratyphi in England and Wales Source: NaTHNaC, December

27 Vivotif - Typhoid fever caused by Salmonella paratyphi A & B Salmonella paratyphi A & B are an important cause of typhoid fever: are clinically indistinguishable from typhoid fever caused by Salmonella typhi As with Salmonella typhi, there is increasing multidrug resistance

28 Salmonella typhi - relevant antigens Salmonella typhi bacteria Vi-Antigen O-Antigen Parenteral vaccines H-Antigen Oral typhoid vaccine

29 Comparison with S. Paratyphi A and B Lipopolysaccaride cell wall called the O antigen is shared by both S. typhi & S. paratyphi S. paratyphi A and B do not contain Vi-antigen S. Typhi S. Paratyphi

30 Typhoid fever vaccination Indicated if: - Destination: Indian subcontinent, Central and West Africa - Other destinations: stay > 1 month - Exposed to poor hygiene (- Where antibiotic-resistance occurs or ceftriaxone is not available) Exception: - Age less less 2 years WHO: International Travel and Health, Geneva 2013

31 Typhoid vaccinations Vivotif (oral): will disappear from the market(?) Typhim Vi (parenteral) (Polysaccharide) What to do in the future for travellers? Critical appraisal of whom and how often to vaccinate Indian subcontinent: cases/ travellers and year, Parts of Indonesia 35

32 Characteristics of Meningococcal Vaccines Is this also true for PS Typhoid Vaccine? Property Polysaccharide Conjugate* Effective in infants No Yes Immune memory No Yes Prolonged duration of protection No Yes Booster effect No Yes Reduction of carriage No Yes Contributes to herd effect No Yes Hyporesponsiveness with repeated dosing Yes *T-lymphocyte response Immune memory No Stephens DS. Trans Am Clin Climatol Assoc 2011;122: Harrison LH. Clin Microbiol Rev. 2006;19:

33 Typhoid vaccinations What to do in the future for travellers? Critical appraisal of whom and how often to vaccinate 37