Viatges de risc i falta d’estoc:
ràbia, febre groga i febre tifoide
Christoph Hatz
Vall d’Hebron Hospital, Barcelona, 6 juny 2014
17. Juni 2014 3
Global (terrestrial) rabies endemicity
Rabies in 150
countries
3.3 billion people at
risk
Density of
dogs
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Rabies epidemiology
Primarily a zoonosis
Global Alliance for Rabies Control, Sept 2013; www.who.int, 2013
Worldwide 55‘000-70‘000 human
deaths/y. reported
Place of bite
Minor replication in muscle; no anti-body production
‚Wandering‘ along nerve to spinal cord
‚Wandering‘ along cord to brain
Major replication in the brain and cord: nerve cells destroyed
Behaviour disturbance -> paralysis -> death
‚Wandering‘ along nerves to various organs, e.g. salivary gland
Replication in salivary gland: excretion with saliva
Transmission by bite
99% of human deaths following
a dog bite
51% of all potential bites in travellers are from dogs
Rabies risk and recommendations for travellers
Rabies disease is (almost) invariably fatal but very rare (45 deaths in travellers from 1990-2013)
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
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Rabies management Pre-exposure
Doses on days 0, 7, 21-28 (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. 2-1-1 (days 0, 7, 21)
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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).
www.who.int/rabies/rabies_post_immunization/en/index.html. accessed 12.1.2012
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;14:173-76 and Dev Biol 2008;131:393-401.
Kuenzli E. Rabies pre- and post-exposure vaccinations, 2012
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Future of rabies management
Shorter pre-exposure regimens: Feasible?
Single visit intradermal application of pre- and post-exposure 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 2010
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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: 137-41 (1994)
Hattwick, 1972; Black, 1986; Orr, 1988; Gilbert, AJTMH 2012
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Monkey bites in travellers
Nice….
.. not so nice!
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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
Shaz, 2003; Gautret, 2007, Ritz, 2009
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Yellow fever: Epidemiology
No yellow fever in Asia
> 200,000 cases each year
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Yellow fever in the 21st 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
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Risk of yellow fever
Residents Africa S America
at risk (disease)
500 Mio (50/100‘000) 250 Mio (10/100‘000)
1965-2005 27‘757 cases reported
under-reported
5624
under-reported
Vacc. + ++
Infect. rate estimate
131/100‘000 in risk areas
1970-2008: 8 fatal yellow fever cases among travelers. How big is the risk of a fatal case? 1/10‘000 in West Africa, 1/ 100‘000 in S America? We do not know the figures as many travelers are vaccinated.
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
B. Beck
Suggested vaccination card
… from the Victoria Falls to Johannesburg
Immunization required by South African authorities
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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. 227-229.
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
Global Burden of Typhoid Fever
Ivanoff et al. (1994) 17 million cases and 600,000 deaths
Crump et al. (2004) 21.6 million cases and 216,000 deaths
Crump et al, 2004, Bulletin of WHO
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)
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Typhoid infection: high risk countries / regions (importation records, Switzerland 1993-2002)
per 100,000 Countries, areas
10 - 100 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, 2008
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Reported cases of S. Typhi & Paratyphi in England and Wales 1992-2002
Source: NaTHNaC, December 2004
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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 multi-drug resistance
Salmonella typhi - relevant antigens
Vi-Antigen
O-Antigen
H-Antigen
Salmonella typhi
bacteria
Oral typhoid
vaccine
Parenteral vaccines
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
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
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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: 10-30 cases/100 000 travellers and year, Parts of Indonesia
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 No
Stephens DS. Trans Am Clin Climatol Assoc 2011;122:115-23. Harrison LH. Clin Microbiol Rev. 2006;19:142-164.
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*T-lymphocyte response Immune memory
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Typhoid vaccinations
What to do in the future for travellers?
Critical appraisal of whom and how often to vaccinate