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