Travel Medicine Update

Joan Ingram ADHB and Auckland Travel Medicine Service (94 Remuera Road, 5240830) Outline • Outbreaks – Chickungunya/ Americas – Zika – Dengue – Pacific Outbreaks – Ebola – MERS – Measles – Antibiotic resistance • Good Pretravel Care Chickungunya • Alpha virus spread by A.aegypti and A.albopictus • Recent outbreaks in Africa, SE Asia and around the Indian Ocean islands then India(2005), New Caledonia ( 2011) and PNG (2012) • Current outbreaks in Tonga, American Samoa, Samoa, Caribbean and Americas • Travellers have taken home and caused outbreaks in Italy, France and Croatia • In a Dutch study 1 Chickugunya case for every 4 dengue

Chickungunya • Acute febrile illness- fever, headache, rash and moderate to severe arthralgia- bilateral symmetric • Resolves in 7 to 10 days • Persistent joint pain and tenosynovitis which can be disabling and continue for up to 12 months • Severe or atypical disease in neonates, elderly, those with underlying medical conditions • Mortality <1%

Chickungunya

• Lymphopenia common • PCR to diagnose early • Rest, analgesics

Chickungunya in Americas

• First report of local transmission of Chickungunya in the Americas when in December 2013 the WHO reported local transmission in Saint Martin • Since then 850,000 cases have been reported from all Caribbean countries apart from Cuba and Brazil, El Salvador, Costa Rica, Panama, Venezuela, Colombia, Guatemala, Guyana, Suriname and French Guiana in the Americas

31 countries or territories but greatest numbers in Dominican Republic, Martinique, Guadeloupe, Haiti, and El Salvador

Up to 30% of population may become infected Zika virus

• Flavivirus related to yellow fever and dengue • Isolated from a sick rhesus monkey from Uganda in 1947 • Subsequent serological studies showed it in numerous African countries and Asia but outbreaks unnoticed • Outbreak on Yap Island in Federated States of Micronesia in 2007- attack rate 15/1,000 but estimated 73% of population seropositive

Zika Virus

• December 2013 French Polynesia especially Tahiti and Moorea- thousands of cases • March- New Caledonia 1,400 cases • Cook Islands- over 900 cases • Over 45 cases diagnosed in New Zealand since March • Fever , headache , nonpurulent conjunctivitis arthralgia and convalescent maculopapular rash • Symptoms 3- 5 days- “mild dengue”

Zika in French polynesia

• Although disease is usually mild during the outbreak in French Polynesia there was a 10 fold increase in Guillian Barre with 40 cases in three months instead of the usual 5 • Possibly associated with the concurrent dengue out break Dengue is increasing dramatically

• Day time biting mosquito • Particularly in urban areas • Vaccine now in phase 3 trials • NS1 test positive early in illness

NZ 2012 Notifiable Disease Report Outbreaks in the Pacific Great website • www.spc.int/phd/epidemics/ • Shows epidemics by country, if increasing or decreasing • In Pacific typically a single serotype of dengue circulates at a time for 4 or 5 years before being replaced by another one • E.g. dengue 3 had not circulated since 1996 but was reintroduced in 2013 • Dengue 3 outbreaks this year- Fiji >25,000 cases (15 deaths), Solomon Islands 1,800 cases, French Polynesia >2,000 cases • Dengue also in Vanuatu, Tuvalu, Tonga, Nauru Pacific Arboviral Outbreaks

• All 3 are notifiable • All 3 have short incubation periods – 2-4 days and usually less than 1 week • viremia for < 5 days and clears when fever settles • PCR in first 5 days then serology • Send samples with full travel history • Dengue- 176 notifications in past 12 mo (cf 90) • Chickungunya- 12 notifications in past 12 mo (cf 0) • Zika- 45 notifications predominantly from Cook Is

Ebola Virus disease

Filovirus – single stranded RNA virus Pleomorphic filaments First identified in 1976 Since then sporadic outbreaks

S K Gire et al. Science 2014;345:1369-1372

Published by AAAS

Started in February in Gueckedou Guinea then to Conakry S K Gire et al. Science 2014;345:1369-1372

Published by AAAS Severe haemorrhagic fever

Figure 3

Source: The Lancet Infectious Diseases 2004; 4:487-498 (DOI:10.1016/S1473-3099(04)01103-X) Terms and Conditions Management

• Isolation and strict barrier nursing – If someone calls in get their contact details and tell them someone will call them back – Call Medical Officer of Health who will arrange transport to hospital – If some one presents put them in a separate room, don’t examine them, call Medical Officer of Health • Exclude other diagnoses • Intensive and supportive care • No proven treatment or post exposure prophylaxis Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV)

• June 2012 in Jeddah a patient had severe respiratory distress and renal failure- virus grown- 6th human coronavirus • Now 855 cases with 333 deaths (CFR 40%) • 723 of then in Saudi Arabia, 73 in UAE • 59 in 20 other countries

• Males and older, underlying illnesses • Nosocomial transmission- 25 % HCWs • No evidence of sustained person to person transmission in the community • Most cases have visited a health care facility or have come in contact with camels or raw camel products while in Saudi Arabia • Hajj - elderly or those with chronic disease have been asked to not go this year

Measles Outbreaks

• PNG, Federated States of Micronesia and Solomon Islands • Philippines- >40,000 suspected and 37,000 confirmed

• Think of it in returning febrile patients with rash • Ensure travellers have been vaccinated Antibiotic resistance is linked to travel

NDM-1 resistance element distributed among a variety of bacteria in samples of drinking water and seepage samples around New Delhi

Lancet Infectious Diseases 2011; 11: 355 Journal of Antimicrobial Chemotherapy Advance Access published May 14, 2013 • Swedish travellers – 262 enrolled – 2.4% were colonised before travel – 226 evaluable participants ESBL-PE from 68 (30%) after return • Travel to India subcontinent OR 24.8 • Asia excluding ISC OR 8.6 • Africa north of Equator OR 4.94 • Age > 65 years OR 7.38 • Diarrhoea during travel 2.4 • Other GI symptoms 2.99 • Another study 5/21 still carriers after 6 months

Risks of various health problems during travel Some travellers are at higher risk

• Those who return home to visit friends and relatives (VFRs) have significantly higher rates of malaria, typhoid, TB and STIs • Children particularly at risk eg Hepatitis A • If you have such patients in your practice try and give them preemptive pre-travel advice

Good pre-travel care

• Advice • Vaccinations • Prophylactic medication-malaria • Self treatment medication- TD, altitude 1. Advise and Discuss

• Always • Sometimes – Insects – Immersion – Ingestions – Altitude – Indiscretions – Inhalation – Injury – Insurance – Injections – Immobility – Medication advice – Immigration Issues

Insects

• Spread many illnesses • DEET containing repellent – Remarkable safety profile – Down to 2 months of age • Permethrin impregnated nets • Vitamin B does not reduce bites • Pregnant women more attractive to mosquitoes Ingestions

• No good evidence that care with oral intake reduces rates of traveller’s diarrhoea – CID 2005; 41: S531-5 • May reduce other food borne illnesses • Restaurant food more risky than that prepared in own kitchen • Alcohol hand wash makes good sense New Water Treatment

• Chlorine dioxide – more potent than chlorine – minimal taste – effective against all water borne pathogens – Aqua Mira or Portable Aqua – Sensitive to sunlight Indiscretions

• Travel increases the probability of casual sex • Travelling alone • HIV is global (40 million infected, most don’t know it) • Many STIs are more common in developing countries and more resistant to treatment • Condoms lower risk • Give them to most travellers

Injuries

• Be especially careful in countries that drive on the right hand side • Avoid travelling alone and at night, bad weather • Use helmets, seat belts etc • Avoid looking like a rich tourist • Keep valuables out of view • Speak up if concerned about driver • Flying may be safer than roads • Don’t swim alone or after drinking alcohol • Don’t feed or play with dogs or monkeys

Road death rates by country

Insurance

• Vital for all travel • Check for exclusions • Read policy carefully to see what is covered, level of excess • Have a special policy if preexisting medical conditions, working overseas, doing “hazardous recreational activities”

Injections

• Travellers end up having injections: 1.5% of Canadian travellers on 1 month trip – J Travel Med 2000; 7: 259-66 • Overuse of injections in many developing countries – BMJ 2003; 327: 1075-78 • Reuse of injection equipment without sterilsation is common • Avoid any puncturing of the skin unless the equipment is sterile

Immobility

• Any form of travel • Risk related to duration of travel • Those with preexisting VTE risk factors are most vulnerable

Immobility • Move legs frequently • Drink plenty of water (not alcohol) • Wear below knee compression stockings: incidence of DVT 19 times lower – Angiology 2001; 52:369-74 • High risk travellers can have clexane injections • Richard Beasley suggests asprin

Medication Advice

• Take a letter from usual Doctor about any chronic illness and usual medications • Have vital medications in two bags in case one is lost • Have a self help kit as medications overseas may be fakes.

Inhalation

• TB, influenza, bird flu, MERS • Dutch study showed 3.3% of travellers per year to areas of high TB endemicity are infected (2.8 per 1000 per month) – Lancet 2000; 356: 461-5 • Advise two step pre-travel mantoux testing with repeat after return or quantiferon gold for certain travellers • BCG for young long term travellers

Immersion

• Avoid fresh water in Africa and most of Middle East • Mekong in Laos • Pockets in Brazil , Suriname, Caribbean

Altitude

• Ascend gradually • Know the symptoms and be prepared to admit it if have them • Never go higher if have symptoms • Descend if symptoms worsen while resting 2. Vaccinate

• Always • Often – National schedule – Hepatitis A ones – Hepatitis B

– Influenza • Sometimes

– Japanese encephalitis – Meningococcal • Occasionally – Rabies – Cholera – Typhoid fever – BCG – Yellow fever Cholera: Dukoral

• Inactivated: killed whole cell V.cholerae and recombinant cholera toxin B-subunit • Cholera uncommon illness in travellers so usually just for health care/ aid workers • Two- thirds of ETEC produce toxin that is similar to cholera toxin so through the B subunit there is some brief protection against ETEC

• Between 19 to 75% of TD is ETEC and about 60% of ETEC have heat labile toxin •Consider it for those at high risk of TD or who would tolerate it poorly

Hepatitis A

• Risk in travellers has declined 10 to 50 fold since 1970s – Clin Infect Dis 2006; 42: 490-7 • Primate studies suggest protection even when given after exposure so not too late to give it just before departure • Don’t need to restart if long interval between doses. Excellent boosting up to 8 years after initial dose • Hepatitis A / hepatitis B combination or hepatitis A / typhoid combinations Hepatitis B

• Most infectious of all blood borne viruses • Virus air dried is infectious for at least one week • Recent study showed incidence in Danish travellers to be almost the same as hepatitis A: Hep A 12.8 and Hep B 10.2 per 100,000 non- immune travel months • Risk increased for males, those travelleing alone or in a group of friends, those having sex during travel Hepatitis B

• Accelerated schedules; 0, 1, 2 month or 0, 7, 21 days should be followed by 4th dose at 12 months (protection then close to 100% and higher titre) • With Twinrix 10 to 15% higher protection and higher titres after 2 doses and higher protection rate in > 60s (88% vs 73%) • Recent study used double dose once before trip and final dose between 4 and 12 months

Intradermal Hepatitis B vaccination for nonresponders

• 0.1ml ID x 4 or 8 sites – both deltoids, both thighs • Check serology at one month then repeat • Good response rate – 2.5 doses on average Influenza • May be the most common vaccine preventable disease of travellers • Cruise ships attack rates 17 to 37 % • Promote the vaccine – J Travel Med 2005; 12: 36-44 Japanese encephalitis

• Spread by night feeding mosquitoes in rural areas of Asia Japanese encephalitis

• Unexpected large outbreaks occur • Seasonality less obvious than previously

• JESPECT-in adults – protection rates are 60- 80 % one year after the 2 dose primary series – Boosting after 1 year results in a 40 fold rise in antibody titres and 100% protection – Antibody decay suggests protection for further 4 years • JESPECT vaccine licensed for children down to 2 months (half dose 2mths to 3 years) • IMOJEV- live chimeric vaccine, single dose, from 1 year of age – Available in Australia (expensive) and Asia (cheaper)

Measles

• Offer measles vaccinations to those who are not fully immunised • People born before 1 January 1969 are considered immune • People born after 1 January 1969 require 2 measles vaccinations to be fully immune Meningococcal vaccine • Menactra: conjugate meningococcal vaccine – Previous (non B) vaccines were polyscaccharide- Menomune and Mencevax ACWY

• In conjugate vaccines the poylsaccharide is conjugated to a protein carrier such as tetanus toxoid or diphtheria toxoid

How polysaccharide vaccines work

• Polysaccharides stimulate B cells by cross-linking the B-cell receptor (BCR) How polysaccharide vaccines work

• Drives the production of immunoglobulins • No production of new memory B cells • Depletion of the memory B-cell pool so subsequent immune responses are decreased How conjugate vaccines work

• The carrier protein from protein–polysaccharide conjugate vaccines is processed by the polysaccharide-specific B cell • Peptides are presented to carrier-peptide-specific T cells, resulting in T-cell help for the production of both plasma cells and memory B cells

How conjugate vaccines work

Conjugate vaccines • Induce T cell dependent response – Occurs from early infancy – More effective in younger infants – First dose primes immune system to stronger response to a booster dose • Reduce nasopharyngeal carriage of N.meningitidis – reduced community transmission -“herd effect” – Seen with introduction of • Conjugate H. influenzae (Hib) • Conjugate pneumococcal vaccines (e.g. Prevenar) • Meningococcal serogroup C conjugate vaccine in UK, Netherlands Invasive pneumococcal disease (PCV7 serotypes) in non-immunised adults > 18 years

Menactra-conjugate quadrivalent

• For 2 to 55 years, single dose • NZ: “need or timing of booster not yet determined” • US :-If 2-6 when vaccinated boost after 3 years – If >7 years boost after 5 years • Not licensed in NZ for < 2 years of age • American recommendations: – 2- 8 months (off label): 2 doses 1 month apart , booster at 12 months – 9- 23 months: 2 doses 3 months apart, boost at 3 years – Asplenic, complement deficiencies, HIV: 2 doses 2 months apart Who to give it to? • Travellers to meningitis belt of Africa – Particularly if during dry season, health care workers, infants and children • Those doing the Hajj pilgrimage (meningococcal vaccine in past 3 years is required) • Consider for adolescents and young adults planning to stay in hostels/ overcrowded conditions • (Routine vaccine in US for 11-12 year olds with a booster at 16 years) • Sahel region from Senegal and Guinea to Ethiopia • Northern Uganda • Eastern DRC • Rift Valley • Malawi • NE Mozambique Polio- new requirements • Only Pakistan, Afghanistan and Nigeria still have endemic polio but exported to 20 other countries in recent years with a spike in cases late last year – Cameroon – Equatorial Guinea – Somalia – Ethiopia – Kenya – Syria Polio- new requirements

• http://www.polioeradication.org/Infectedcountries /PolioEmergency.aspx#sthash.lCe6RgnG.dpuf • People departing Cameroon, Pakistan, Syria and Equatorial Guinea after a stay of > 4 weeks need to be able to show proof of polio vaccination between 4 weeks and 12 months previously • Booster for endemic countries and those with polio in past 3 years

Rabies Studies

• 1.11 and 3.56 per 100 travellers to SE Asia reported bites or licks in an airport departure study at Bangkok airport

Nationality Percent bitten or % Unvaccinated licked Australian/ NZ 4.6 85

European 3.4 75

North American 2.9 86

East Asian 2.8 71

South Asian 0.4 66 Rabies Exposures

Country Incidence of Bites or Licks Myanmar 7.79 Cambodia 5.92 Laos 4.29 Thailand 4.08 Philippines 2.85 Vietnam 2.33 Indonesia 1.73 Singapore 1.43 Malaysia 0.95 Who to vaccinate?

• Children – Half the victims of dog bites – More likely to bitten on head • Travellers to Asia – GeoSentinel study per 1,000 ill returned travellers – SE Asia: 124 – South Central Asia: 90 – South America: 25 – Central America: 13 – Sub Saharan Africa: 9

Who to vaccinate?

• Travellers to countries where cell culture vaccine not available – Pakistan, Burma, Bangladesh • Long term/ expats • Those likely to be exposed to animals • People in remote locations • Anyone who wants it How to vaccinate- IM

• Verorab 3 doses given on days 0,7 and 28 (21 days minimum): 0.5 ml IM • Highly immunogenic • Probably no need for future pretravel boosters • If bitten travellers need to get two boosters How to vaccinate-ID

• Cheaper alternative: 0.1 ml ID d 0,7 and 28 • Must check for efficacy day 35 – 42 as only about 95% effective so 6 weeks to do • Only 12 months protection • Will need a booster prior to future travel • Not if immunsuppression • Quicker option 2 doses of 0.1ml ID on day 0 and 2 more on d 7, single 5th dose and blood test on day 21-28

Educate all travellers about rabies

• Important to explain that in most parts of the world rabies is possible • Try and avoid mammal bites especially dogs but any mammal including bats • If bitten wash wound well • If vaccinated: booster as soon as possible then another 3 days later If previously unvaccinated

• 4 doses of vaccine on days 0, 3, 7, 14

• Rabies immune globulin (RIG) 20 IU/kg body weight infiltrated at site of bite

• Acceptable vaccines are cell culture ones rather than nerve tissue (reactogenic and low immunogenicity) – Human diploid cell vaccine (HDCV) – RabivacTM — purified vero cell vaccine (PVRV) – Verorab, Imovax, Rabies vero, TRC VerorabTM — purified chicken embryo cell vaccine (PCECV) – RabipurTM — purified chicken embryo vaccine (PCECV) – Lyssavac NTM — purified duck embryo vaccine (PDEV)

Typhoid Fever

• Risk varies by destination: – South Asia 1/3,500 travellers (plus Samoa) – Sub Saharan Africa and South America 1/50,000- 100,000 – Caribbean and Central America less than 1/300,000 • Risk increased in VFRs, achloryhydria, asplenia • Protection following typhoid fever is neither complete nor enduring

Oral typhoid vaccine

• Vivotif now available again • Live attenuated vaccine containing Ty21a strain which is deficient in an enzyme so it can’t metabolise galactose • Galactose is present in the gut so vaccine bacteria accumulate galactose and lyse- not detected in stools 3 days after ingestion Efficacy

• No studies in travellers • In endemic areas 50 to 80% • May provide some protection against paratyphi B Dosage/ administration • Keep refrigerated • 3 doses on alternate days e.g. 1,3 and 5 for those above 6 years of age • Swallow whole, not chewed • One hour before a meal with cold or lukewarm drink • Complete 1 week before potential exposure • Optimal booster timing unclear: 3 years • In America they have a 4 dose primary series and boost at 5 years Contraindication and precautions • Immunodeficiency including HIV , drug induced • Acute febrile illness or GI illness • Pregnancy • Concurrent antibiotics (wait > 72 hours after stopping antibiotic) • Optimally wait 3 days before starting antimalarials but mefloquine, malarone & chloroquine probably Ok

Adverse effects

• Generally mild- constipation, abdominal cramps, diarrhoea, nausea, vomiting, anorexia, fever, headache, rash Yellow Fever Vaccination

• Between 1970 & 2009 9 cases in travellers • 8 died, 1 had been vaccinated and survived • Live attenuated vaccine • Two reasons for giving it: – Protect traveller from illness – To cross borders

Yellow Fever Vaccination • Single dose, over 9 months • About a third feel unwell in 3 to 7 days after vaccination. Generally mild • Serious adverse events: – anaphylaxis- 1 in 100,000 – neurologic-0.4-0.8 per 100,000 (1.6 >60, 2.3>70) – viscerotropic- (65% mortality) 0.4 per 100,000 risk factors: older age (1 >60, 2-3 >70) and thymus disease

Currently 10 years duration but is probably going to be extended

Not for immuocompromised, pregnancy, breast feeding Yellow fever map

Malaria • 2001 to 2010 estimated 1.1 million lives saved due to multi pronged strategy- treated nets, spraying, Rapid Diagnostic Tests, Artesemin Combination Treatment • Funding levelled off between 2010 and 12 so progress may stop or reverse • Rates in travellers had fallen but have increased again over the past 3 years

Proportionate morbidity for malaria (malaria cases per 1,000 ill returned travellers)

NZ 2012 Notifiable Disease Report

PNG –Rotary Against Malaria

2.5 million nets distributed between 2009 and 2011 Chemoprophylaxis

• Chloroquine • Malarone- “preferred” • Doxycycline • Mefloquine- “niche drug” –pregnant – 10-15% don’t tolerate it – 1% serious side effects – Women, low BMI tolerate it less well – “never would have been approved in modern world of drug development” Doxycycline inhibits protein synthesis in Plasmodial resident bacteria no effect until second erythrocytic cycle

Pros Cons • Cheap • Not for pregnancy , <8 years • Prevents some additional diseases • GI upset, oesophagitis & ulceration, • No resistance photosensitivity, vaginal • OK with renal failure yeast • Drug interactions Malarone

Pros Cons • Well tolerated • Not pregnancy, • Paediatric tablets breastfeeding or < 5Kg • Stop after 7 days • Expensive • Not in severe renal impairment Mefloquine

Pros Cons • Pregnancy • n & v, abdo pain, dizziness, vertigo, sleep disturbances • Mefloquine resistance • Not for psych hx, seizure, cardiac conduction abnormalities • Not good for last minute trips

Antimalarials and warfarin

• 10 antibiotics including doxycycline can increase the risk of bleeding • Mefloquine may enhance effect of warfarin • Not much data on malarone but a report of enhanced effect with proguanil • Get a baseline INR, start antimalarials some weeks before departure and check after a week of prophylaxis, check while away and after stopping

P. knowlesi

• Zoonosis in SE Asia- Sarawak, Sabah, Palawan, Thailand, Burma, Singapore • Primarily in Macaque monkeys • Increasing reports of human infection since 2004 • Resembles P. malariae morphologically, differentiate with PCR • Clinically – febrile illness daily fever spikes, thrombocytopenia, CRP • Most cases uncomplicated but can be severe

Rapid Diagnostic Test (RDT)

Negative- Positive- Immediate microscopy Treatment, micro < 3 hours within 3 hours

Switch to IV if density > 2%, Repeat RDT daily Daily micro till negative for if fever persists asexual parasites Artesimin derivatives • Highly active against all malaria species asexual forms and gametocytes (less transmission) • Short half lives so recrudescence possible • Combinations improve cure rates and delay resistance • WHO endorses ACTs as first line treatment where P.falciparum predominates • No adjustment for renal or hepatic impairment • No drug interactions • Well tolerated • Artemether-lumefantrine (Riamet) - Uncomplicated malaria, 3 day treatment course ,must be taken with food (preferably fatty)

Artemisinin Resistance

• Spreading from Thai – Cambodia border area

Diarrhoea

• Norovirus causes between 10 and 16% of TD • Acute onset of relatively uncomfortable diarrhoea suggests bacterial or viral cause • Gradual onset of relatively tolerable diarrhoea more likely to be protozoal • “antibiotic self treatment may not be as benign as we thought” David Shlim • Swiss and Dutch suggest loperamide only • Shlim still thinks each traveller should have some antibiotics • Norfloxacin- levels in gut quite high • Norovirus causes between 10 and 16% of TD • Persistent changes in bowel habit- Post infectious irritable bowel disease

Altitude

• Acetazolamide 125mg twice a day from the day before flying over 3,200m and for the first few days – Increased urination, tingling fingers and toes • Recent study- inhaled budesonide 200 bd vs dexamethasone 4mg bd vs placebo • From 400m to 3900m by car • AMS B 23%vs 30% Dexa vs 60 % Placebo Summary

• Knowledge about current outbreaks to help you prepare travellers and to help you manage them if ill after travel • Pretravel preparation – Advice – Vaccination – Prophylaxis- malaria – Self treatment- TD, altitude Bed bugs- bad souvenir • Inspect where you are going to sleep for bugs (red- brown ovals 4- 7 mm), their faeces (black dots) or blood from previous occupants • If seen try to sleep somewhere else • If not move bed away from head board, sleep fully clothed, put on repellent and shower after waking • Keep possessions in suitcase in plastic bag in bathroom or on a chair in middle of room

Advice for travellers to China

• Keep away from poultry and livestock and avoid visiting live “wet” animal markets