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Home , Travel medicine, Tropical medicine

: An Introduction to Common and Emerging Pathogens

Dr. Michael Payne Medical Microbiologist April 11th, 2017 Faculty/Presenter Disclosure

UBC Faculty: Michael Payne

Relationships with commercial interests:

– Grants/Research Support: None

– Speakers Bureau/Honoraria: None

– Consulting Fees: None

– Other: Medical Microbiologist, Providence Consultant, Vancouver Coastal Health Travel

Outline

• Introduction to the field of

• Overview of the most common found in returning Canadian Travellers

• , diagnosis, treatment and prevention of common travel related diseases

• • Travellers Diarrhea • Zika /Dengue/Chikungunya • • • Typhoid Fever • • Meningococcal meningitis

Introduction to Travel Medicine

• Travel medicine is devoted to the health of travelers who visit foreign countries

• It is an interdisciplinary specialty concerned with: – Prevention of infectious diseases during travel – Personal safety of travelers – Avoidance of environmental risks

• r

International is growing rapidly! • f • r

Canadians travel internationally often, 32.3 million in 2015, spending $29.4 billion US Key Organizations

Travel Resources

• t • t • r National Advisory Committee on Immunization (NACI) • t BC Immunization Resource

• t Online Subscription Services

• t

Teitelbaum P. (CATMAT) Travel medicine resources for Canadian practitioners. CCDR: Volume 41-05, May 7, 2015 • r • r Overview of the most common infections found in returning Canadian Travelers

• No denominator data to guide absolute risk

• However, approximately, 20-70% of travellers will develop an illness while abroad/on return Adapted from Open Medicine 2014;8(1)e20

Common Travel Related Diseases Case 1

• A 40 year old male presents to a BC emergency room with a 5 day history of: – fever – abdominal pain – headache

• He returned 10 days ago from 6 week trip to Ghana, where he was a supervisor at a mining operation

Investigations for Fever in Returning Traveller

• y

CATMAT. Fever In The Returning International Traveller Initial Assessment Guidelines. 2011 Blood Smears

• Historically, collected using finger prick specimen (Is actually preferred specimen)

• Now typically use EDTA blood Blood Smears

• y

MMWR. June 3, 2005 / 54(SS02);39-40 Malaria Rapid Diagnostic Tests (RDT)

• RDTs are lateral flow immuno- chromatographic antigen-detection tests

• They detect malaria parasite antigens in blood

• Are rapid (15 minutes), and can be performed in areas without access to microscopy

Example

• t

http://www.alere.com/en/home/product-details/binaxnow-malaria.html http://www.who.int/malaria/areas/diagnosis/rapid-diagnostic-tests/about-rdt/en/ Comparison of Methods

• t

CATMAT. Canadian Recommendations for the Prevention and Treatment of Malaria. 2014. Patient Results

• y

https://phil.cdc.gov/phil/details.asp?pid=4884 Patient Results

• y

Plasmodium falciparum, with a parasitemia of 3% https://www.cdc.gov/malaria/diagnosis_treatment/rdt.html Parasitemia

• Calculated for all positive smears

• Is used to help estimate severity of , and response to

• Having a parasitemia of ≥2% is associated with more severe disease • t

https://www.cdc.gov/dpdx/resources/pdf/benchAids/malaria/Parasitemia_and_Lifecycle.pdf Malaria

• 3.2 billion, 1/2 world's population is at risk

• ~ 214 million malaria cases occurred in 2015

• ~ 438,000 malaria deaths occurred in 2015 – About 90% of deaths occurred in Africa – 66% of ALL deaths were in children <5 yo in Africa • t • r

http://www.ecologyasia.com/verts/mammals/long-tailed_macaque.htm • t

https://www.cdc.gov/malaria/about/biology/ • h

Kiszewksi et al., 2004. American Journal of and Hygiene 70(5):486-498. • r

http://whqlibdoc.who.int/publications/2008/9789241596756_eng.pdf • y From: Malaria in Travelers: A Review of the GeoSentinel Surveillance Network

Clin Infect Dis. 2004;39(8):1104-1112. doi:10.1086/424510

Date of download: 4/3/2017 © 2004 by the Infectious Diseases Society of America Malaria is Decreasing!

• y • y Malaria Treatment

• Back to the case!

• Our gentleman has a high parasitemia and is infected with the most severe species, P. falciparum

• Would need to be admitted and treated with intravenous artesunate • y

Treatment Guidelines from The Medical Letter • Vol. 11 (Suppl) • 2013 Prevention

• On further history, our gentleman did not take malaria prophylaxis medicals, due to fear of side-effects

• Malaria prophylaxis drugs are ~95% effective

• Options are: – - (Malarone) – – – Prevention

• Also important to use other prevention methods, such as: – Insecticide treated bed nets – DEET 30% or Picaridin 20% – Wear clothing that covers as much skin as possible – Avoid activities between dusk and dawn Case 2

• A 25 year old woman presents to the ER, returning from a trip Costa Rica 3 days ago

• She describes a 5 day history of: – Fever – Headache – Rash – Generalized muscle and joint pain Further History

• She was there for 2 weeks

• She remained in city of San Jose, but reports receiving many mosquito bites

• No other exposures (Food, freshwater, new sexual contacts)

• t Arboviruses

• Zika, dengue and chikungunya are all spread by Aedes aegypti and A. albopictus mosquitoes

• They cause a similar clinical syndrome

• Their geographic range has been rapidly expanding over the past decade Zika Outbreak

• t • Recent cases in Miami and Texas

• Main concerns are microcephaly and Guillain-Barré syndrome • t

http://apps.who.int/iris/bitstream/10665/254507/1/zikasitrep2Feb17-eng.pdf?ua=1 Zika in Latin America

• r Dengue “Breakbone Fever”

• 50-100 million people are infected each year – approximately 3.2 million severe cases and 9000 deaths

• The dengue virus (DEN) comprises four distinct serotypes

• If you have with one type you are more susceptible to severe disease if infection with a different serotype • t Chikungunya

• An alphavirus, first described in Tanzania in 1952, "that which bends up”

• Has spread in range, with an outbreak in Latin America in 2013-2015 causing millions of cases Diagnosis

• For all viruses, PCR from blood is most useful in first 7 days, after this time, serology is used

• However, for Zika and Dengue, cross reaction of serology is a problem with other flaviviruses: – Yellow Fever – Japanese encephalitis – West Nile virus Diagnosis of Zika

http://www.bccdc.ca/Health-Professionals-Site/Documents/Zika%20Information%20for%20HCP22June2016.pdf Back to the Case

• As the patient had 5 days of symptoms, PCR of blood was sent – positive for Zika virus

• The patient is married (Husband travelled with her) – Wondering how long to wait before attempting to get pregnant • CDC now recommends all men with possible Zika virus exposure who are considering attempting conception wait at least 6 months after symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic)

• Women with possible Zika virus exposure are recommended to wait at least 8 weeks after symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic) before attempting to get pregnant. Treatment

• NONE 

Prevention

• Daytime mosquito precautions with 30% DEET or 20% picaridin

• Limit mosquito populations: • Pesticide spraying • Elimination of breeding sites

• Don’t travel to anywhere fun 

Vaccines

• CYD-TDV/Dengvaxia is a quadravalent Dengue vaccine, which was recently endorsed by the WHO and licensed in multiple countries

• Has not been evaluated for travellers

• Zika vaccine research is ongoing, with clinical trials in progress Case 3

• A 22 year old medical student is travelling overseas for a 2 month clinic placement in both Kampala, Uganda and Nairobi, Kenya

• They are wondering about Yellow Fever vaccination as their university said it would be needed for entry Yellow Fever

• Is a flavivirus spread by Aedes spp. and Haemagogus spp. mosquitoes

• It causes fever, hepatitis and in severe cases, hemorrhage

• For a 2-week stay, the estimated risks for illness due to yellow fever for an unvaccinated traveler visiting an endemic area is: – West Africa are 50 per 100,000 – South America are 5 per 100,000 • Yellow fever risk areas

https://www.cdc.gov/yellowfever/maps/ • t Prevention

• Yellow fever vaccination is recommended for travellers to risk areas – In addition, it is REQUIRED by many countries, if the traveller is coming from a YF endemic country

• Therefore, certificates are issued to prove vaccination status

• Vaccine, is a live strain of YF, and can rarely cause severe reactions – Highest risk in age <9 months and >60 years

• t Case 3

• Given risk of disease, and the fact that Kenya would require proof of vaccination – Patient was vaccinated for YF, with certificate given Case 4

• A 24 year old male is travelling with 3 friends through SE Asia for 3 weeks, in April

• They have an open itinerary, but will visit: – Vietnam – Laos – Thailand – Bali – Cambodia

• They will be staying mostly in cities and

• They have read about Japanese encephalitis virus, and want to know if getting the vaccine is needed Japanese encephalitis virus (JEV)

• JEV is a single-stranded RNA virus that belongs to the genus Flavivirus

• JEV virus is transmitted by Culex species

• The virus is maintained in an enzootic cycle between mosquitoes and primarily pigs and wading birds • r Japanese encephalitis virus (JEV)

• Most people infected will not become ill, (1/25-1/1000) – If develop symptoms 20-30% will die – Of survivors, 30-50% will have longterm neurological or psychological sequelae

• Incidence in susceptible populations in endemic areas is ~5-50 cases/100,000 children/year

Japanese encephalitis virus (JEV)

• Risk in travellers is low! – From 1973- 2013, 68 JEV cases among travelers were published or reported to CDC – 2 cases were reported in a large GeoSentinel review (1 Cambodia, 1 Thailand)

Ann Intern Med. 2013 March 19; 158(6): 456–468. • t Japanese encephalitis virus (JEV)

• New vaccine for JEV (Ixiaro) was approved in 2011 – Inactivated vero cell culture-derived – 2 doses at 0 and 28 days • Accelerated series at 0 and 7 days has also been studied

• Little data on effectiveness, but after 2 doses, 96% of adults and 100% of children developed protective neutralizing antibodies

Journal of Travel Medicine 2015; Volume 22 (Issue 4): 225–231 Japanese encephalitis virus (JEV) • Booster dose (3rd dose), if at continued risk, should be given at 1 year – Subsequent study has show protection likely last for 10 years after 1st booster dose

• Vaccine is very $$$$$ – Cost is $200/dose

JEV Key Messages

• Risk to traveller is low, consider if: – Travel during high transmission season (Summer to fall) – Long term stay (Longer than 30 days in rural areas) – Consider in shorter stays if spending time outdoors at night – Active JEV outbreak occurring

• Risk needs to be balanced with cost, can also use mosquito avoidance techniques

CATMAT, Japanese Encephalitis, 2011. Case 4

• Patient is travelling for less than 30 days and will be in mainly urban areas

• Therefore, vaccination not given Case 5

• A 18 year old student returned from a month long trip to India 10 days ago

• He was staying with family in Chandigarh

• He presents with a 2 day history of fever, abdominal pain and headache Typhoid Fever

• Typhoid fever is caused by Salmonella Typhi (Salmonella Paratyphi), through ingestion of contaminated food or water – 10% case fatality rate (untreated, low income countries), this is <1% with appropriate treatment in high income countries – 2-5% of people can become asymptomatic chronic carriers

• The acute illness is characterized by: – prolonged fever, headache, nausea, loss of appetite, and constipation or sometimes diarrhea – Incubation period is typically 8-14 days http://www.who.int/immunization/diseases/typhoid/en/ Canadian Immunization Guide. Typhoid Vaccine Typhoid Fever

• 21 million cases worldwide annually, with 222,000 deaths

• Was the most common vaccine preventable disease in GeoSentinel database (2010)

• Approximately, 117 cases per year in Canada

• Diagnosed by blood, stool or urine cultures

• t Risk to Traveller

• The estimated risk of developing travel associated typhoid is about: – 1/3,000 travellers for travel to the South Asia – 1/50,000–100,000 for travel to Sub-Saharan Africa, North Africa and the Middle East, or South America – < 1/300,000 for travel to the Caribbean and Central America

• Risk of infection/severe disease increased if: – Anatomical and functional asplenia – Children – Duration of travel (>2 weeks) – Visiting friends or relatives – Achlorhydria or use of acid suppression therapy – HIV or other immunocompromised patients

CATMAT, Typhoid Fever. Treatment

• Treatment is with ceftriaxone or ciprofloxacin for 7-14 days – Our case is treated with ceftriaxone for 14 days

• On further history the patient has a summer job in a

• Need to ensure three negative stools before returning to work – Healthcare workers – Daycare workers/attendees – Food handlers Vaccine

• There are 3 vaccine types available for S. Typhi in Canada: – Salmonella Typhi Vi capsular polysaccharide vaccine for injection (Typh-P) • Protection for 3 years – Typh-P combined with hepatitis A – Live, oral, attenuated TY21A typhoid vaccine (Typh-O) • Protection for 7 years

• Efficacy of all is ~50-60% for preventing Typhoid disease – Some cross protection for S. Paratyphi (Typh-O only)

Canadian Immunization Guide, Typhoid Vaccine. Vaccine

• CATMAT recommends using the typhoid vaccine where risk to traveller exceeds 1 in 10,000

• Therefore, only travellers to South Asia would qualify – (Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan and Sri Lanka)

• For other destinations consider if: – Children – visiting friends and relatives – longer duration of travel (>2 weeks) – achlorhydria or use of acid suppression therapy – Patient preference Key Messages

• Typhoid fever is a serious illness, with 68-90% of cases in returning travellers requiring hospitalization – Indicated to for travellers to South Asia, perform risk assessment for other travellers

• Both Typh-P and Typh-O provide 50-60% protection

• Typh-O has a longer duration of protection, but must be balanced with increased adverse events, cost and contraindications Case 6

• 34 year old male seen in the ER on March 12th with travel to Mexico from February 21st to 29th

• Developed fever/chills, abdominal pain 15 days after return

Bloodwork Showed

• ALT 6500 • AST 2500

• He was jaundiced on clinical examination Hepatitis A

• RNA virus of the Picornaviridae family, genus Hepatovirus

• Causes acute hepatitis, and is transmitted by the fecal-oral route • Long incubation period (15-50 days)

• For young children (<6 years old), most infections are asymptomatic or mild

• Older children and adults typically have symptoms, some groups are at higher risk of severe hepatitis: • Immunocompromised patients • Chronic • Elderly

Risk to Travellers

• In a GeoSentinel review from 2007-2011, there were 120 cases of acute hepatitis A – Pre-travel visit for 18.3% of cases Ann Intern Med. 2013 March 19; 158(6): 456–468.

Vaccine 28 (2010) 6653–6657 • Is no where safe??? – 282 cases of HAV in Hawaii • t Diagnosis

• Serology for hepatitis A IgM and IgG detect acute infection and immunity, respectively

• Out case was positive for IgM only

• He recovered fully – Family contacts need to be followed up with/vaccinated – He was not a health care work, food handler or a day care staff Vaccine

• Inactive vaccine, given at 0 and 6-12 months

• Due to long incubation, can be given up to the day of travel

• When used for pre-exposure, HA vaccine is 90- 97% effective in preventing clinical disease

Canadian Immunization Guide. Hepatitis A Vaccine. Recommendations

• In BC, publically funded for individuals with: – Hemophilia A or B – Chronic liver disease – HIV – HSCT – MSM – Illicit drug use – Inmates – Close contacts of hepatitis A case

• Recommended, not free for: – Food handlers – Travellers Duration of Protection

• Protection from a 2 dose schedule likely lasts from 20 years, to life

• Therefore, routine booster doses are not recommended at this time in Canada

Canadian Immunization Guide. Hepatitis A Vaccine. Case7

• A 22 year old male returned 3 weeks ago from a 7 day trip to Puerto Vallarta

• He had an episode of acute diarrhea on day 3 of his trip, which improved after 1 day

• He continues to have abdominal upset and intermittent diarrhea Illness Course

• Traveller’s Diarrhea usually presents within 3 to 4 days of travel

• Symptoms typically last 3-4 days – Incapacitating symptoms typically only last up to 1 day (12-50% of patients)

• A health care visit occurs for 10-20% of travellers – 30-60% take medication

CATMAT Statement on Travellers’ Diarrhea, 2015. Duration of Symptoms • Most patients have resolution in 3-4 days

• If last longer than 2 weeks is categorized as chronic diarrhea (2- 10%)

JAMA, March 4, 1983. Vol 249, No 9. • GI illness was the diagnosis in 45% of returning ill travelers!

• t

MMWR / July 19, 2013 / Vol. 62 / No. 3 Risk by Region

• g

JAMA January 6, 2015 Volume 313, Number 1 Risk by Types of Travel • Highest risk travellers are those on – is less risky – Luxury accommodations are not necessarily protective

• Backpackers and adventure travelling has been associated with higher rates of TD

• Summer travel and high rainfall increase risk

• passengers have lower risk of TD – However, are at greater risk of large gastro-enteritis outbreaks

Eur J Epidemiol. 1989 Mar;5(1):74-81. JAMA, March 4, 1983. Vol 249, No 9. Age Differences

• Older patients (>60 years old) are less likely to suffer from acute TD

J Travel Med 2012; 19: 169–177 Common Pathogens

• t

Am. J. Trop. Med. Hyg., 80(4), 2009, pp. 609–614 Diagnosis Diagnosis

• t

BCGuidelines.ca (Infectious Diarrhea) Case 7

• Stool culture, ova and parasite were negative

• Patient was diagnosed with post-infectious irritable bowel syndrome

• His symptoms slowly improved over a 1 month period Prevention

• “boil it, cook it, peel it, or forget it” makes biological sense but little data supports its use – Review in 2005 examined 8 studies, of which 7 showed no correlation between types of food selected and risk of TD

– Very few travellers actually adhere to these recommendations

Other Preventive Methods • Preparing your own food is protective • Water Purification methods • Hand washing • Probiotics

Prevention of Traveler’s Diarrhea, CID 2005:41 (Suppl 8). Vaccination Oral Cholera Vaccine (Killed whole cells plus recombinant B-subunit (WC-rBS)

• There is only 1 licensed vaccine in Canada for prevention of Cholera and TD, Dukoral®

• It is composed of: – Heat inactivated V. cholerae O1 Inaba classic strain – Formalin inactivated V. cholerae O1 Inaba El Tor strain – Heat and formalin inactivated V. cholerae O1 Ogawa classic strain – Recombinant non-toxic cholera toxin B subunit

• Efficacy is about 86% for epidemic cholera and approximately 25% for overall travellers' diarrhea – Protection for Enterotoxigenic Escherichia coli (ETEC) lasts 3 months

PHAC. National Advisory Committee on Immunization (NACI). http://healthycanadians.gc.ca/publications/healthy-living-vie-saine/4-canadian-immunization-guide-canadien- immunisation/index-eng.php?page=3 Treatment

• First line treatment is loperamide “Immodium”

• Antibiotics are reserved for severe disease – Ciprofloxacin/azithromycin Colonization with Multi-drug resistant (MDR) Bacteria • MDR Enterobacteriaceae are resistant to 3rd generation cephalosporins (ESBL) +/- carbapenems (CRE)

• Limited options are available for their treatment

• Previously, a major risk factor was receiving health care overseas • Now have evidence that any travel to developing countries may place patients at higher risk of acquisition Risk of Acquisition of MDR Bacteria

• t

Antimicrobials Predispose to ESBL-PE, CID 2015:60 (15 March). Risk of Acquisition of MDR Bacteria

• Loperamide alone not associated with increased risk • Highest risk loperamide plus an antibiotic

EID. Vol. 22, No. 1, January 2016 Outcomes of Travellers’ Diarrhea

• TD is associated with important secondary illnesses: • Guilliane Barré syndrome • Reactive arthritis • Post infectious irritable bowel syndrome (IBS) • Chronic diarrhea

J Travel Med 2013; 20: 303–312. Aliment Pharmacol Ther 2015; 41: 1029–1037. Case 8

• A 21 year old university student is volunteering for an NGO, building schools, for 1 month in Nigeria

• Her trip departs on January 15th and she is wondering if she needs the meningococcal vaccine

Meningococcal Meningitis

• is caused by Neisseria meningitidis

• The five major serogroups most commonly associated with invasive disease are A, B, C, Y and W135 – Serogroup B and C most common in Canada • t

NACI. Advice for the use of the Multicomponent Meningococcal Serogroup B (4CMenB) Vaccine, 2014. • t • t • t Meningococcal Meningitis Vaccines

• Monovalent conjugate meningococcal vaccines (Men-C-C)

• Quadrivalent conjugate meningococcal vaccines (Men-C-ACYW) – Menactra® (meningococcal groups A, C, Y, and W-135 polysaccharides conjugated to diphtheria toxoid protein) – Menveo™ (meningococcal groups A, C, Y and W-135 oligosaccharides conjugated to CRM197 protein)

• Multicomponent meningococcal vaccine (4CMenB) – Bexsero® (meningococcal porin A [PorA], factor H binding protein [fHbp], neisserial antigen 2091 [GNA2091], heparin binding antigen [NHBA], neisserial antigen 1030 [GNA1030], and Neisserial adhesion A [NadA] surface proteins) Meningococcal meningitis

Travellers to the Hajj and Umrah pilgrimages – Large outbreaks of W-135 in 2000, 2001

– Required (Saudi Arabia) quadrivalent conjugate vaccination(A,C,Y,W-135) 10 days before arrival and within the last 3 years, need certificate • All travellers 2 years and older

– MenB not required, unless active outbreak occurring Meningococcal meningitis

• Is recommended for travellers to the African meningitis belt – Particularly during high transmission season (Dec to June)

• Can be considered if traveller is going to be a student, living in confined areas – Not needed for clinicians – Needed for laboratory works

• Travellers do not need to receive 4CMenB vaccine unless there is evidence of an outbreak that is known to be caused by serogroup B that can be prevented by the vaccine

CATMAT. Statement on Meningococcal Disease and the International Traveller. 2015. 4CMenB

• Use in BC and Canada still being determined

• 66% of the overall proportion of Canadian serogroup B meningococcal strains are predicted to be susceptible to the 4CMenB vaccine

N Engl J Med 2016;375:220-8. Case 8

• Given patient is travelling for a month, during the dry season, quadravalent vaccine was given Outline

• Introduction to the field of travel medicine

• Overview of the most common infections found in returning Canadian travelers

• Epidemiology, diagnosis, treatment and prevention of common travel related diseases

• Malaria • Travellers Diarrhea • Zika /Dengue/Chikungunya • Hepatitis A • Yellow Fever • Typhoid Fever • Japanese Encephalitis • Meningococcal meningitis

The End

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