The Immune The Immune Suppressed Suppressed TravellerTraveller

Stan Houston MD DTM&H FRCPCStan Houston MD DTM&H FRCPC

Dep’t of Medicine & School of Public Dep’t of Medicine & School of Public Health, University of AlbertaHealth, University of Alberta

Director, Northern Alberta HIV ProgramDirector, Northern Alberta HIV Program

Declaration of ConflictDeclaration of Conflict

I do not accept gifts, meals etc., from I do not accept gifts, meals etc., from industryindustry

Any honoraria, regardless of source, are Any honoraria, regardless of source, are treated identically, they go into a fund to treated identically, they go into a fund to support the U of A link with Makerere support the U of A link with Makerere University in UgandaUniversity in Uganda

I am involved in pharmaceutical research I am involved in pharmaceutical research studies in HIVstudies in HIV

Why This Topic?Why This Topic?

A growing number of patients with previous A growing number of patients with previous cancer therapy, on corticosteroids or other cancer therapy, on corticosteroids or other immune suppressive drugs, transplant immune suppressive drugs, transplant recipients and HIV-infected individuals, are recipients and HIV-infected individuals, are travelling more adventurously. travelling more adventurously.

The information available on which to base the The information available on which to base the advice you give them, is very limited.advice you give them, is very limited.

Have Transplant, Will Have Transplant, Will Travel (Toronto) Travel (Toronto) travel travel

outside US, Canadaoutside US, Canada J Travel Med 2004;11:37-43J Travel Med 2004;11:37-43 36% had recently travelled outside US/Canada36% had recently travelled outside US/Canada Only 66% of transplant recipients sought pre-Only 66% of transplant recipients sought pre-

travel advice; (80% of those who didn’t were travel advice; (80% of those who didn’t were going to the tropics) going to the tropics) 78% who got advice, got it from transplant team78% who got advice, got it from transplant team

18% took along presumptive Rx for diarrhoea18% took along presumptive Rx for diarrhoea 3% took antimalarials3% took antimalarials 4% got Hep A vaccine, 5% live vaccines4% got Hep A vaccine, 5% live vaccines 5% ran out of immune suppressive medication5% ran out of immune suppressive medication

HIV-infected Travellers (TO)HIV-infected Travellers (TO)outside US, Canadaoutside US, Canada

CMAJ 2005;172:884-8.CMAJ 2005;172:884-8.

44% sought health advice; only 13% from 44% sought health advice; only 13% from a travel clinica travel clinic

6% ran out of medications6% ran out of medications Only 21/56 who should have taken Only 21/56 who should have taken

malaria prophylaxis received itmalaria prophylaxis received it

ObjectivesObjectives

To define what we mean by immune To define what we mean by immune suppressedsuppressed

To identify some of the issues specific to To identify some of the issues specific to certain conditions (e.g. HIV, transplant) certain conditions (e.g. HIV, transplant)

To touch on the impact of immune suppression To touch on the impact of immune suppression on specific travel-related diseases and travel on specific travel-related diseases and travel health interventions health interventions

To introduce you to the new CATMAT To introduce you to the new CATMAT guidelinesguidelines

Warning!Warning!

Some of this is dense and boring and Some of this is dense and boring and supported by limited evidence (not me, supported by limited evidence (not me, the subject matter!).the subject matter!).

KJ, 52 y.o. Indian born KJ, 52 y.o. Indian born CanadianCanadian

Renal transplant 2003Renal transplant 2003 Transplant functioning well on cyclosporine, Transplant functioning well on cyclosporine,

low dose prednisonelow dose prednisone

Plans 6/52 visit to her home area in rural Plans 6/52 visit to her home area in rural PunjabPunjab

FP, 59 y.o. semi-retired FP, 59 y.o. semi-retired businessmanbusinessman

HIV-infectedHIV-infected On antiretroviral therapyOn antiretroviral therapy Stable CD4 >400, undetectable viral loadStable CD4 >400, undetectable viral load

Plans E. African safari with his partnerPlans E. African safari with his partner

HV, 72 y.o. Red Deer HV, 72 y.o. Red Deer womanwoman

On prednisone 40 mg. daily for vasculitisOn prednisone 40 mg. daily for vasculitis Plans a 2 week Amazon cruisePlans a 2 week Amazon cruise

Definition of “Immune Definition of “Immune Suppressed” for This Suppressed” for This DiscussionDiscussionImmune SuppressedImmune Suppressed HIV infection (depends on CD4 count)HIV infection (depends on CD4 count) Transplantation (depends on organ, timing)Transplantation (depends on organ, timing) Corticosteroid therapyCorticosteroid therapy Cytotoxic therapy (methotrexate etc.)Cytotoxic therapy (methotrexate etc.) TNF TNF αα inhibitors (Remicaid etc.) inhibitors (Remicaid etc.) SplenectomySplenectomy

NotNot Age, diabetes, cirrhosis or most previously Age, diabetes, cirrhosis or most previously

treated cancerstreated cancers

Main interactions between Main interactions between immune suppression immune suppression & travel health advice & travel health advice

Potential for increased susceptibility to Potential for increased susceptibility to infections & measures to mitigate these risks infections & measures to mitigate these risks

Vaccine concerns Vaccine concerns safety of live vaccinessafety of live vaccines possible decreased vaccine efficacypossible decreased vaccine efficacy

Other potential problems include access to Other potential problems include access to specialised drugs and the potential for specialised drugs and the potential for complex drug interactionscomplex drug interactions

The Immune Suppressing The Immune Suppressing DiseasesDiseases

CancerCancer People shouldn’t (and usually won’t) travel People shouldn’t (and usually won’t) travel

during acute chemo- or radiotherapy courseduring acute chemo- or radiotherapy course Most cancers, cured or in remission, are Most cancers, cured or in remission, are

associated with minimal immune suppressionassociated with minimal immune suppression Hormonal therapies (breast, prostate cancer) not Hormonal therapies (breast, prostate cancer) not

immune suppressiveimmune suppressive *Hodgkins disease, some lymphomas, have *Hodgkins disease, some lymphomas, have

sequelae of cell mediated immune deficiency sequelae of cell mediated immune deficiency even after cure (ask the oncologist)even after cure (ask the oncologist)

Some treatments may be immune suppressive Some treatments may be immune suppressive (corticosteroids etc; see below)(corticosteroids etc; see below)

HIV specific issuesHIV specific issues Discrimination, immigration requirementsDiscrimination, immigration requirements

http://travel.state.gov/travel/tips/brochures/brochures_http://travel.state.gov/travel/tips/brochures/brochures_1230.html1230.html

Susceptibility to infection correlates with CD4 Susceptibility to infection correlates with CD4 cell count: cell count: > 500 ~ normal, 200-500 = mild-mod, > 500 ~ normal, 200-500 = mild-mod,

<200 = substantial, <50 = severe<200 = substantial, <50 = severe Antiretroviral drugsAntiretroviral drugs

Assured supplyAssured supply Drug interactions (clinical significance not clear)Drug interactions (clinical significance not clear)

Ritonavir Ritonavir ↓ atovaquone levels; Atovaquone ↑ zidovudine ↓ atovaquone levels; Atovaquone ↑ zidovudine levels (a colleague is working on HIV/malaria interactions)levels (a colleague is working on HIV/malaria interactions)

Risk of conditions with Risk of conditions with ↑ ↑ risk in HIV infectedrisk in HIV infected TB, endemic fungi; TB, endemic fungi; & pneumococcal disease, non-typhoidal Salmonella& pneumococcal disease, non-typhoidal Salmonella

Transplant PatientTransplant Patient Depends on transplanted organ; time post-Depends on transplanted organ; time post-

transplant transplant Degree of immune suppression:Degree of immune suppression:

Successful Successful stem cell (stem cell (bone marrow) > 2 yearsbone marrow) > 2 years < < renal renal < < heart or liver heart or liver << lung or small intestine lung or small intestine << recent stem cell recent stem cell

May have compromised renal (or liver) functionMay have compromised renal (or liver) function Drug interactions with immune suppressives are Drug interactions with immune suppressives are

commoncommon Chloroquine ↑ cyclosporine levelsChloroquine ↑ cyclosporine levels? Pre-travel blood ? Pre-travel blood

levels levels So do azithromycin & cipro, but short courses probably So do azithromycin & cipro, but short courses probably

not a problemnot a problem Vaccine stuffVaccine stuff

Timing—routine vaccines coordinated with Tx programTiming—routine vaccines coordinated with Tx program Live vaccines a concernLive vaccines a concern Monitoring seroconversion, double dosing (hep B),Monitoring seroconversion, double dosing (hep B),

SplenectomySplenectomy

Main risk is pneumococcal sepsisMain risk is pneumococcal sepsis ↑ ↑ risk of malaria of little practical risk of malaria of little practical

importance because risk is high for any importance because risk is high for any non-immunenon-immune

Other Immunosuppressive Other Immunosuppressive AgentsAgents Methotrexate Methotrexate Azathiaprine (Imuran)Azathiaprine (Imuran) Cyclophosphamide (Cytoxan)Cyclophosphamide (Cytoxan)

Difficult to estimate or quantitate degree of Difficult to estimate or quantitate degree of immune suppression, but can be severeimmune suppression, but can be severe

Note: patients on high dose Note: patients on high dose hydroxychloroquine (Plaquenil) for rheumatic hydroxychloroquine (Plaquenil) for rheumatic disease do not need chloroquine and should disease do not need chloroquine and should probably not take mefloquineprobably not take mefloquine

TNF TNF αα Inhibitors Inhibitors (Remicaid etc.)(Remicaid etc.) Increased risk of TB activation and endemic Increased risk of TB activation and endemic

fungal infectionsfungal infections

Corticosteroids (many indications)Corticosteroids (many indications) Consensus re significant immune suppression:Consensus re significant immune suppression:

Dose Dose >> 20 mg./day prednisone or equivalent 20 mg./day prednisone or equivalent Duration Duration >> 2 weeks 2 weeks Advice analogous to HIV with CD4 <200Advice analogous to HIV with CD4 <200 Probable increased risk of TBProbable increased risk of TB Risk of Risk of Strongyloides Strongyloides hyperinfectionhyperinfection

The Travel-Related The Travel-Related DiseasesDiseases

Travellers’ DiarrhoeaTravellers’ Diarrhoea Patients with renal dysfunction e.g. transplant Patients with renal dysfunction e.g. transplant

patients on cyclosporine, at increased risk of patients on cyclosporine, at increased risk of renal failure from dehydrationrenal failure from dehydration

HIV and other immunosuppressed hosts at HIV and other immunosuppressed hosts at ↑ ↑ risk of invasive, bacteremic non-typhoidal risk of invasive, bacteremic non-typhoidal Salmonella, less commonly, CampylobacterSalmonella, less commonly, Campylobacter

Profound immunosuppression turns Profound immunosuppression turns Cryptosporidia (and Microsporidia) from an Cryptosporidia (and Microsporidia) from an acute, self-limited disease to a chronic oneacute, self-limited disease to a chronic one

No clear association with other “routine” No clear association with other “routine” organisms such as toxinigenic organisms such as toxinigenic E. coli, E. coli, Giardia Giardia & Entameba& Entameba

Diarrhoea treatments probably OK for almost Diarrhoea treatments probably OK for almost all immunosuppressed patients (? Bismuth)all immunosuppressed patients (? Bismuth)

TD: adviceTD: advice

Reinforce usual advice, especially re: Reinforce usual advice, especially re: hydrationhydration

You could make a case for DukoralYou could make a case for Dukoral™ ™ here, at least for prosperous travellers.here, at least for prosperous travellers.

MalariaMalaria

Splenectomy associated with Splenectomy associated with ↓ clearance of ↓ clearance of malaria parasitesmalaria parasites

HIV associated with increased risk & density of HIV associated with increased risk & density of parasitemia (malaria also associated with ↑ HIV parasitemia (malaria also associated with ↑ HIV replication)replication)

But it doesn’t really impact travel advice since But it doesn’t really impact travel advice since falciparum malaria is a life threatening illness falciparum malaria is a life threatening illness even in the immune competenteven in the immune competent

TBTB Risk of TB Risk of TB exposureexposure

approximates local transmission risk, e.g. approximates local transmission risk, e.g. 3%/year in some low income country settings3%/year in some low income country settings

Some activities, e.g. health care in high Some activities, e.g. health care in high prevalence countries, prevalence countries, very highvery high risk, possible risk risk, possible risk of MDR (or XDR) TB exposureof MDR (or XDR) TB exposure

Risk of TB activation/reactivationRisk of TB activation/reactivation HIV most potent factor known for the reactivation HIV most potent factor known for the reactivation

of latent tuberculosis infection; ~ 50% risk of latent tuberculosis infection; ~ 50% risk depending on HIV therapydepending on HIV therapy

HIV also associated with increased risk of HIV also associated with increased risk of progressive 1progressive 1ee disease, & re-infection post Rx disease, & re-infection post Rx

Other immune suppressive conditions, e.g. Other immune suppressive conditions, e.g. transplant, Remicaid, also transplant, Remicaid, also ↑ risk of TB activation↑ risk of TB activation

Tuberculin skin test less sensitive in the Tuberculin skin test less sensitive in the immune suppressed immune suppressed (sensitivity of Quantiferon(sensitivity of Quantiferon™™ not yet clear in this not yet clear in this

setting)setting)

TB—AdviceTB—Advice

Inform travellers, especially the Inform travellers, especially the profoundly immune suppressed re: riskprofoundly immune suppressed re: risk

Avoid health care and other high risk Avoid health care and other high risk settings settings

Do before-and-after skin tests Do before-and-after skin tests High index of suspicion for TB if High index of suspicion for TB if

unexplained illness developsunexplained illness develops

StrongyloidesStrongyloides

The only helminth (worm) that can cause The only helminth (worm) that can cause opportunistic infectionopportunistic infection

Latent infection can persist for decades, Latent infection can persist for decades, usually in immigrants from tropical LIC’susually in immigrants from tropical LIC’s

Life threatening “hyperinfection” can then occur Life threatening “hyperinfection” can then occur with immunosuppressionwith immunosuppression

Immunosuppressed travellers should probably Immunosuppressed travellers should probably be warned particularly against walking barefootbe warned particularly against walking barefoot

Travel-Related Diseases Travel-Related Diseases without Significant without Significant InteractionInteraction

DengueDengue Worms other than Worms other than StrongyloidesStrongyloides

STI’sSTI’s

Some, especially syphilis, can behave Some, especially syphilis, can behave more aggressively in the immune more aggressively in the immune suppressedsuppressed

Exotic diseasesExotic diseases Brucellosis, scrub typhus, leptospirosis—no Brucellosis, scrub typhus, leptospirosis—no

recognized associationrecognized association Chagas’ disease (Chagas’ disease (T. cruzi) T. cruzi) can cause brain can cause brain

abscesses in AIDS and transplant patients; abscesses in AIDS and transplant patients; infection almost never seen in travellersinfection almost never seen in travellers

African trypanosomiasis (sleeping sickness), African trypanosomiasis (sleeping sickness), very rare in travellers, may have poorer very rare in travellers, may have poorer treatment response in the presence of HIVtreatment response in the presence of HIV

Leishmaniasis clearly associated with HIV, Leishmaniasis clearly associated with HIV, may be transmitted by needle sharing, may be transmitted by needle sharing, different species, more resistant to treatment, different species, more resistant to treatment, in presence of HIVin presence of HIV

Endemic fungi: Endemic fungi: Histoplasma, Penicillium Histoplasma, Penicillium ↑ ↑ risk risk of diseaseof disease

VaccinesVaccines

Don’t work as well in the immune suppressedDon’t work as well in the immune suppressed In HIV, Hep A & B vaccine response correlates with In HIV, Hep A & B vaccine response correlates with

CD4 countCD4 count Transplant patients: timing is criticalTransplant patients: timing is critical Hence occasional consideration of use of immune Hence occasional consideration of use of immune

globulin (Hep A, measles)globulin (Hep A, measles)

Killed vaccines are safe (if sometimes less Killed vaccines are safe (if sometimes less effective than in normal hosts)effective than in normal hosts) Theoretical concerns about enhancing HIV replication Theoretical concerns about enhancing HIV replication

or transplant rejection appear not clinically validatedor transplant rejection appear not clinically validated

Specific Vaccines in the Specific Vaccines in the Immune SuppressedImmune Suppressed

DPT--updateDPT--update Dukoral—consider for the wealthy & risk Dukoral—consider for the wealthy & risk

intolerant immune suppressed travellerintolerant immune suppressed traveller Hep A—of course. Hep A—of course.

Marked fall-off in response with immune suppressionMarked fall-off in response with immune suppression Consider ISG if very immune suppressedConsider ISG if very immune suppressed

Hep B: double dose for the immune suppressedHep B: double dose for the immune suppressed Rabies: check serologic responseRabies: check serologic response Typhoid & polio: injectablesTyphoid & polio: injectables

Live VaccinesLive Vaccines Live vaccines should be given to Live vaccines should be given to

immune suppressed travellers only after immune suppressed travellers only after an individualized assessment of an individualized assessment of exposure riskexposure risk and and degree of degree of immunosuppressionimmunosuppression

Vaccines, cont’dVaccines, cont’d BCG—neverBCG—never MeaslesMeasles

Disease common in many low income Disease common in many low income countriescountries

Disease very severe in immune suppressedDisease very severe in immune suppressed OneOne case report of vaccine-related disease case report of vaccine-related disease

in HIVin HIV So, in immunosuppressed travellers: So, in immunosuppressed travellers:

Assess immunity (history, serology if unclear)Assess immunity (history, serology if unclear) Consider vaccine in HIV patients with CD4 > 200 Consider vaccine in HIV patients with CD4 > 200

or equivalentor equivalent Possible role for ISGPossible role for ISG

Live VaccinesLive Vaccines

Yellow FeverYellow Fever Inform immunosuppressed travellers of riskInform immunosuppressed travellers of risk Mosquito avoidance (mostly daytime)Mosquito avoidance (mostly daytime) Give a waiver certificate if exposure risk very Give a waiver certificate if exposure risk very

low or negligible (east Africa safari areas)low or negligible (east Africa safari areas) Give the vaccine to high risk travellers with Give the vaccine to high risk travellers with

CD4 > 200 or equivalentCD4 > 200 or equivalent

KJ, 52 y.o. Indian born KJ, 52 y.o. Indian born CanadianCanadian

Renal transplant 2003Renal transplant 2003 Transplant functioning wellTransplant functioning well

Plans 6/52 visit to her home area in rural Plans 6/52 visit to her home area in rural PunjabPunjab

KJKJ

Assume or confirm Hep A immunity Assume or confirm Hep A immunity Mefloquine or Atovaquone/Proguanil probably OK; Mefloquine or Atovaquone/Proguanil probably OK;

consider early initiation or loading & measurement of consider early initiation or loading & measurement of levelslevels

Safety of bismuth unclear if creatinine clearance Safety of bismuth unclear if creatinine clearance reduced. reduced.

Vaccines: typhoid (injectable), JEV if indicated, polio, Vaccines: typhoid (injectable), JEV if indicated, polio, consider meningococcalconsider meningococcal

Maybe this is a Dukoral candidate, if prosperous and Maybe this is a Dukoral candidate, if prosperous and risk-averse!risk-averse!

She should have been TST tested pre-transplant—do She should have been TST tested pre-transplant—do post travel TSTpost travel TST

FP, 59 y.o. semi-retired FP, 59 y.o. semi-retired businessmanbusinessman

HIV-infectedHIV-infected On antiretroviral therapy: tenofovir, On antiretroviral therapy: tenofovir,

lamivudine, ritonavir & atazanavirlamivudine, ritonavir & atazanavir Stable CD4 >400, undetectable viral loadStable CD4 >400, undetectable viral load

Plans E. African (Tanzania) safari with Plans E. African (Tanzania) safari with his partnerhis partner

FP, the planFP, the plan

Near normal host; main concerns would be immigration Near normal host; main concerns would be immigration issues, assured medication supply, drug interactionsissues, assured medication supply, drug interactions

Usual diarrhoea advice & preparationsUsual diarrhoea advice & preparations Mefloquine probably first choice for prophylaxis Mefloquine probably first choice for prophylaxis

(theoretical drug interaction concerns with (theoretical drug interaction concerns with atovaquone/proguanil)atovaquone/proguanil)

Usual vaccines (he would be expected to respond) Usual vaccines (he would be expected to respond) except I would be inclined to give yellow fever a miss except I would be inclined to give yellow fever a miss since his exposure risk is near zero.)since his exposure risk is near zero.)

TB a concern if he has close contact with locals in TB a concern if he has close contact with locals in crowded settingscrowded settings

Reinforce safe sexReinforce safe sex

HV, 55 y.o. Red Deer HV, 55 y.o. Red Deer womanwoman

On high dose steroidsOn high dose steroids Plans a 2 week Amazon cruisePlans a 2 week Amazon cruise

H.V. H.V.

Inform re: risk including yellow feverInform re: risk including yellow fever Encourage itinerary that minimizes jungle Encourage itinerary that minimizes jungle

exposureexposure Emphasize mosquito protectionEmphasize mosquito protection I think I would give her a YF vaccine I think I would give her a YF vaccine

waiverwaiver Consider ISG (hep A)Consider ISG (hep A) Other interventions as per routineOther interventions as per routine

ConclusionsConclusions You are likely to see increasing #’s of immune You are likely to see increasing #’s of immune

suppressed travellerssuppressed travellers They can be pretty complicatedThey can be pretty complicated Their physicians may not be up to speed on Their physicians may not be up to speed on

travel related issues, but should provide travel related issues, but should provide information re: degree of immune suppressioninformation re: degree of immune suppression

ResourcesResources CATMAT guidelinesCATMAT guidelines A drug interaction program A drug interaction program Canadian immunization guidelinesCanadian immunization guidelines The physician or program re: degree of immune The physician or program re: degree of immune

suppression suppression