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
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