Transcript Document

TB
Is it a Travel Risk?
What Can We Do About It?
Stan Houston
Department of Medicine &
School of Public Health, University of Alberta
Objectives
 Review
current information re: TB in
travellers and in health care workers in low
income countries
 Discuss strategy options and priorities,
including use of IGRA (blood test for latent
tuberculosis infection)
TB biology & epidemiology
First Step: transmission
 Transmission by airborne droplet nuclei from
someone with active pulmonary TB to the lung of
a susceptible host (much less commonly M.
bovis from milk)
Second Step: progression to active disease
 In immune competent host infected with M.
tuberculosis,
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+/- 90% risk of no disease (skin test or perhaps IGRA,
only indicator of infection)
Preventable by “chemoprophylaxis”
5% risk of early disease
or “treatment of latent TB infection”
5% risk of late disease
.
}
Risk of TB disease =
 Risk
of exposure to/infection with,
Mycobacterium tuberculosis
and
 Likelihood of activation/reactivation 
active disease
Risk Factors for Infection
with M. tuberculosis in travellers
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Prevalence in destination population
Duration of travel
Type of contact with local population
Environmental conditions, e.g. ventilation and
sunlight (natural UV)
 So…risk of infection in
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Tourist to E. Africa staying @ Nairobi Hilton & tented
tourist camp X 2 wks <<
Cross Africa or Asia backpacker staying in local
accommodation, drinking in local bars X 3 mo or child
going to India to visit grandparents <<
Doctor working in sub Saharan African hospital X 1 yr
Risk in Special Circumstances:
Health Care Workers
 Estimates
of the annual risk of LTBI
ranged from 0.5% to14.3%
 The attributable risk for TB disease in
HCWs ranged from 25 to 5,361 per
100,000 per year.
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Rajnish Joshi, Arthur L. Reingold, Dick Menzies, Madhukar Pai*
Tuberculosis among Health-Care Workers in Low- and MiddleIncome Countries: A Systematic Review. PLoS Medicine
2007;3:2376
Health Care Workers in Africa
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Nursing students experienced 19.3 TST
conversions per 100 person-years (95%
confidence interval 95% CI, 14.2-26.2
conversions per 100 person-years)
 Polytechnic school students (controls)
experienced 6.0 (95% CI, 3.5 10.4) conversions
per 100 person-years.
 The rate of difference was 13.2 conversions
(95% CI, 6.5 20.0) per 100 person-years.
• Corbett et al. Nursing and Community Rates of
Mycobacterium tuberculosis Infection among Students in
Harare, Zimbabwe Clin Infect Dis 2007;44:317-23
Is there a risk on the plane?
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a highly infectious TB source case (i.e., 108 infectious
quanta per hour) travels as a passenger on an 8.7-hour
flight. We estimate an average risk of TB transmission on
the order of 1 chance in 1,000 for all passengers
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…modeling suggests that almost all TB risk to
passengers on commercial airliners appears to occur in
the same cabin with the infectious TB source case, and
that within the same cabin the risk appears to decrease
exponentially with distance from the source.
• Risk Anal. 2004 Apr;24(2):379-88.
• N Engl J Med. 1996 Apr 11;334(15):933-8
Risk of TB Infection in Travellers
Cobelens et al. Lancet 2000;356:461-5
 1072
BCG-negative long term (3-12 mo.
planned) travellers to high incidence
(annual risk of infection > 1%) countries
 Had to be Holland-born, no BCG, not
immune suppressed
 Pre-travel TST (one step) and post-travel
TST with parallel atypical mycobacterial
skin test
Cobelens cont’d: Risk of TST
conversion
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67 excluded
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19 first TST not read, 4 “incomplete data”,
44 PPD > 1mm.
34% lost to follow up
3.5/1000 (2.0-6.2)person months overall
2.8 (1.2-5.5) in non-health care workers
7.9 (2.2-20.3) in health care workers associated
with a risk of 5.34 compared to non-HCW
2 cases of active TB
Other Small Studies
 Travellers
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on Hajj from Singapore
Pre & post-travel IGRA (Quantiferon ™, not
TST!
Median trip duration 34 days
10% conversion, 8.6% reversion (from + to -!)
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Wilder-Smith. Trop Med Internat Hlth 2005;10:336-9
VFR’s
 Studies
show that visiting the homeland is
a risk for TB infection especially in kids.
• Pediatrics 2001;107:999
• Br J Dis Chest 1984;78:248
• Clinical Infectious Diseases, volume 43 (2006),
pages 1185–1193
Risk of Disease, given Infection
with M. tuberculosis
Menzies D in Canadian TB Standards.
TB Disease in Travellers
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Cases of TB have long been recognized, albeit
uncommonly, 2.5-5% among returned travellers
presenting with illness.
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Ansart et al. Illnesses in travelers returning from the tropics: a
prospective study of 622 patients. J Travel Med 2005;12:312-18
(Paris)
O’Brien et al. Illness in returned travelers and
immigrants/refugees: the 6-year experience of two Australian
infectious diseases units. (Australia)
Because of long incubation period for active
disease, travel-related TB may be greatly
underestimated
Prevention of TB in Travellers:
Possible Strategies
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Do nothing—diagnose and treat the TB when it
occurs Reider H. Clin Infect Dis 2001;33:1393-6
Avoid contact (limited applicability except
perhaps for the immune suppressed)
BCG
Test for latent TB infection, specifically new
infection, and treat (chemoprophylaxis)
Pre-exposure drug prophylaxis (this has been
proposed but will not be discussed further)
Prevention 1.
Minimize Risk of Exposure
 We
can advise travellers of the risk but
health care work is probably the main
specific identifiable high risk activity
 Focus on those at higher risk of activation,
ie immune suppressed
Prevention: 2. BCG
 BCG:
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pros & cons
Efficacy in many good trials varied from < 0 to
> 80! (many hypotheses to explain this)
Greater consensus that it prevents life
threatening disseminated disease in infants
No evidence of efficacy, definite evidence of
harm, in the immune compromised who need
protection most
May complicate interpretation of TST (could
be solved by IGRA test)
Meta-analysis of Prospective
Randomized Studies Of BCG
Estimate of efficacy and 95% confidence intervals
Clemens et al. JAMA 1983;249:2362-2369.
One Hypothesis: The Efficacy of BCG Has Declined Due
To Serial Passage of the Vaccine Organism in Culture
BCG
Efficacy
TST Conversions
By number of passages in culture of the study BCG strain
Behr M, Small P. Nature 1997;389:133-4
BCG Efficacy in the Prevention of TB
Meningitis and Miliary TB
(Case control studies)
-100
-50
0
50
100
Localización
del Estudio
Argentina
Sao Paulo, Brasil
N° Total de
Casos
18
68
Belo Horizonte, Brasil
Argentina
Indonesia
Inglaterra
Papua Nueva Guinea
45
15
15
7
32
Prevention 3. TST & TLTBI
(prophylaxis)
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Whom to test?
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Do you need a baseline TST? If so, a two-step?
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Only test people to whom you would offer prophylaxis
Exposure risk
Disease risk
Would a positive pre-travel TST change your plan?
What is the likelihood of a positive pre-travel TST?
Vs. inconvenience (& non-compliance) and imprecision
of the test
Compliance?!!!! Especially including 8 week posttravel test
Problems with the TST
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False negatives
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More frequent in the immune suppressed (who of
course, need this information most!)
False positives
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BCG (though less often than believed)
Exposure to environmental mycobacteria
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Skill, variability in reading
 The boosting phenomenon
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The likelihood of boosting correlates with the
probability of past exposure to TB
Two visits to apply and read the test (X2 for 2
step)
Interferon γ (gamma) Release Assays
IGRA
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Blood test
Purpose: detection of infection with M.
tuberculosis
 Principle:
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Blood exposed in the lab to purified, specific M.
tuberculosis antigens (which are not present in BCG
or most environmental mycobacteria)
If lymphoctyes previously sensitized to M.
tuberculosis, they will produce interferon γ, which can
be measured.
Two versions: Quantiferon gold (used here) & T
SPOT-TB™
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Menzies D. et al. Ann Intern Med. 2007 Mar 6;146(5):340-54. (metaanalysis on IGRA)
Canadian tuberculosis committee. Interferon gamma release assays for
latent tuberculosis infection. Canadian Communicable Disease Report
2007;33:1-18.
IGRA: advantages & limitations
Advantages
 Virtually eliminates false positives due to cross reactions from BCG,
environmental mycobacteria
 Eliminates difficulties, variation in reading
 1 visit
Limitations
 Not clear that it really measure the same biologic phenomenon as
the TST? (may “fade” after treatment of active TB)
 Sensitivity & specificity uncertain (no gold standard)
 Less well studied in groups such as immunocompromised
 Unknown ability to predict development of active TB (which TST
does)
 Cost
Current Role
 Clarification of a positive TST where false positivity is suspected
 Not a primary screening tool
Problems with the TST and TLTBI
(Prophylaxis) Strategy
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Compliance with obtaining pre-travel advice
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**Compliance with post travel TST!
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Highest risk groups, eg VFR’s least likely
Cobelens: 61% , 33% of whom required extra calls
MacPherson 86 (17%) completed the pre-travel and
post-travel protocol
Houston 50/90 (55%) in spite of house calls to read the
TST!
Travellers Health Services, Edmonton, in 3.5 years,
705/3302 (21%)
Compliance with chemoprophylaxis
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64% in US clinic Nolan, JAMA 1999;281:1014-8
< 40% of residents in a teaching hospital South Med J
1985;78:1061-64
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Efficacy vs. resistant organisms likely decreased
“Expert” Recommendations
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CDC yellow book 2005-6
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UK Department of Health (2001)
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For travel > 1 month to high incidence countries, especially if
working with local population, BCG (if immune competent & TST-)
WHO 2007
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Pre, post travel TST for travellers with specific high risk activities
Those anticipating prolonged or repeated exposure to consider a
2 step baseline
“BCG vaccine is of limited use for travellers but may be advised
for infants and young children in some situations”
“For travellers from low-incidence countries who may be exposed
to infection in relatively high-incidence countries (e.g. health
professionals, humanitarian relief workers, missionaries), a
baseline tuberculin skin test is advisable in order to compare with
retesting after return. If the skin reaction to tuberculin suggests
recent infection, the traveller should receive, or be referred for,
treatment for latent infection”.
CATMAT
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Watch this space! New recommendations coming
So what should we do?
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TB is not a priority concern for many low risk
travellers
Identify those at particularly high risk, especially
health workers, perhaps long term expatriates
Identify & inform any immune compromised
travellers re: risk of TB, limitations of risk
reduction and means of reducing exposure
Any use of BCG rare and highly selective (see
above)
Focus on the high risk traveller
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Health care worker
? Long term expatriate with extensive local contact
*High risk of activation (immune suppressed)
The following criteria based on duration of
their exposure and TB incidence in the
country visited, can be used to guide the
indication for TST surveillance: CIII
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Acid-fast bacilli (AFB) smear-positive pulmonary
TB incidence rate of country visited and duration
of visit
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> 200/100,000 and > 3 months;
100-199/100,000 and > 6 months;
50-99/100,000 and > 12 months.
> 50/100,000 and > 1 month of very high risk contact,
particularly direct patient contact in health care, but
perhaps also including work in prisons, homeless
shelters, refugee camps or inner city slums.
 Only
a small proportion of travellers meet
these criteria
 Children < 5 years are a priority
Pre-travel testing?
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Consider pre-travel TST only if documentation of
conversion would determine decision to offer
prophylaxis, particularly if high risk exposure
history
 Consider 2 step baseline particularly if repeated
TST’s planned
 Converters (or post travel positives) should be
referred to TB services for consideration of
TLTBI (after ruling out active disease)
Interferon Gamma Release Assay
“IGRA”
 No
role in routine screening
 May use IGRA to confirm TST positivity in
selected situations
BCG: possible limited role
 Infants,
small children in high exposure
setting
 Health worker exposed to MDR or XDR
TB
 Traveller unable or unwilling to participate
in the TST/chemoprophylaxis strategy
Diagnosing TB
 A history
of exposure in a high prevalence
setting should raise the possibility of TB in
assessing a patient with an unexplained
illness
Conclusions
 Travel
to high TB prevalence countries can
be associated with a risk of infection with
M. tuberculosis and even the development
of active TB
 Consideration of a TB intervention should
be limited to a small, select group of
travellers based on anticipated high risk
of exposure or high risk of progression
to active disease