1. TB Is it a Travel Risk? What Can We Do About It? Stan Houston Department of Medicine & School of Public Health, University of Alberta

2. 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)

3. 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, +/- 90% risk of no disease (skin test or perhaps IGRA, only indicator of infection) +/- 90% risk of no disease (skin test or perhaps IGRA, only indicator of infection) 5% risk of early disease 5% risk of early disease 5% risk of late disease 5% risk of late disease }.}. Preventable by “chemoprophylaxis” or “treatment of latent TB infection”

4. Risk of TB disease =  Risk of exposure to/infection with, Mycobacterium tuberculosis and and  Likelihood of activation/reactivation  active disease

5. Risk Factors for Infection with M. tuberculosis in travellers  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 Tourist to E. Africa staying @ Nairobi Hilton & tented tourist camp X 2 wks << 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 << 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 Doctor working in sub Saharan African hospital X 1 yr

7. 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. Rajnish Joshi, Arthur L. Reingold, Dick Menzies, Madhukar Pai* Tuberculosis among Health-Care Workers in Low- and Middle- Income Countries: A Systematic Review. PLoS Medicine 2007;3:2376 Rajnish Joshi, Arthur L. Reingold, Dick Menzies, Madhukar Pai* Tuberculosis among Health-Care Workers in Low- and Middle- Income Countries: A Systematic Review. PLoS Medicine 2007;3:2376

8. Health Care Workers in Africa  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;44:317-23Corbett et al. Nursing and Community Rates of Mycobacterium tuberculosis Infection among Students in Harare, Zimbabwe Clin Infect Dis 2007;44:317-23

9. Is there a risk on the plane?  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  …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.Risk Anal. 2004 Apr;24(2):379-88. N Engl J Med. 1996 Apr 11;334(15):933-8N Engl J Med. 1996 Apr 11;334(15):933-8

10. 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

11. Cobelens cont’d: Risk of TST conversion  67 excluded 19 first TST not read, 4 “incomplete data”, 19 first TST not read, 4 “incomplete data”, 44 PPD > 1mm. 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

12. Other Small Studies  Travellers on Hajj from Singapore Pre & post-travel IGRA (Quantiferon ™, not TST! Pre & post-travel IGRA (Quantiferon ™, not TST! Median trip duration 34 days Median trip duration 34 days 10% conversion, 8.6% reversion (from + to -!) 10% conversion, 8.6% reversion (from + to -!) Wilder-Smith. Trop Med Internat Hlth 2005;10:336-9 Wilder-Smith. Trop Med Internat Hlth 2005;10:336-9

13. VFR’s  Studies show that visiting the homeland is a risk for TB infection especially in kids. Pediatrics 2001;107:999Pediatrics 2001;107:999 Br J Dis Chest 1984;78:248Br J Dis Chest 1984;78:248 Clinical Infectious Diseases, volume 43 (2006), pages 1185–1193Clinical Infectious Diseases, volume 43 (2006), pages 1185–1193

14. Risk of Disease, given Infection with M. tuberculosis

15. Menzies D in Canadian TB Standards.

16. TB Disease in Travellers  Cases of TB have long been recognized, albeit uncommonly, 2.5-5% among returned travellers presenting with illness. Ansart et al. Illnesses in travelers returning from the tropics: a prospective study of 622 patients. J Travel Med 2005;12:312- 18 (Paris) 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) 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

17. Prevention of TB in Travellers: Possible Strategies  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)

18. 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

19. Prevention: 2. BCG  BCG: pros & cons Efficacy in many good trials varied from 80! (many hypotheses to explain this) Efficacy in many good trials varied from 80! (many hypotheses to explain this) Greater consensus that it prevents life threatening disseminated disease in infants 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 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) May complicate interpretation of TST (could be solved by IGRA test)

20. Clemens et al. JAMA 1983;249:2362-2369. Meta-analysis of Prospective Randomized Studies Of BCG Estimate of efficacy and 95% confidence intervals

21. BCG Efficacy TST Conversions By number of passages in culture of the study BCG strain Behr M, Small P. Nature 1997;389:133-4 One Hypothesis: The Efficacy of BCG Has Declined Due To Serial Passage of the Vaccine Organism in Culture

22. BCG Efficacy in the Prevention of TB Meningitis and Miliary TB ( Case control studies) -100 -50 0 50 100 Localización N° Total de del EstudioCasos Argentina18 Sao Paulo, Brasil 68 Belo Horizonte, Brasil45 Argentina15 Indonesia15 Inglaterra 7 Papua Nueva Guinea32

23. Prevention 3. TST & TLTBI (prophylaxis)  Whom to test? Only test people to whom you would offer prophylaxis Only test people to whom you would offer prophylaxis Exposure risk Exposure risk Disease risk Disease risk  Do you need a baseline TST? If so, a two-step? Would a positive pre-travel TST change your plan? Would a positive pre-travel TST change your plan? What is the likelihood of a positive pre-travel TST? What is the likelihood of a positive pre-travel TST? Vs. inconvenience (& non-compliance) and imprecision of the test Vs. inconvenience (& non-compliance) and imprecision of the test  Compliance?!!!! Especially including 8 week post- travel test

24. Problems with the TST  False negatives More frequent in the immune suppressed (who of course, need this information most!) More frequent in the immune suppressed (who of course, need this information most!)  False positives BCG (though less often than believed) BCG (though less often than believed) Exposure to environmental mycobacteria Exposure to environmental mycobacteria  Skill, variability in reading  The boosting phenomenon The likelihood of boosting correlates with the probability of past exposure to TB 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)

25. Interferon γ (gamma) Release Assays IGRA  Blood test  Purpose: detection of infection with M. tuberculosis  Principle: Blood exposed in the lab to purified, specific M. tuberculosis antigens (which are not present in BCG or most environmental mycobacteria) 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. 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™ Menzies D. et al. Ann Intern Med. 2007 Mar 6;146(5):340-54. (meta- analysis on IGRA) Menzies D. et al. Ann Intern Med. 2007 Mar 6;146(5):340-54. (meta- analysis on IGRA) Canadian tuberculosis committee. Interferon gamma release assays for latent tuberculosis infection. Canadian Communicable Disease Report 2007;33:1-18. Canadian tuberculosis committee. Interferon gamma release assays for latent tuberculosis infection. Canadian Communicable Disease Report 2007;33:1-18.

26. 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

27. Problems with the TST and TLTBI (Prophylaxis) Strategy  Compliance with obtaining pre-travel advice Highest risk groups, eg VFR’s least likely Highest risk groups, eg VFR’s least likely  **Compliance with post travel TST! Cobelens: 61%, 33% of whom required extra calls Cobelens: 61%, 33% of whom required extra calls MacPherson 86 (17%) completed the pre-travel and post-travel protocol MacPherson 86 (17%) completed the pre-travel and post-travel protocol Houston 50/90 (55%) in spite of house calls to read the TST! Houston 50/90 (55%) in spite of house calls to read the TST! Travellers Health Services, Edmonton, in 3.5 years, 705/3302 (21%) Travellers Health Services, Edmonton, in 3.5 years, 705/3302 (21%)  Compliance with chemoprophylaxis 64% in US clinic Nolan, JAMA 1999;281:1014-8 64% in US clinic Nolan, JAMA 1999;281:1014-8 < 40% of residents in a teaching hospital South Med J 1985;78:1061-64 < 40% of residents in a teaching hospital South Med J 1985;78:1061-64  Efficacy vs. resistant organisms likely decreased

28. “Expert” Recommendations  CDC yellow book 2005-6 Pre, post travel TST for travellers with specific high risk activities Pre, post travel TST for travellers with specific high risk activities Those anticipating prolonged or repeated exposure to consider a 2 step baseline Those anticipating prolonged or repeated exposure to consider a 2 step baseline  UK Department of Health (2001) For travel > 1 month to high incidence countries, especially if working with local population, BCG (if immune competent & TST-) For travel > 1 month to high incidence countries, especially if working with local population, BCG (if immune competent & TST-)  WHO 2007 “BCG vaccine is of limited use for travellers but may be advised for infants and young children in some situations” “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”. “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 Watch this space! New recommendations coming Watch this space! New recommendations coming

29. So what should we do?  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 Health care worker Health care worker ? Long term expatriate with extensive local contact ? Long term expatriate with extensive local contact *High risk of activation (immune suppressed) *High risk of activation (immune suppressed)

30. 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  Acid-fast bacilli (AFB) smear-positive pulmonary TB incidence rate of country visited and duration of visit > 200/100,000 and > 3 months; > 200/100,000 and > 3 months; 100-199/100,000 and > 6 months; 100-199/100,000 and > 6 months; 50-99/100,000 and > 12 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. > 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.

31.  Only a small proportion of travellers meet these criteria  Children < 5 years are a priority

32. Pre-travel testing?  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)

33. Interferon Gamma Release Assay “IGRA”  No role in routine screening  May use IGRA to confirm TST positivity in selected situations

34. 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

35. 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

36. 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