Canada Communicable Disease Report

Risk Assessment and Prevention of Tuberculosis Among Travellers

Preamble

The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public-health advice relating to tropical infectious disease and health risks associated with international travel. PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.

Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out here in may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.

Introduction

One third of the world’s population is infected with Mycobacterium tuberculosis. Over nine million people developed active tuberculosis (TB) in 2007, most in developing countries. An estimated 1.3 million deaths occurred among HIV-uninfected TB cases and an estimated 456,000 more in HIV-infected TB patients. TB remains a leading infectious cause of death in adults in many low income countries and the leading cause of death among HIV-infected individuals worldwide. The global picture of TB is increasingly complicated by drug resistance and the HIV epidemic ⁽¹⁾.

TB has been recognized as a health problem of returned travellers ^(2,3). Although the proportion of TB cases in low prevalence countries which are attributable to travel is unknown, limited data suggest that in some cases, infection may have been acquired during recent travel to high TB incidence countries ^(4-6). Because of the long interval between infection with M. tuberculosis and development of disease, the association with travel-related exposure may be under recognized.

TB transmission and natural history

Tuberculosis is an airborne infection. Droplet nuclei produced by a source individual with active pulmonary TB are inhaled by a susceptible host. The majority of people infected with M. tuberculosis never become symptomatic or ill and are said to have latent tuberculosis infection (LTBI). Overall, it is estimated that approximately 10% of those infected will ultimately develop active tuberculosis with approximately half of that risk in the first one to two years after exposure, the other half being distributed over the remainder of the infected person’s life. An individual’s risk of progression of infection with M. tuberculosis to active disease is greatly influenced by the presence of other factors; particularly those affecting the cell mediated immune response.

The overall risk of a traveller developing active tuberculosis therefore depends on 1) the risk of exposure/infection (refer to Figure 1), and 2) the risk of progression to active disease among infected individuals (refer to Table 1).

Estimating the risk of TB exposure in travellers

The risk of infection with M. tuberculosis increases with the duration of exposure and is likely to be associated with the degree of direct contact with local people in a high incidence country and with the conditions of contact, specifically, ventilation and ultraviolet light including sunlight.

The results of the only large prospective study ⁽⁷⁾ of TB infection in travellers demonstrated that the risk of infection, defined as conversion of the tuberculin skin test (TST), approximated the risk of transmission in the local population of the destination country. In a retrospective study, tuberculin positivity was strongly associated with duration of travel to high prevalence countries ⁽⁸⁾. A study of returned Peace Corps volunteers showed TST conversion rates intermediate between those of the U.S. population and the rates reported in the study mentioned above ⁽⁹⁾.

The annual risk of infection (TST conversion) varies from 0.5 - 4% per year in low income countries and correlates approximately with the incidence of smear positive pulmonary TB in the population. Rates of active TB vary widely among different geographic regions of the world. To illustrate the extremes, estimated TB incidence exceeds 1000/100,000 in a few specific communities in Africa ⁽¹⁰⁾, by comparison with less than 1/100,000 among Canadian born non-Aboriginal people. WHO estimated smear positive TB rates for all WHO member nations are available from the Public Health Agency of Canada (PHAC) website and estimates of TB incidence by country can also be obtained online from the World Health Organization (WHO).

Figure 1: WHO Estimated Sputum Smear Positive Pulmonary TB Rate per 100 000 (3 year average*) by Country

Source: PHAC website [cited 2009 May]. Available from: http://www.phac-aspc.gc.ca/tbpc-latb/itir-eng.php .

Note: a three year average is used to adjust for unstable rates in some jurisdictions. The WHO estimated rates are used, rather than the country/territory reported incidence rates, as they adjust for under-reporting of cases in some jurisdictions and are more indicative of the current risk of being infected while in the country/territory.

Among specific activities on the part of travellers, working in hospitals in high incidence countries is associated with a particularly high risk. The proportion of patients presenting to outpatient clinics, emergency departments and medical wards, who have infectious TB is very high in many high incidence countries, especially where HIV is co-endemic. The risk to health care workers, of acquiring M. tuberculosis infection (or active tuberculosis) has been found to be high in many low income country settings, with tuberculin skin test conversion as high as 14% per year in a systematic review ⁽¹¹⁾. In the teaching hospitals of Harare, Zimbabwe where rates of both TB and HIV were very high, the annual incidence of TST conversion in student nurses was 13% (95% CI, 6.5-20.0%) higher than in an otherwise similar control group of polytechnic students ⁽¹²⁾. Health care work was the only independent risk for TST conversion among the travellers followed by Cobelens, with a risk more than 5 times higher among health care workers than among other travellers ⁽⁷⁾.

The risk of TB exposure may also be increased in other settings such as prisons in low income countries, as it is in wealthy countries. In Brazil, the prevalence of active TB in prisoners was 70 fold greater than in the general Brazilian population ⁽¹³⁾. Refugees also appear to be associated with a much higher risk of TB than either the source or host populations ^(14-16) implying an increased risk of exposure for those working in refugee camp settings. Canadian immigrants visiting friends and relatives (VFRs) are likely to represent a group at higher risk, perhaps due to their closer contact with the local population, as several studies have shown an association between TST positivity and return travel to the country of origin ⁽⁵⁾, particularly among children ^(4,17,18). Orphanages are not anticipated to be particularly high risk settings since children, even when they have active TB, are less likely to be infectious.

Risk of TB transmission during commercial air travel

The risk of transmission of TB on all large commercial jet aircraft is very low in part due to the fact that air is exchanged and filtered approximately 20 times per hour during cruising, with lower exchange rates during descent and while on the ground ⁽¹⁹⁾. When TB contact tracing has been done on commercial air passengers due to exposure to an active case of TB on the same flight, only a few cases of infection with M. tuberculosis are thought to have been acquired ⁽²⁰⁾, but no active case attributable to travel on a commercial aircraft has been recognized to date ⁽¹⁹⁾. The greatest risk of acquiring TB on an aircraft appears to be on flights of > 8 hours duration and for those sitting within 2 rows of the index case ^(19,21).

Risk of Developing Active Tuberculosis among Those Who Have Acquired M. tuberculosis Infection

HIV infection is the risk factor most strongly associated with progression of Mycobacterium tuberculosis infection to active TB; the absolute risk is estimated at ~10%/year, greatest in those with advanced immune suppression and partially reduced by antiretroviral therapy ^(22-24). Organ transplantation and immune suppressive treatments including new agents such as blockers of tumour necrosis factor (TNF) alpha ⁽²⁵⁾, depending on the degree of immune suppression, along with silicosis and chronic renal failure, also substantially increase the risk of TB reactivation. Other, relatively common conditions such as diabetes, cigarette smoking, chest X-ray evidence of prior TB infection and being less than 90% of ideal body weight are associated with increased risk of reactivation, albeit to a lesser degree (refer to Table 1).

Prevention of Tuberculosis in Travellers

Several strategies have been proposed for the prevention of TB in travellers. In order for any TB prevention intervention in travellers to be feasible and as cost effective as possible, it must be strictly targeted to those at highest risk of exposure (high TB incidence in the destination country, longer duration of stay, and specific activities, particularly health care work) or at markedly increased risk of progressing to active disease if infected (i.e., immune suppression). Children, particularly < 5 years of age, should be given particular priority in consideration of post travel surveillance for TB because of their potentially greater risk of progressive tuberculosis, the difficulty of diagnosing TB disease in children, and the low risk of hepatotoxicity from isoniazid treatment of LTBI in this age group.

Minimizing exposure

Because of the airborne route of transmission, minimizing exposure in settings where the risk of transmission is high may be difficult in practice for most travellers to achieve consistently or reliably, depending on the purpose of travel. Emphasis on avoiding crowded, poorly ventilated indoor environments or health care settings may be particularly appropriate for infants or profoundly immune suppressed travellers.

Bacillus Calmette-Guérin (BCG) Vaccine

The Bacillus Calmette-Guérin (BCG) vaccine continues to be recommended selectively for travellers by the UK ⁽²⁷⁾, and in exceptional cases, the WHO ⁽²⁸⁾ and Canada ⁽²⁹⁾.

After more than 80 years of use, billions of doses administered and many large and well conducted prospective and case control studies, the efficacy of BCG remains unclear ^(30,31). Efficacy in prospective studies ranged from 0 to >80%. A number of hypotheses have been put forward to explain these extraordinarily discrepant results, including the effects of exposure to environmental mycobacteria ⁽³²⁾, and the decline of BCG efficacy over time due to repeated passage in vitro ⁽³³⁾. The evidence is somewhat more consistent for a protective effect against life threatening or disseminated disease in children less than five years of age ^(34-36). There is evidence of decreased BCG efficacy in immunocompromised individuals ⁽³⁷⁾ and good evidence of a substantial risk of disease due to dissemination of the vaccine bacillus in these patients ⁽³⁸⁾. A frequently overestimated but nonetheless real concern in relation to BCG use has been that the vaccine would complicate interpretation of the tuberculin skin test and thus the diagnosis of latent tuberculosis infection ⁽³⁹⁾. The increasing availability of interferon gamma release assays (IGRA) may reduce this concern since this test appears to avoid “false positive” results attributable to BCG exposure ^(40-41). Because of these problems and limitations, BCG would only be considered in exceptional situations such as immune competent travellers in whom the risk of TB was thought to be substantial and where the preferred alternatives (see below) were not an option for one or more of several possible reasons. A high risk of exposure to multidrug resistant tuberculosis (MDRTB) has been suggested as a possible indication for BCG since the preferred regimen and the efficacy of treating latent infection with MDRTB strains are unknown.

Table 1: Risk Factors for the Development of Active TB Among Persons Infected with Mycobacterium tuberculosis

Risk Factor	Estimated Risk of TB Relative to Persons with No Known Risk Factor
Source: Menzies, R & Khan, K Diagnoses of Tuberculosis Infection and Disease (26).
HIGH RISK
Acquired immunodeficiency syndrome (AIDS)	110-170
Human immunodeficiency virus (HIV) infection	50-110
Transplantation (related to immunosuppressant therapy)	20-74
Silicosis	30
Chronic renal failure requiring hemodialysis	10-25
Carcinoma of head and neck	16
Recent TB infection (≤ 2 years)	15
Abnormal chest x-ray – fibronodular disease	6-19
INCREASED RISK
Treatment with glucocorticoids	4,9
Tumor necrosis factor (TNF)-alpha inhibitors	1.5-4
Diabetes mellitus (all types)	2.0-3.6
Underweight (< 90% ideal body weight; for most persons this is a body mass index ≤ 20)	2-3
Young age when infected (0-4 years)	2.2-5.0
Cigarette smoker (1 pack/day)	2-3
Abnormal chest x-ray – granuloma	2
LOW RISK
Infected person, no known risk factor, normal chest x-ray (“low risk reactor”)	1

Pre-travel prophylaxis

Prophylactic isoniazid during travel, for particularly high risk individuals or travel itineraries has been suggested ⁽⁴²⁾ but there is neither evidence nor precedent to support this strategy. Its feasibility and acceptability might be anticipated to be very poor and a substantial risk of drug induced hepatitis would be anticipated from expanded use of isoniazid under unmonitored conditions. Therefore this strategy would not be recommended for travellers under any circumstance.

Detection and treatment of latent tuberculosis infection

In North America, the most widely recommended strategy for the prevention of TB in travellers is to identify those who have been infected with M. tuberculosis and recommend treatment of latent tuberculosis infection (LTBI) ⁽⁴³⁾. Treatment of LTBI has been shown to decrease the subsequent development of active TB in individuals with latent TB infection, by as much as 90% if the TB strain is isoniazid-sensitive, and 9 months of isoniazid is taken with a high level of compliance ^(43,44).

A key problem in the implementation of any preventive measure against tuberculosis in travellers is that of completion of all the pre- and post-travel steps required. First, many travellers, including some of those at highest risk for TB exposure such as foreign born Canadians returning to visit friends and relatives (VFR’s), do not seek travel advice at all ⁽⁴⁵⁾. Among those attending travel clinics, tuberculosis is perhaps understandably not identified by either travellers or travel-health professionals as a high priority. The need for two pre-travel visits to plant and read a tuberculin skin test is a practical obstacle which is doubled if two-step testing is performed. In practice, however, the largest gap between recommendations and compliance appears to involve the post-travel TST — the central element of this prevention strategy. Most travellers do not seem inclined to return to the travel clinic after their trip. In several studies, completion of post travel TST and reading was 61% among study subjects in spite of reminder calls ⁽⁴⁶⁾, 55% among 90 study subjects, for whom the investigator actually made house calls to read the TST ⁽⁴⁷⁾, and 17% of 506 subjects in another Canadian study ⁽⁴⁸⁾. In a busy Canadian travel clinic where the staff were highly motivated to promote TST follow up, only 705 (21%) of 3302 travellers who received a pre-travel TST, returned for post travel follow up ⁽⁴⁹⁾. Finally, even when latent tuberculosis infection is diagnosed, compliance with treatment is highly variable (ranging from 50-70% in most situations) ^(50-51), further limiting the potential benefit of this strategy. These difficulties further emphasize the need to target any TB prevention measures to those at highest risk.

As in other contexts, a TST should be performed only when the result is likely to impact management decisions, such as a decision to recommend treatment of LTBI. An important consideration is the risk of isoniazid toxicity, which is related to age--rare before age 20 but increasing with age subsequently--and the presence of underlying liver disease or alcohol abuse.

The TST has several important limitations. False positives can occur due to BCG (although this effect is less common than is widely assumed, especially if the BCG was given at birth and more than 10 years previously ^(39,52) or due to other factors such as exposure to environmental mycobacteria ^(39,53). False negatives are particularly likely in those with depressed cell mediated immunity, for example advanced HIV — a group in which identification of M. tuberculosis infection would be particularly important. Accurate reading of the TST requires a trained and experienced individual ⁽⁵³⁾. Finally, the TST requires 2 visits by the traveller to the clinic for each test.

Since the risk of developing active tuberculosis is higher in recently acquired than remotely acquired infection, there are situations (more advanced age, liver disease, etc.), where the benefits of treatment of LTBI would only outweigh the risks if there were reasonable confidence that a positive skin test reflected recently acquired infection. Hence, some recommendations suggest a pre-travel “baseline” TST ⁽²⁸⁾. Among Canadian-born non-aboriginals, in the absence of specific risks such as a history of contact with a known case of TB, work in a health care setting or prior residence or extensive travel in higher prevalence communities, the likelihood of a positive “baseline” TST is so low that it is reasonable to assume it is negative without the need to perform a test prior to travel.

A “baseline” TST, before travel, is therefore desirable when:

1. there is a history or likelihood of prior TB exposure which is substantially higher than that of the general, non-aboriginal Canadian-born population, and
2. the traveller has risk factors for isoniazid toxicity such as older age or liver disease, which would preclude a recommendation of isoniazid unless a positive skin test were known to represent a recent conversion.

Cost Effectiveness of Detecting and Treating Travel- Acquired LTBI

A decision analysis comparing four strategies for screening travellers to Mexico, Haiti or the Dominican Republic, found a single post travel test to be most cost effective across a broad range of assumptions, and cost saving for longer trips or with higher risk of exposure ⁽⁵⁴⁾, although the individuals in the model were not representative of all potential Canadian travellers.

An initial two step TST is particularly indicated for any individual who is anticipated to need repeated TST surveillance in the future because of ongoing TB exposure risk, i.e.: health care workers, whether travel-related or not.

Recently, a new approach to diagnosing latent tuberculosis infection has been developed—the interferon γ (gamma) release assays (IGRA). Two commercial tests using this principle are available—Quantiferon-TB Gold In Tube™ and T SPOT-TB™. These tests appear to be considerably more specific (to result in fewer false positives) than the TST ⁽⁴⁰⁾ since they are based on recombinant antigens found almost exclusively in M. tuberculosis. Reading is standardized in the laboratory and only a single visit is required. However, they appear to measure somewhat different biologic properties than does the TST. There is limited experience with their use in children, in immunocompromised hosts, and with serial testing. Their ability to predict risk of future TB activation is unknown, and they are more costly.

Recommendations

Table 2 presents evidence-based medicine categories for the strength and quality of the evidence for the recommendations that follow.

Table 2: Strength and quality of evidence summary sheet

Categories for the strength of each recommendation
Adapted from Macpherson DW. Evidence-based medicine. CCDR 1994 vol. 20 (17) (55).
CATEGORY	DEFINITION
A	Good evidence to support a recommendation for use.
B	Moderate evidence to support a recommendation for use.
C	Poor evidence to support a recommendation for or against use.
D	Moderate evidence to support a recommendation against use.
E	Good evidence to support a recommendation against use.
Categories for the quality of evidence on which recommendations are made
GRADE	DEFINITION
I	Evidence from at least one properly randomized, controlled trial.
II	Evidence from at least one well designed clinical trial without randomization, from cohort or case-controlled analytic studies, preferably from more than one centre, from multiple time series, or from dramatic results in uncontrolled experiments.
III	Evidence from opinions or respected authorities on the basis of clinical experience, descriptive studies, or reports of expert committees.

Recommendations	EBM Rating
1. Information should be available to travellers going to high TB incidence countries, particularly those who will be in high transmission settings such as health care work, regarding the risk of TB and the risk factors for transmission. Travellers should be advised to avoid consumption of unpasteurized milk, to prevent acquisition of brucellosis and other organisms as well as M. bovis.	BIII
2. Travellers whose itineraries meet the criteria outlined in Table 3 (below) of: TB incidence in the destination country, travel duration, and individual activity, should be advised to undergo TST testing post travel.	BIII
3. Travellers at increased risk of progressing to active disease: a) those with substantial immune suppression (i.e.: those considered high risk according to Table 1, as well as patients undergoing treatment with glucocorticoids, patients taking TNF-alpha inhibitors, and patients with diabetes mellitus); and b) children < 5 years of age should be identifi ed as part of pre-travel assessment and advised of the potential risk of TB infection and disease and the limitations of available preventive measures. They should be advised to return for a post travel TST, if their potential TB exposure risk exceeds that of “low risk” mainstream tourism travel even if it does not meet the exposure criteria specified under Recommendation 2, above.	BII
4. For travellers who do not meet the exposure or individual risk criteria defined above, (i.e.: most travelers), surveillance for tuberculosis infection is not routinely warranted.	DIII
5. When indicated, the tuberculin skin test should be placed by a qualified health professional and interpreted at 48-72 hours by a health professional with training and proficiency in reading of TSTs, following current Canadian guidelines (56). (Note: TST is not indicated if the traveller has a history of previous TB disease or a previously documented positive TST).	BII
6. For most travellers in whom a post travel TST is indicated, a single post travel TST only, is the most appropriate strategy. The post-travel TST should be done ≥ 8 weeks after the individual has left the high incidence country.	AI
7. Among those travelers for whom a post travel TST is indicated, the following selected groups should undergo a pre-travel TST, preferably two step, to establish a true baseline, so that if a post-travel test is positive, infection can be assumed to have occurred recently.
Individuals who, because of increased risk of isoniazid toxicity, would be candidates for treatment of LTBI only if infection M. tuberculosis (TST conversion) were known to have occurred recently: e.g. persons with pre-existing liver disease, ongoing alcohol abuse or travellers ≥ 50 years (age 20-50 years is a grey zone where the decision must take into consideration other factors affecting risk as well as the traveller's preference) and who have a high likelihood of previous M. tuberculosis exposure: (born or lived in a high incidence country, history of health care work, previous contact with infectious TB).	BIII
Individuals who will be entering a serial TST screening program for occupational reasons or because of anticipated ongoing exposure risk in future years.	BII
8. Travellers with demonstrated TST conversion should be assessed by a qualified TB specialist for consideration of treatment of LTBI after excluding the presence of active disease. TST positive children should be assessed promptly by a physician with expertise in childhood tuberculosis.	AI
9. Current knowledge does not support a role for IGRA as a primary screening test for TB infection either pre- or post-travel.	DII
10. BCG may be considered for long term travellers to high prevalence countries in the following exceptional circumstances:
Young children who are anticipated to have no access to regular TST follow up testing Individuals who may have extensive occupational exposure to multidrug-resistant (MDR) tuberculosis Travellers who for reasons of logistics, drug toxicity or intolerance, or personal choice, are expected not to be able to utilize the recommended surveillance strategy or chemoprophylaxis regimens.	CIII
11. Tuberculosis should always be considered in the differential diagnosis if the traveller presents at any subsequent time with persistent unexplained symptoms that could be consistent with tuberculosis. AII care providers for immune suppressed individuals who have travelled to high incidence countries should maintain a high index of suspicion for TB regardless of the TST result, if the individual experiences unexplained illness.	BIII

Table 3: Criteria for TST Testing Post Travel (for addressing Recommendation #2)

Incidence smear (+) TB in destination country	Duration of travel
≥ 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 a hospital or indoor setting, but possibly including work in prisons, homeless shelters, refugee camps or inner city slums.

Figure 2: A summary of the decision making model to guide TB Testing in Travellers.

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