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Tuberculosis in travellers
Travel Medicine and Infectious Disease (2003) 1, 205–212
www.elsevierhealth.com/journals/tmid
Tuberculosis in travellers Victoria J. Johnstona, Alison D. Granta,b,* a
Hospital for Tropical Diseases, University College London Hospitals, London, UK Clinical Research Unit, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
b
Received 22 July 2003; received in revised form 6 November 2003; accepted 10 November 2003
KEYWORDS Tuberculosis; Travel; Preventive medicine
Summary Tuberculosis (TB) incidence is increasing in many countries which are popular with international travellers. The development of active TB is a two-stage process; the risk of acquiring new TB infection depends primarily on the risk of contact with an individual with infectious TB, and the risk of disease on the immune status of the newly infected person. The risk of TB infection is low for most holiday-makers, but among long-term travellers to countries with high TB incidence, the risk may be similar to that experienced by the local population (0.5 – 2.5% per year); the risk to people working in health care is particularly high. Effective pre-travel advice involves assessing the traveller’s risk of TB infection and disease. Recommendations on the prevention of TB in travellers vary between countries. Possible strategies include avoidance of exposure; BCG vaccination; and tuberculin skin testing before and after travel, with preventive therapy for those whose post-travel skin tests indicate recent infection. For those at highest risk of progression to disease, there may be value in preventive therapy during travel to reduce the risk of new TB infection. Further information on the contribution of recent travel to incident TB in industrialised countries would be valuable. q 2004 Elsevier Ltd. All rights reserved.
Introduction About one-third of the world’s population is thought to be infected by Mycobacterium tuberculosis. Each year there are an estimated 8.7 million new cases of tuberculosis (TB) globally and 1.7 million deaths.1 The burden of disease is unequally distributed: 22 countries account for 80% of all new cases, and India and China - both highly populated nations - account for nearly half of all cases. However, the highest incidence rates per capita are found in sub-Saharan Africa (Fig. 1) where rising *Corresponding author. Tel.: þ44-20-7927-2304; fax: þ44-207637-4314. E-mail address: [email protected]
incidence is largely attributed to the HIV epidemic.2 Many national TB control programmes are increasingly overstretched by this growing burden of disease, particularly in countries where public health infrastructure is weak. In many industrialised countries, recent increases in TB incidence are concentrated among migrants from high-incidence countries.3 International travel is increasing: between 1993 and 1997, worldwide international arrivals, by any form of transport, increased by between 27% (from Europe) and 46% (from the Middle East).4 Many countries with high TB incidence are increasingly popular travel destinations, whether to visit family and friends, to work, or for tourism. The World Tourist Organisation has predicted an 80% increase
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V.J. Johnston, A.D. Grant
Figure 1 Estimated global TB incidence rates, 2001. Source: WHO (available at: www.who.int/gtb/publications/ globrep/downloadpage.html, accessed 28 October 2003).
in travel to long haul destinations between 1995 and 2010.4 In this review, we examine the available data on the risk of TB when travelling from a low incidence to a high incidence country and discuss possible ways to reduce this risk.
Risk of TB among travellers The risk of an individual developing active TB as a consequence of international travel depends on, firstly, the risk of acquiring new TB infection, and, secondly, the risk of that infection progressing to active disease.
Risk of acquiring TB infection The risk of acquiring new TB infection depends primarily on the probability of contact with a person with infectious TB and will be determined by the prevalence of TB in the areas visited, the duration of time spent there and the degree of close contact with infectious individuals. For example, an individual working in a health care setting in southern Africa will be at far greater risk of
acquiring infection than a tourist visiting the same country. Acquisition of TB infection is usually defined as conversion from a negative to a positive tuberculin skin test (TST), or a positive TST in a child. Interpretation of the TST is more difficult in individuals who have had Bacillus Calmette-Gue ´rin (BCG) vaccination, who may have positive skin tests, though a strongly positive reaction is more likely to be attributable to TB than to BCG.5 A further complication is the phenomenon of ‘boosting’, whereby individuals with previous mycobacterial infection may have a larger response to a second skin test, even in the absence of recent exposure to infection. Foreign travel was identified as a risk factor for a positive TST in two studies from the United States, both among mainly Hispanic children. Lobato and Hopewell found that children in California who had travelled to a country with high TB incidence for more than a week were more likely to have a positive TST, and this association was stronger if the child was born in the United States rather than abroad. The median duration of travel was one month; over half the children stayed with their grandparents.6 Saiman et al. similarly found foreign
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travel to be a risk factor for a positive TST among children in New York.7 In a study of BCG-naı¨ve Dutch adults attending a pre-travel clinic, Cobelens et al. found that travel to countries with high TB prevalence was an independent risk factor for a positive TST, and that the association became stronger as the duration of travel increased.8 The same researchers investigated risk factors for TST conversion in a prospective cohort study of immune-competent, BCG-naı¨ve, TST-negative Dutch travellers visiting areas with high TB prevalence for at least three months.9 The study population were young (mean age 27.2 years), with the majority on vacation (43%) or travelling for educational purposes (39%); 16% were involved in health care work. The overall incidence rate of TB infection was 3.5 per 1000 person months of travel (95% confidence interval (CI) 2.0 – 6.2), or about 4% per year (Table 1). The risk of TB infection was greater with longer duration of travel; the only independent risk factor identified was health care work (adjusted rate ratio 5.4, 95% CI 1.2 – 24.3). If health care workers were excluded, the incidence rate was 2.8 per 1000 person months of travel (95% CI 1.2 –5.5). This approximates to an average annual incidence rate of 3.4%, which is similar to the annual risk of TB infection among the local population in many developing countries (estimated at 0.5 – 2.5%10). The estimate in this study could have been inflated by selective loss to follow-up: those who attended for follow-up were more likely to be female, Table 1 Risk of TB infection and disease among BCG-naı¨ve individuals travelling from low to high TB incidence regions. Population
Risk (per year Reference of travel, %)
Risk of TB infection Long-term travellers from Netherlands, BCG-naı¨ve Overall excluding health care workers health care workers only health care workers with direct patient contact
Cobelens 2000 9 4.2 3.4 9.5 11.8
Peace Corps volunteers, BCG-naı¨ve Overall 0.5–0.7 Selected African countries .3.5
Houston 199711
Risk of active TB disease Long-term travellers from Netherlands, BCG-naı¨ve Overall
Cobelens 20009 0.7
involved in health care or education and to have travelled to Africa, and may have perceived themselves to be at higher risk of TB. BCG-naı¨ve Peace Corps volunteers going from the United States to developing countries also have high TST conversion rates, with overall rates of between 0.5 and 0.7 per 100 volunteer years, depending on the geographical area.11 Two African countries and one Asian country had rates greater than 3.5 per 100 volunteer years. No data were available on the risks for health care workers compared with workers in other fields. These studies have investigated the risk of TB infection in selected groups of individuals travelling to areas with high TB incidence. The children from the United States were mostly visiting friends and relatives; the Dutch adults and United States Peace Corps volunteers (none of whom had received BCG) were travelling for long periods and having closer contact with the local population than the typical ‘package’ tourist. This underlines the need for a careful pre-travel evaluation in which the risk of acquiring TB infection is assessed. Clearly, duration of travel will be important, as will the risk of contact with an infectious individual. Health care work is a particular risk: even in countries with low TB incidence, health care workers are at higher risk of TB infection12 – 15 and active TB disease.16 Infection with TB during air travel has been documented on a number of occasions. However the overall risk is low, requiring prolonged exposure (greater than 8 hours) and close proximity to the infected person,17,18 and the risk is probably no greater than with other forms of transport.19
Risk of developing TB disease In immunocompetent individuals the lifetime risk of progression from infection to active TB is estimated at around 10%.20,21 The risk varies with age,20,22 and is greatest in the first few years following infection.21 – 23 The estimates of lifetime disease risk generally assume continuing exposure to new infection and so may be overestimates for travellers whose duration of exposure is more limited. Individuals with suppressed immune function either secondary to disease (e.g. HIV infection, diabetes mellitus, chronic renal failure) or immunosuppressant medications (e.g. corticosteroids) have a greater risk of progressing to disease. The annual risk of progression to active TB in patients co-infected with HIV and TB (in the absence of antiretroviral therapy) is estimated at around 10%10,24 – 28 although this varies widely, depending on the degree of immunosuppression.26,29 For example, in an Italian study, the risk of active TB among HIV-infected, TST-positive
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individuals varied from 2.6 per 100 person years in individuals with a CD4 count above 350 £ 109/l to 13.3 per 100 person years among those with CD4 counts below 200 £ 109/l.26 The risk for a traveller who has acquired TB infection through travel subsequently progressing to active disease will therefore be primarily determined by the individual’s immune status and the presence or absence of underlying disease. A number of studies have attempted to evaluate the contribution of recent travel to a high incidence country to the risk of developing active TB. In a study among Asian immigrants to London in the late 1970s, the risk of TB notification diminished with increasing time since arriving from or visiting Asia.30 The association was particularly striking for individuals who were not known to have been in contact with TB in the United Kingdom. This finding was supported by a study in the north of England where a similar association between risk of TB notification and time since arrival from or last visit to the Indian sub-continent was observed.31 In the cohort study mentioned earlier by Cobelens et al., the incidence of active TB among Dutch long-term travellers to high incidence countries was 0.6 per 1000 person months of travel, equating to an incidence rate of active TB of 0.72% per year.9 In summary, the risk of acquiring TB infection during travel to a high incidence country depends on the duration and type of travel undertaken. For most holidaymakers the risk will be low, but for some groups of travellers the risk may be similar to that among the local population; health care work is a particular risk. The risk of developing active disease once infected varies widely, depending on host factors, particularly immune status.
Preventing TB in travellers All individuals travelling to high-incidence countries should be assessed and counselled with respect to, firstly, their risk of acquiring new TB infection and, secondly, the risk of new infection progressing to active disease. Three main strategies may be used to minimise the risk of developing active TB: avoidance of exposure, BCG vaccination and preventive therapy.
Avoidance of exposure Travellers should where possible avoid exposure to infection, particularly those who are at higher risk of developing active TB. For example, individuals with HIV infection should be counselled (as they are
V.J. Johnston, A.D. Grant in the United Kingdom, for example32) against health care work involving contact with patients with infectious TB. This is even more important in some high-incidence countries where facilities for respiratory isolation of infectious patients are few or non-existent.
BCG vaccination The BCG vaccine is a live attenuated strain of Mycobacterium bovis. Its use is widespread, despite controversy about its efficacy. It gives around 80% protection against disseminated and miliary TB,33 but estimates of its efficacy against pulmonary TB show wide geographical variation, ranging from 0 to 80%.34 Vaccine efficacy is higher with greater distance from the equator. 35 Differences in exposure to environmental mycobacteria, which may reduce vaccine efficacy, are thought to account for at least part of this variation. There is no direct evidence on the efficacy of BCG among travellers. Most BCG efficacy trials have been performed in children or adolescents and there are few data concerning efficacy in adults. There is some evidence that BCG vaccination may be protective in TST-negative health care-workers, even though many of the studies had methodological problems.13 It has been suggested that BCG may be more effective against primary TB infection36 and if so it might be useful in travellers with no previous exposure to infection, but other data do not support this idea.37 The protective effect of BCG vaccination may wane with time, although the pattern of change in protection over time is not consistent between studies.37,38 The Medical Research Council trial of BCG among schoolchildren in the United Kingdom found a protective effect lasting for at least 15 years.23 There is little evidence that protection against pulmonary disease lasts more than 15 years, but lack of data does not necessarily indicate lack of effect.37 Currently, although revaccination is routine in many countries, there is no clear evidence that this provides additional protection; the results of a trial of repeat BCG vaccination among Brazilian schoolchildren are awaited. Despite the controversies surrounding BCG, several authors believe that it is of benefit in reducing the incidence of TB among TST-negative adult health care workers,13,39 and similarly it may be useful for travellers to high incidence regions. In addition if travel is to areas where the prevalence of drug-resistant TB is high (illustrated in Fig. 2) then the balance would be weighed more in favour of BCG rather than a strategy of treatment of latent infection. Serious side effects of BCG are rare, but
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Figure 2 Percentage of new TB cases with multi-drug resistance, 2000. Source: WHO Stop TB Department (data from J Infect Dis, 2002;185:1197-1202).
local ulceration with scarring is common and temporary regional lymph node enlargement may develop. Ultimately, more effective vaccines to prevent TB are needed. Until these become available, we suggest offering BCG to long-term travellers to countries with high TB incidence, on the basis that the risks of vaccination are small, and travellers may prefer an uncertain degree of protection to none, particularly if there is a high risk of acquiring drug-resistant infection. In addition to tropical areas, it would be logical to include countries in the former Soviet Union and Eastern Europe where TB incidence is also high.19 Unfortunately, BCG is contraindicated among many individuals at highest risk of rapid progression to TB disease, such as those with symptomatic HIV infection: other contraindications include a positive TST and previous BCG vaccination.
Tuberculin skin testing and preventive therapy for skin test converters An alternative strategy is to use TST before and after travel to assess if a traveller has acquired TB infection, and offer preventive therapy (also called
treatment of latent infection or chemoprophylaxis) to skin test converters, after the possibility of active disease has been excluded. A 12-month course of isoniazid reduces the risk of developing active TB by up to 90%40 but nine months of isoniazid may be the optimal duration.41 The British Thoracic Society recommends either a six-month course of isoniazid or three months of isoniazid and rifampicin for chemoprophylaxis;32 in the United States, nine months of isoniazid is suggested; 42 the alternative recommendation for a shorter regime using rifampicin and pyrazinamide has recently been withdrawn because of concerns about hepatotoxicity. 43 The effectiveness of this strategy depends upon an individual who is adherent and an organism which is sensitive to the drugs chosen. In a TB clinic in the United States, 64% of individuals starting isoniazid preventive therapy completed treatment.44 Adherence to preventive therapy among physicians in the United States has been found to be poor:12,14 less than 40% of hospital physicians with a positive TST completed a course of preventive therapy.14 The risk of adverse reactions to the agents used also needs to be taken into account. The most important risk from isoniazid is hepatotoxicity: the risk is greater with increasing
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age and in individuals with pre-existing liver disease.42 In practice, this strategy is labour intensive for both physician and traveller, requiring at least two clinic visits (one to place the skin test and one to read it) both pre- and post-travel for those at risk of acquiring infection, or more if it is felt necessary to control for ‘boosting’ by adopting a two-step approach to pre-travel testing for individuals with initially negative skin tests. Cobelens et al. found that 39% of travellers failed to attend for post-travel TST and 33% of those who attended required extra telephone calls to ensure adherence.45 Skin tests have inherent problems of poor repeatability46 and false negatives may occur, for example if the individual is immunocompromised, or because of poor operator technique. Finally, it requires an adequate supply of tuberculin, which has recently been unavailable in the United Kingdom. Overall, many clinicians would find this approach impractical. Assays based on interferongamma secreting T cells responding to ESAT-6, an antigen highly specific to the M. tuberculosis complex, have potential to diagnose latent TB infection with greater sensitivity and specificity than the TST, 47 but are not yet routinely available.
Prevention of infection Rarely, it may be worth considering using isoniazid or other antituberculous agents taken during travel to try to prevent new TB infection. One might expect that if antituberculous drugs such as isoniazid can prevent TB infection progressing to disease, they may also be able to prevent the establishment of TB infection. The evidence for the efficacy of this strategy is limited,48 and it should probably only be considered for individuals thought to be at high risk both of acquiring new TB infection and of progression to active TB, such as an HIV-infected person with advanced immunosuppression travelling to an area of high TB incidence for a prolonged period. As discussed earlier, effectiveness will depend on the infecting strain being sensitive to the drug given, and adequate adherence to treatment. If this strategy were used, it is unclear whether a full course of preventive therapy would be required after return or whether a shorter course would be effective.
Treatment of tuberculosis cases as they arise All of the strategies described above have their disadvantages. An alternative option would be to
V.J. Johnston, A.D. Grant
treat cases as they arise, on the basis that tuberculin skin testing and treatment of skin test converters is unsatisfactory, as discussed above, and that the evidence for efficacy of BCG among travellers is weak.18 This approach, however, is not without problems. Firstly, diagnosis may be delayed, especially among individuals who are not recognised to have a higher risk of TB.49 Secondly, from a public health perspective, individuals who develop pulmonary TB may infect others, and this would be a particularly serious problem among health care workers.
International recommendations for the prevention of TB in travellers The World Health Organization guidelines50 recommend that long-term travellers (greater than three months) travelling from low- to highincidence countries and who are at risk of TB infection (e.g. individuals working in health facilities or prisons) should have TSTs pre- and post-travel. Newly-acquired infection should be treated accordingly. BCG vaccination is considered to be of limited use in travellers with the exception of infants under 6 months and young children, and health care workers, with the caveats that adults with positive TST reactions greater than 5 mm and individuals with symptomatic HIV infection should not be vaccinated. Revaccination is not recommended. The United Kingdom recommendations51 highlight the risk to families of migrants returning to visit relatives abroad but state that risk to other travellers is limited. BCG is recommended for visits longer than one month to high risk countries (incidence rate over 40 per 100,000), particularly if living or working with the local population. Contraindications include a TST reaction greater than 5 mm (or Heaf grade 2 or above), previous BCG, systemic corticosteroid treatment and HIV infection. In the United States,52 travellers are advised to avoid exposure to infectious TB. Pre- and post-travel TST is recommended for travellers anticipating prolonged exposure to TB (routine contact with hospital, prison or homeless shelter populations), followed by treatment of latent TB infection for skin test converters. It is suggested that individuals working in health care settings be educated about the use of personal respiratory protective devices (N-95 respirators). BCG vaccination is not routinely recommended.
Tuberculosis in travellers
Conclusions Pre-travel advice should include an assessment of the risk of acquiring TB infection during travel, and the risk of that infection progressing to TB disease. Advice should be given about reducing the risk of exposure. We concur with United Kingdom recommendations that BCG vaccination should be offered (with appropriate exclusions) to individuals on longer trips to high-incidence countries, particularly if the trip is to an area with a high prevalence of multi-drug resistant TB. Travellers may alternatively be offered the option of pre- and post-travel TST and preventive therapy in the event of acquiring new TB infection, but this will require multiple clinic visits and good adherence to treatment. Occasionally it may be appropriate to offer preventive therapy during and after travel, especially for HIV-infected individuals with advanced immunosuppression who are at particularly high risk of progression to disease, but this strategy will similarly depend on good adherence to therapy. Ultimately, better vaccines, better diagnostic tests for infection and disease, and ways to reduce the duration of treatment are needed to reduce the global public health problem of TB. Among people living in countries with low TB incidence, the contribution of recent travel to the overall risk of developing active TB disease is unclear. This is of particular interest for individuals who have migrated from a high incidence country, who are at higher risk of TB, and further data on this issue may be helpful to guide strategies to reduce TB incidence among these communities.
Acknowledgements Alison Grant is supported by a UK Department of Health Public Health Career Scientist award.
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40. International Union Against Tuberculosis Committee on Prophylaxis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. Bull World Health Organ 1982;60:555—564. 41. Comstock GW. How much isoniazid is needed for prevention of tuberculosis among immunocompetent adults? Int J Tuberc Lung Dis 1999;3:847—850. 42. Centers for Disease Control and Prevention, Targeted tuberculin testing and treatment of latent tuberculosis infection. Morb Mortal Wkly Rep 2000;49(RR-6):1—51. 43. CDC, Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection - United States, 2003. Morb Mortal Wkly Rep 2003;52:735—739. 44. Nolan C, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy. JAMA 1999;281: 1014—1018. 45. Cobelens FG, Draayer-Jansen EW, Schepp-Beelen JC, van Gerven PJ, van Kessel RJ, van Deutekom H. Limited tuberculin screening participation amongst travellers to countries with high tuberculosis incidence; reason to consider BCG vaccination for some travellers. Ned Tijdschr Geneeskd 2003;147:561—565. 46. Fine PE, Bruce J, Ponnighaus JM, Nkhosa P, Harawa A, Vynnycky E. Tuberculin sensitivity: conversions and reversions in a rural African population. Int J Tuberc Lung Dis 1999;3:962—975. 47. Lalvani A, Pathan AA, McShane H, et al. Rapid detection of Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells. Am J Respir Crit Care Med 2001; 163:824—828. 48. Ferebee S. Controlled chemoprophylaxis trials in tuberculosis: a general review. Adv Tuberc Res 1970;17:28—106. 49. Rodger A, Jaffar S, Paynter S, Hayward A, Carless J, Maguire H. Delay in the diagnosis of pulmonary tuberculosis, London, 1998-2000: analysis of surveillance data. BMJ 2003;326: 909—910. 50. World Health Organization, International travel and health. Geneva: World Health Organisation; 2003. 51. Department of Health. Health information for overseas travel. London: The Stationery Office, 2001. 52. Centers for Disease Control and Prevention, Health information for international travel 2003-2003. Atlanta: US Department of Health and Human Services, Public Health Service; 2003.
www.elsevierhealth.com/journals/tmid
Tuberculosis in travellers Victoria J. Johnstona, Alison D. Granta,b,* a
Hospital for Tropical Diseases, University College London Hospitals, London, UK Clinical Research Unit, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
b
Received 22 July 2003; received in revised form 6 November 2003; accepted 10 November 2003
KEYWORDS Tuberculosis; Travel; Preventive medicine
Summary Tuberculosis (TB) incidence is increasing in many countries which are popular with international travellers. The development of active TB is a two-stage process; the risk of acquiring new TB infection depends primarily on the risk of contact with an individual with infectious TB, and the risk of disease on the immune status of the newly infected person. The risk of TB infection is low for most holiday-makers, but among long-term travellers to countries with high TB incidence, the risk may be similar to that experienced by the local population (0.5 – 2.5% per year); the risk to people working in health care is particularly high. Effective pre-travel advice involves assessing the traveller’s risk of TB infection and disease. Recommendations on the prevention of TB in travellers vary between countries. Possible strategies include avoidance of exposure; BCG vaccination; and tuberculin skin testing before and after travel, with preventive therapy for those whose post-travel skin tests indicate recent infection. For those at highest risk of progression to disease, there may be value in preventive therapy during travel to reduce the risk of new TB infection. Further information on the contribution of recent travel to incident TB in industrialised countries would be valuable. q 2004 Elsevier Ltd. All rights reserved.
Introduction About one-third of the world’s population is thought to be infected by Mycobacterium tuberculosis. Each year there are an estimated 8.7 million new cases of tuberculosis (TB) globally and 1.7 million deaths.1 The burden of disease is unequally distributed: 22 countries account for 80% of all new cases, and India and China - both highly populated nations - account for nearly half of all cases. However, the highest incidence rates per capita are found in sub-Saharan Africa (Fig. 1) where rising *Corresponding author. Tel.: þ44-20-7927-2304; fax: þ44-207637-4314. E-mail address: [email protected]
incidence is largely attributed to the HIV epidemic.2 Many national TB control programmes are increasingly overstretched by this growing burden of disease, particularly in countries where public health infrastructure is weak. In many industrialised countries, recent increases in TB incidence are concentrated among migrants from high-incidence countries.3 International travel is increasing: between 1993 and 1997, worldwide international arrivals, by any form of transport, increased by between 27% (from Europe) and 46% (from the Middle East).4 Many countries with high TB incidence are increasingly popular travel destinations, whether to visit family and friends, to work, or for tourism. The World Tourist Organisation has predicted an 80% increase
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Figure 1 Estimated global TB incidence rates, 2001. Source: WHO (available at: www.who.int/gtb/publications/ globrep/downloadpage.html, accessed 28 October 2003).
in travel to long haul destinations between 1995 and 2010.4 In this review, we examine the available data on the risk of TB when travelling from a low incidence to a high incidence country and discuss possible ways to reduce this risk.
Risk of TB among travellers The risk of an individual developing active TB as a consequence of international travel depends on, firstly, the risk of acquiring new TB infection, and, secondly, the risk of that infection progressing to active disease.
Risk of acquiring TB infection The risk of acquiring new TB infection depends primarily on the probability of contact with a person with infectious TB and will be determined by the prevalence of TB in the areas visited, the duration of time spent there and the degree of close contact with infectious individuals. For example, an individual working in a health care setting in southern Africa will be at far greater risk of
acquiring infection than a tourist visiting the same country. Acquisition of TB infection is usually defined as conversion from a negative to a positive tuberculin skin test (TST), or a positive TST in a child. Interpretation of the TST is more difficult in individuals who have had Bacillus Calmette-Gue ´rin (BCG) vaccination, who may have positive skin tests, though a strongly positive reaction is more likely to be attributable to TB than to BCG.5 A further complication is the phenomenon of ‘boosting’, whereby individuals with previous mycobacterial infection may have a larger response to a second skin test, even in the absence of recent exposure to infection. Foreign travel was identified as a risk factor for a positive TST in two studies from the United States, both among mainly Hispanic children. Lobato and Hopewell found that children in California who had travelled to a country with high TB incidence for more than a week were more likely to have a positive TST, and this association was stronger if the child was born in the United States rather than abroad. The median duration of travel was one month; over half the children stayed with their grandparents.6 Saiman et al. similarly found foreign
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travel to be a risk factor for a positive TST among children in New York.7 In a study of BCG-naı¨ve Dutch adults attending a pre-travel clinic, Cobelens et al. found that travel to countries with high TB prevalence was an independent risk factor for a positive TST, and that the association became stronger as the duration of travel increased.8 The same researchers investigated risk factors for TST conversion in a prospective cohort study of immune-competent, BCG-naı¨ve, TST-negative Dutch travellers visiting areas with high TB prevalence for at least three months.9 The study population were young (mean age 27.2 years), with the majority on vacation (43%) or travelling for educational purposes (39%); 16% were involved in health care work. The overall incidence rate of TB infection was 3.5 per 1000 person months of travel (95% confidence interval (CI) 2.0 – 6.2), or about 4% per year (Table 1). The risk of TB infection was greater with longer duration of travel; the only independent risk factor identified was health care work (adjusted rate ratio 5.4, 95% CI 1.2 – 24.3). If health care workers were excluded, the incidence rate was 2.8 per 1000 person months of travel (95% CI 1.2 –5.5). This approximates to an average annual incidence rate of 3.4%, which is similar to the annual risk of TB infection among the local population in many developing countries (estimated at 0.5 – 2.5%10). The estimate in this study could have been inflated by selective loss to follow-up: those who attended for follow-up were more likely to be female, Table 1 Risk of TB infection and disease among BCG-naı¨ve individuals travelling from low to high TB incidence regions. Population
Risk (per year Reference of travel, %)
Risk of TB infection Long-term travellers from Netherlands, BCG-naı¨ve Overall excluding health care workers health care workers only health care workers with direct patient contact
Cobelens 2000 9 4.2 3.4 9.5 11.8
Peace Corps volunteers, BCG-naı¨ve Overall 0.5–0.7 Selected African countries .3.5
Houston 199711
Risk of active TB disease Long-term travellers from Netherlands, BCG-naı¨ve Overall
Cobelens 20009 0.7
involved in health care or education and to have travelled to Africa, and may have perceived themselves to be at higher risk of TB. BCG-naı¨ve Peace Corps volunteers going from the United States to developing countries also have high TST conversion rates, with overall rates of between 0.5 and 0.7 per 100 volunteer years, depending on the geographical area.11 Two African countries and one Asian country had rates greater than 3.5 per 100 volunteer years. No data were available on the risks for health care workers compared with workers in other fields. These studies have investigated the risk of TB infection in selected groups of individuals travelling to areas with high TB incidence. The children from the United States were mostly visiting friends and relatives; the Dutch adults and United States Peace Corps volunteers (none of whom had received BCG) were travelling for long periods and having closer contact with the local population than the typical ‘package’ tourist. This underlines the need for a careful pre-travel evaluation in which the risk of acquiring TB infection is assessed. Clearly, duration of travel will be important, as will the risk of contact with an infectious individual. Health care work is a particular risk: even in countries with low TB incidence, health care workers are at higher risk of TB infection12 – 15 and active TB disease.16 Infection with TB during air travel has been documented on a number of occasions. However the overall risk is low, requiring prolonged exposure (greater than 8 hours) and close proximity to the infected person,17,18 and the risk is probably no greater than with other forms of transport.19
Risk of developing TB disease In immunocompetent individuals the lifetime risk of progression from infection to active TB is estimated at around 10%.20,21 The risk varies with age,20,22 and is greatest in the first few years following infection.21 – 23 The estimates of lifetime disease risk generally assume continuing exposure to new infection and so may be overestimates for travellers whose duration of exposure is more limited. Individuals with suppressed immune function either secondary to disease (e.g. HIV infection, diabetes mellitus, chronic renal failure) or immunosuppressant medications (e.g. corticosteroids) have a greater risk of progressing to disease. The annual risk of progression to active TB in patients co-infected with HIV and TB (in the absence of antiretroviral therapy) is estimated at around 10%10,24 – 28 although this varies widely, depending on the degree of immunosuppression.26,29 For example, in an Italian study, the risk of active TB among HIV-infected, TST-positive
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individuals varied from 2.6 per 100 person years in individuals with a CD4 count above 350 £ 109/l to 13.3 per 100 person years among those with CD4 counts below 200 £ 109/l.26 The risk for a traveller who has acquired TB infection through travel subsequently progressing to active disease will therefore be primarily determined by the individual’s immune status and the presence or absence of underlying disease. A number of studies have attempted to evaluate the contribution of recent travel to a high incidence country to the risk of developing active TB. In a study among Asian immigrants to London in the late 1970s, the risk of TB notification diminished with increasing time since arriving from or visiting Asia.30 The association was particularly striking for individuals who were not known to have been in contact with TB in the United Kingdom. This finding was supported by a study in the north of England where a similar association between risk of TB notification and time since arrival from or last visit to the Indian sub-continent was observed.31 In the cohort study mentioned earlier by Cobelens et al., the incidence of active TB among Dutch long-term travellers to high incidence countries was 0.6 per 1000 person months of travel, equating to an incidence rate of active TB of 0.72% per year.9 In summary, the risk of acquiring TB infection during travel to a high incidence country depends on the duration and type of travel undertaken. For most holidaymakers the risk will be low, but for some groups of travellers the risk may be similar to that among the local population; health care work is a particular risk. The risk of developing active disease once infected varies widely, depending on host factors, particularly immune status.
Preventing TB in travellers All individuals travelling to high-incidence countries should be assessed and counselled with respect to, firstly, their risk of acquiring new TB infection and, secondly, the risk of new infection progressing to active disease. Three main strategies may be used to minimise the risk of developing active TB: avoidance of exposure, BCG vaccination and preventive therapy.
Avoidance of exposure Travellers should where possible avoid exposure to infection, particularly those who are at higher risk of developing active TB. For example, individuals with HIV infection should be counselled (as they are
V.J. Johnston, A.D. Grant in the United Kingdom, for example32) against health care work involving contact with patients with infectious TB. This is even more important in some high-incidence countries where facilities for respiratory isolation of infectious patients are few or non-existent.
BCG vaccination The BCG vaccine is a live attenuated strain of Mycobacterium bovis. Its use is widespread, despite controversy about its efficacy. It gives around 80% protection against disseminated and miliary TB,33 but estimates of its efficacy against pulmonary TB show wide geographical variation, ranging from 0 to 80%.34 Vaccine efficacy is higher with greater distance from the equator. 35 Differences in exposure to environmental mycobacteria, which may reduce vaccine efficacy, are thought to account for at least part of this variation. There is no direct evidence on the efficacy of BCG among travellers. Most BCG efficacy trials have been performed in children or adolescents and there are few data concerning efficacy in adults. There is some evidence that BCG vaccination may be protective in TST-negative health care-workers, even though many of the studies had methodological problems.13 It has been suggested that BCG may be more effective against primary TB infection36 and if so it might be useful in travellers with no previous exposure to infection, but other data do not support this idea.37 The protective effect of BCG vaccination may wane with time, although the pattern of change in protection over time is not consistent between studies.37,38 The Medical Research Council trial of BCG among schoolchildren in the United Kingdom found a protective effect lasting for at least 15 years.23 There is little evidence that protection against pulmonary disease lasts more than 15 years, but lack of data does not necessarily indicate lack of effect.37 Currently, although revaccination is routine in many countries, there is no clear evidence that this provides additional protection; the results of a trial of repeat BCG vaccination among Brazilian schoolchildren are awaited. Despite the controversies surrounding BCG, several authors believe that it is of benefit in reducing the incidence of TB among TST-negative adult health care workers,13,39 and similarly it may be useful for travellers to high incidence regions. In addition if travel is to areas where the prevalence of drug-resistant TB is high (illustrated in Fig. 2) then the balance would be weighed more in favour of BCG rather than a strategy of treatment of latent infection. Serious side effects of BCG are rare, but
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Figure 2 Percentage of new TB cases with multi-drug resistance, 2000. Source: WHO Stop TB Department (data from J Infect Dis, 2002;185:1197-1202).
local ulceration with scarring is common and temporary regional lymph node enlargement may develop. Ultimately, more effective vaccines to prevent TB are needed. Until these become available, we suggest offering BCG to long-term travellers to countries with high TB incidence, on the basis that the risks of vaccination are small, and travellers may prefer an uncertain degree of protection to none, particularly if there is a high risk of acquiring drug-resistant infection. In addition to tropical areas, it would be logical to include countries in the former Soviet Union and Eastern Europe where TB incidence is also high.19 Unfortunately, BCG is contraindicated among many individuals at highest risk of rapid progression to TB disease, such as those with symptomatic HIV infection: other contraindications include a positive TST and previous BCG vaccination.
Tuberculin skin testing and preventive therapy for skin test converters An alternative strategy is to use TST before and after travel to assess if a traveller has acquired TB infection, and offer preventive therapy (also called
treatment of latent infection or chemoprophylaxis) to skin test converters, after the possibility of active disease has been excluded. A 12-month course of isoniazid reduces the risk of developing active TB by up to 90%40 but nine months of isoniazid may be the optimal duration.41 The British Thoracic Society recommends either a six-month course of isoniazid or three months of isoniazid and rifampicin for chemoprophylaxis;32 in the United States, nine months of isoniazid is suggested; 42 the alternative recommendation for a shorter regime using rifampicin and pyrazinamide has recently been withdrawn because of concerns about hepatotoxicity. 43 The effectiveness of this strategy depends upon an individual who is adherent and an organism which is sensitive to the drugs chosen. In a TB clinic in the United States, 64% of individuals starting isoniazid preventive therapy completed treatment.44 Adherence to preventive therapy among physicians in the United States has been found to be poor:12,14 less than 40% of hospital physicians with a positive TST completed a course of preventive therapy.14 The risk of adverse reactions to the agents used also needs to be taken into account. The most important risk from isoniazid is hepatotoxicity: the risk is greater with increasing
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age and in individuals with pre-existing liver disease.42 In practice, this strategy is labour intensive for both physician and traveller, requiring at least two clinic visits (one to place the skin test and one to read it) both pre- and post-travel for those at risk of acquiring infection, or more if it is felt necessary to control for ‘boosting’ by adopting a two-step approach to pre-travel testing for individuals with initially negative skin tests. Cobelens et al. found that 39% of travellers failed to attend for post-travel TST and 33% of those who attended required extra telephone calls to ensure adherence.45 Skin tests have inherent problems of poor repeatability46 and false negatives may occur, for example if the individual is immunocompromised, or because of poor operator technique. Finally, it requires an adequate supply of tuberculin, which has recently been unavailable in the United Kingdom. Overall, many clinicians would find this approach impractical. Assays based on interferongamma secreting T cells responding to ESAT-6, an antigen highly specific to the M. tuberculosis complex, have potential to diagnose latent TB infection with greater sensitivity and specificity than the TST, 47 but are not yet routinely available.
Prevention of infection Rarely, it may be worth considering using isoniazid or other antituberculous agents taken during travel to try to prevent new TB infection. One might expect that if antituberculous drugs such as isoniazid can prevent TB infection progressing to disease, they may also be able to prevent the establishment of TB infection. The evidence for the efficacy of this strategy is limited,48 and it should probably only be considered for individuals thought to be at high risk both of acquiring new TB infection and of progression to active TB, such as an HIV-infected person with advanced immunosuppression travelling to an area of high TB incidence for a prolonged period. As discussed earlier, effectiveness will depend on the infecting strain being sensitive to the drug given, and adequate adherence to treatment. If this strategy were used, it is unclear whether a full course of preventive therapy would be required after return or whether a shorter course would be effective.
Treatment of tuberculosis cases as they arise All of the strategies described above have their disadvantages. An alternative option would be to
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treat cases as they arise, on the basis that tuberculin skin testing and treatment of skin test converters is unsatisfactory, as discussed above, and that the evidence for efficacy of BCG among travellers is weak.18 This approach, however, is not without problems. Firstly, diagnosis may be delayed, especially among individuals who are not recognised to have a higher risk of TB.49 Secondly, from a public health perspective, individuals who develop pulmonary TB may infect others, and this would be a particularly serious problem among health care workers.
International recommendations for the prevention of TB in travellers The World Health Organization guidelines50 recommend that long-term travellers (greater than three months) travelling from low- to highincidence countries and who are at risk of TB infection (e.g. individuals working in health facilities or prisons) should have TSTs pre- and post-travel. Newly-acquired infection should be treated accordingly. BCG vaccination is considered to be of limited use in travellers with the exception of infants under 6 months and young children, and health care workers, with the caveats that adults with positive TST reactions greater than 5 mm and individuals with symptomatic HIV infection should not be vaccinated. Revaccination is not recommended. The United Kingdom recommendations51 highlight the risk to families of migrants returning to visit relatives abroad but state that risk to other travellers is limited. BCG is recommended for visits longer than one month to high risk countries (incidence rate over 40 per 100,000), particularly if living or working with the local population. Contraindications include a TST reaction greater than 5 mm (or Heaf grade 2 or above), previous BCG, systemic corticosteroid treatment and HIV infection. In the United States,52 travellers are advised to avoid exposure to infectious TB. Pre- and post-travel TST is recommended for travellers anticipating prolonged exposure to TB (routine contact with hospital, prison or homeless shelter populations), followed by treatment of latent TB infection for skin test converters. It is suggested that individuals working in health care settings be educated about the use of personal respiratory protective devices (N-95 respirators). BCG vaccination is not routinely recommended.
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Conclusions Pre-travel advice should include an assessment of the risk of acquiring TB infection during travel, and the risk of that infection progressing to TB disease. Advice should be given about reducing the risk of exposure. We concur with United Kingdom recommendations that BCG vaccination should be offered (with appropriate exclusions) to individuals on longer trips to high-incidence countries, particularly if the trip is to an area with a high prevalence of multi-drug resistant TB. Travellers may alternatively be offered the option of pre- and post-travel TST and preventive therapy in the event of acquiring new TB infection, but this will require multiple clinic visits and good adherence to treatment. Occasionally it may be appropriate to offer preventive therapy during and after travel, especially for HIV-infected individuals with advanced immunosuppression who are at particularly high risk of progression to disease, but this strategy will similarly depend on good adherence to therapy. Ultimately, better vaccines, better diagnostic tests for infection and disease, and ways to reduce the duration of treatment are needed to reduce the global public health problem of TB. Among people living in countries with low TB incidence, the contribution of recent travel to the overall risk of developing active TB disease is unclear. This is of particular interest for individuals who have migrated from a high incidence country, who are at higher risk of TB, and further data on this issue may be helpful to guide strategies to reduce TB incidence among these communities.
Acknowledgements Alison Grant is supported by a UK Department of Health Public Health Career Scientist award.
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