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Each year, an estimated 80 million people travel from countries with a low incidence of Mycobacterium tuberculosis [tuberculosis (TB)] to countries with a high incidence.1 The risk of acquiring TB for such travelers is unknown, although some studies have estimated the risk to be between 2 and 12% for those whose travel places them at high risk.2,3 Up to 10% of these people will ultimately develop active disease.4 In addition to threatening the health of individuals, TB acquired while traveling may contribute to the global spread of multidrug-resistant (MDR) TB.5,6 There are currently no evidence-based guidelines on screening travelers for latent TB infection.

Interferon-gamma release assays (IGRAs) are a novel diagnostic test whose role in detecting TB acquisition is still being defined. In light of recent studies examining the risk of acquiring TB during travel, this article discusses the advantages and disadvantages of IGRAs in screening travelers for latent TB. This review was based upon a search in PubMed using the terms “travellers,”“screening,”“latent tuberculosis,”“interferon-gamma release assays,”“diagnosis,”“quantiFERON,” and “T-SPOT.TB.” Bibliographies of retrieved studies were additionally examined.

TB Pathogenesis, Infection, and Latency to Active Disease

  1. Top of page
  2. TB Pathogenesis, Infection, and Latency to Active Disease
  3. Risk Factors for Infection and Active Disease
  4. The Treatment of Latent (Subclinical) Disease
  5. Existing Recommendations for Infection Prevention and Screening
  6. Interferon-Gamma Release Assays
  7. Does the Advent of IGRAs Make Screening in Travelers Worthwhile?
  8. Acknowledgment
  9. Declaration of Interests
  10. References

The natural history of TB following inhalation is well understood. In a minority of people, replication of the organism overwhelms the immune system, leading to primary TB. In the remainder, the organism’s growth is contained by alveolar macrophages coinciding with the development of cellular immunity. This phase is characterized by proliferation of T lymphocytes, release of cytokines, macrophage activation, and encapsulation of the mycobacteria within granulomas, where they persist in a latent viable state. In these individuals, evidence of infection has historically been demonstrated by a positive Mantoux test or tuberculin skin test (TST). While these people remain immune competent, the risk of reactivation is low. However, in those whose immune function is compromised by extremes of age, immunosuppressive medications (eg, steroids), or comorbidities such as human immunodeficiency virus (HIV) or end-stage renal failure, the disease may reactivate and produce clinical disease. For those with a positive TST, the lifetime risk of developing clinical disease is 3% to 11%,7 the risk being greatest in the first 2 years postinfection.8

Risk Factors for Infection and Active Disease

  1. Top of page
  2. TB Pathogenesis, Infection, and Latency to Active Disease
  3. Risk Factors for Infection and Active Disease
  4. The Treatment of Latent (Subclinical) Disease
  5. Existing Recommendations for Infection Prevention and Screening
  6. Interferon-Gamma Release Assays
  7. Does the Advent of IGRAs Make Screening in Travelers Worthwhile?
  8. Acknowledgment
  9. Declaration of Interests
  10. References

Acquisition of TB requires close contact with an infectious individual. Travel to endemic regions is a risk factor for TB acquisition,9 although this is difficult to quantify. Differences in background prevalence of latent infections and limitations of the historic TB diagnostic tests make the degree of risk very difficult to estimate.

Our literature search revealed only five studies examining the risk of acquiring latent TB during travel: four used TST and one used IGRAs. TB acquisition was detected by conversion from a negative pretravel to a positive post-travel test result (Table 1). Although heterogeneous with regard to the travelers studied, they demonstrate that for selective groups, the risk of acquiring latent TB is an important health consideration. Travel destination is likely to be the main determinant of risk, suggested by the finding that the incidence of TB in long-term travelers approaches that of the local population.2 For high-risk countries, the annual incidence is 1.0 to 2.5.13 Other risks identified include duration of travel for more than 3 months6 and activities undertaken while abroad. Factors linked to excess risk include health care work (relative risk 2.3),2 the travel by immigrants back to their place of origin, or visiting friends and relatives14 where close contact with infected individuals in confined spaces is likely to occur. Missionaries and workers with ethnic minorities or in refugee camps are also thought to be at increased risk.15,16 Other than for health care workers, the relative risk has not been defined, but given the diversity of destinations and behaviors within the traveling population, the risk of acquiring TB is likely to vary considerably.

Table 1.  Summary of studies examining the risk of acquiring latent TB during travel
Number of travelersTest usedDestinationDurationActivityPercent with positive pretravel testIncidence of test conversionCumulative incidence of test conversion (%)Reference
  1. TB = tuberculosis; NA = data not available; TST = tuberculin skin test; IGRA = interferon-gamma release assay.

656TSTCountries with annual TB  incidence of 1% or more23 wk (median)Vacation (43%), education  (39%), professional  purposes (16%)43.5/1,000 person- months1.8Cobelens and  colleagues2
47TSTMesoendemic to hyperendemic  TB transmission zones>1 moNANANA12.7Anonymous3
NATSTDeveloping countriesNAPeace Corps volunteersNA0.42–0.58/1,000  person-monthsNAHouston10
44,070TSTDeveloping countriesNAPeace Corps volunteers2.91.28/1,000  person-monthsNAJung and  Banks11
149IGRASaudi Arabia34 d (median)Hajj pilgrims56NA10Wilder- Smith and  colleagues12

In selected subgroups of travelers, the risk of progression from latent to active disease may be greater than other groups. These include children, individuals on immunosuppressive treatment, and those with comorbidities including HIV, silicosis, end-stage renal failure, hematological malignancies, and malnutrition.3 For example, those coinfected with HIV have a 7% to 10% risk per annum of developing active disease.17

The Treatment of Latent (Subclinical) Disease

  1. Top of page
  2. TB Pathogenesis, Infection, and Latency to Active Disease
  3. Risk Factors for Infection and Active Disease
  4. The Treatment of Latent (Subclinical) Disease
  5. Existing Recommendations for Infection Prevention and Screening
  6. Interferon-Gamma Release Assays
  7. Does the Advent of IGRAs Make Screening in Travelers Worthwhile?
  8. Acknowledgment
  9. Declaration of Interests
  10. References

Guidelines for treatment of latent TB recommend administration of isoniazid monotherapy for 6 to 9 months.18,19 This reduces the lifetime risk of subsequent active TB by approximately 90%.20 The benefit is most apparent in those who have recently been infected and those at high risk of progression to active disease. While standard therapy for active pulmonary TB is equally efficacious, it requires multidrug therapy to be taken in the setting of symptomatic disease. Treatment of early disease also benefits the community by preventing secondary cases and geographic spread of the disease.

Potentially offsetting these benefits are an increased risk of poor compliance with treatment of latent TB (between 27 and 76%)21 and the global emergence of MDR TB to which isoniazid and other first-line treatments of latent TB are ineffective.22 Furthermore, treatment of latent disease has an associated risk, primarily isoniazid-associated hepatotoxicity. Although the majority of travelers are young and lack comorbidities, it is those most likely to benefit from screening and treatment of latent TB who are at greatest risk of treatment toxicity because of age or underlying illness such as HIV or alcoholic liver disease.

Existing Recommendations for Infection Prevention and Screening

  1. Top of page
  2. TB Pathogenesis, Infection, and Latency to Active Disease
  3. Risk Factors for Infection and Active Disease
  4. The Treatment of Latent (Subclinical) Disease
  5. Existing Recommendations for Infection Prevention and Screening
  6. Interferon-Gamma Release Assays
  7. Does the Advent of IGRAs Make Screening in Travelers Worthwhile?
  8. Acknowledgment
  9. Declaration of Interests
  10. References

A variety of potential means for preventing TB infection in travelers exists including avoidance of exposure, Bacillus Calmette–Guérin (BCG) vaccination, and prophylaxis in high-risk populations.23 Screening for acquisition of latent TB during travel may also help prevent progression to active TB disease, although its value is debated.23,24 The Infectious Diseases Society of America/American Thoracic Society recommends screening for latent TB in persons recognized as being at high risk of having recently acquired infection, without explicitly mentioning returned travelers.20 The World Health Organization endorses screening in travelers from low-incidence countries who may be exposed to infection in relatively high-incidence countries (eg, health professionals, humanitarian relief workers, missionaries).25 The Centers for Disease Control and Prevention travel recommendations suggest screening in those who anticipate prolonged exposure to TB (eg, hospital, prison, or homeless shelter workers).26

Interferon-Gamma Release Assays

  1. Top of page
  2. TB Pathogenesis, Infection, and Latency to Active Disease
  3. Risk Factors for Infection and Active Disease
  4. The Treatment of Latent (Subclinical) Disease
  5. Existing Recommendations for Infection Prevention and Screening
  6. Interferon-Gamma Release Assays
  7. Does the Advent of IGRAs Make Screening in Travelers Worthwhile?
  8. Acknowledgment
  9. Declaration of Interests
  10. References

Akin to measurement of cutaneous delayed-type reactivity by TST, IGRAs detect host cellular immune responses to M tuberculosis in whole-blood samples.1 This is achieved by in vitro exposure of T lymphocytes to TB-specific antigens and then quantifying the amount of interferon (IFN) produced. The QuantiFERON TB assay (Cellestis, Victoria, Australia) uses an enzyme-linked immunosorbent assay to measure IFN production. The T-SPOT TB test (Oxford Immunotec, Oxford, UK) uses the elispot technique in which individual T cells are counted by direct visualization of their cytokine release after exposure to TB-specific antigens.

Studies of latent TB are hindered by the absence of a gold standard. Instead, studies compare the outcome of IGRAs and TSTs among persons with a very low risk of infection (ie, healthy controls) with persons with a high risk of infection (ie, active TB patients). A recent meta-analysis examined the test characteristics of IGRAs and TSTs using this methodology. The sensitivities of the IGRAs were 76% (QuantiFERON) and 90% (T-SPOT TB) compared to 77% for the TST.27 The main advantage of IGRAs over TST is improved specificity. The first generation of IGRAs used purified protein derivative, whereas the second-generation assays used more specific tuberculous antigens such as ESAT-6 and CFP-10. The specificities of the latest IGRAs are 98% (QuantiFERON) and 93% (T-SPOT TB)27 compared to 66% for TST.28 None of the studies included in the meta-analysis specifically examined returned travelers.

IGRAs have features more suitable for screening than TST, but they are still not validated as, unlike TST, their capacity to predict progression to active TB has not been proven.29 The distribution of test values and a cutoff level in target populations needs to be better defined.30

An additional problem in interpretation of IGRAs is seroreversion, defined as a change from a positive to a negative result on repeat testing. Of 152 pilgrims who tested positive prior to attending the Hajj, 13 (8.6%) had reversion on post-Hajj screening.12 Whether this represents fluctuations in immune status or poor test reproducibility is unknown. Changes in the immune status during travel could conceivably stem from intercurrent stress (eg, lack of sleep), intercurrent illness, or new infection with TB. In health care workers, rates of seroreversion of 24% have been described.31 The value of IGRAs when performed serially is therefore unclear.30

Does the Advent of IGRAs Make Screening in Travelers Worthwhile?

  1. Top of page
  2. TB Pathogenesis, Infection, and Latency to Active Disease
  3. Risk Factors for Infection and Active Disease
  4. The Treatment of Latent (Subclinical) Disease
  5. Existing Recommendations for Infection Prevention and Screening
  6. Interferon-Gamma Release Assays
  7. Does the Advent of IGRAs Make Screening in Travelers Worthwhile?
  8. Acknowledgment
  9. Declaration of Interests
  10. References

Wilson and Jungner identified criteria for validity of a screening program.32 Four are disease-related and require that the disease be an important health problem, that there be an understanding of the natural history of the disease together with a detectable early stage, and also a likelihood that early treatment will be more beneficial than late treatment. These are met by our knowledge of TB. The remaining criteria relate to features of the screening test and resultant intervention and are summarized in Table 2.

Table 2.  IGRAs and the features required to validate a screening test (adapted from Wilson and Jungner32)
CriteriaIn favor of screening with IGRAsAgainst screening with IGRAs
  1. IGRA = interferon-gamma release assay; TB = tuberculosis; BCG = Bacillus Calmette–Guérin.

The test should be acceptable.• Single visit per test.• Serial attendances. One study showed only 61% compliance.33
• Results within 24 h
Intervals for repeating the test should be determined.• Testing at least 3 mo post-travel is recommended.34 
Adequate provisions for the extra workload resulting  from screening.• Could be performed in conjunction with existing   pre- and post-travel blood tests.• Need for specimen processing within 12 h of collection by   experienced laboratory staff.
The risks, both physical and psychological, should  be less than the benefits.• The test incurs no physical harm.• Risk of isoniazid-associated hepatotoxicity. Symptomatic   hepatitis occurs in 0.6% and has on occasion been fatal.35
• The benefits outweigh risks of treatment in recently acquired TB.• Difficult to identify high-risk travelers.
The costs should be balanced against the benefits.• In a model of close TB contacts in which the prevalence of TB   was 29%, screening using IGRAs costs between 11,000 and   24,000 euros per life year gained.36• A cost-effectiveness analysis not performed.
 • Mathematical modeling shows it is only cost-effective if the   risk is high.37
 • IGRAs are only more cost-effective in those who had received   prior BCG vaccination.37

The final and most important criterion for a screening test is that it is useful for detection in the early stage of disease. Traditionally, for latent TB, this has relied upon TST. However, the TST has many limitations in screening. These include poor sensitivity and specificity, the need for repeat visits, reader error, potential for a “booster” effect, and difficult interpretation in the context of prior BCG vaccination or nontuberculous mycobacterial infection. Compared to TST, IGRAs are less affected by these issues.

The utility of a screening tool is dependent upon the positive predictive value (PPV) and negative predictive value (NPV) rather than on sensitivity or specificity, as predictive values give additional consideration to the pretest probability (or risk) of disease in the target population.38 The risk of acquiring TB in returned travelers varies widely. If, for instance, the risk of a traveler acquiring latent TB during a given period is 2%, then using the sensitivity and specificity of IGRAs drawn from the recent meta-analysis,27 the PPV is just 25% and the NPV is 99%. As a subsequent confirmatory test for latent TB does not exist, a PPV of 25% is too low to be a useful screening test, as this would result in an unacceptable rate of overtreatment with potentially toxic medications. Therefore, the test would only seem to be useful in particularly high-risk situations.

In conclusion, while most of the criteria for validity of using IGRAs as a screening test are met, a lack of understanding of the risk of latent TB in travelers, the uncertainty generated by seroreversions, and the absence of a cost-effectiveness analysis cause significant limitations to our potential to make a recommendation. At best, there may be value in targeting specific groups. From a public health or an individual’s perspective, one could consider the value to be highest in screening those with highest risk of exposure (eg, occupational) or extended duration of travel (eg, at least 3 months in high-endemic areas) or a high risk of progression to clinical disease (eg, the immune compromised). However, screening would only be useful in an individual who would agree to undertake and remain compliant with treatment if indicated.

It is important that travelers receive an individualized pretravel risk assessment based upon underlying comorbidities along with destinations, duration, and activities planned. Travelers should be advised to avoid close contact with patients with active TB, and those working in the health care setting should follow existing infection control recommendations39 to the greatest degree possible.

References

  1. Top of page
  2. TB Pathogenesis, Infection, and Latency to Active Disease
  3. Risk Factors for Infection and Active Disease
  4. The Treatment of Latent (Subclinical) Disease
  5. Existing Recommendations for Infection Prevention and Screening
  6. Interferon-Gamma Release Assays
  7. Does the Advent of IGRAs Make Screening in Travelers Worthwhile?
  8. Acknowledgment
  9. Declaration of Interests
  10. References